Myoclonus epilepsy with ragged-red fibers
Jun. 10, 2021
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This article includes discussion of Lesch-Nyhan disease, Lesch-Nyhan syndrome, HGPRT deficiency, HPRT deficiency, and hypoxanthine-guanine phosphoribosyltransferase deficiency. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
In this article, the author reviews classic Lesch-Nyhan disease and more mildly affected Lesch-Nyhan disease variants. These metabolic disorder presentations result from mutations in the HPRT1 gene, which encodes for the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HGprt). Lesch-Nyhan disease is an X-linked genetic disorder characterized by hyperuricemia, intellectual disability, early-onset hypotonia with later onset of a predominantly dystonic movement disorder, dysarthric speech, and compulsive self-injury with self-mutilation accompanied by an extended cognitive and behavioral phenotype.
Studies in an Hprt1-deficient mutant mouse model and PET imaging studies have documented dopaminergic dysfunction with basal ganglia involvement. Management of hyperuricemia with allopurinol, dental management, orthopedic management, and use of protective equipment, along with behavioral interventions, is mandatory. Pharmacological treatment targets stabilization of mood and anxiety management. S-adenosylmethionine (SAMe), a physiological intermediate in methylation and transsulfuration, may have beneficial effects in selected patients who can tolerate the drug. Deep brain stimulation has been demonstrated in several case reports and series to reduce self-injury and aggression, and in some to modify dystonia.
• Lesch-Nyhan disease is a metabolic disorder resulting from deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase that is involved in recycling the purines hypoxanthine and guanine.
• This X-linked genetic disorder is associated with hyperuricemia, intellectual disability, early hypotonia and dystonic movement disorder, dysarthric speech, and compulsive self-injury with self-mutilation.
• Lesch-Nyhan disease is characterized by an extended behavioral, neurologic, and neurocognitive phenotype.
• Studies in an HPRT1-deficient mutant mouse model and PET imaging studies have documented dopaminergic dysfunction.
• Management of hyperuricemia with allopurinol, dental management, orthopedic management, and use of protective equipment, along with behavioral interventions, is mandatory.
Lesch-Nyhan disease was initially described in 1964 in 2 brothers, 4 and 8 years of age (89). The younger brother had been diagnosed with cerebral palsy and presented with hematuria. Both he and his brother had intellectual disability, movement disorder with dystonia, renal stones, and self-biting. Subsequently, hypoxanthine-guanine phosphoribosyltransferase (HGprt) was identified as the missing enzyme involved in this metabolic disorder (136). The majority of patients with classical Lesch-Nyhan disease have low or undetectable levels of the hypoxanthine-guanine phosphoribosyltransferase enzyme, rarely more than 1%. Becker and associates localized the gene to the long arm of the X chromosome (q26-q27) (10). The complete amino acid sequence for hypoxanthine-guanine phosphoribosyltransferase 1 (HPRT1) gene was described by Wilson and associates, and the organization of the HPRT1 gene (approximately 44 kb; 9 exons) was described by Kim and associates (157; 84).
Eads and colleagues used x-ray crystallography to describe the 3-D structure of the hypoxanthine phosphoribosyltransferase 1 protein and reported the effects of single amino acid substitutions on the stability and activity of hypoxanthine phosphoribosyltransferase 1 (33). Xu and colleagues described kinetic mechanisms of HPRT1 function (160). Jiralerspong and Patel provided a comprehensive review of regulation of the HPRT1 gene that includes both in vivo and in vitro approaches (80). Lowenstein provided a review of the prospects for gene therapy (93), and Young and Palmour discussed promises and limitations of gene research for HPRT1 deficiency (163). Gene Reviews provides a comprehensive review of HPRT1 deficiency, including metabolic aspects (106). Fu and colleagues examined genotype-phenotype correlations in Lesch-Nyhan disease (44). They summarized 615 known genetic mutations, their influence on the gene product, and their relationship to the clinical phenotype. Overall, the disease depends on how mutations influence enzyme activity. However, there are exceptions involving additional genetic and nongenetic factors that influence genotype-phenotype correlations (15).
Lesch-Nyhan disease includes the following features: hyperuricemia, intellectual disability (intellectual developmental disorder), hypotonia and early onset movement disorder, and later dystonia, dysarthric speech, and compulsive self-injury (usually beginning with the eruption of teeth) (89). At birth, infants with Lesch-Nyhan disease have no apparent neurologic dysfunction and seem to develop normally for 3 to 6 months before developmental retardation and neurologic signs become evident. However, before 3 months of age, hypotonia, recurrent vomiting, and difficulty with secretions may be evident. At approximately 6 to 12 months of age, extrapyramidal signs appear, primarily dystonia. Jinnah and colleagues studied 44 patients ranging in age from 2 to 38 years and characterized the motor syndrome as severe action dystonia that is superimposed on a baseline hypotonia (78). Earlier studies have listed choreoathetosis and spasticity as characteristic, but this was not confirmed in this large case series. The authors suggest these other extrapyramidal and pyramidal signs may occur but that dystonia is the essential feature. They attribute earlier descriptions of the motor syndrome possibly to differences in terminology for motor disorder. An early study by Watts and colleagues based on a smaller case series also emphasizes dystonia (154).
Thus, spasticity is a variable feature of unclear cause. It may become apparent during the developmental period or in some instances, later in life. For example, Shewell and Thompson reported evidence of atlantoaxial instability in a patient who presented with neck pain and progressive quadriplegia (139).
The degree of intellectual disability is usually reported to be in the mild-to-moderate range, although some individuals test in the low-normal range of intelligence. Matthews and colleagues completed an initial evaluation and a 4-year follow-up investigation of the cognitive status of 6 subjects with classical Lesch-Nyhan disease at a mean age of 17 years 10 months (range 14 years 9 months to 23 years) using the Stanford-Binet Intelligence Scale: IV (96; 97). Each of the 4 domains assessed by this battery of tests (verbal reasoning, abstract and visual reasoning, quantitative, and short-term memory) were compared with previous findings of the same subjects at their initial evaluation. The results suggest that although the subjects generally continued to acquire new information and skills over time, their standardized test scores decline, indicating that a plateau was reached in their skill levels relative to their peers.
Deficits were noted in working memory, particularly on tasks that involve considering multiple features simultaneously (96; 97). Because test scores are influenced by difficulty in testing the subjects due to their movement disorder and dysarthric speech, overall intelligence may be underestimated (08). Schretlen and colleagues compared 15 patients with Lesch-Nyhan disease to 9 variant cases, with no self-injury and enzyme levels ranging from 1.8% to 20%, and 13 normal adolescents and adults (131). Testing revealed qualitatively similar cognitive deficit profiles in both patient groups. The variants produced test scores that were intermediate between those of patients with classic Lesch-Nyhan disease and normal participants on nearly every cognitive measure.
The age of onset of self-injury may be as early as 1 year and occasionally as late as the teens (154). Self-injury occurs even though all sensory modalities, including the pain sense, are intact. Hall and colleagues found that the onset of self-injury is different from that of autism and other developmental disabilities; self-injurious behaviors in Lesch-Nyhan disease were sudden and violent in onset, instead of gradually emerging over time as was the case in the other developmental disabilities (60).
Usually, self-injurious behavior is expressed as self-biting; however, other patterns of self-injurious behavior may emerge with time. When 64 families (mean age of individual 16 years 7 months, standard deviation 11 years 2 months; age range 1 to 40 years) were surveyed regarding self-injury of their family members, the most common initial mode of self-mutilation and the most frequently cited past or current behavior was biting of lips or fingers (126).
Characteristically, the fingers, mouth, and buccal mucosa are mutilated. Self-biting is intense and causes tissue damage, often leading to amputation of fingers and loss of tissue around the lips. The biting may lead to the extraction of primary teeth. The biting pattern is often asymmetrical in that the patient preferentially mutilates the left or right side of the body. The topography of the behavior is different from that seen in other intellectual disability syndromes of self-injury, where self-hitting and head banging are the most common initial presentations. Moreover, the intensity of the self-injurious behavior generally requires that the patient be restrained. Despite the movement disorder, when restraints are taken away, the individual with Lesch-Nyhan disease may appear terrified, and he may quickly and accurately place a finger in the mouth. He may ask for restraints to prevent elbow movement and self-injury, and when the restraints are placed or replaced, the patient may appear relaxed and more good humored (104). Dysarthric speech may result in interpersonal communication problems; yet, higher-functioning children can express themselves fully and may participate in their treatment. Hemiballismic arm movements may create difficulty as the raised arm can be interpreted as a threatening gesture by others, rather than an aspect of the movement disorder.
The self-mutilation is conceptualized as a compulsive behavior that the child tries to control, but generally is unable to resist. Older individuals become more adept at finding ways to control the self-injury, including enlisting the help of others and notifying them when restraints can be removed. In the older child, self-injury may progress to deliberate self-harm and compulsive aggression towards others. The individual with Lesch-Nyhan disease may inflict injury to others through pinching, grabbing, hitting, or by using verbal forms of aggression. Afterwards, he may apologize for this behavior and say that it was out of his control. The language pattern is also characteristic and consists of repeated ambivalent statements that are most commonly accompanied by anxiety and coprolalia. Other associated maladaptive behaviors may develop later including head or limb banging, eye poking, pulling of fingernails, and psychogenic vomiting.
Self-injury is the characteristic feature of classic Lesch-Nyhan disease but it is not characteristic of Lesch-Nyhan variants (HGprt enzyme more than 2%). Schretlen and colleagues compared 22 patients with Lesch-Nyhan disease, 11 with Lesch-Nyhan variants, and 11 healthy controls (134). Those with a diagnosis of Lesch-Nyhan disease were rated with severe self-injury, aggression toward others, anxious-depressed symptoms, distractibility, motor stereotypies and disturbing interpersonal behaviors. Those with Lesch-Nyhan variants did not show self-injury and were intermediate between Lesch-Nyhan disease cases and controls on several scales. A prospective multicenter international study of Lesch-Nyhan disease variants examined neurologic manifestations in 46 patients 3 to 65 years of age from 34 families (72). Motor abnormalities were found in 42 patients (91%) and ranged from subtle clumsiness to severely and disabling generalized dystonia. Cognitive functioning was affected in 31 patients (67%), but never severe. None of the patients showed self-injurious behaviors; however, maladaptive behaviors were common. Only 3 patients showed no evidence of neurologic dysfunction. They were most similar to classic Lesch-Nyhan disease cases in regard to their attention deficits.
Jinnah and colleagues assessed eye movements in 22 patients with varying degrees of hypoxanthine phosphoribosyltransferase 1 deficiency (76). In 7 patients with moderate enzyme deficiency, ocular motility was clinically normal, but in 15 patients with severe enzyme deficiency (HGprt enzyme less than 1%) ocular motility was grossly abnormal. In patients with classic Lesch-Nyhan disease (HPRT1 less than 1%), fixation on target was interrupted by frequent unwanted saccades toward minor visual distractions. Voluntary saccades were associated with an initial head movement or eye blink in all of these patients. When head motion was prevented, voluntary saccades were frequently delayed and at times absent. In contrast, saccade speed, reflexive saccades, and other reflexive eye movements appeared normal. Four patients with classic Lesch-Nyhan disease showed mild blepharospasm and 2 had ocular tics. Such disturbances of ocular motility are consistent with dysfunction of the basal ganglia or its connections with ocular motor centers in the prefrontal cortex or midbrain.
An understanding of the molecular disorder has led to effective drug treatment for those aspects of the disease that are related to uric acid accumulation and subsequent arthritic tophi, renal stones, and neuropathy. Yet, reduction in uric acid has not influenced the neurologic and behavioral aspects of Lesch-Nyhan disease. Children who have been treated from birth for uric acid elevation have behavioral and neurologic symptoms, despite never having high levels of uric acid. The most significant complications are renal failure and self-mutilation.
A Caucasian male with classic Lesch-Nyhan disease presented with a dystonic movement disorder, mood lability, self-injurious behavior, and deliberate self-harm. He was first diagnosed at 2.5 years of age.
The family history was significant for learning disability in the patient’s mother who left school in 7th grade at the age of 15. Into adulthood, she continued to have difficulty with reading (read at the 4th grade level), spelling, and math and reported anxiety symptoms. A maternal cousin had a history of drug abuse. The patient’s father abused the mother during the pregnancy, hitting her in the abdomen during the last trimester. There was no family history of alcohol or other substance abuse or major mental illness in the father’s family. The patient’s parents were married 10 years, but they separated periodically during this time and eventually divorced. The mother remarried and remained married for 6.5 years but eventually divorced again. The stepfather remained emotionally very close to the patient.
There was a family history of Lesch-Nyhan disease in 7 male family members including the patient. His maternal great-uncle, 2 maternal uncles, 2 maternal cousins, and his brother were affected. The maternal great-uncle died at 2 years of age. One maternal uncle died at 9 years; another died at 23 years. The cousin died in his early 20s. The patient’s brother died of pneumonia at 18 years of age. The patient’s mother, grandmother, and maternal aunt were HPRT1 carriers, as was the 16-year-old first cousin. There was no family history of depression, suicidal ideation, or other mental illness.
The patient was the product of a normal, full-term pregnancy and delivery; birth weight was 8 lb. He returned home with mother at 3 days of age. There was no medication or drug use during pregnancy (no alcohol, cigarettes, or other substances). During the last month of pregnancy, the mother reported that the fetus was “jerking around.” She attributed this to her husband beating her (hitting her in the stomach) in the last month of the pregnancy.
There was concern with the pregnancy because the mother had 2 brothers with a then unknown neurologic disease, and her first child was affected; however, at the time of the patient’s birth, the diagnosis had not yet been reported in the medical literature—the paper describing the disease was published in 1964, the year of his birth.
In regard to the patient’s development, his mother became concerned at the age of 3 to 4 months because he was a floppy baby and could not hold things in his hands. Because of his floppiness, a towel was wrapped around his waist to hold him in a high chair. It was not until the age of 6 to 7 months that he began to hold on to objects. His mother would grind his food at home because he could not feed properly. He began having tonic-clonic seizures at 3 to 4 months of age and was started on phenobarbital (his older brother also had a seizure disorder). As he grew older, he began to crawl and speak, but he did not speak well enough to be understood until 6 years of age.
Following an ultimatum from the patient’s father that the children leave the home or he would, the patient was placed, undiagnosed, at a state hospital at 2 years of age along with his older brother, who was then 3.5 years old. At about 2.5 years of age, he was seen by Dr. Jay Seegmiller from the National Institutes of Health who diagnosed Lesch-Nyhan disease. According to Dr. Seegmiller (personal communication), the patient and his brother were the fourth and fifth cases to be diagnosed with this syndrome. He entered a rehabilitation program and eventually was placed in leg braces. He began to self-injure with finger biting at approximately 6 years of age. This was a problem for him for many years, one that required the continuous use of arm restraints. He has not bitten his fingers for 2 or 3 years and never bit his lips, so his teeth were not removed as is the case with many other affected individuals.
The patient remained at the center until his adulthood with regular visits from his mother and, at 22 years of age, he graduated from school. As an adult, he entered an alternative living program that allowed him to remain in the community. Currently, he lives in an apartment with community support and attends a day program that includes computer training; he makes greeting cards and banners.
The chief complaint from his caregiver is: “He goes through depressed times and wants to harm himself about every 6 months.” When he was younger, he would bang his head, requiring the use of a helmet to prevent injury. Now, when frustrated with others, he harms himself by throwing himself from his wheelchair. Moreover, he attempted suicide by trying to jump out of a car. On still another occasion, he got a knife and said he would kill himself. He periodically is demoralized and says he is tired of being in “that body.” He will arch his back and may hurt others by throwing his head back and butting others. When he does harm others, he shows remorse. He is aware of the impulse to injure himself and tries to avoid it or to elicit the help of others in doing so, but he warns them not to get too close to him. At times, he curses at others and has used inappropriate sexual talk. If he has upset others, he will apologize. There is a history of psychiatric admissions, and the patient has been seen for outpatient counseling for mood and behavior problems linked to his demoralization and depression as a result of his syndrome.
Mutations in the HPRT1 gene, which encodes the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HGprt), cause Lesch-Nyhan disease and more mildly affected Lesch-Nyhan disease variants. The metabolic abnormality results from an abnormal gene product–a deficiency in the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGprt) (127). This enzyme is normally present in each cell in the body, but its concentration is highest in the brain, especially in the basal ganglia. The deficient enzyme, hypoxanthine-guanine phosphoribosyltransferase (HGprt), is important in recycling both guanine and hypoxanthine. Absence of HGprt prevents the normal metabolism of hypoxanthine, resulting in excessive uric acid production and manifestations of gout, unless specific drug treatment is carried out (ie, allopurinol). The full disease requires the virtual absence of the enzyme.
Although the correlation between residual hypoxanthine recycling activity and disease severity has received the most attention, both hypoxanthine and guanine recycling and the resultant compensatory changes in the de novo synthesis of purines are important to understanding the full pathogenesis.
To assess the relevance of guanine recycling and compensatory changes in the de novo synthesis of purine studies, fibroblast cultures were established for 21 healthy controls and 36 patients with a broad spectrum of disease severity related to HGprt deficiency (46). Hypoxanthine recycling, guanine recycling, steady-state purine pools, and de novo purine synthesis was determined. Strong correlation between disease severity and either hypoxanthine or guanine recycling was found. Such results refine our understanding of the potential sources of phenotypic heterogeneity in Lesch-Nyhan disease and its variants.
Thus, the deficient enzyme, HGprt, is important in recycling both guanine and hypoxanthine (45). To clarify which of these purines is most important in pathogenesis Schretlen and colleagues selectively assayed hypoxanthine (Hprt) and guanine (Gprt) recycling in skin fibroblasts from 17 persons with Lesch-Nyhan disease, 11 with an attenuated variant of the disease (LNV), and 19 age-, sex-, and race-matched healthy controls (130). Activity levels of both enzymes differed across groups (p < 0.0001), but only Gprt distinguished patients with Lesch-Nyhan disease from those with LNV (p < 0.05). Gprt also showed slightly stronger correlations than Hprt, with 13 of 14 measures of the clinical phenotype, including the severity of dystonia, cognitive impairment, and behavioral abnormalities. These authors concluded that loss of guanine recycling might be more closely linked to the neurologic and behavioral phenotype of Lesch-Nyhan disease/ Lesch-Nyhan variant phenotype than loss of hypoxanthine recycling. Findings such as these suggest that loss of guanine recycling may be more tightly linked to the Lesch-Nyhan disease/Lesch-Nyhan variant phenotype than loss of hypoxanthine recycling (137). Moreover, patients with inherited GTP cyclohydrolase deficiency show clinical features of dystonia in common with Lesch-Nyhan disease.
Page and Nyhan reported that hypoxanthine-guanine phosphoribosyltransferase levels are related to the extent of motor symptoms, presence or absence of self-injury, and possibly to the level of cognitive function (114). Partial deficiency in hypoxanthine-guanine phosphoribosyltransferase (Kelley-Seegmiller syndrome) is associated with hyperuricemia (95) and variable neurologic dysfunction; its severity is inversely correlated with the amount of residual hypoxanthine-guanine phosphoribosyltransferase activity. Most commonly, partial hypoxanthine-guanine phosphoribosyltransferase deficiency leads to a severe form of gout. However, Schretlen and colleagues compared 15 classic Lesch-Nyhan cases with 9 variants and 13 normal controls. Five of 9 partial variant patients (HPRT levels 1.8 to 20%) had IQ scores below 70 and had deficits in working memory (131). Due to the enzyme deficiency hypoxanthine accumulates in the cerebrospinal fluid, but uric acid does not; it is not produced in the brain and does not cross the blood-brain barrier. Puig and colleagues describe clinical experience with 22 patients from 18 Spanish families reviewing the spectrum of clinical presentations (122). Thus, the effect of HPRT1 gene mutations on residual HGprt enzyme activity is the most relevant factor contributing to disease phenotype. Attenuated clinical phenotypes are associated with residual enzyme function, whereas the most severe phenotype is usually associated with null activity. In cases of gouty arthritis with urate overproduction, a careful evaluation for motor impairments or neurocognitive abnormalities may help to identify attenuated variants of Lesch-Nyhan disease for better management (44).
Visser and colleagues summarize evidence linking Lesch-Nyhan disease to dysfunction of the basal ganglia including motor circuits (extrapyramidal features), oculomotor circuits (disturbances of ocular motility), and corticostriate circuits (cognition and behavioral control) (151).
In investigating the pathogenesis and pathophysiology for the behavior disorder in this disease, both anatomical and neurochemical studies have been undertaken (Harris 1995). Harris and colleagues reported that in routine MRI readings, mild cerebral atrophy was evident in 2 of 7 Lesch-Nyhan patients when compared to normal controls (no comment was made by the radiologist about the basal ganglia). Yet, volumetric studies of these 7 patients with Lesch-Nyhan disease demonstrated a 34% decrease in caudate volume (p < .001), a 17% decrease in total cerebral volume (p < .03), and a 12% decrease in putamen volume (p = .19) (65). However, the classical behavioral phenotype cannot be fully explained by basal ganglia dysfunction alone. A larger study involving 21 classic cases, 17 variant cases, and 33 control subjects documented neuroanatomical abnormalities that extend beyond the basal ganglia (132). Compared to healthy controls, in patients with classic Lesch-Nyhan disease and variant cases that involve the basal ganglia, limbic, and frontotemporal regions, there was sparing of the parieto-occipital regions.
These findings are consistent with neuropsychiatric aspects of the Lesch-Nyhan disease behavioral and cognitive phenotype. Patients with the classic presentation had a 20% reduction in intracranial volume (17% reduction in grey matter volume and 26% reduction in white matter volume) compared to healthy controls. The variant cases patients’ grey matter volumes were reduced, and between those classic cases and healthy controls, classic cases demonstrated additional grey matter volume reductions in the temporal lobe and adjacent lateralized structures whereas variant cases showed additional reductions in lingual and precuneus regions and sparing of right frontal and temporal areas. Classic patients had reduced volume in the ventral striatum and prefrontal areas when compared to variant cases. These differences between classic and variant cases might provide clues to neural differences between the phenotypes.
Schretlen and associates followed up on the neuroimaging findings of white matter volume reduction (133). In a subsequent study they examined and compared Lesch-Nyhan disease and LNV patient groups. They found reduced volume in medial inferior white matter regions in Lesch-Nyhan disease cases. Compared with LNV, the Lesch-Nyhan disease group showed larger reductions in inferior frontal white matter adjoining limbic and temporal regions and the motor cortex. This study provides additional evidence that Lesch-Nyhan disease primarily involves substantial white matter volume abnormalities besides those found in the basal ganglia. Clusters of reduced white matter volume identified in this study affect brain regions linked to the neurobehavioral phenotype.
Davanzo measured in vivo proton spectra in 4 patients with Lesch-Nyhan disease and 4 control subjects matched for age and sex from voxels (1.5 cm3) placed in the prefrontal cortex and striatum. The patients with Lesch-Nyhan disease had decreased metabolites, especially N-acetylaspartate and glutamate/glutamine, in the prefrontal cortex as compared with the control group (24). These findings suggest axonal loss in the prefrontal area for this population. Harris and colleagues found reductions in N-acetylaspartate in Lesch-Nyhan variant cases (HPRT 1.8% to 8%) in both basal ganglia and prefrontal cortex suggesting that a continuum of deficit exists (66). Using proton magnetic resonance spectroscopy, they found insignificant reductions in the N-acetylaspartate metabolite, a measure of neuronal density and function (p less than 0.05), in the caudate, putamen, and medial frontal cortex. Significant reductions (p less than 0.002) in the n-acetyl aspartate to creatine ratio were noted in both caudate and putamen. Caudate creatine metabolite levels were significantly different between patient and control groups (p less than 0.05), but choline levels were normal in both patient groups. These studies suggest neuronal loss or dysfunction in the basal ganglia and medial frontal region in classic Lesch-Nyhan disease and partial HPRT1 deficiency (135; 63).
Genetics. The gene involved in Lesch-Nyhan disease is on the X-chromosome and, therefore, occurs in males (occurrence in females is extremely rare) (109; 09; 64; 26; 124).
Dauphinot and colleagues compared the transcriptome from human Lesch-Nyhan disease fibroblasts to normal human fibroblasts using a microarray with 60,000 probes corresponding to the entire human genome (23). Using stringent criteria, they identified 25 transcripts whose expression was significantly different between Lesch-Nyhan disease and control cells. These genes were confirmed by quantitative RT-PCR to be dysregulated in Lesch-Nyhan disease cells. They identified affected genes that belonged to specific processes such as cell cycle and cell-division processes, and metabolic and nucleic acid processes, providing new insights into Lesch-Nyhan disease pathogenesis.
Guibinga and associates demonstrated that HGprt deficiency causes dysregulated expression of key genes essential for striatal patterning, most notably the striatally-enriched transcription factor B-cell leukemia 11b (Bcl11b) (56). They found that downregulated expression of Bcl11b in HGprt-deficient immortalized mouse striatal (STHdh) neural stem cells was accompanied by aberrant expression of some of its transcriptional partners and other striatally-enriched genes, including the gene encoding dopamine- and cAMP-regulated phosphoprotein 32 (DARPP-32). Furthermore, components of the BDNF/TrkB signaling, a known activator of DARPP-32 striatal expression and effector of Bcl11b transcriptional activation, are markedly increased in HGprt-deficient cells and in the striatum of a HPRT1 knockout mouse. The authors proposed that the purine metabolic defect caused by HPRT-deficiency may provide neuroprotection to striatal neurons and may affect key genes and signaling pathways that underlie the neuropathogenesis of Lesch-Nyhan disease.
MicroRNAs, critical in the transcriptional regulation of genes, are dysregulated in Lesch-Nyhan disease. Guibinga proposed a model to explain how a gene such as HPRT, responsible for housekeeping metabolic functions, can have pleiotropic effects on disparate genes and signal transduction pathways (55). The proposed model suggests that HPRT1 mRNA transcripts may act as competitive endogenous RNAs (ceRNAs) engaged in multiregulatory cross talk between key neural transcripts and miRNAs.
Pathology. Early studies reported no abnormality following detailed histopathology and electron microscopy (154). Pathological findings were nonspecific, including loss of neuron and gliosis of the cerebral cortex and focal demyelination of the cerebral white matter. A subsequent summary of neuropathological findings in 31 cases suggested that chronic cerebellar lesions, identified in 9 cases, were the most frequently documented abnormality. Focal gliosis, multiple foci of cell loss, and regional loss of granule neurons exceeding the loss of Purkinje neurons were also reported (27).
Göttle and colleagues conducted histopathological studies using autopsy tissue from 5 Lesch-Nyhan disease cases and 6 controls (53). Specific findings were replicated in brain tissue from an HGprt-deficient knockout mouse using immunoblots, and in a cell model of HGprt deficiency by flow-activated cell sorting (FACS). These extensive histological studies of Lesch-Nyhan disease brains found no signs suggestive of a degenerative process or other consistent abnormalities in any brain region. Yet neurons of the substantia nigra from the Lesch-Nyhan disease cases did show reduced melanization and reduced immunoreactivity for tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis. The comparison mouse model showed reduced tyrosine hydroxylase expression in the striatum and the FACS revealed significantly reduced tyrosine hydroxylase immunoreactivity compared to the control parent line. These results are consistent with a neurochemical phenotype involving dopaminergic neurons not linked with a degenerative process. These authors suggest that purine recycling pathways and the neurochemical integrity of the dopaminergic phenotype are related.
Neurotransmitter metabolism. The pathogenesis and pathophysiology of the neurologic symptoms are not established; however, abnormalities in neurotransmitter metabolism have been demonstrated (92) in 3 autopsied cases. The behavior is not caused by hyperuricemia or excess hypoxanthine because partial variants with hyperuricemia do not self-injure (02) and infants treated for hyperuricemia alone from birth do still develop self-injurious behavior. Hyperuricemia results from the absence of the hypoxanthine phosphoribosyltransferase enzyme in the purine salvage pathway. Untreated hyperuricemia may lead to renal failure and early death.
Biochemical alterations have been assessed in 4 ways (61): (1) direct measurement of neurotransmitters in brain tissue (92), (2) measurement of neurotransmitters and their metabolites in cerebrospinal fluid (141) and measurement of adenosine, dopamine, and serotonin receptors in peripheral lymphocytes of Lesch-Nyhan patients (47), (3) clinical response to neurotransmitter precursor treatment, (4) measurement of the presynaptic dopamine transporter using PET scanning (159) or 18F fluorodopa (37).
First, Lloyd and associates have directly examined different brain regions postmortem for indices of dopamine, norepinephrine, serotonin, gamma amino butyric acid, and acetyl choline function in basal ganglia and other brain areas from 3 patients (13, 14, and 27 years of age) who died with Lesch-Nyhan disease (92). Lloyd and colleagues compared the pathological material from patients with material from age-matched control subjects without neurologic disease. They found that all 3 patients with Lesch-Nyhan disease had low hypoxanthine phosphoribosyltransferase 1 levels (less than 1% in striatal tissue and 1% to 2% of that of controls in thalamus cortex). The finding that the adenosine phosphoribosyltransferase (APRT), the phosphoribosyltransferase for adenine, another amino purine, was normal in these patients demonstrated that there was no general deficit in purine metabolism. There was a functional loss of 65% to 90% of the nigrostriatal and mesolimbic dopamine terminals; however, the cells of origin in the substantia nigra had normal dopamine levels. Low dopamine levels and decreased levels of homovanillic acid, its main metabolite, as well as low levels of the synthesizing enzymes, dopamine decarboxylase, esterase, and hydroxylase, were noted in terminal-rich dopamine areas including the caudate nucleus, putamen, and nucleus accumbens. These authors concluded that the neurochemical changes in this disorder may be related to functional abnormalities, possibly resulting from a diminution of arborization or branching dendrites, rather than cell loss.
A decrease in striatal cholinergic function was also noted, but norepinephrine and gamma amino butyric acid concentrations from representative areas were normal, whereas the serotonin level was slightly elevated. Saito and colleagues confirmed dopamine reduction in the caudate in 2 additional autopsied Lesch-Nyhan patients (15 and 32 years of age) who were never on neuroleptic medications. Using immunohistochemical methods they found that dopamine D1 and D2 receptors and methionine-enkephalin immunoreactivities were increased in the putamen, but less significantly in the caudate. They found no difference between subjects and controls in substance P and methionine enkephalin immunoreactivities in nociceptor-conducting structures. Tyrosine-hydroxylase immunoreactivity was not decreased in the substantia nigra. The number of medium-spiny neurons was increased in the caudate, but not in the putamen (128). Moreover, Yeh and colleagues reported impaired differentiation of HPRT1-deficient dopaminergic neurons demonstrating HHPRT 11-deficient PC12 mutants that have a normal or near-normal dopamine content (55% to 97% of that of wild-type cells) fail to undergo neuronal differentiation induced by nerve growth factor when the de novo pathway of purine synthesis is partially inhibited (161). However, nerve growth factor-induced differentiation is near normal under these conditions in PC12 Hprt1-deficient mutants containing much lower dopamine levels (less than 8% of that of wild type cells), indicating a neurotoxic effect of the endogenous dopamine in the mutants. The degree of inhibition of the de novo pathway of purine synthesis was the same in both classes of Hprt1-deficient mutants. Expression of Bcl2 in a PC12 mutant that has a normal dopamine content allowed partial nerve growth factor induced differentiation suggesting that the apoptotic pathway might be involved in the failure of differentiation when the de novo pathway of purine synthesis is partially inhibited.
Boer and colleagues provide additional evidence of defective arborization of dopaminergic dendrites (12). They monitored the differentiation in vitro of dopaminergic neurons that were cultured from HGprt-deficient knockout mice. Dopaminergic neurons cultured from Hprt1-deficient mice showed a decelerated rate of outgrowth of dendrites when compared to control neurons. After 8 days in culture, there was a 32% smaller average total length of dendrites per neuron (p less than 0.025). Finding of abnormal dendrite outgrowth in Hprt1-deficient mutant mice suggests a defective neurodevelopmental process. However, in the HGprt1-deficient mouse model these effects are subtle and might be metabolically induced. When Golgi-Cox histochemistry was used to evaluate the fine structure of medium spiny I neurons from the striatum and in the pyramidal projection neurons of layer 5 of the cerebral cortex in HGprt1-deficient mice, neurons from both regions demonstrated a normal distribution, orientation, and gross morphology. There was no evidence for an abnormal developmental process or degeneration. However, both regions demonstrated a paucity of neurons with very long dendrites and a reduction in dendritic spines depending on the distance from the cell body (101).
To investigate the nature of the relationship between HGprt deficiency and dopamine, a mouse MN9D dopaminergic neuronal cell line was used to prepare 10 sublines lacking Hprt1. Dopamine was selectively reduced as a consequence of reduction in mRNAs encoding tyrosine hydroxylase, the dopamine transporter, the vesicular monoamine transporter, monoamine oxidase B, catechol-O-methyltransferase, and GTP-cyclohydrolase 1. These findings suggest purine recycling is a metabolic process of specific importance to the molecular phenotype of dopaminergic neurons (90). This work has been extended to demonstrate increases in mRNAs for engrailed 1 and 2 transcription factors that play key roles in the specification and survival of dopamine neurons. Such increases in mRNA were joined by increases in engrailed proteins. The restored HGprt reverted engrailed expression toward normal levels. This suggests that HGprt and engrailed are functionally related. Findings were verified in SK-N-BE(2) M17 neuroblastoma cells. Overexpression of engrailed may correlate with disease severity (16). These results are consistent with the effect of HPRT deficiency on dopamine neurons through the influence of early developmental mechanisms.
Further support of the effect of HGprt deficiency on dopamine function comes from the effect of this deficiency on the differentiation of neurons in the well-established human (NT2) embryonic carcinoma neurogenesis model (58). HGprt-deficient NT2 cells demonstrate aberrant expression of several transcription factors and DNA markers, thus, documenting aberrant neurogenesis in HPRT deficiency in this model. These authors investigated the expression of microRNA miR181a in HGprt-deficient human SH-SY5Y neuroblastoma cells (57). They reported that dysregulation of dopamine pathways was associated with aberrant expression of miR181a in these neuroblastoma cells, but not in HPRT-deficient fibroblasts. Guibinga and colleagues have extended their studies seeking to correlate the defect in purine metabolism to neural related abnormalities finding that HPRT1 deficient neuronal cell lines have reduced CREB expression and intracellular cyclic adenosine monophosphate (cAMP) (59). They propose that HPRT1 deficiency alters the cAMP/PKA signaling pathway, and thus suggest a mechanistic insight into possible causes of Lesch-Nyhan disease.
Human neural stem cells provide yet another model system and tool to investigate the pathophysiology of HGprt deficiency and to more broadly seek therapeutic approaches (21). HGprt deficiency leads to dysregulation dopamine-related developmental functions in human induced pluripotent stem (iPS) cells. Kang and colleagues conducted gene expression studies during neuronal differentiation of HGprt deficient murine ESD3 embryonic stem cells (81). In this model, HGprt knockdown causes a switch from neuronal to glial gene expression and dysregulates many cell cycle functions, RNA metabolism, DNA replication and repair, and multiple neurotransmission systems.
Allen and Davis treated neonatal rats with either 6-hydroxydopamine or vehicle intracisternally (04). On maturation, rats receiving 6-hydroxydopamine were assigned to 4 groups, with 2 of the 4 groups receiving intraventricular 5,7-dihydroxytryptamine bilaterally. At 94 days of age, animals were injected with either the SKF dopamine D1 agonist, or m-chlorophenylpiperazine, a 5-HT2C agonist, in an attempt to produce behaviors such as stereotypical chewing, head-nodding, self-biting, and self-mutilation. Both SKF-38393 and m-chlorophenylpiperazine induced the elicited behaviors in animals receiving 6-hydroxydopamine alone. Animals receiving 5,7-dihydroxytryptamine additionally, did not show any of the target behaviors in response to the dopamine D1 agonist SKF-38393, but exhibited a much higher sensitivity to m-chlorophenylpiperazine. Pretreatment with SCH-23390 in animals receiving 6-hydroxydopamine alone prevented SKF-38393-induced target behaviors, but not those induced by m-chlorophenylpiperazine. Pre-treatment with mianserin partially antagonized the effects of both SKF-38393 and m-chlorophenylpiperazine in these same animals. In groups receiving both neonatal 6-hydroxydopamine and adult 5,7-dihydroxytryptamine, mianserin was effective in reducing m-chlorophenylpiperazine-induced behaviors, whereas SCH-23390 was largely ineffective. These authors suggest that a serial relationship exists between the D1 and 5-HT2C receptor systems in the neostriatum of animals receiving neonatal 6-hydroxydopamine lesions.
Saito and Takashima propose that increased serotonergic action in the striatum may be necessary for the appearance of self-injurious behavior. They note that pharmacological evidence is consistent with the efficacy of serotonin agonists and antagonists for the treatment of the self-mutilation in Lesch-Nyhan disease (129).
Second, changes in cerebral spinal fluid neurotransmitters and their metabolites and measurement of adenosine, dopamine, and serotonin receptors in lymphocytes of Lesch-Nyhan patients have been reported in Lesch-Nyhan disease. Serum dopamine-hydroxylase was found to be altered, and low levels of homovanillic acid were observed in the cerebrospinal fluid in 1 case of Lesch-Nyhan disease (141). Moreover, 5-hydroxy indoleacetic acid has also been reported to be decreased.
Ernst and colleagues examined peripheral indices of adrenergic, noradrenergic, and monoamine oxidase function in children and young adults with Lesch-Nyhan disease (n = 11), and healthy subjects (n = 9). Blood samples were assayed for concentrations of epinephrine, norepinephrine, and 3-methoxy-4-hydroxyphenylglycol. Epinephrine levels were 245% higher, significantly higher (p < .00), in Lesch-Nyhan patients, but 3-methoxy-4-hydroxyphenylglycol levels were lower by 42% (p < .00) compared to the control group. No group differences were noted in norepinephrine plasma levels. IQ scores tested by Stanford Binet Intelligence Scale correlated with epinephrine in the Lesch-Nyhan group (r = 0.77, p = .009), but not in the control group. The abnormally low 3-methoxy-4-hydroxyphenylglycol levels, in the context of normal norepinephrine levels, indicates low monoamine oxidase activity, either as a primary deficit, or as secondary adaptive changes to lower norepinephrine levels (38).
Adenosine, dopamine, and serotonin, the neurotransmitters implicated in Lesch-Nyhan disease pathogenesis, act by binding to specific G-protein coupled receptors in the synaptic membrane. Garcia and colleagues reported an imbalance in adenosine, dopamine, and serotonin receptors and suggested that rather than focusing on the isolated disturbance of 1 neurotransmitter, the balance among them should be considered in psychopharmacologic treatment (47).
Third, temporary improvement in self-injury has been reported in several patients following the administration of the serotonin precursor L-5-hydroxytryptophan, both with and without a peripheral decarboxylase inhibitor (Carbidopa) (102; 104). When the drug was given without interruption for several months, the self-injury reappeared.
Fourth, Wong and colleagues have found in vivo reductions in the presynaptic dopamine transporter using 11C WIN 35,428 in 6 individuals, ages 19 to 35 years old, with Lesch-Nyhan disease (159); Ernst and associates have demonstrated presynaptic reductions with 18F fluorodopa in 12 subjects, 10 to 20 years of age (37). Both of these PET findings are consistent with the finding of Lloyd and associates. WIN 35,428 binding was also significantly correlated with the extent of motor disability, but did not appear to correlate with the extent of self-injurious behavior. These studies suggest that dopaminergic dysfunction in the basal ganglia may contribute to the expression of dystonia (63).
The mechanism leading to the dopamine abnormality has been studied in a mutant mouse model addressing the hypothesis that oxidant stress causes damage or dysfunction of nigrostriatal dopamine neurons in a knockout mouse model; the authors assessed several markers of oxidative damage and free radical scavenging systems (153). Striatal dopamine systems of the mutant mice were more vulnerable to a challenge with the neurotoxin 6-hydroxydopamine, but they were not protected by cross-breeding the mutants with transgenic mice overexpressing superoxide dismutase 1. The authors provide evidence for increased oxidative stress, but the failure to protect the knockout mice by overexpressing superoxide dismutase 1 argues that oxidative stress is not the sole process responsible for the loss of striatal dopamine.
Aberrant pyridine nucleotide metabolism could play an important role in the pathophysiology of Lesch-Nyhan disease. Nicotinamide adenine dinucleotide plus ATP depletion in the developing brain could restrict DNA repair, leading to neuronal damage or loss by apoptosis and, with GTP depletion, affect neurotransmitter synthesis and basal ganglia dopaminergic neuronal systems (40). In CSF, measures of purine metabolites showed no difference in Lesch-Nyhan disease and Lesch-Nyhan disease variants indicating that hypoxia can be excluded as a factor in the severe neurologic deficits in Lesch-Nyhan disease (39).
Dopamine and adenosine systems. Although the mechanism whereby hypoxanthine phosphoribosyltransferase 1 deficiency leads to the neurologic and behavioral symptoms is unclear, guanine triphosphate and adenosine have profound effects on neural tissues. An important functional link between purine nucleotides and the dopamine system involves guanine, the precursor of guanine triphosphate (138). The requirement for guanine triphosphate in signal transduction through the dopamine receptor-agonist interaction provides an essential functional link of hypoxanthine phosphoribosyltransferase 1 to the dopamine system. The binding of dopamine to its receptor leads either to an activation (D1 receptor) or an inhibition (D2 receptor) of adenylcyclase. Both processes are mediated by guanine triphosphate-binding proteins that have an absolute dependence on guanosine diphosphate in the guanosine diphosphate/guanine triphosphate exchange for cellular activation (reduced amounts of guanine nucleotides might interfere with this process). Thus, the absence of hypoxanthine-guanine phosphoribosyltransferase may potentially affect dopamine systems due to limited recycling of guanine. Moreover, a deficiency of guanine based purines could affect the modulation of glutamatergic neurotransmission (30). Messina and colleagues report that guanine nucleotide depletion induces differentiation and aberrant neurite outgrowth in human dopaminergic neuroblastoma units (100). They propose that because the basal ganglia has the highest level of HGprt activity in the brain, guanine nucleotide depletion in the region may be linked to abnormal development in this brain region.
Dopamine and adenosine systems are also linked in other ways (ie, adenosine may play a neuroprotective role in preventing neurotoxicity) (86). In animal models adenosine agonists mimic the biochemical and behavioral actions of dopamine antagonists (42), whereas adenosine receptor antagonists can act as functional dopamine agonists. Torres and colleagues characterized adenosine transport in peripheral blood lymphocytes from Lesch-Nyhan disease patients and found reduced levels suggesting that hypoxanthine affects adenosine transport (146). Studies of purine pools and their metabolism were carried out in rat PC6-3 cells, a PC12 pheochromocytoma subclone that undergoes differentiation with nerve growth factor. Subclone findings demonstrate an increase in most purines following neuronal differentiation. The loss of HPRT mediated purine recycling is associated with significant loss of dopamine and its metabolites, indicating an important connection of purine and dopamine pathways. The mechanism through which intracellular purines regulate dopamine levels is not known (52).
Animal models. Two types of animal models have been produced for Lesch-Nyhan disease (71). The first is a behavioral model that simulates the self-injury and involves dopamine depletion (14) and the second is molecular models based on embryonal stem cell modification (69; 85). First, Breese and colleagues reported a relationship between dopaminergic supersensitivity and self-injury in an experimental animal model (14). When neonatal (5 day old) and adult rats that were not hypoxanthine-phosphoribosyltransferase 1-deficient were administered 6-hydroxydopamine to denervate basal ganglia regions, it was found that the age when neural function is disrupted is related to the type of motor and behavioral symptoms observed. Neonatally treated rats demonstrated self-mutilation when challenged as adults with L-dopa or a D1 dopamine agonist. This self-injurious behavior was not demonstrated in the adult rats treated with 6-hydroxydopamine. Self-biting was seen in the lesioned animals when they were challenged as adults with a dopamine agonist; however, untreated adult rats did not show this behavior. Based on this work, the neonatal rat treated with 6-hydroxydopamine is proposed as a model of the dopamine deficiency observed in Lesch-Nyhan disease. The effect is thought to involve predominantly the D1 dopamine receptor because self-biting was blocked best by a D1 dopamine antagonist. In support of involvement of the D1 receptor is a study of the neonatal lesion model by Papadeas and colleagues (116). These authors found that priming with the D1 agonist SKF-38393 leads to selective alterations in the morphology of pyramidal neuron apical dendrites (dendritic remodeling) in the prelimibic area of the medial prefrontal cortex. Pretreatment with inhibitors prevented these changes. These findings suggest that repeated stimulation of D1 receptors in adulthood interacts with developmental loss of dopamine to modify neuronal signaling and dendritic morphology in the mature prefrontal cortex (116).
Pickel and colleagues have found a compensatory increase in striatal enkephalin (following dopamine depletion) that may contribute to self-injurious behavior (118). Postnatal administration of the D1 dopamine agonist, SKF-38393, has been reported to reverse the neonatal dopaminergic-induced changes in striatal enkephalin and substance P systems and support a role of drugs affecting the D1 receptors in treatment (142). If replicated these findings may enhance our understanding of the role of D1 receptors in the postnatal development of Lesch-Nyhan disease. Finally, Goldstein and colleagues found dopamine induced self-mutilative biting behavior in monkeys with unilateral ventral tegmental lesions (50).
Second, the HGprt deficient mouse has been introduced as an animal model of Lesch-Nyhan disease. Two hypoxanthine-guanine phosphoribosyltransferase 1-deficient strains of mice have been produced; 1 strain by retroviral interruption of the human HPRT1 gene in the embryonic stem cells (85) and the other through the selection of embryonic stem cells for spontaneous mutations in the hypoxanthine phosphoribosyltransferase 1 gene (69). In both instances, the mouse strains produced have nondetectable levels of hypoxanthine-guanine phosphoribosyltransferase enzyme. Neither strain shows the spontaneous behavioral abnormalities or neurologic presentation seen in patients with Lesch-Nyhan disease. Tests of cognitive functions and motor functions give normal results in these animals. Engle and colleagues demonstrated that double knock-out HGprt and Aprt-deficient mice also do not show behavioral abnormalities (36).
The absence of behavioral changes in the mice may relate to the presence of uricase (an enzyme that is present in rodents, but not in primates) or possibly to increased activity of the alternative adenine phosphoribosyltransferase metabolic pathway in the mouse. To account for difference in mice and humans Keebaugh and colleagues suggest that the HPRT1 gene belongs to a gene family composed of 3 groups consisting of the HPRT1 gene, the phosphoribosyl transferase domain containing protein 1 (PRTFDC1), and the HPRT1L genes (82). They propose that Prtfdc1 was more recently inactivated in the mouse lineage during evolution and rescues HGprt deficiency, accounting for the disparity between HGprt-deficient humans and mice.
With regard to dopamine, during the first 8 weeks of postnatal development dopamine levels in whole-brain extracts from the mutant mice (Hprt1-) failed to increase at rates comparable to normal animals, resulting in 40% lower dopamine levels throughout adulthood. Regional analysis in adult animals showed the caudoputamen to be the most severely affected region, with dopamine deficits of 48% to 64%. Dopamine levels in other regions were normal or less severely affected (79). Moreover, reductions in the dopamine transporter of 35% to 40% also have been identified in the same species (79). These results suggest an abnormality in the dopamine system despite apparently normal spontaneous behavior. When amphetamine was administered in high doses to these mice, significant increases were observed in stereotypic and locomotive behavior in comparison to control animals (77). Moreover, older mice (22 to 24 months of age) traumatize their ears and their flanks from overgrooming, a form of mouse stereotypy. As a result of the amphetamine challenge response and the aging changes, additional behavioral investigations are needed. Jinnah and colleagues investigated striatal dopamine loss in 5 different HPRT-deficient strains of mice carrying 1 of 2 different Hprt1 gene mutations. Caudoputamen dopamine concentrations were significantly reduced in all 5 of the strains, with deficits ranging from 50.7% to 61.1%. Mesolimbic dopamine was significantly reduced in only 3 of the 5 strains, with a range of 31.6% to 38.6%. The reduction of caudoputamen dopamine was age dependent, emerging between 4 and 12 weeks of age. Tyrosine hydroxylase and aromatic amino acid decarboxylase, 2 enzymes responsible for the synthesis of dopamine, were reduced by 22.4% to 37.3% and 22.2% to 43.1%, respectively (75). These results demonstrate that HPRT deficiency is strongly associated with a loss of basal ganglia dopamine. The magnitude of dopamine loss measurable is dependent on the genetic background of the mouse strain used, the basal ganglia subregion examined, and the age of the animals at assessment. In a study in Hprt1 knockout mice adenosine neurotransmission was potentially linked to neurobehavior through increased expression of adenosine A1 receptor mRNA (11).These findings point to the possibility that adenosinergic alteration in Lesch-Nyhan disease may be the initial event in a chain of events resulting in basal ganglia dysfunction involving the dopamine system.
Neuronal changes caused by HGprt-deficient mice are not restricted to the dopamine system but also affect histaminergic neurotransmission. Tschirner and associates found that in addition to a decrease of dopamine and 3-methoxytyramine (3-MT) concentrations in the cerebral hemisphere, HGprt-deficient mice exhibited significantly reduced 1-methylhistamine (1-MH) and 1-methylimidazole-4-acetic acid (1-MI4AA) concentrations in the brain hemisphere and medulla (150). 1-MI4AA also was significantly decreased in the cerebellum.
With the emergence of recombinant adeno-associated virus-mediated homologous recombination and somatic cell nuclear transfer (SCNT), gene knock out procedures are being conducted in species other than rodents. For example, a generation of genetically modified knockout rabbits has been established (162). Male and female gene knockout fibroblast cell lines were established using different strategies. However, when male HPRT knockout cells were used for SCNT, no live rabbits were obtained. But when female HPRT(+/-) cells were used for SCNT, live, healthy rabbits were generated. These cloned HPRT(+/-) rabbits were fertile at maturity. This technology may be used in the genetic manipulation of other species.
Cell culture. Pelled and colleagues characterized purine nucleotide metabolism in primary astroglia cultures from Hprt1-deficient mice (117). The HGprt1-deficient astroglia exhibited the basic abnormalities in purine metabolism reported before in neurons and various other HGprt1-deficient cells. The following abnormalities were found: absence of detectable uptake of guanine and of hypoxanthine into intact cell nucleotides, 27.8% increase in the availability of 5-phosphoribosyl-1-pyrophosphate, 9.4-fold acceleration of the rate of de novo nucleotide synthesis, manifold increase in the excretion into the culture media of hypoxanthine (but normal excretion of xanthine), enhanced loss of label from prelabeled adenine nucleotides (loss of 71% in 24 h, in comparison with 52.7% in the normal cells) due to 4.2-fold greater excretion into the media of labeled hypoxanthine. In addition, the Hprt1-deficient astroglia were shown to contain lower cellular levels of ADP, ATP, and GTP, indicating that the accelerated de novo purine synthesis does not compensate adequately for the deficiency of salvage nucleotide synthesis, and higher level of UTP, probably due to enhanced de novo synthesis of pyrimidine nucleotides (117). Thus, altered nucleotide content in the brain may have a role in the pathogenesis of the neurologic deficit in Lesch-Nyhan syndrome. Ma and colleagues propose that hypoxanthine impairs morphogenesis and enhances proliferation of a neuroblastoma model of Lesch-Nyhan syndrome (94). They found that HGPRT-deficient B103-4C neuroblastoma, a neuronal model of Lesch-Nyhan disease, proliferated less and differentiated more than their Hprt1-positive B103 counterparts. These authors determined whether differences in proliferation and differentiation would occur when these cells were cultured in the presence of hypoxanthine or in a hypoxanthine and serum-free chemically defined media. In media with 1% serum, hypoxanthine significantly increased the proliferation of both cell lines with a greater effect on B103-4C cells. In 1% serum media, hypoxanthine increased differentiation of B103, but decreased B103-4C differentiation. In the hypoxanthine and serum-free chemically defined media, B103 proliferated far more than B103-4C, but both cell types differentiated to the same extent. These authors suggest that elevated levels of hypoxanthine in the CNS in Lesch-Nyhan disease might affect neuronal development and hypoxanthine may play a role in abnormal neuronal development in the disease.
The prevalence of the classical syndrome is generally estimated at 1 in 100,000 to 1 in 380,000 (20). However, based on the number of known cases in the United States, it may be as rare as 1 in 800,000 to 1 in 1.2 million. A population study of Lesch-Nyhan disease in the United Kingdom identified cases born between 1988 and 2003 (98). Thirty-one live born males were identified in 2008 for a prevalence of 1 in 2 million. Over 20 years of study, the mean incidence rate in the United Kingdom was 0.18 per 100,000 live births. In addition, partial variants of the disorder are known that show considerable variation in the extent of residual hypoxanthine phosphoribosyltransferase 1 activity (112; 114). The incidence of partial variants is not known. Those with the classical syndrome rarely survive the third decade; however, lifespan may be normal for those with partial variants without severe renal involvement.
Lesch-Nyhan disease is a genetic disorder, and the best means of prevention is through screening for the enzyme defect or HPRT1 mutations. Precise molecular methodologies are available for carrier and prenatal diagnosis (03). Due to the large number of known mutations, O’Neill has developed a cloning assay that allows determination of carrier status when the HPRT1 mutation is not known or is difficult to determine; carrier status can be determined in 10 days (111). As this condition is extremely rare, this approach is used primarily in those families with an affected family member. Most families have a unique mutation; 302 different mutations in 271 families have been reported (73; 74). Two cases have been reported with a normal HPRT1 cDNA and the defect; these cases attributed to a defect in the regulation of the gene or a defect in HPRT1 gene expression regulation (25; 48). Although rare, in 1 family a single mutation led to 3 different phenotypes in 5 related family members (68).
Because there may be delays in determining the mutation, there continues to be a place for enzyme analysis (108). Although uncultured chorionic villi may be used for prenatal diagnosis by direct enzyme assay, Nyhan suggests that the use of cultured amniocytes or chorionic villi cells for enzyme assay is preferable (105). For mutation carrier status O’Neill developed a peripheral blood T lymphocyte cloning assay that uses resistance to the purine analogue 6-thioguanine to measure the frequency of cells in females expressing a mutant HPRT1 allele (111). This assay allows determination of the carrier status of females even when the HPRT mutation is not yet known or is difficult to determine. Information on carrier status is available within 10 days. Willers advises caution about relying on only indirect genetic diagnosis even with intragenic markers (155). He presents the first evidence of concomitant somatic and germline mosaicism in Lesch-Nyhan syndrome.
X chromosome inactivation ratios of normal females can range from a highly skewed ratio of 0:100 to a 50:50 ratio. In Lesch-Nyhan disease female carriers are usually asymptomatic. However, in a study of the X chromosome inactivation pattern of HPRT deficiency carrier females, as a group, 75% of HPRT deficiency carrier females presented skewed X chromosome inactivation. The authors found that in Lesch-Nyhan disease families, the presence of skewed X chromosome inactivation is more sensitive for carrier diagnosis than in Lesch-Nyhan disease variant families. However, they conclude that this test is not accurate for carrier diagnostic purposes (149).
Preimplantation diagnosis with in vitro fertilization has been successfully accomplished. Ray and colleagues report success of this procedure in a couple with a child with Lesch-Nyhan disease (123). Prior to preimplantation diagnosis there were 5 therapeutic terminations and 3 spontaneous abortions. In the successful procedure, the mutation was characterized, and a nested PCR protocol was designed that allowed the efficient amplification of the affected loci followed by the detection of the mutant allele by restriction digestion. Three preimplantation genetic diagnosis cycles were carried out using this specific diagnostic test before the successful pregnancy that resulted in the birth of a healthy unaffected baby girl. In another case, a woman had undergone tubal ligation, and the couple wanted to have another child. Preimplantation genetic diagnosis with in vitro fertilization resulted in a singleton pregnancy. Direct mutation detection by mini-sequencing and parallel analysis of an informative linked marker was used as an alternative strategy for molecular diagnosis (19).
Gene editing techniques that use the CRISPR-Cas9 system to guide RNAs to direct the Cas9 endonuclease to cleave target sequences are being used with hypoxanthine phosphoribosyltransferase (HPRT). One research group developed a transient transfection-based method and successfully enriched targeted cells by co-targeting the HPRT gene (91).
Differential diagnosis includes other causes of infantile hypotonia and dystonia. Most commonly, children are diagnosed as having athetoid cerebral palsy. When a diagnosis of cerebral palsy is suspected in an infant with a normal prenatal, perinatal, and postnatal course, Lesch-Nyhan syndrome should be considered.
The preliminary diagnosis is ordinarily based on the physical and behavioral phenotype. The presence of dystonia in conjunction with self-injury and hyperuricemia is usually diagnostic. With partial deficiency the diagnosis will be less clear. In virtually all cases hyperuricemia and the increased secretion of uric acid are present. Serum levels of uric acid that exceed 4 to 5 mg uric acid/dL and a uric acid to creatinine ratio of 3 to 4 or more are highly suggestive of hypoxanthine phosphoribosyltransferase 1 deficiency, especially when associated with neurologic symptoms. The definitive diagnosis requires an analysis of the hypoxanthine phosphoribosyltransferase 1 enzyme. HPRT1 is assayed in an erythrocyte lysate where patients with classic Lesch-Nyhan disease have enzyme activity that is close to 0% and those with partial variants show values between 0% and 60% (112). The enzyme activity in partial variants shows little correlation with the clinical phenotype (138). The intact cell assay in skin fibroblasts provides a good correlation between enzyme activity and the severity of the disease (113). Molecular techniques are also used primarily in the identification of carriers (138; 03). Puig and colleagues evaluated female heterozygotes for HPRT1 deficiency and found an enhanced purine nucleotide degradation and purine overproduction (121). An elevated hypoxanthine or xanthine excretion rate differentiated most heterozygotes for HPRT1 deficiency from noncarrier women, thus, these findings could be useful for carrier diagnosis.
Psychiatric management utilizes combined psychosocial support, behavioral and pharmacological treatment in conjunction with protective equipment, and dental management (62). Medical management emphasizes the prevention of renal failure by pharmacological treatment of hyperuricemia with administration of allopurinol and efforts to reduce self-mutilation through behavioral management, the use of restraints, and the removal of teeth. The dosage of allopurinol, a xanthine dehydrogenase (formerly called xanthine oxidase) inhibitor, must be carefully monitored because excessive dosage can result in xanthinuria and xanthine urolithiasis (147). Sikora and colleagues report acute renal failure in a 9-year-old boy with Lesch-Nyhan disease due to xanthine urolithiasis from excessive doses of allopurinol (140). GLUT9 is a renal tubular urate transporter single nucleotide polymorphism that influences the renal handling of uric acid and modulates serum urate levels. In HPRT deficiency those having allele A of rs16890979 in the GLUT9 gene present with a lower serum urate concentration at diagnosis, before allopurinol treatment is instituted, and require lower allopurinol doses to maintain serum urate levels (148). Febuxostat is a potential alternative to allopurinol. Like allopurinol, febuxostat is a xanthine oxidase inhibitor that prevents uric acid production and lowers elevated serum uric acid levels. Unlike allopurinol, it is a thiazolecarboxylic acid derivative, not a purine base analog.
Pharmacological approaches to decrease anxiety, self-injury, and spasticity with medication have met with mixed results. Oral supplementation with S-adenosylmethionine has been introduced as a treatment for self-injury and aggression (49; 31; 17) for selected patients; its effects are described in this summary under pharmacological treatments.
Bone marrow transplantation. A bone-marrow transplant was carried out in the United States in a 22-year-old Lesch-Nyhan patient (107), based on the possibility that the CNS damage is produced by a circulating toxin. The authors postulated that an unknown neurotoxic substance of low molecular weight might cause CNS dysfunction. Although the transplantation was successful and restored the HGprt enzyme activity in the patient's peripheral blood cells, no change in neurologic symptoms or behavior resulted. PET scanning was carried out before and after the bone marrow transplant using 11C NMSP, a D2 dopamine receptor ligand, as the ligand, but no changes were demonstrated in receptor density following the transplantation (Harris 1995). Because it might be too late to reverse the cerebral symptoms in an adult, a second bone-marrow transplantation was attempted in Germany in a 16-month-old boy who had begun to show signs of psychomotor retardation (35). Neither this patient nor 2 other preschool-affected children on whom bone marrow transplantation was performed survived the procedure. Wojcik employed a mouse model of Lesch-Nyhan disease to assess the efficacy of bone marrow transplant in ameliorating the decrease in striatal dopamine levels and behavioral hypersensitivity to amphetamine. Marrow-ablated adult Hprt1-deficient mice were transplanted with marrow from congenic Hprt1-expressing mice. Bone marrow transplant altered neither the neurochemical nor the behavioral phenotypes in either Hprt1-expressing or Hprt1-deficient mice (158). Barring any important species differences, these results suggest that bone marrow transplant, in its present form, may not be an effective therapy for Lesch-Nyhan disease. Thus, to date, no evidence justifies the claim that bone marrow transplantation is a beneficial treatment approach; it remains an experimental and potentially dangerous procedure.
Partial exchange transfusion. Two patients received partial exchange transfusions every 2 months for 3 to 4 years (34). Erythrocyte hypoxanthine phosphoribosyltransferase 1 activity was 10% to 70% of normal during this period, but no reduction of neurologic or behavioral symptoms was apparent.
Due to the lack of success with bone-marrow transplantation and enzyme transfer using partial exchange transfusion, the HPRT1 gene should be targeted to cells in the CNS to address the neurologic and behavioral symptoms (138). This approach has been used by infecting mice in vivo by direct intrathecal injection of a recombinant Herpes simplex type 1 virus vector containing the human HPRT1 gene (115). Human hypoxanthine phosphoribosyltransferase 1 was detected in the brains in these animals, but not in tissues outside the CNS.
Behavioral treatment. The behavioral phenotype of self-injury must be considered in addition to the pathogenesis and pathophysiology in treatment programs. Patterns of self-injury vary among genetic syndromes. A review of self-injury in those with severe to profound intellectual disability and in 12 genetic syndromes demonstrates these differences (Huisman et al 2017). In Lesch-Nyhan disease behavioral techniques alone, using operant conditioning approaches, have not proved to be an adequate general treatment and have limited effectiveness. Yet, Nyhan notes that behavioral procedures do have some selective success in reducing self-injury, although generalization outside the experimental setting may be problematic (104); patients under stress may revert to their previous self-injurious behavior. Children with self-injury can alert the examiner to when it is safe to release the restraints. Thus, communication with the child and social supports are key in administering behavioral treatments. In a rat model of Lesch-Nyan disease, Stodgell and colleagues reported that environmental training (food-maintained fixed-ratio discrimination training) reversed 6-hydroxydopamine-induced striatal dopamine depletion (144).
Behavioral approaches address reducing the self-injurious behavior and treating phobic anxiety associated with being unrestrained (87). A behavioral treatment program utilizes several techniques, among which are systematic desensitization, extinction, and differential reinforcement of other (competing) behaviors (43). In addition to these behavioral approaches, stress management has been recommended to assist patients in developing more effective coping mechanisms.
Individuals with Lesch-Nyhan disease do not respond to contingent electric shock or other behavioral measures that ordinarily result in a suppression of self-injury. In this disorder an increase in self-injury is observed when aversive methods (ie, shock) are utilized (06). Duker reported that behavioral reduction strategies, such as contingent electric finger shock with response prevention, increased self-injury in 5 cases studied; however, time outs and reinforcement of behavior that is not self-injurious led to substantial reduction in a controlled setting. The affected person may choose another means of self-injury when the targeted means is prevented (32). Olson and Houlihan review the behavioral treatments that have been used in treating individuals with Lesch-Nyhan disease and discuss the strengths and weaknesses of various behavioral methods (110).
Use of restraints. In a survey conducted by Anderson and Ernst, 18 patients (45%) surveyed were restrained 100% of the time, 8 patients (20%) were restrained 75% of the time, and 5 patients (12%) were never in restraints (07). The time in restraints was associated with the age of onset of self-injury in that the older the patient was at the onset of self-injury, the less time was used for restraint. Twenty-nine patients (72%) were always restrained at night, and 8 patients (20%) were never restrained at night. All of the patients who were never restrained at night had a significantly later onset of self-injury. The individual with Lesch-Nyhan disease frequently participated in making decisions in regard to restraints and the type of restraints that were used. One half of the group asked to be restrained in a particular way and 17 patients (42%) insisted on restraint techniques that would logically be considered ineffective, like a light-weight glove, small bandage, or something else that could not physically prevent biting. When family members were surveyed about the patient's attitude toward restraints, 35 to 40 family members (87.5%) said the patient was at ease when restrained and liked to be restrained. Only 3 patients (0.7%) said they did not want to have restraints on. The time in restraints may potentially be reduced with systematic treatment programs.
Dental management. Cusumano and colleagues state that there have been no standard methods established to prevent the self-biting in Lesch-Nyhan disease (22). Preventive dental treatments must be developed for each patient based on clinical findings. The first method to be utilized should be a nonsurgical splint or mouth guard. If it proves to be unsuccessful then the benefits of surgical procedures should be considered. Twenty-four of 40 patients (60%) had teeth extracted to prevent self-injury in a family survey conducted by Anderson and Ernst (07). In the families where this was done, the family members endorsed tooth extraction as a way to manage self-biting. Fifteen of 40 patients (37.5%) had tried a protective mouth guard designed by a dentist. Of this group, three quarters said that it never worked, whereas 3 patients (20%) found the mouth guard to be helpful. A fabricated palatal plate has been used to raise the anterior bite. Although requiring adjustment, it proved satisfactory in assisting the healing of soft tissue damage and was still effective during a 3-year, 8-month follow-up period (41). A more conservative approach than extracting all teeth was successfully carried out in 2 siblings (88). The authors carried out vital pulpotomy and coronal resection. By maintaining the root portion of the teeth in the bone, it is expected that preservation of the alveolar bone can be achieved.
Goodman and colleagues analyzed the records of 5 Lesch-Nyhan disease patients who used mouth guards to spare the teeth and previously published cases on the use of dental devices to spare teeth in Lesch-Nyhan disease (51). Dental extraction ultimately was required in 4 of the 5 cases. Dental devices are being recommended, but failure rates are high.
Anxiety management. Anxiety may present itself through posturing, facial grimacing, and increases in choreoathetoid and spastic movements. Careful explanation should be given about what is to follow when initiating a medical or behavioral procedure that is given at a cognitive level that the patient is able to understand. The patient should be allowed to respond and give permission before proceeding with the behavioral program. Relaxation procedures may be taught, particularly those that encourage the patient to relax various body parts. Music may be utilized in conjunction with stress-reducing exercises.
Orthopedic management. The orthopedic problems and results of treatment of 9 Lesch-Nyhan patients were reviewed by Sponseller and colleagues. They found associated orthopedic problems included hip subluxation or dislocation (9 of 18 hips), fractures (3), autoamputation, infections (3), minor scoliosis, and contractures in referred patients. They report that Lesch-Nyhan disease patients can safely undergo orthopedic procedures, and that the results of surgery are satisfactory and similar to those of patients with spastic cerebral palsy. All 7 of the patients who had hip surgery maintained good reduction at 6-year mean follow-up. With adequate cast technique, fractures and hip subluxation and dislocation were treated successfully (143). The treating orthopedist must consider the increased incidence of heterotopic ossification in this population, and potential complications such as hardware failure or femur fracture, if appropriate immobilization is not carried out.
Parental intervention. Most parents selected stress reduction and awareness of the patient's needs as the most effective in reducing self-injury (07). Families reported that their most common methods for dealing with self-injury were attending to physical comfort and adjusting restraints, talking to the child, finding something more interesting, and getting what the child needed. The least commonly used interventions were the strict behavioral approaches, such as to stop talking, to turn away, or to take away something that is liked. On the other hand, positive behavioral techniques of reinforcing appropriate behavior was rated effective by almost one half of the families.
Pharmacotherapy. Drug treatments using diazepam, haloperidol, clomipramine, L-dopa, and pimozide (154) have not been successful in eliminating self-injury. Another approach is to use dopamine agonist or antagonist treatment. Fluphenazine, which is a mixed D1/D2 dopamine antagonist, has been used in 2 patients with Lesch-Nyhan disease (50). Motor control improved and self-injurious behavior was decreased in one 20-month-old patient with self-biting of the fingers at 18 months. Yet after discontinuation of fluphenazine, there was a definite escalation of the self-injury. A second patient, 15 years of age, showed no improvement on fluphenazine, and showed a worsening of symptoms with increased biting behavior after it was discontinued. Harris and associates found no clinical response to a fixed dose of fluphenazine and used PET scanning to demonstrate that a 7 mg single dose of fluphenazine (blood level 4.1 ng/mL) showed limited blocking of a D1 antagonist (SCH 23390) (67).
In the Anderson and Ernst parent survey, 35 to 40 patients (87.5%) had used medication for self-injury or agitation. Seven classes of medications were tried in the 40 patients surveyed: benzodiazepines in 21 patients, neuroleptics in 13 patients, antidepressants in 4 patients, opiate antagonists in 4 patients, chloral hydrate in 1 patient, beta blockers in 1 patient, and carbidopa-levodopa in 1 patient. Of 35 patients who used medication, 20 were continuing to use medications at the time of the survey. The medications found to be most effective on a short- and long-term basis were the benzodiazepines, particularly diazepam. Neuroleptics were used by 13 patients, and 4 patients were using them long-term. Naltrexone, which had been utilized by 4 patients, was not found to be effective. None of the families reported the use of medication for compulsive behaviors (07). An open-label trial of levodopa showed no benefit (152). All 6 participants stopped the medication early because of loss of effect or worsening of motor symptoms. More promising are case reports of the reduction of self-injurious behavior with atypical antipsychotics such as risperidone (05), carbamazepine (125), and gabapentin (99), but these require further confirmation.
Oral supplementation with S-adenosylmethionine has been introduced as a treatment for self-injury and aggression (49; 31; 17). S-adenosylmethionine (SAMe) has theoretical therapeutic potential to replenish the brain purine nucleotide pool. It is a precursor for 3 pathways: transmethylation, transsulfuration, and aminopropylation. Moreover, it provides an adenosyl moiety that can be salvaged to form adenosine mononucleotide (AMP) that is a substrate to form ATP and GTP. Following a case report (49) that self-injury was eliminated after 1 and a half years of treatment with S-adenosylmethionine of a 43-year-old man with Lesch-Nyhan disease (daily dose of 800 mg twice day), 2 institutional review board approved open-label trials have been reported (31; 17). Both were add-on trials and current medications were continued. In the first of these (17), oral supplementation was initiated in 4 maternally-related Malaysian children (at day 3 of life, then at 2, 4, and 10 years of age) from 2 families (including 1 girl) and an unrelated Chinese Malaysian boy (age 12 years). All 5 patients had substantial reduction in self-injury and aggression and milder reduction of dystonia. Doses ranged from 21 to 39 mg/kg per day. All patients have been treated for over 1 year.
The second open-label trial conducted in Italy reported that the 4 patients who tolerated the drug at target dosing had beneficial effects; however, most of subjects enrolled did not complete the trial because they reported worsening symptoms on the lower doses. This study was an open-label, dose escalation trial lasting 12 months and utilized standardized behavioral rating scales. It enrolled 11 classic cases and 3 variant cases ages 18 to 49 years. Seven discontinued in the first 2 months because of increased anxiety and excitability. In other instances, there was worsening of self-injury and increased excitement that prevented dose escalation. The authors recommend further study in a randomized, control trial. Issues for further study are age at the time of initiation of treatment, systematic monitoring of dosing, and further consideration for reasons for variability of response. The authors suggest that response variability lies not within the HPRT mutations but in some other biochemical pathway. Additional trials are warranted.
Animal studies indicate that the D1 dopamine receptor antagonist ecopipam is a candidate to suppress self-injurious behavior in Lesch-Nyhan disease. A double-blind, 3-period, crossover trial of a single dose of ecopipam in people with Lesch-Nyhan disease enrolled 10 patients (83). The trial was terminated early because of side effects that occurred when the drug was administered in a single large dose without a titration phase. Participants who completed the trial were eligible to remain on the drug in an open-label extension phase lasting a year. One patient who continued maintained a demonstrable reduction in self-injurious behavior for more than a year with no apparent side effects. Thus, despite limited data due to early termination, the drug appeared to reduce self-injurious behavior in most cases suggesting further study to establish an appropriate dosing regimen.
Deep brain stimulation. Bilateral chronic stimulation of the globus pallidus internus for control of dystonic movements in a 19-year-old man with Lesch-Nyhan disease has been reported (145). His self-mutilating behavior unexpectedly disappeared after chronic stimulation. At a 3-month follow-up, he no longer needed gloves and arm protectors, and at a 24-month follow-up, there was no self-mutilating behavior. The family refused a recommendation that the stimulation be stopped to see if the effects were reversed. The onset of the effects of stimulation on self-injury was gradual. His dystonia was 33% improved on the Burke-Fahn-Marsden Dystonia rating scale. This is single case report with no reversal procedure; further investigation is necessary regarding this approach to treatment. Deep brain stimulation has been carried out in two 12-year-old boys in Switzerland. Within 3 months the authors report the disappearance of “many self-mutilating” behaviors and a decrease in dystonic movements. Pallidal electrophysiological activity was recorded in these 2 patients during the deep brain stimulation surgery and microrecordings were performed on 162 neurons (119). In both patients, firing rates were similar in the globus pallidus externus and globus pallidus internus portions of the limbic track, while the motor globus pallidus externus fired at a higher frequency than the motor globus pallidus internus. Thus, the authors propose that motor symptoms in these 2 cases might result from motor globus pallidus internus inhibition. Subsequently, these authors directly stimulated globus pallidus neurons in 1 deep brain stimulation case and found that local deep brain stimulation induces a reversible inhibition of neuron firing rate while concurrently exciting the main afferents to and/or efferents from the GPi resulting in a strong GPi inhibition (120).
Moreover, not only self-injury, but also aggressive behavior, may respond to deep brain stimulation (18). Reduction in aggressiveness within the first week of limbic stimulation was marked in a 16-year-old boy. Lip and tongue biting, attitudes, coprolalia, and aggressive spitting at others became under control. With improved behavior, neuroleptics were decreased and tooth extraction was avoided. His feeding improved, as did his self-esteem and the extent of distress on family members. The authors provided a before and after videotape showing changes in behavior. Four leads were used. Two were in the anteroventral palladium and 2 in the posterior pallidum. The behaviors returned when the stimulation was turned off. Resumption of stimulation resulted in cessation of behaviors once again. Children as young as 7 years old have been successfully treated for self-injury with deep brain stimulation. Two-and-a-half years after implantation of deep-brain stimulation, this patient, with single electrode placement to each side of the brain, has decreased dystonia and complete absence of self-injurious behaviors (29).
Abel and associates described a 15-year-old boy who underwent bilateral placement of globus pallidus internus and deep brain stimulation electrodes for the treatment of generalized dystonia (01). His self-mutilating behavior gradually disappeared several weeks after the start of GPi stimulation but returned when the right lead was fractured. The findings suggest that neurobehavioral features of self-injury in Lesch-Nyhan disease is lateralized and that contralateral GPi stimulation is responsible for lateralized improvement in self-injurious behavior.
The deep brain stimulation reports are all case studies. Further research is needed, particularly regarding the effects of deep brain stimulation on both self-injury and aggression.
Sudden death. Sudden death is of concern in Lesch-Nyhan disease and may occur despite comprehensive case management. Although there are several causes, respiratory events are common and should be singled out, more so than cardiac events. In a report involving 8 cases Neychev and Jinnah discuss the risk for aspiration, laryngospasm, central apnea, breath holding spells, and high cervical spine damage injury, drawing attention to acute management of respiratory events (103). Breathing events in addition to chest imaging may warrant special tests including endoscopy of the airway, EEG, polysomnography, and imaging of the brain, or spine, or both.
Prenatal diagnosis is available for mothers of affected children by measurement of HPRT1 and APRT in chorionic villus samples or in cultured amniotic fluid cells (54). Preimplantation diagnosis has been offered in some medical centers for couples who prefer selection prior to pregnancy rather than during pregnancy (13; 28). This procedure has been used most commonly for X-linked diseases where embryos have either been selected for female sex or for specific diagnosis of single gene defects. Ray and colleagues report preimplantation diagnosis with in vitro fertilization (123). Cram and colleagues successfully used preimplantation genetic diagnosis with in vitro fertilization for a woman who had undergone tubal ligation and wanted another child (19).
Anesthesia is used for dental procedures and diagnostic tests requiring immobility, such as imaging studies. A variety of anesthetic agents have been used including methohexital, thiopental, propofol, ketamine, and nitrous oxide. Among these, propofol is preferred because of its rapid emergence and antiemetic effects (156).
Caution is required in the use of anesthesia especially because of the risk of aspiration. Propofol is useful because of its antiemetic effects.
James C Harris MD
Dr. Harris of Johns Hopkins University has no relevant financial relationships to disclose.See Profile
Raphael Schiffmann MD
Dr. Schiffmann of Baylor Scott & White Research Institute received research grants from Amicus Therapeutics, Takeda Pharmaceutical Company, Protalix Biotherapeutics, and Sanofi Genzyme.See Profile
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