Myoclonus epilepsy with ragged-red fibers
Jun. 18, 2022
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Support: service@medlink.com
Editor: editor@medlink.com
ISSN: 2831-9125
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This article includes discussion of adenylosuccinate lyase deficiency, ADSL deficiency, adenylosuccinase deficiency, adenylosuccinate lyase deficiency type I, and adenylosuccinate lyase deficiency type II. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Adenylosuccinate lyase (ADSL) deficiency is an autosomal recessive defect of purine metabolism, affecting purinosome assembly and reducing metabolite fluxes through purine de novo synthesis and purine nucleotide recycling pathways. The purinosome is a multienzyme complex of the de novo purine synthesis (DNPS) enzymes (including adenylosuccinate lyase) that cells transiently assemble in their cytosol on depletion or increased demand of purines. The study of purinosome formation in skin fibroblasts of the patients with adenylosuccinate lyase deficiency showed that significant differences of purinosome assembly exist among individual cases with adenylosuccinate lyase deficiency and that the ability to form purinosomes inversely correlates with the severity of the phenotype. This finding corroborates the hypothesis that the phenotypic severity of adenylosuccinate lyase deficiency is mainly determined by structural stability and residual catalytic capacity of the corresponding mutant adenylosuccinate lyase protein complex, as this is prerequisite for the formation and stability of the purinosome and at least partial channeling of SAICAR through the DNPS pathway. Adenylosuccinate lyase deficiency can, therefore, be diagnosed by detection of elevated metabolites along the DNPS pathway (succinylpurines) in patients’ body fluids. The diagnosis may be delayed or missed because patients can present with nonspecific features, such as developmental delay, autism spectrum disorder, and epilepsy.
• The clinical presentation of adenylosuccinate lyase (ADSL) deficiency varies greatly with respect to age of onset, clinical manifestations, and rate of disease progression. | |
• Patients with adenylosuccinate lyase deficiency can present with nonspecific symptoms, such as developmental delay, autism spectrum disorder, or epilepsy including infantile spasms. | |
• Due to lack of specific features and later onset of symptoms, diagnosis of patients is difficult, and simple selective screening procedures are indispensable in avoiding undiagnosed cases. | |
• Selective screening for adenylosuccinate lyase deficiency should be performed in patients who have neurologic disease without clear etiology, especially if MRI findings such as delayed or lack of myelination, white matter abnormal signal, and atrophy of the cerebrum and/or cerebellum are also present. | |
• Detection of succinylpurines in body fluids by high-performance liquid chromatography or liquid chromatography-tandem mass spectrometry is the preferred biochemical test for adenylosuccinate lyase deficiency. | |
• Greater awareness of adenylosuccinate lyase deficiency among general pediatricians, neonatologists, pediatric neurologists, and radiologists is the key to identifying the disorder in the early stage. |
Adenylosuccinate lyase (ADSL, also termed adenylosuccinase) catalyzes 2 steps in the synthesis of purine nucleotides: the conversion of succinyl aminoimidazole carboxamide ribotide (SAICAR) into aminoimidazole-carboxamide ribotide (AICAR), the eighth step of the de novo pathway, and the formation of adenosine monophosphate (AMP) from adenylosuccinate (S-AMP), the second step in the conversion of inosine monophosphate (IMP) into AMP. Both reactions release fumarate. Together with adenylosuccinate synthetase and AMP deaminase, adenylosuccinate lyase also forms the purine nucleotide cycle.
Adenylosuccinate lyase deficiency, the first enzyme deficiency reported in the de novo pathway of purine synthesis in man, was discovered in the course of a systematic study of amino acids in cerebrospinal fluid before and after acid hydrolysis (25). In 3 children with severe psychomotor retardation and autistic features, this procedure released abnormally large, equimolar amounts of aspartate and glycine. The additional identification by gas chromatography of an equimolar amount of ribose, led to a search for purine compounds. Anion-exchange high pressure liquid chromatography (HPLC) of deproteinized, but not hydrolyzed, cerebrospinal fluid, plasma, and urine revealed the presence of 2 UV absorbing compounds that were undetectable in control samples. They were identified as succinyl aminoimidazole carboxamide riboside (SAICA-riboside) and succinyl-adenosine (S-Ado). These succinylpurines are the products of the dephosphorylation, by 5'-nucleotidase(s), of SAICAR and S-AMP, respectively.
In profoundly intellectually disabled patients with adenylosuccinate lyase deficiency, cerebrospinal fluid (CSF) concentrations of both succinylpurines are 100 µmol/l to 200 µmol/l, and S-Ado/SAICA-riboside ratios are between 1 and 2. In adenylosuccinate lyase-deficient patients with milder clinical pictures, CSF concentrations of SAICA-riboside are in the same range, but those of S-Ado tend to be higher. This results in S-Ado/SAICA-riboside ratios above 2, even reaching 4 to 5 in a less intellectually impaired patient (27). In urine, the concentrations of the succinylpurines can reach up to 5 µmol per mg creatinine, and their ratio reflects that in CSF.
More recent studies, however, have shown that the ratio of the accumulating S-Ado and SAICAr in body fluids is not predictive of phenotype severity; rather, it may be secondary to the degree of the patient's development (ie, to the age of the patient at the time of a sample collection) (84). Ray and colleagues have shown a nonlinear dependence of the activities on the substrate ratios due to competitive binding, distinct difference in the behaviors of the different mutations, and S-Ado/SAICAr ratios in patients that could be explained by inherent properties of the mutant enzyme (58; 59).
Although the clinical picture of adenylosuccinate lyase deficiency is extremely variable, descriptive classification systems have described patients’ phenotypes as severe type I form, milder type II form, and fatal neonatal form (32; 35).
Fatal neonatal form of adenylosuccinate lyase deficiency. Recently, a larger number of patients with a neonatal form have been reported (van den Berghe et al 1998; Jurkiewicz et al 2007; 53; 32; 35; 43). These patients presented with fatal neonatal encephalopathy with a lack of spontaneous movement (“floppy infant”), respiratory failure, and intractable seizures, which resulted in early death within the first weeks of life. Additionally, it has been reported that adenylosuccinate lyase deficiency may have prenatal manifestations, with impaired intrauterine growth, microcephaly, fetal hypokinesia (with all its consequences up to arthrogryposis and pulmonary hypoplasia), and a loss of fetal heart rate variability (53).
Type I adenylosuccinate lyase deficiency. Most of the patients reported so far have adenylosuccinate lyase deficiency type I (severe form) with a purely neurologic clinical picture characterized by severe psychomotor retardation, early onset of seizures, and microcephaly. These patients present within the first months of life and the further evolution is characterized by developmental arrest, lack of eye-to-eye contact, and in some patients, coma vigil (27; 39; 72; 37; 32; 35; 19; 43; 31). In addition to hypotonia or hypertonia, extrapyramidal movement disorders, including paroxysmal dyskinesias and dystonias, have been observed (31; 06). Severe cortical visual impairment corresponding to the degree of encephalopathy may also be a feature of the severe phenotype (43).
With the exception of microcephaly, there are usually no dysmorphic features. However, there is 1 report of 2 patients in whom brachycephaly was associated with a long, flat philtrum and thin upper lip (22).
Patients have also been diagnosed with intractable convulsions within the first days to weeks after birth (44; 65; 75; 37; 55; 32; 35).
Type II adenylosuccinate lyase deficiency. Patients with type II (moderate or mild form), who develop symptoms within the first years of life, usually suffer from slight to moderate psychomotor retardation and transient contact disturbances (27; 76; 32; 35; 2014b). Seizures, if present, appear later, often between the second and fourth year of life (09; 29), but also reported starting as late as ninth year of life (19). Speech impairment with a minimal use of words was noticed in contrast with a higher degree of receptive and nonverbal communication skills (19). Another described problem is ataxia, which may be the cause of increasing gait disturbance.
In a recent review of type II patients, clinical findings indicated that there is often mild neurologic involvement with no or very low incidence of seizures, and less frequently, autistic features (33). In general, children were born after uncomplicated pregnancies, and the family history and birth were normal. Delayed motor milestones were evident in all patients, ranging from mild to moderate. Seizures were present in about 30% of these patients and were never the first sign of the mild adenylosuccinate lyase deficiency (33). Long-term follow-up of these patients showed no obvious signs of disease progression (33).
The disease manifests symptoms along a continuum, and despite the utility of communicating with the 3 descriptive categories, there are no fixed parameters to ascribe a particular patient to a single category (34). The majority of adenylosuccinate lyase-deficient children are born after uncomplicated pregnancies with normal birth and family history. The neonatal period in mild form might be normal with growth parameters in the normal range. In severe type of the disease, neurologic symptoms might occur soon after birth. Neurologic symptoms are the most common and prominent clinical problems associated with adenylosuccinate lyase deficiency. Particularly common neurologic presentations include acute encephalopathy, chronic encephalopathy, and behavioral abnormalities. These may occur in various nonspecific combinations with seizure, for example, a patient with infantile spasms, moderate global developmental delay, and normal brain MRI (52).
Neurologic manifestations | Presentation | Tests/referrals |
Acute encephalopathy (with seizures) | • typically a normal pregnancy, at or near term, with a normal birth weight • remains well in the early hours or days of life • early signs are non-specific, such as poor feeding, lethargy, vomiting, abnormalities of tone and irritability • later problems may include drowsiness, fits, hiccups, myoclonus, apneic episodes, marked hypotonia, irritability with cycling movements and coma • cerebral edema may develop, contributing to the relentless deterioration if not treated | • pediatric observation • neurologic consultation • ultrasonography of the central nervous system (CNS) by fontanel • electrophysiological examinations • MRI, CT of CNS |
Chronic encephalopathy (with or without seizures) | Developmental delay and psychomotor retardation • tends to be global, affecting all spheres of development to some extent • severe irritability, impulsivity, aggressiveness, and hyperactivity are also common among infants • psychomotor retardation is usually progressive • psychomotor retardation is usually associated with other objective evidence of neurologic dysfunction, such as disorders of tone, seizures, pyramidal tract signs or evidence of extrapyramidal deficits | • neurologist consultation • psychologist consultation • physiotherapist consultation • electrophysiological examinations • MRI, CT of CNS |
Seizures | • often onset of epilepsy in the first year of life • clinical picture is usually complex and epilepsy is one of various other associated neurologic symptoms, such as mental retardation, hypotonia, and microcephaly • convulsions may have a very early onset and be the reason for which the infant is referred to a neurologist in the first months of life, despite the presence of other, less easily identified symptoms such as delayed psychomotor acquisitions or muscle tone disorders • general characteristics of seizures are as follows: onset in the first months of life, usually partial with migrant onset and multifocal; simple partial motor semiology of brief duration; and successive appearance, often closely related to partial seizures, tonic seizures, spasms, and massive myoclonus • resistance to drug treatment is often | • neurologist consultation • EEG • EMG • MRI, CT of CNS |
Behavioral abnormalities | • autistic features (failure to make eye-to-eye contact, repetitive behavior, agitation, temper tantrums, autoaggressivity) | • psychologist consultation |
Other | • hypotonia, (axial and generalized) • peripheral hypertonia | • neurologist consultation • MRI, CT of CNS |
(Contributed by Dr. Agnieszka Jurecka.)
Magnetic resonance imaging of the brain. Head imaging abnormalities include atrophy of the cerebral cortex, corpus callosum, cerebellar vermis, delayed/lack of myelination, anomalies of the white matter, and lissencephaly (Van den Berghe 1997; 72; 37; 55; 67; 15; 51; 43; 30). White matter abnormalities may vary slightly from case to case and are present in the majority of patients. The combination of hypomyelination with psychomotor retardation should allow a suspicion of diagnosis of this disorder in the proper clinical setting. Magnetic resonance spectroscopy of white matter abnormalities can suggest adenylosuccinate lyase deficiency if specific metabolites are detected as discussed below but has been described in too few patients to be used in ruling out the diagnosis. Follow-up brain MRI imaging and ongoing clinic visits may also prove to be useful and objective tools in assessing patient status.
The prognosis for survival of adenylosuccinate lyase-deficient patients is variable. Several of those presenting with neonatal or early infancy epilepsy have died within the first months of life. In patients with severe cognitive impairment, further evolution is characterized by absent or minimal progression of psychomotor development and persistence of autistic behavior, except for occasional improvement of eye contact. Patients with less severe cognitive impairment have reached adult age.
Case 1. The patient is a girl who is the second child of unrelated, healthy Belgian parents. Their first child is healthy. Pregnancy and delivery were normal. Weight was 3750 grams, and length was 53 cm. At the age of 2 years 8 months she was admitted for evaluation of psychomotor retardation, autistic features, and failure to thrive (weight 12.4 kg, length 93 cm, head circumference 48.1 cm). Developmental age (Gesell) was 9 months for gross motor skills but 5 to 6 months for other developmental domains. Autistic behavior was striking with impaired eye contact, repetitive manipulation of toys, grimacing, and incessant crying without apparent reason. Funduscopic examination was normal. She also ground her teeth and bit herself. There was moderate axial hypotonia with normal tendon reflexes. Routine biochemical analyses of blood and urine and the work-up for metabolic disorders were negative. Auditory, somatosensory, and visual-evoked responses were normal. Nerve conduction velocities and electromyography were also normal. Computed tomography and magnetic resonance imaging of the brain showed hypoplasia of the vermis of the cerebellum. Analysis of urine and cerebrospinal fluid revealed accumulation of succinylpurines, with S-Ado/SAICA-riboside ratios of 1.1 to 1.5. Adenylosuccinate lyase deficiency type I was diagnosed.
Case 2. The second patient is a girl who is the second child of unrelated Dutch parents. During the neonatal period neurologic impairment was suspected, and at the age of 2 years 11 months she was admitted for investigation. Weight was 12 kg but weight gain had been decelerating since the age of 2 years. Height was 93.5 cm, and head circumference was 50.5 cm. Motor development was at the level of 1½-years, and speech development was at the level of 1 year. Eye contact was impaired and reaction to auditory stimuli was poor, but auditory evoked potentials were normal. At the age of 3 years, electroencephalography showed diffuse slowing without signs of epilepsy. Computed tomography and magnetic resonance imaging of the brain showed slight cerebral hypotrophy. On re-evaluation at the age of 4 years, psychomotor development was at the level of 2.5 years, and electroencephalography was normal. Analysis of urine and cerebrospinal fluid revealed accumulation of succinylpurines, with S-Ado/SAI CA-riboside ratios of 3.7 to 4.7. Adenylosuccinate lyase deficiency type II was diagnosed.
Case 3. The third patient is the second daughter of unrelated Polish parents. Her older sister is healthy. Pregnancy and delivery were normal. Weight was 3550 grams, and length was 58 cm. Shortly after birth she was noted to have hypotonia and she developed feeding problems. At the age of 7 days, the patient presented with tonic-clonic seizures and was hospitalized. During the following days, she presented with repeated episodes of apnea and status epilepticus. She remained on artificial ventilation until her death at 2.5 months of age. Brain MRI revealed generalized atrophy of the cerebrum, abnormally thin corpus callosum, and lack of myelination. Analysis of cerebrospinal fluid revealed accumulation of succinylpurines, with S-Ado/SAICA-riboside ratios of 0.92. Mutation analysis on the neonatal screening card of the patient revealed compound heterozygosity for the p.Y114H and p.T242I mutations. The fatal neonatal type of adenylosuccinate lyase deficiency was diagnosed.
The disorder is caused by the deficient activity of adenylosuccinate lyase, an enzyme that intervenes once in the de novo synthesis of both guanine and adenine nucleotides and a second time in that of the latter.
Individual intermediates of de novo purine synthesis have potent regulatory and cytotoxic properties and, therefore, are under physiologic conditions either undetectable or present in very low (micromolar) concentrations in cellular extracts and/or body fluids (38). Efficiency of de novo purine synthesis at such low concentrations of individual intermediates is ensured by the dynamic assembly and disassembly of the cytosolic multienzyme complex, the “purinosome” (03; 54). Impairment of the conversion of the 2 substrates of the enzyme, SAICAR and S-AMP, leads to the formation of their dephosphorylated derivatives, SAICA-riboside and S-Ado, respectively. These metabolites accumulate in cerebrospinal fluid and urine, and to a minor extent in plasma.
Pathogenesis. Adenylosuccinate lyase deficiency is inherited as an autosomal recessive trait. In humans the adenylosuccinate lyase (ADSL) gene spans approximately 23 kb on chromosome 22 (22q13.1q13.2) (Van Keuren et al 1987; 18). It consists of 13 exons and its promoter has typical features of house-keeping genes. The adenylosuccinate lyase gene is transcribed in most of the tissues into 2 transcript variants that are produced by alternative splicing of exon 12. The full-length variant encodes an active adenylosuccinate lyase protein composed of 484 amino acids. The alternatively spliced variant encodes a variant missing 59 amino acids (residues 397-456). This variant is catalytically inactive and its biological relevance is not clear yet (36).
To date, over 50 different adenylosuccinate lyase mutations have been identified in individuals with adenylosuccinate lyase deficiency. The majority of identified mutations are missense mutations, and most patients are compound heterozygotes (71). The most commonly identified mutation, c.1277G>A (p.Arg426His), accounts for about one third of patient alleles; however, there is significant phenotypic variability even among the 14 reported patients homozygous for this variant (14). Many patients have private variants unique to their families. Other types of pathogenic mutations have also been identified, including splice site mutations (Marie et al 1999; 85; 45) and a promoter mutation, which was found in 3 unrelated patients (50).
Most characterized mutations lead to structural instability of the enzyme, without modifications of its kinetic properties, and decrease activity with S-AMP and SAICAR in parallel. The severity of the clinical symptoms has a tendency to correlate with residual activity. A R303C mutation, found in 2 independent, mildly cognitively impaired type II patients, is thermostable and displays markedly less activity with S-AMP than with SAICAR. This provides an explanation for the markedly higher S-Ado/SAICA-riboside ratios in type II patients (74; 57).
In a recent study, it has been demonstrated that various mutations of adenylosuccinate lyase destabilize the various degrees of purinosome assembly, and that the ability to form purinosomes correlates with clinical phenotypes of individual adenylosuccinate lyase patients (05).
Purinosome. Adenylosuccinate lyase (ADSL) deficiency is a defect of purine metabolism affecting purinosome assembly and reducing metabolite fluxes through purine de novo synthesis and purine nucleotide recycling pathways. The purinosome is a multienzyme complex of the de novo purine synthesis (DNPS) enzymes (including ADSL) that cells transiently assemble in their cytosol on depletion or increased demand of purines (03).
The study of purinosome formation in skin fibroblasts of the patients with ADSL deficiency showed that significant differences of purinosome assembly exist among individual cases with adenylosuccinate lyase deficiency and that the ability to form purinosomes inversely correlates with the severity of the phenotype. This finding corroborates the hypothesis that the phenotypic severity of adenylosuccinate lyase deficiency is mainly determined by structural stability and residual catalytic capacity of the corresponding mutant adenylosuccinate lyase protein complex, as this is prerequisite for the formation and stability of the purinosome and at least partial channeling of SAICAR through the DNPS pathway (84; 79). The use of CRISPR-Cas9 editing of HeLa cells has confirmed the disruption of purinosome formation in the setting of ADSL deficiency (04).
Pathophysiologic mechanisms. Hypotheses regarding the pathogenesis include toxicity of high levels of SAICAR, S-AMP, or their metabolites, deficiency of the de novo purine biosynthetic pathway, or lack of a completely functional purine cycle in muscle and brain (34).
Toxic effects of intermediates. The signs and symptoms of adenylosuccinate lyase deficiency may be secondary to the neurotoxic effects of the accumulating succinylpurines. The observation of less severe intellectual impairment in patients with similar SAICA-riboside levels but S-Ado/SAICA-riboside ratios above 2, suggest that SAICA-riboside is the offending compound, and that S-Ado could protect against its toxic effects. However, this is not known to be true, as when the activity of the enzyme against both substrates was measured separately (non-competitively), patients exhibited a proportional decrease in enzyme activity against both substrates (36). When the activity was measured with both substrates present and competing against each other for the same residual enzyme activity, this proportionality was altered in one way or another, depending on the specific mutation (59). Alternatively, the abnormal ratio might be explained by a different rate of transport of these succinylpurines across membranes (36); for example, it is known that SAICA-riboside is transported by ABCC5 (28).
The finding that infusion of SAICAr to rats induces neuronal damage in specific regions of the hippocampus is consistent with this hypothesis (69). To date, however, most attempts to demonstrate evidence of neurotoxicity of the succinylpurines have failed. In particular, because S-Ado and SAICAr are analogs of adenosine and glutamate, it was hypothesized that they might modify the CNS effects of adenosine or disrupt glutamatergic neurotransmission, but this hypothesis was disproven (70). The accumulation of SAICAR in a C. elegans model of adenylosuccinate lyase deficiency was shown to alter cholinergic neurotransmission (16).
Of note, in HeLa cells with adenylosuccinate lyase deficiency induced via CRISPR-Cas9, an accumulation of AICAR was also noted (04). This finding is quite puzzling because AICAR is a metabolite distal to the metabolic block; the authors hypothesized that AICAR might be provided via an alternative pathway of histidine biosynthesis, which is known to cross-talk with the DNPS pathway in yeast (60). However, a pathway for histidine biosynthesis in humans is not known to date.
Deficiency of purine nucleotides. Deficient synthesis of purine nucleotides caused by adenylosuccinate lyase deficiency has been hypothesized to have detrimental effects during embryo development, primarily depending on de novo purine synthesis. Although adenylosuccinate lyase deficiency might be expected to lead to decreased synthesis of purine nucleotides, normal levels of the latter were measured in various patients’ tissues (77). This can be explained by residual activity of adenylosuccinate lyase (25; 27), and by the supply of purines via the purine salvage pathway, involving the enzymes hypoxanthine-guanine phosphoribosyltransferase, adenine phosphoribosyltransferase and adenosine kinase. Another line of evidence arguing against purine deficiency as the pathomechanism comes from the worm model of disease; in this model, creating a double knockout of adenylosuccinate lyase and the enzyme just proximal to it in the DNPS pathway leads to a masking of the phenotype (11). In fact, these authors have advocated blockage of this proximal enzyme as a potential therapeutic approach. Nevertheless, a deficiency of purine nucleotides could occur in some hitherto unidentified cell types with profound deficiency of adenylosuccinate lyase and low activity of the salvage pathway. Indeed, the lack of fertility in a worm model of the disease was shown to be related to reduced DNPS, even though there was no significant decrease in purine metabolite concentrations (16). Similarly, the expression of a trifunctional protein participating in DNPS is known to be 20 times higher in human prenatal than in postnatal cerebellum (07), and the degree of DNPS is also known to decrease dramatically after birth in rat brains (01; 02). Little is known about the actual purine levels in the living brain and about the regulation of purine synthesis during embryogenesis, which might be affected by deficits in purine metabolism (34).
Impairment of energy metabolism. Adenylosuccinate lyase also participates in the purine nucleotide cycle along with AMP deaminase and adenylosuccinate synthetase, and the impairment of this cycle in adenylosuccinate lyase deficiency has also been suggested to cause the disorder. Purine nucleotide cycle controls the level of fumarate, a Krebs cycle intermediate, and of AMP, particularly maintaining the ATP/AMP ratio in muscles (76).
The exact prevalence of adenylosuccinate lyase deficiency is unknown. Known disease-causing mutations and protein-truncating variants are present in the ExAC population database at a 1 in 557 carrier frequency, giving a conservative estimate of 1 in 1.25 million disease frequency (17). The true prevalence is likely higher because many patients have missense mutations unique to the family; in addition, there are likely many such mutations that have not yet been ascertained in undiagnosed patients.
To date, over 80 patients with adenylosuccinate lyase deficiency have been reported in populations across the world. Most of them have been identified in the low countries: Belgium, the Netherlands, Czech Republic, and Poland (25; 37; 36; 53; 32; 35). Other patients have been identified in Australia (67; 78), China (47), Colombia (09), France (22), Germany (Kohler et al 2007; 53), Italy (55; 57), Malaysia (10), Morocco (25; 68; 19), Norway (50), Portugal (15), Spain (09; 56), Turkey (36; 66), the United Kingdom (51; 10; 43), and the United States (36; 66).
An adenylosuccinate lyase deficiency database is available at http://www1.lf1.cuni.cz/udmp/adsl.
Differential diagnoses of adenylosuccinate lyase deficiency include:
• Neurologic disorders with intractable seizures and encephalopathy (Table 2) | |
• Other inborn errors of purine and pyrimidine (P/P) metabolism with neurologic manifestations. (Table 3) |
Disease (abbreviation, | Neurologic manifestations | Other symptoms | Inheritance | Diagnostic examinations and tests (metabolites) |
Adenylosuccinate lyase deficiency (ADSL, 103050) | • Type I: hypotonia, seizures often intractable, profound PMR, autistic features • Type II: mild/moderate PMR, behavioral disturbances • Neonatal form: severe encephalopathy with hypotonia, seizures | • Dysmorphic features • Microcephaly | Autosomal recessive | Urine or other body fluid HPLC for succinylpurines (S-Ado↑, SAICAr↑) |
Angelman syndrome (105830) | • Usually normal birth and neonatal course • Epilepsy, with characteristic notched-delta EEG pattern in some patients • Severe developmental delay • Gait ataxia • Typical behavioral features including happy demeanor | • Acquired microcephaly • Light skin and hair in patients with deletions including OCA2 | Typically isolated | • DNA methylation analysis of Prader-Willi syndrome/Angelman syndrome critical region (80% of patients) • UBE3A sequencing (11%) |
Pyridoxine-dependent epilepsies (ALDH7A1, 266100; PROSC, 617290) | • Early onset in the neonatal or infant period • Intractable seizures • Encephalopathy and developmental delay | • Lactic acidosis in some patients • Response to administration of vitamin B6 (pyridoxine) | Autosomal recessive | • Empiric treatment with pyridoxine • Urine alpha-aminoadipic semialdehyde (AASA) or delta1-piperideine-6-carboxylate (P6C) |
Pyridox(am)ine-5'-phosphate oxidase deficiency (PNPO, 610090) | • Neonatal epileptic encephalopathy • Variable response to pyridoxine; response to pyridoxal 5’-phosphate • Developmental delay | • Microcephaly | Autosomal recessive | • Empiric treatment with pyridoxal 5’-phosphate • PNPO gene sequencing |
Fumarase deficiency (FH, 606812) | • Infantile-onset, severe, progressive mitochondrial encephalopathy • Epilepsy, potentially status epilepticus with developmental regression • Hypotonia • Brain malformations • Optic atrophy | • Acute metabolic acidosis • Dysmorphic features | Autosomal recessive | • Urinary organic acid analysis: fumarate, as well as Krebs cycle intermediates such as malate and succinate • Lactate and pyruvate in blood • Fumarase activity measurement (both cytosolic and mitochondrial activities decreased) |
3-phosphoglycerate dehydrogenase deficiency (PHGDH, 601815) | • Seizures • Psychomotor retardation • Hypertonia | • Congenital microcephaly • Ichthyosis • Response to oral serine | Autosomal recessive | CSF amino acid measurement (decreased serine and glycine) |
Biotin-responsive holocarboxylase synthetase deficiency (HLCS, 253270) | • Seizures • Ataxia and death if untreated | • severe metabolic acidosis • Skin rash • Hyperammonemia • Thrombocytopenia • Response to treatment with biotin | Autosomal recessive | Urinary organic acid analysis: lactate, 3-hydroxybutyrate and acetoacetate (due to PC deficiency); 3-methylcrotonate, 3-methylcrotonylglycine, 3-hydroxyisovalerate (due to 3-MCC deficiency); and propionate, 3-hydroxypropionate, methylcitrate, tiglyglycine (due to PCC deficiency) |
Biotin-responsive biotinidase deficiency (BTD, 253260) | • Commonly present between 3-6 months of life • Seizures • Failure to thrive, developmental delay, hypotonia, and ataxia • Optic atrophy | • Metabolic acidosis • A skin rash resembling seborrheic • Dermatitis • Alopecia • Dramatic response to treatment with biotin | Autosomal recessive | Decreased serum/plasma biotinidase activity • Urine for organic acids such as 3-hydroxyisovalerate (not always present) |
GLUT1 deficiency (SLC2A1, 606777) | • Spectrum of onset and severity; infantile onset in severe form • Generalized and focal epilepsies including myoclonic, atonic, and absence seizures • Acquired microcephaly • Spasticity, ataxia, and dystonia possible • Generally responds well to treatment with a ketogenic diet | Autosomal dominant | Simultaneous measurement of plasma and CSF glucose after 4-hour fast (hypoglycorrhachia based on absolute CSF glucose, usually < 60; often decreased ratio of CSF to plasma glucose < 0.4) SLC2A1 sequencing and deletion/duplication analysis | |
Nonketotic hyperglycinemia/Glycine encephalopathy (GAMT, GLDC, GCSH, 605899) | • Early onset, usually neonatal • Rapidly progressive encephalopathy with virtually no secondary biochemical abnormalities • Microcephaly | Autosomal recessive | CSF and plasma amino acid measurement (increased CSF glycine and CSF/plasma glycine ratio) | |
D-2-hydroxyglutaric aciduria (D2HGDH, 600721; IDH2, 613657) | • Neonatal or early-onset epileptic encephalopathy, including infantile spasms • Hypotonia and developmental delay • Multifocal white matter injuries | Cardiomyopathy (type 2) | autosomal recessive | urinary organic acid analysis (D-2-hydroxyglutarate, sometimes succinate) |
Mitochondrial glutamate transporter deficiency or early infantile epileptic encephalopathy 3 (SLC25A22, 609304) | • Neonatal and infantile-onset epileptic encephalopathies, including early myoclonic encephalopathy and migrating partial seizures of infancy • Hypotonia and developmental delay • Microcephaly • Milder presentation with developmental delay and childhood-onset seizures | Autosomal recessive | Hyperprolinemia may be seen on plasma amino acids. Biochemical evaluation may be normal. Lipid-containing vacuolated fibroblasts on electron microscopy SLC25A22 sequencing | |
Peroxisomal biogenesis defects (Zellweger syndrome, ZS, 214100) | • Early onset in the first few hours after birth • Profound hypotonia, nystagmus, seizures | • Typical abnormalities of face and skull • Jaundice, hepatomegaly | Autosomal recessive | Routine laboratory studies (elevation of bilirubin and transaminases, hypoalbunimemmia, prolonged prothrombin and partial thromboplastin times) • Plain radiographs of the long bones (abnormal punctate calcifications in the epiphyses of the knees and other joints) • Ultrasound examination of the abdomen (hepatomegaly, kidneys with cystic changes) • CT scans of the head (cerebral dysgenesis with subcortical cystic changes) |
Mitochondrial respiratory chain disorders | • Nystagmus, dystonia, ophthalmoparesis and optic atrophy • Encephalopathy • Hypotonia • Acute ataxia • Myoclonic seizures • Lethargy | • Failure to thrive, growth delay • Mild hearing loss • Myopathic facies • Myopathy cardiomyopathy • Respiratory failure, apnea • Liver failure • Tubulopathy • Premature death | Dominant or autosomal recessive, the strictly matrilineal inheritance observed with mtDNA point mutations or X-linked recessive | Laboratory tests (lactic acidosis) |
Molybdenum cofactor deficiency (sulfite oxidase/xanthine oxidase/aldehyde oxidase deficiency, MOCS1, MOCS2, GPHN, 252150) • Isolated sulfite oxidase deficiency (SUOX, 272300) • Isolated sulfite oxidase deficiency | • Classic onset within the first week or two of birth; later-onset forms • Intractable tonic-clonic seizures • Mental retardation | • Dislocated lenses • Microcephaly • Dysmorphic features | Autosomal recessive | • Urinary sulfite dipstick testing • Urine thiosulfate and S-sulfocysteine • Plasma total homocysteine (decreased) • MRI of the brain (early cerebral edema followed rapidly by marked cerebral and cerebellar atrophy, multicystic changes, signs of hypomyelination of white matter) |
Menkes disease (ATP7A, 309400) | • Hypotonia • Failure to thrive • Intractable seizures • Severe developmental retardation • Abnormal muscle tone | • Brittle hair • Hypothermia • Chronic diarrhea • Recurrent urinary tract infections | X-linked recessive | • Skeletal radiographs (generalized osteopenia, Wormian bones in the skull, classic metaphyseal lesions) • Markedly decreased copper I and ceruloplasmin levels in plasma |
Disease (abbreviation, OMIM No) | Neurologic manifestations | Other symptoms | Inheritance | Diagnostic metabolites (tests*) |
Adenylosuccinate lyase deficiency (ADSL, 103050) | Type I: hypotonia, seizures often intractable, profound PMR, autistic features Type II: mild/moderate PMR, behavioral disturbances Neonatal form: severe encephalopathy with hypotonia, seizures | Dysmorphic features, microcephaly | Autosomal recessive | S-Ado↑, SAICAr↑ |
AICAR transformylase and IMP cyclohydrolase deficiency (ATIC, 608688) | PMR, epilepsy, congenital blindness | Dysmorphic features | Autosomal recessive | AICAr↑, SAICAr↑, S-Ado↑ |
Dihydropyrimidinase deficiency (DPH, 222748) | Variable neurologic symptoms: seizures, mental retardation, delay in speech development, growth retardation, spastic quadriplegia/asymptomatic | Dysmorphic features, microcephaly, congenital microvillus atrophy1, toxicity to 5-fluorouracil | Autosomal recessive | dhU↑, dhT↑, U↑, T↑ |
Dihydropyrimidine dehydrogenase deficiency (DPD, 274270) | Variable neurologic symptoms: seizures, mental retardation, acutely developed lethargy, cerebral palsy, hypertonia, growth retardation, autistic behavior, ocular anomalies / asymptomatic | Microcephaly, toxicity to 5-fluorouracil | Autosomal recessive | U↑, T↑ |
Hypoxanthine-guanine phosphoribosyltransferase deficiency (HPRT, 308000): • Lesch-Nyhan disease (LND) • HPRT-related hyperuricemia (HRH) • HPRT-related hyperuricemia with neurologic deficit without behavioral changes (HRND) | Choreoathetosis, dystonia, spastic quadriplegia, psychomotor retardation, self-mutilation (only LND), mild or no neurologic symptoms in HRH | Crystalluria, urolithiasis, acute renal failure, gouty arthritis, megaloblastic anemia | X-linked recessive | UA↑, hyp↑ |
Molybdenum cofactor deficiency (MOCS1, MOCS2, GPHN, 252150) | Neonatal: intractable seizures, feeding difficulties, profound developmental delay, alternations in muscle tone, ocular lens dislocation Late presentation: motor or language delay, minor behavioral problems, lens dislocation | Dysmorphic features, microcephaly, renal stones | Autosomal recessive | (Hypo-)xan↑, sulfite↑, thiosulfate↑, s-sulfocystine↑, cystine↓, UA↓ |
Purine nucleoside phosphorylase deficiency (PNP, 164050) | Variable neurologic abnormalities: failure to thrive, mental/motor retardation, ataxia, hyper/hypotonia | Immunodeficiency (lymphocytes T), recurrent infections especially viral, malignancies, autoimmune disease | Autosomal recessive | (d)Ino↑, (d)Guo↑, dGTP↑ (RBC), UA↓ |
Phosphoribosyl-pyrophosphate synthase superactivity (PRPS1, 300661) | Early onset: severe neurodevelopmental impairment, sensorineural deafness | Early onset: dysmorphic features Late juvenile: gouty arthritis, nephropathy, urolithiasis, no neurologic deficit | Autosomal recessive | UA↑ |
CAD deficiency/uridine-responsive epileptic encephalopathy (CAD, 616457) | Infantile-onset epileptic encephalopathy with global developmental delay; initially normal brain MRI Late-stage loss of skills and progressive brain atrophy Marked clinical response to uridine, 100 mg/kg/day | Normocytic anemia with anisopoikilocytosis, acanthocytes, or schistocytes; dyserythropoietic bone marrow; potentially diarrhea due to intestinal disaccharidase deficiency | Autosomal recessive | Clinical biomarker not yet available CAD gene sequencing |
Uridine monophosphate synthase deficiency (UMPS, 258900) | Global developmental delay with failure to thrive; epilepsy in one case Clinical response to uridine supplementation | Orotic acid crystalluria with or without megaloblastic anemia; sometimes congenital malformations and immunodeficiency | Autosomal recessive | • OA↑, Or↑ |
Ureidopropionase deficiency (UPB1, 606673) | Variable neurologic symptoms: encephalopathy, hypo-/hypertonia, PMR, seizures, dystonia, optic atrophy / asymptomatic | Scoliosis, congenital anomalies of urogenital and colorectal system2 | Autosomal recessive | dhU↑, dhT↑, NC-BALA↑, NC-BAIB↑ |
The wide clinical spectrum of the disease accounts for possible difficulties in differential diagnosis with neurologic disorders, especially those with intractable seizures and encephalopathy.
In the neonatal period, the differential diagnosis should include the 5 treatable disorders that can present with intractable seizures in neonates: pyridoxine-dependent epilepsy, pyridox(am)ine-5'-phosphate oxidase deficiency, folinic acid-responsive seizures, 3-phosphoglycerate dehydrogenase deficiency, and hyperinsulinemic hypoglycemia (Saudubray et al 2006). Biotin-responsive holocarboxylase synthetase deficiency can also rarely present with neonatal seizures. In the first months of life, biotin-responsive biotinidase deficiency and GLUT1 deficiency (which is treated with the ketogenic diet) can also present with intractable seizures. Other inborn errors of metabolism less amenable to treatment can present in the neonatal period with severe epilepsy, including nonketotic hyperglycinemia, D-2-hydroxyglutaric aciduria, mitochondrial glutamate transporter defect, peroxisomal biogenesis defects, respiratory chain disorders, molybdenum cofactor and isolated sulfite oxidase deficiency, and Menkes disease. In infancy, the association of seizures and autistic features should prompt consideration of Angelman syndrome and Rett syndrome.
Greater awareness of adenylosuccinate lyase deficiency amongst pediatricians, neonatologists, pediatric neurologists, and also radiologists is the key to identifying the disorder in the early stage.
Specialty | Key clinical features |
Neonatology | • impaired intrauterine growth • fetal hypokinesia (with all its consequences, up to arthrogryposis and pulmonary hypoplasia) • loss of fetal heart rate variability • lack of spontaneous movement (“floppy infant”) • respiratory failure • seizures • microcephaly • acute encephalopathy (with seizures) |
Pediatrics | • psychomotor retardation (slight to severe) • developmental delay • contact disturbances • seizures |
Emergency care pediatrics | status epilepticus |
Pediatric neurology | • seizures • psychomotor retardation • developmental delay • behavioral abnormalities (failure to make eye-to-eye contact, repetitive behavior, agitation, temper tantrums, autoaggressivity) • hypotonia sometimes followed by spasticity • ataxia • dystonia and dyskinesias |
Genetics | • psychomotor retardation • developmental delay • subtle dysmorphisms |
Radiology | • atrophy of the cerebral cortex, corpus callosum, cerebellar vermis • lack of myelination • delayed myelination • anomalies of the white matter • lissencephaly |
(Contributed by Dr. Agnieszka Jurecka.)
Diagnosis requires the following (34):
• Demonstration of succinyl aminoimidazole carboxamide riboside (SAICAr) and succinyladenosine (S-Ado) in extracellular fluids such as plasma, cerebrospinal fluid, and/or urine, using HPLC with UV detection or HPLC-MS | |
• Mutation analysis—genomic and/or cDNA sequencing of adenylosuccinate lyase gene and characterization of mutant proteins |
Diagnosis is supported by the following (34):
• Evidence of clinical phenotype | |
• Demonstration of SAICAr and S-Ado in extracellular fluids such as urine, cerebrospinal fluid, and/or plasma, using simple screening tests such as Bratton-Marshall or thin-layer chromatography | |
• Analysis of adenylosuccinate lyase enzyme activity in cultured skin fibroblasts at an accredited laboratory to demonstrate large decrease of adenylosuccinate lyase activity. Although adenylosuccinate lyase enzyme activity levels may different between testing laboratories, adenylosuccinate lyase activity in diagnosed adenylosuccinate lyase patients is generally between 2% to 20% of the lower limit of normal adenylosuccinate lyase activity (61). Enzyme assay in lysates is not completely reliable due to tissue heterogeneity of adenylosuccinate lyase defect (53) |
In patients with white matter abnormalities on MRI, proton magnetic resonance spectroscopy may help suggest the diagnosis as the abnormal-appearing areas may contain abnormal peaks corresponding to S-Ado at 8.3 ppm and SAICAr at 7.5 ppm (21; 85). It should be noted, however, that these metabolites fall outside of the usual chemical shift range evaluated during clinical neuroimaging procedures (0 to 4 ppm).
Biochemical diagnostic methods. The deficiency of adenylosuccinate lyase activity results in accumulation of SAICAR and S-AMP in the cells and the presence of enormously elevated concentrations of their dephosphorylated forms, SAICA-riboside (SAICAr) and S-Ado in extracellular fluids—urine and CSF, and to a lesser extent also in plasma (34). SAICAr and S-Ado are present in low micromolar concentrations in body fluids of controls (65; 38). In patients, concentrations of both metabolites range from 5 to 10 umol/L in plasma, 100 to 200 umol/L in CSF, and are found in the millimolar range in urine (25). Several methods have been described for selective screening of subjects with adenylosuccinate lyase deficiency that allow identification of either 1 or 2 of the relevant compounds in body fluids.
The preferred diagnostic methods are HPLC-DAD or LC-MS/MS because these allow detection of both SAICAr and SAdo and their deribosylation products (40; 34). In particular, high-throughput urine screening techniques for adenylosuccinate lyase deficiency have been developed using HPLC combined with electrospray ionization (ESI) tandem mass spectrometry (MS/MS) (24; Hartmann et al 2006; 78). These methods allow rapid and specific screening for disorders of purine and pyrimidine metabolism with use of liquid urine samples or urine-soaked filter paper strips. A similar LC-MS/MS based assay for dried blood spots has also been described (Zikanova et al. 2015).
Other methods used include a modified Bratton-Marshall test (41), thin-layer chromatography (TLC) for identification of SAICAr (80), S-Ado (46) and both nucleosides (26), isolation of SAICA riboside and S-Ado with a cation exchange resin and determination of A270/A250 ratio (UV absorbance of the ammonia eluate at 270 and 250 nm) (13), capillary electrophoresis (Gross et al 1995; 23), and high resolution proton magnetic resonance spectroscopy (21). However, although the Bratton-Marshall test and TLC with Pauly reagent detect excessive urinary SAICA riboside, false-negative results have been reported due to bacteria-mediated deribosylation of SAICAr and S-Ado in urine (40). In addition, because the Bratton-Marshall test detects free primary aromatic amines, false-positive results may be observed in patients who receive antibiotics such as sulfonamides (for which the test was initially devised), anticonvulsants (including clonazepam, nitrazepam, and lamotrigine), or other medications that contain or have metabolites containing this group.
SAICA-riboside and S-Ado elevations also occur in 2 other conditions: AICA-ribosuria (AICAR transformylase/IMP cyclohydrolase deficiency) and, to a lesser degree, fumarase deficiency. One patient has been reported with AICA-ribosuria--a female infant with dysmorphic features, severe neurologic defects, and congenital blindness. She had significant elevations of SAICAr and S-Ado detectable in urine and CSF. In contrast to adenylosuccinate lyase deficiency, these findings were associated with massive excretion of AICA-riboside, the dephosphorylated counterpart of AICAR, one of the products of adenylosuccinate lyase (49).
Further studies led to the identification of a deficiency of the bifunctional enzyme that catalyzes the final steps of purine biosynthesis AICAR transformylase/IMP cyclohydrolase (ATIC).
Fumarase deficiency has been associated with less pronounced elevations of succinylpurines in one patient who had dysmorphic features, brain malformations, severe developmental delay with progressive hypotonia, hepatosplenomegaly, and neutropenia (82). S-Ado (8.4 umol/l) and SAICAr (7.6 umol/l) were detected in CSF but not in urine, likely due to dilution below the detection limit of the test. These succinylpurine levels were clearly abnormal, with S-Ado 6 times the upper limit of the reference range but lower than the 100 to 200 umol/l concentrations typical for adenylosuccinate lyase deficiency. Succinylpurine elevations in fumarase deficiency are hypothesized to reflect inhibition of adenylosuccinate lyase by excessive fumarate as fumarate is the first product released in both of the adenylosuccinate lyase-catalyzed reactions and acts as a weak inhibitor of this enzyme in vitro. The authors proposed that accumulation of succinylpurines in the central nervous system might contribute to the pathogenesis of fumarase deficiency (82).
Enzymatic diagnosis of adenylosuccinate lyase deficiency is possible in liver, preferably fresh tissue because the enzyme is unstable to freezing and thawing (73). Cultured skin fibroblasts are less appropriate for diagnosis because adenylosuccinate lyase activity is variable in this tissue, and only partially deficient in patients.
Prenatal diagnosis is limited to families having a previous child with adenylosuccinate lyase deficiency and is based on mutational analysis for at-risk fetuses. Diagnostic testing may be conducted for prenatal diagnosis on viable fetal cells from chorionic villi, cultured amniotic fluid cells, or in the newborn dried blood spots (48).
Selective screening for adenylosuccinate lyase deficiency. The wide clinical spectrum of the disease accounts for possible difficulties in differential diagnosis with neurologic disorders, especially those with intractable seizures and encephalopathy (08; 34). For this reason, it is be important to develop protocols and diagnosis when adenylosuccinate lyase deficiency is suspected in order to avoid useless investigations and treatments. The marked clinical heterogeneity justifies systemic screening for the disorder in patients with the following symptoms (34):
• Newborns and infants with hypotonia and acquired microcephaly | |
• Unexplained psychomotor retardation | |
• Unexplained developmental delay | |
• Unexplained seizures especially intractable | |
• MRI findings such as atrophy of the cerebral cortex, corpus callosum, cerebellar vermis, lack of myelination, delayed myelination, anomalies of the white matter |
No specific FDA-approved treatment is available for adenylosuccinate lyase deficiency. Several supplements have been used empirically in a small number of patients, all aimed at replenishing hypothetically deficient adenine nucleotides in adenylosuccinate lyase-deficient tissues. Four patients were treated for several months with oral supplements of adenine (10 mg/kg per day) and allopurinol (5 to 10 mg/kg per day), the latter to avoid conversion of adenine by xanthine oxidase into poorly soluble 2,8-dihydroxyadenine. However, the only clinical or biochemical improvement was minimal acceleration of growth (27). Therapeutic trials performed with D-ribose (10 mmol/kg per day) and uridine (2 mmol/kg per day) in a single patient have shown reduction of seizure frequency, but this effect was not sustained (63; 62). D-ribose treatment was ineffective in 9 patients (32; 35; 56; 47) other than subjectively improved motor function and communication in 1 patient (47). S-adenosylmethionine, which can enter the central nervous system, was tried in 1 patient at up to 35 mg/kg per day (78). In contrast to encouraging results in a few patients with other purine biogenesis disorders, there was no clear clinical response to treatment from 5 to 25 months of age, other than a subjective decline in head control and visual fixation when supplementation was stopped briefly at 9 months of age. Urine succinylpurines were also unchanged, suggesting that treatment did not lead to feedback inhibition of de novo purine biosynthesis. The authors hypothesized that SAICAr neurotoxicity might explain this lack of response, as a potential mechanism of pathogenesis that was not addressed by purine supplementation.
Seizure management in adenylosuccinate lyase deficiency involves standard anticonvulsants. For example, myoclonic seizures have been treated with valproic acid in combination with other drugs, such as clobazam and levetiracetam (45; 47). Infantile spasms may be resistant to treatment (43; 85). However, patients have had cessation of spasms with therapies including high-dose prednisolone (81) and vigabatrin, which normalized EEG in one patient (78; 52), although they subsequently developed other types of seizures.
Use of the ketogenic diet for intractable epilepsy has been reported in 5 patients with adenylosuccinate lyase deficiency, 4 of whom had some improvement in seizure control. One patient with neonatal-onset epilepsy was seizure-free on the ketogenic diet from ages 2 to 5 years but developed a metabolic hyperchloremic acidosis with Fanconi syndrome, which resolved a month after cessation of the diet (31). A patient with infantile spasms did not respond to the ketogenic diet (85). Another patient with generalized tonic and clonic seizures had a 95% reduction in seizure frequency when the ketogenic diet was started at 7 years of age, with 2 years follow-up (33). Finally, a pair of monozygotic twins with neonatal seizure onset started on the ketogenic diet at 3 months of age and had 14 months of seizure freedom with no other anticonvulsants followed by recurrence of seizures (47). One patient also had improvement of nonepileptic paroxysmal dyskinesias and dystonias on the ketogenic diet (06).
A mouse model of the disorder has not yet been published; homozygous knockout of the mouse ADSL ortholog is lethal prior to weaning (12). Recently, cellular and nematode models of adenylosuccinate lyase deficiency have been described, which could lead to improved understanding of the disease and subsequent development of effective treatment (79; 11).
Surgical biopsy specimens of liver and kidney have been obtained under general anesthesia that was well tolerated.
Carlos R Ferreira MD
Dr. Ferreira of the National Institutes of Health has no relevant financial relationships to disclose.
See ProfileSho T Yano MD
Dr. Yano of the National Institutes of Health has no relevant financial relationships to disclose.
See ProfileTyler Reimschisel MD
Dr. Reimschisel of Vanderbilt University has received contracted research grants from Shire.
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