Myoclonus epilepsy with ragged-red fibers
Jun. 10, 2021
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This article includes discussion of nonketotic hyperglycinemia, glycine encephalopathy, non-ketotic hyperglycinemia, non ketotic hyperglycinemia, atypical non-ketotic hyperglycinemia, hereditary hyperglycinemia, idiopathic hyperglycinemia, and ketotic hyperglycinemia. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Nonketotic hyperglycinemia is an autosomal recessive inborn error of metabolism that commonly presents in the neonatal period with hypotonia, intractable seizures, apneic attacks, and a burst-suppression pattern EEG. Plasma and cerebrospinal fluid glycine concentrations are substantially increased as a result of a deficiency in liver and brain glycine cleavage enzyme activity. Mutations in the P and T protein genes account for the vast majority of cases, but there is emerging evidence of defects in other pathways, notably lipoic acid synthesis, which can result in defects in the glycine cleavage enzyme system and other enzymes. The rapid onset and often short clinical course mean that many cases may remain undiagnosed. The authors review this disorder, with emphasis on the early diagnosis, management, and options for genetic testing.
• Nonketotic hyperglycinemia is an important cause of neonatal encephalopathy.
• No effective treatment is available, and diagnosis is essential for prognostication and genetic counseling.
• A diagnosis of nonketotic hyperglycinemia can only be confirmed by enzyme or DNA analysis.
• Late-onset variants present with a very broad range of neurologic signs and symptoms.
“Idiopathic hyperglycinemia” or “hereditary hyperglycinemia” historically referred to a group of metabolic disorders associated with an elevation of glycine concentrations in body fluids. Soon after the first patient was described in 1961 (16), it became apparent that there were two different forms of hyperglycinemia, each representing a distinct condition. “Ketotic hyperglycinemia,” the originally described condition, was characterized by acute ketoacidosis, neutropenia, thrombocytopenia, and vomiting precipitated by infections or the intake of protein leading to coma and early death. These patients have subsequently been recognized as having organic acidemias such as methylmalonic and propionic acidemia. “Nonketotic hyperglycinemia,” or “glycine encephalopathy,” on the other hand, was characterized by lethargy, hypotonia, unresponsiveness, seizures, and severe mental retardation without ketoacidosis, neutropenia, or thrombocytopenia. The biochemical basis of nonketotic hyperglycinemia was defined in the late 1960s. Gerritsen and colleagues demonstrated hypo-oxaluria and postulated a defect in glycine oxidase (25). A defect in glycine catabolism was subsequently demonstrated (06; 12; 58). By this time, it became apparent that many patients previously reported as having idiopathic/congenital hyperglycinemia with hyperglycinuria actually represented examples of nonketotic hyperglycinemia (40; 50; 11). The structure of the glycine cleavage system was elucidated in the 1970s (33) and the molecular and genetic basis subsequently defined. Over 150 patients have been described in the literature and the clinical phenotype is now known to include a number of atypical nonketotic hyperglycinemia variants.
Nonketotic hyperglycinemia has a broad range of phenotypes, ranging from the severe neonatal type to the transient form.
The most common is the neonatal type of nonketotic hyperglycinemia, accounting for as many as 87.5% of cases in a series of 32 patients reported by Tada (56); other data, however, suggest that the proportion of the milder forms of the condition is higher (31). Severely affected infants are typically born following uneventful pregnancies and appear normal at birth. After a short symptom-free interval ranging from hours to days (rarely more than 48 hours), patients develop lethargy, refusal of feeds, hypotonia, hiccups, and depressed neonatal reflexes. Rapid progression of the neurologic symptoms leads to seizures, apneic attacks, and coma. Most require assisted ventilation. Laboratory studies such as blood counts, liver transaminases, renal function tests, anion gap, organic acids, and lactate and ammonium levels are usually normal. The diagnosis is only suggested by elevated plasma, urine, and CSF glycine concentrations. An EEG at this stage shows a burst suppression pattern and brain imaging may reveal dysgenesis of the corpus callosum and moderate to severe brain atrophy of gray matter structures, including globus pallidus, hippocampus, cerebral cortex, and thalamus, and in severe cases the cerebellum (54).
As dysgenesis of the corpus callosum has frequently been reported at birth, it has been suggested that brain damage occurs in utero (64). Further evidence suggestive of in utero damage includes reports of abnormal fetal movements and fetal hiccups in affected pregnancies. In addition, elevated CSF glycine concentrations have been found at birth, and a burst-suppression pattern on EEG has been reported as early as 30 minutes after birth. Congenital malformations (club foot, hernias, and cryptorchism) occur in many severe cases (29).
Even with assisted ventilation, approximately 30% of infants die in the neonatal period (63; 38). Survivors usually regain spontaneous respiration by two to three weeks and subsequently have a picture of profound psychomotor retardation with a severe seizure disorder. Neonatal reflexes such as the suck reflex may be regained transiently and some early developmental milestones may be achieved with treatment, but these are lost within a few weeks to months. The EEG pattern changes to hypsarrhythmia after the first month and a variety of seizures including myoclonic jerks, tonic spasms, and tonic-clonic convulsions are seen. Intractable seizures eventually occur despite treatment. Muscular hypotonia is prominent in the neonatal period, but thereafter, spasticity supervenes. Death occurs between three months to five years of age, often as a result of intractable seizures.
The late-onset variant (“atypical nonketotic hyperglycinemia”) has been described in a smaller number of patients with heterogenous symptomatology (30; 61; 23). Patients may present in the neonatal period, infancy, or later (21; 10). The course is highly variable. The presentation in the atypical neonatal form may be similar to the classical form, but the subsequent outcome is better. Mental retardation, seizures, and behavioral abnormalities are prevalent in both infantile and late onset forms, whereas the phenotype in late onset atypical nonketotic hyperglycinemia is more heterogeneous. Some patients display progressive neurodegeneration following a period of normal development, whereas others can have slow development leading to mild mental retardation in adulthood. Yu and colleagues reported a family of three siblings presenting with autism and a varying severity of seizures (Yu et al 2013). Late-onset patients with normal intellect, progressive spastic paraparesis, leukodystrophy, and optic atrophy have also been described (53; 17). The oldest reported patient was 50 years old, who presented with a movement disorder, drooled, was nonverbal, had limited facial expression and constant tremor, and history of myoclonic jerks (48).
The occurrence of atypical forms is somewhat controversial and can only be confirmed by demonstrating a deficiency of the glycine cleavage enzyme system or identifying pathologic mutations in one of the subunits genes.
Transient nonketotic hyperglycinemia has been described in at least 10 patients (05; 37). These patients present in an identical manner to patients with neonatal nonketotic hyperglycinemia with elevated CSF/plasma glycine ratios and a burst-suppression pattern EEG. Plasma and CSF glycine levels spontaneously return to normal by two weeks to eight weeks. Many of these patients, especially those who have required assisted ventilation, have gone on to develop severe mental retardation, but others have been developmentally normal subsequently. The etiology is believed to be due to an immaturity of the glycine cleavage system in the liver and brain; however, this has never been demonstrated. Familial recurrence of transient nonketotic hyperglycinemia has not been described.
The long-term outlook of patients with neonatal nonketotic hyperglycinemia remains poor. Severe mental retardation, intractable seizures and limited survival are almost universal despite treatment. Apnea and ventilator dependency in the first two weeks to three weeks of life offer a limited opportunity for withdrawal of active support and should be considered amongst the management options; however, the clinical, ethical, and legal considerations of withdrawal can be complicated because of the occasional occurrence of patients with transient forms of nonketotic hyperglycemia.
The natural history of nonketotic hyperglycinemia was described in a group of 65 patients by Hoover-Fong and colleagues (31). This study revealed a striking gender-related difference in mortality and developmental progress: girls with the disorder did much worse than boys: girls had an earlier age at death and a poorer developmental outcome.
The results of this study must be interpreted with caution, however, because the diagnosis of nonketotic hyperglycinemia was based on plasma and CSF glycine concentrations alone in most of the subjects. Only 11 cases were confirmed by enzymological or mutational analysis.
Hennermann and colleagues reviewed 45 patients in an attempt to devise a system for predicting outcome in patients with severe nonketotic hyperglycinemia (29). Seizures occurred in all individuals with nonketotic hyperglycinemia but remained persistent and intractable only in those affected severely. Cerebral malformations, early spasticity, hiccupping, microcephaly, and characteristic EEG patterns (burst suppression in neonates, hypsarrhythmia in infants) are associated with a poor outcome. Hyperactivity and choreiform movements are typically associated with less severe nonketotic hyperglycinemia whereas cerebral and extracerebral malformations always predict a very poor outcome. Clinical severity could not be predicted by plasma glycine levels or the CSF:plasma glycine ratios.
Patients presenting in infancy had a better chance of making some developmental progress (50%) than those with neonatal onset (19%) (29). However, development is generally poor in all cases as those with the less severe form only learn to babble or speak a few words. Unlike the study reported by Hoover-Fong and colleagues, there were no significant gender differences in outcome. Furthermore, benzoate treatment appeared to show a positive effect on all forms of nonketotic hyperglycemia in this study.
Swanson and colleagues assessed 124 patients and concluded that an accurate prediction of outcome was possible in most patients using a combination of factors available in the neonatal period (55). These factors included the following:
1. Glycine levels greater than 230 uM indicated severe outcome, whereas a CSF:plasma glycine ratio of 0.08 or lower predicted attenuated outcome; however, there was significant overlap.
2. Brain malformations were rarely seen in milder forms, whereas severe malformations (corpus callosum agenesis or cerebellar cyst with hydrocephalus) only occurred in patients with severe nonketotic hyperglycinemia or neonatal death.
3. The glycine index (calculated by subtracting glycine intake in food from the dose of sodium benzoate needed to normalize plasma glycine levels divided by body weight) correlated strongly with outcome, being highest in severely affected patients.
Predicting prognosis based on age at onset alone was inaccurate, though onset at four months or later was associated with attenuated nonketotic hyperglycinemia.
Clinical and biochemical severity was no different between P or T protein defects. Two mutations with no enzyme activity are associated with severe outcome, whilst at least one mutation with residual enzyme activity generally results in attenuated nonketotic hyperglycinemia. Divergent outcomes for the same genotype indicate a contribution of other factors.
Case 1: Neonatal nonketotic hyperglycinemia. A female infant was born spontaneously at 38 weeks following an uneventful pregnancy. The birth weight, length, and head circumference were each on the 50th percentiles. Apgar scores were 9 at one minute and 9 at five minutes. She was transferred to the postnatal ward. She was listless, sleepy, and fed poorly in the first 24 hours. On the second day, she was noted to be floppy and intermittently apneic. She was transferred to the neonatal unit where initial investigations including blood counts, liver transaminases, and renal function tests were normal, and septic screen including CSF microscopy and culture were negative. Blood gases revealed respiratory acidosis, and ammonium and bicarbonate levels were normal. She was intubated and ventilated. Oxygen requirements were minimal with assisted ventilation, and respiratory acidosis was easily corrected. Further investigations included echocardiography (normal), EEG (burst suppression pattern), and lactate and creatine kinase levels (normal). A plasma amino acid profile revealed high levels of glycine; CSF glycine levels were also markedly elevated. MRI scanning showed enlarged subdural spaces, mild ventricular dilatation, dysgenesis of the corpus callosum and normal parenchyma. The diagnosis of nonketotic hyperglycinemia was confirmed by glycine cleavage enzyme assay on a liver biopsy. She remained apneic until day 10 when some spontaneous respiration resumed. Extubation was possible by day 13 after which her tone improved and she started showing some responses to the environment. Treatment with sodium benzoate, dextromethorphan, and anticonvulsants commenced after the diagnosis of nonketotic hyperglycinemia was made.
Tube feeding was necessary for the first three weeks after which she was able to feed orally. The infant was able to fix her gaze after four weeks but did not develop a social smile. She was always restless during and between feeds and by eight weeks, she had episodes of incessant crying and intermittent twitching. At this point, the ability to visually fix and follow was lost. On examination, she was centrally and peripherally hypertonic; neonatal reflexes were present. She lost the ability to feed orally at three months and tube feeds had to be reintroduced. No further developmental progress was observed subsequently. The episodes of twitching and restlessness initially responded to stepwise increases in the doses of sodium benzoate, dextromethorphan, and anticonvulsant medications, but by six months there were frequent minor convulsions despite maximal doses of these medications. Intermittent dystonic posturing also became apparent at this point and was treated with baclofen. She died at the age of nine months following a prolonged seizure and respiratory failure.
Case 2: Atypical nonketotic hyperglycinemia. The male infant was born at term following an uneventful pregnancy. He was admitted to the hospital with a history of poor feeding at six weeks of age. There was no history of hiccupping or apnea. On examination he was sleepy, poorly responsive, and generally hypotonic. Reflexes were preserved and no other abnormalities on examination were noted. Investigations revealed no evidence of infection. Tests for plasma electrolytes, renal function, liver transaminases, ammonium, and lactate were normal. Plasma and urine amino acid profiles revealed elevated glycine levels. CSF glycine levels were moderately elevated as was the CSF/plasma glycine ratio, suggesting a diagnosis of nonketotic hyperglycinemia. The diagnosis was confirmed by demonstrating low glycine cleavage enzyme activity in a liver biopsy specimen. Treatment for this condition was started. EEG and MRI of the brain were normal. Over the next few days, the infant’s tone and responsiveness improved though he started to have intermittent twitching episodes, which were well controlled with anticonvulsant medication. He made slow and steady developmental progress over the next few years on treatment with benzoate, dextromethorphan, and anticonvulsants. He continued having intermittent seizures, mainly absences but with intermittent tonic-clonic seizures. An EEG at three years of age showed excess slow-wave activity with intermittent high-amplitude bursts during sleep. At the age of five years, his developmental level was that of a two year old. He was able to feed himself, walk, and speak a few meaningful words. He had a behavioral disorder characterized by poor communication skills, poor sleep pattern, and episodes of severe temper tantrums.
A defect in the glycine cleavage enzyme system (GCS) leads to markedly increased concentrations of glycine in urine, plasma, and cerebrospinal fluid. Although there is no evidence that the high concentration of glycine affects any nonneural functions, the high levels in the brain lead to serious neurologic problems, although the precise mechanism(s) are not known.
Glycine is a major component of dietary proteins and predominantly synthesized in the body from serine, which itself can be synthesized from glucose (45). It participates in a myriad of biosynthetic and detoxification reactions. Its major route for degradation is the glycine cleavage enzyme system, which ultimately converts it to carbon dioxide and ammonium. The complex is only expressed at significant levels in brain, kidney, and liver, although low levels can be detected in transformed lymphoblasts and placental tissue.
Whilst the liver degrades the majority of body glycine, the enzyme in the brain has a crucial role. Glycine is a major synaptic neurotransmitter having mixed inhibitory and excitatory functions (09). Catabolism of glycine is essential to regulate the extracellular concentration of this neurotransmitter.
A substantial deficiency of glycine cleavage enzyme activity leads to markedly increased concentrations of glycine in urine, plasma, and cerebrospinal fluid. Whereas there is no evidence that the high concentration of glycine affects any nonneural functions, the high levels in the brain lead to serious neurologic problems.
Genetics. The enzyme is located on the inner mitochondrial membrane and consists of a complex of four polypeptides (P, H, T, and L proteins) encoded by four different genes. It requires the cofactors pyridoxal phosphate, tetrahydrofolate, lipoic acid, and NAD.
Abnormalities have been found in the P, T, and H subunits in patients with nonketotic hyperglycinemia. The L-protein is shared by a number of other dehydrogenases, and defects in this subunit produce a different clinical and biochemical phenotype.
The genes for the P (glycine decarboxylase, GLDC), T (aminomethyl transferase, AMT), and H (glycine cleavage system H protein, GSCH) proteins have been isolated and their genes have been cloned. Pathologic mutations have been reported in all three of these genes in individuals with nonketotic hyperglycinemia. Coughlin and colleagues compiled a comprehensive review of mutations in 578 nonketotic hyperglycinemia families, with 484 different mutations described (19).
There is emerging evidence that a deficiency of the glycine cleavage enzyme system can also be caused by mutations in genes other than those encoding the four functional subunits, notably genes involved in lipoic acid production. Lipoic acid is one of the cofactors required for GCS activity. In addition, lipoic acid is also required for proper functioning of pyruvate dehydrogenase complex, branched-chain ketoacid dehydrogenase, and alpha-ketoglutarate dehydrogenase.
Several patients with defects in this pathway have now been reported and variously termed multiple mitochondrial dysfunction syndrome or variant nonketotic hyperglycinemia. Mutations have been reported in the NFU1, BOLA3, LIAS and GLXR5 genes, which are all involved in Fe-S cluster synthesis and synthesis of lipoic acid (15; 44; 42; 10). These patients present with various manifestations of mitochondrial dysfunction, such as seizures, ataxia, hypotonia, weakness, leukodystrophy, optic atrophy, cardiomyopathy, and deafness. Plasma and CSF glycine levels are typically elevated, though often not to the level seen in classic nonketotic hyperglycinemia. Alanine and lactate may also be raised but not always.
A mutation in the IBA57 gene, also involved in the biosynthesis of mitochondrial [Fe-S] proteins, has been reported in siblings with a similar clinical phenotype. Although the activity of the glycine cleavage enzyme was not measured, the patients did have elevated glycine and PDH deficiency (02).
Pathophysiology. Glycine is a major component of dietary proteins and predominantly synthesized in the body from serine, which itself can be synthesized from glucose (45). It participates in a myriad of biosynthetic and detoxification reactions. Its major route for degradation is the glycine cleavage enzyme system, which ultimately converts it to carbon dioxide and ammonium (33).
Whilst the liver degrades the majority of body glycine, the glycine cleavage enzyme in the brain has a crucial role. Glycine is a major synaptic neurotransmitter having mixed inhibitory and excitatory functions; it has excitatory effects as a co-agonist of NMDA receptors in the cerebral cortex, whereas it has inhibitory effects in the spinal cord and the brain stem (09). Catabolism of glycine is essential to regulate the extracellular concentration of this neurotransmitter.
The failure to remove glycine effectively from the intercellular fluid is the likely cause of the neurologic symptoms. The presence of brain malformations in affected individuals suggests that this excess in intercellular glycine may result in prenatal developmental abnormalities. Postnatally, its effects are postulated to cause seizures and brain damage through excitatory effects at the cortical level, whereas its inhibitory effects on the brain stem and spinal cord are believed to cause hiccupping, apnea, and hypotonia (67; 39; 57; 26). High glycine concentrations have also been shown to induce bioenergetic dysfunction in the brains of young rats by impairing the functions of citric acid cycle, the respiratory chain, Na+, K+ ATPase, and mitochondrial creatine kinase (14).
Nonketotic hyperglycinemia has been described in a wide range of ethnic groups. In the United Kingdom we estimate the disease frequency to be approximately 1 in 100,000 based on the number of diagnoses over a 23-year period. However, the early onset of the disorder and, in many cases, rapid death, may result in many cases being undiagnosed. From genetic studies, the estimated incidence is 1:76,000 live births (19).
Nonketotic hyperglycinemia is inherited as an autosomal recessive disorder. With appropriate genetic counseling antenatal testing can be offered to pregnant women. The glycine cleavage enzyme is expressed at a low level in first trimester uncultured chorionic villus (28). Antenatal diagnosis can be performed by assay of glycine cleavage enzyme measuring the release of 14CO2 from (1-14C) glycine in homogenates of uncultured chorionic villus samples. The experience with this test has been reported in more than 300 fetuses, and three false negative diagnoses have been documented (36; 08). There are no reports of false positive diagnoses, although not all antenatal tests have been audited. A particular problem is the relatively high proportion of samples (10% to 15%) with activities that are low but not definitively diagnostic of an affected fetus. The absence of expression in cultured chorionic villus samples or amniotic fluid cells means there is no possibility for a follow up test for confirmation. Measurement of amniotic fluid supernatant glycine has proved unreliable.
The method of choice for antenatal diagnosis for this disorder is DNA analysis. However, the number and complexity of the genes and the absence of common mutations hinders progress. With advances in DNA testing it is anticipated that most patients will be offered DNA testing.
Carrier detection by measurement of transformed lymphoblast glycine cleavage enzyme is unreliable (07). Liver biopsy is an invasive procedure and has never been reported to date for use in carrier detection. DNA analysis is the method of choice for detecting carrier status although the absence of common mutations limits its value in unrelated partners.
Hyperglycinemia is a common secondary response to a number of acquired and inherited conditions.
Hypoxic-ischemic encephalopathy, neonatal sepsis, cerebral dysgenesis, intracranial hemorrhage, drug withdrawal, intrauterine infection, pyridoxine dependency, hypoglycemia, and hypocalcemia can cause acute neonatal encephalopathy similar to that seen in neonatal nonketotic hyperglycinemia. Some metabolic disorders such as sulfite oxidase deficiency, congenital disorders of glycosylation, respiratory chain defects, urea cycle defects, maple syrup urine disease, propionic acidemia, and methylmalonic acidemia can also present with neonatal encephalopathy in the first few days of life. Patients with a defect in glycine transporter GlyT1 show many features of classical neonatal nonketotic hyperglycinemia, both clinically and biochemically (04). Patients with x-linked cobalamin deficiency (HCFC1) can show abnormal glycine concentrations similar to that in nonketotic hyperglycinemia, likely due to a regulatory gene effect (49).
Hyperglycinemia is a feature of a number of organic acidemias including propionic, methylmalonic, and isovaleric acidemias as well as beta-ketothiolase deficiency. Other rare metabolic conditions associated with hyperglycinemia include D-glyceric aciduria, congenital disorder of glycosylation type 1a, and hyperprolinemia type II. Valproate therapy is believed to cause elevated plasma glycine levels by partially inhibiting the glycine cleavage enzyme. Malnutrition, debilitating disease, and starvation have also been reported to be associated with hyperglycinemia. Glycine can be artifactually raised in plasma as a result of hemolysis.
Hyperglycinemia can occur in defects of Fe-S cluster and lipoic acid synthesis. Pyruvate dehydrogenase complex deficiency can also cause lactic acidosis.
Elevated CSF glycine levels have been reported in accidental and nonaccidental brain injury, hypoxic-ischemic encephalopathy of the newborn, chronic renal failure, valproate therapy, and leukoencephalopathy with vanishing white matter. Perhaps the most common cause of elevated CSF glycine concentrations is blood contamination of CSF as a result of a traumatic lumbar puncture. A study on 22 infants with encephalopathy revealed that elevated cerebrospinal fluid glycine was encountered in a variety of clinical conditions, most commonly hypoxic ischemic encephalopathy (01).
Radiology, neurophysiology, and histopathological studies. In the first few weeks of life in the neonatal form, an EEG characteristically reveals a burst suppression pattern. By one to three months, the EEG pattern changes to hypsarrhythmia. After one year of age, hypsarrhythmia is routinely seen in sleep, but the awake tracing changes to a slow background with multifocal epileptiform discharges (41). Other neurophysiological findings include prolonged latencies on brain stem evoked auditory responses and abnormal visual evoked responses. Variable EEG findings occur in the atypical forms of nonketotic hyperglycinemia.
CT and MRI findings in the neonatal form include thinning of the corpus callosum; moderate to severe brain atrophy of gray matter structures, including globus pallidus, hippocampus, cerebral cortex, and thalamus, and in severe cases the cerebellum; delayed myelination; and progressive vacuolating myelinopathy (54). MRI spectroscopy studies have demonstrated elevated intracerebral glycine, lactate, and creatine as well as decreased glutamine and citrate levels in neonatal-onset patients (24; 62). Atypical cases can have normal MRI scans.
At autopsy, spongiform degeneration of myelinated areas of the brain with vacuolation and thinning of myelin has been described on brain histopathology. Electron microscopy has revealed splitting of the myelin lamellae (52; 51).
Biochemical tests. Urinary and plasma glycine concentrations are usually increased several fold above the upper limit of normal. However, other conditions, in particular organic acid disorders, can result in increased glycine concentrations; therefore, it is important that these be excluded. In addition, plasma glycine may be increased in a poor-quality blood specimen (eg, when hemolyzed) or in a urine specimen that has deteriorated. Sometimes plasma glycine concentrations may not be grossly increased. Therefore, the best biochemical screening test for nonketotic hyperglycinemia is simultaneous quantitation of plasma and CSF glycine. Usually the CSF glycine is increased several fold above the upper limit of normal and the CSF/plasma glycine ratio is greater than 0.080 (where both are expressed in the same units) (07). Atypical forms may have ratios as low as 0.04. However, care has to be taken to avoid blood contamination in the CSF sample as erythrocytes have high glycine content and can give spuriously increased results. Diagnosis should not be based solely on an increased CSF to plasma glycine ratio, and the plasma and urine glycine concentrations should be taken into account. A low level of contamination of CSF, together with an only marginally elevated plasma glycine, may give a spuriously elevated ratio. Patients may often also show lactic acidemia due to the apneic episodes potentially leading to an investigation of a respiratory chain disorder.
Assessment of in vivo activity of the glycine cleavage enzyme has been described using a stable isotope, [1-13C]glycine, which is administered enterally and measures exhaled 13CO2 (34). If available, this noninvasive enzymatic assay may be useful in confirming the diagnosis.
Enzymology and molecular testing. The multiplicity of causes of hyperglycinemia and problems in interpreting CSF glycine concentrations make it important, when possible, to confirm the diagnosis by additional testing. The glycine cleavage enzyme can be assayed in a needle liver biopsy (28). The sample should be frozen immediately and stored frozen until analysis. However, some patients with T protein defects can show normal activity in the assay of whole glycine cleavage enzyme complex activity (our unpublished work). In the absence of a liver biopsy, the enzyme can be assayed in transformed lymphocytes established from a blood sample, although this analysis is generally not reliable.
DNA analysis is complicated by the lack of common mutations in the GLDC or AMT genes, meaning full sequencing may often be required. Mutations in the P protein gene (GLDC) account for the majority of nonketotic hyperglycemia cases (approximately 63% to 80%) (18; 35; Kure et al 2007; 19). Mutations reported to date in the GLDC gene include the S564I mutation, which is prevalent in Finnish patients and the R515S mutation found in up to 40% of Caucasians, particularly those from the UK (60; 19). Deletions and duplications spanning one or more exons of the GLDC gene have been found on approximately 20% of alleles in nonketotic hyperglycemia patients of different ethnic origins (19). Screening for these deletions by MLPA analysis provides a rapid way of picking up a significant number of mutations (34).
Defects in the T protein gene (AMT) account for the remaining cases; only one patient has been described with mutations in the H protein. Like the GLDC gene, most mutations in the AMT gene are private; however, the R320H mutation accounts for up to 16% of alleles in AMT (19).
The presence of copy number variants in the GLDC gene and upstream mutations in AMT means that whole exome sequencing and gene panel approaches could likely miss a significant number of nonketotic hyperglycinemia patients because these mutations are often not detected.
Alternatively, if sufficient liver tissue is available an enzyme assay can be used to distinguish between T and P protein defects (60). In cases where only one mutation is defined, linkage analysis using polymorphic intronic markers can be used for antenatal diagnosis and carrier detection in informative families. As most mutations are private, it is difficult to make any definitive genotype-phenotype correlation; however, some mutations associated with residual enzyme activity have been associated with an attenuated phenotype (19).
Seven patients with the late onset form of the disorder showed no mutations in the T, P, or H protein genes. The authors speculated that these may be due to defects in genes other than those coding for the glycine cleavage enzyme system (35). Consequently, the “atypical forms” of nonketotic hyperglycinemia may constitute an entirely separate clinical entity. As described above, mutations in genes associated with the production of lipoic acid, a cofactor for the glycine cleavage enzyme system, have been reported in some patients with multiple enzyme deficiencies. It is likely that other genes remain to be identified in some patients with nonketotic hyperglycinemia.
Many therapeutic strategies have been attempted to treat the progressive neurologic degeneration associated with nonketotic hyperglycinemia, but none of these has been effective.
Symptomatic treatment includes nasogastric tube feeding, anticonvulsant polytherapy, and developmental interventions, such as occupational therapy, physiotherapy, and speech therapy. Long-term survivors are prone to developing severe skeletal problems, including kyphoscoliosis, contractures, joint dislocations, and fractures that may need symptomatic management (47).
Glycine-free, glycine- and serine-free, and protein-restricted diets have been reported to reduce plasma glycine levels but have had no effect on seizure frequency or developmental progress (38). Sodium benzoate, which conjugates glycine to form hippurate, has been used in doses of 150 to 750 mg/kg/day to reduce plasma and CSF glycine levels (26). Treatment with sodium benzoate appeared to provide the best improvement (mainly a decrease in seizures) but was dependent on dose and disease severity (29). Other measures to reduce glycine levels such as exchange transfusion and the administration of ursodeoxycholic acid (to conjugate glycine) have also been unsuccessful (56).
There is growing evidence that a ketogenic diet can benefit seizure control in some patients with nonketotic hyperglycinemia (20; 32).
Attempts at treatment have involved the usage of NMDA receptor blocking agents. Oral ketamine administration in doses of 5 to 8 mg/kg/day has been successful in improving neurologic symptoms in some cases (46; 13). The antitussive medication dextromethorphan is metabolized to dextrorphan, an antagonist of the NMDA receptor and has been reported to improve neurologic symptoms in a number of cases in doses of 5 to 22 mg/kg/day. Hamosh and colleagues have reported results of a long-term study of the treatment of four infants with nonketotic hyperglycinemia using a combination of high-dose sodium benzoate (500 to 750 mg/kg/day) and dextromethorphan (3.5 to 22 mg/kg/day) with follow up over three months to six years (27). With benzoate treatment, plasma glycine levels normalized and CSF glycine levels fell significantly. Dextromethorphan appeared to improve seizure control in three of the four patients and these patients were reported as being alive and moderately to severely retarded at ages of six to eight years. One patient died at three months despite being treated early. Other investigators have also reported some benefit from this treatment combination (66; 03).
Currently, a combination of high-dose benzoate, dextromethorphan, and anticonvulsants appears to offer the best (if unsatisfactory) approach to treatment. Sodium valproate and vigabatrin are contraindicated as they may precipitate acute encephalopathy with or without chorea (43; 59). Several newer anticonvulsants such as felbamate and topiramate act on glutaminergic pathways and may also be useful, but studies of these agents on seizure control and long-term outcome of nonketotic hyperglycinemia have not been reported.
The atypical forms of nonketotic hyperglycinemia have been treated along similar principles as neonatal nonketotic hyperglycinemia with sodium benzoate, dextromethorphan, and anticonvulsants. The outcome has been extremely variable in the small number of confirmed reported cases, so it is difficult to draw conclusions about the effectiveness of therapy.
The severe life limiting nature of this disorder means no pregnancies in neonatal onset patients have been reported to date. Two successful pregnancies with normal offspring have been reported in one patient with atypical nonketotic hyperglycinemia (22).
Tim Hutchin PhD
Dr. Hutchin of Birmingham Children's Hospital has no relevant financial relationships to disclose.See Profile
Jennifer Friedman MD
Dr. Friedman of the University of California San Diego has no relevant financial relationships to disclose.See Profile
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