Applegarth and Toone (2001) reviewed the laboratory diagnosis of glycine encephalopathy and confirmed 9 mutations in the T protein and 8 mutations in the P protein.
Tan et al. (2007) reported that they screened 733,527 babies ... Applegarth and Toone (2001) reviewed the laboratory diagnosis of glycine encephalopathy and confirmed 9 mutations in the T protein and 8 mutations in the P protein. Tan et al. (2007) reported that they screened 733,527 babies over 8 years as part of the New South Wales Newborn Screening Program and subsequently diagnosed 9 babies with nonketotic hyperglycinemia. Two had newborn glycine levels above their cutoff and presented within 72 hours. The remaining patients could not have been diagnosed by newborn screening without an unacceptably high recall rate. Tan et al. (2007) concluded that babies with nonketotic hyperglycinemia were not usually identifiable by newborn screening strategies available at that time. - Prenatal Diagnosis Hayasaka et al. (1990) described prenatal diagnosis of nonketotic hyperglycinemia by enzymatic analysis of the glycine cleavage system in chorionic villi. Toone et al. (1994) described their experience with direct assay of glycine cleavage enzyme in chorionic villus samples in 50 at-risk pregnancies. Applegarth et al. (2000) reported 3 false-negative prenatal diagnostic results using direct measurement of glycine cleavage enzyme activity in uncultured chorionic villus tissue from 290 pregnancies at risk for glycine encephalopathy. Because of these false negatives, Applegarth et al. (2000) counseled that there is a gray zone of uninterpretable activity where affected and normal enzyme values overlap, and suggested that there is an approximately 1% chance of a pregnancy with a normal chorionic villus sample activity resulting in an affected child. Kure et al. (1999) performed prenatal diagnosis for NKH by enzymatic analysis of chorionic villus samples in 28 families and by DNA analysis in 2 families. In 26 families, enzymatic analysis of the glycine cleavage system (GCS) yielded an unambiguous diagnosis; inconclusive results in 2 families were due to borderline GCS activity. A second chorionic sample was analyzed in both these families. In one case, GCS activity was normal in the second specimen and the baby did not have NKH. In the other case, Kure et al. (1999) again found extremely low GCS activity in a second specimen, but a healthy baby was born. The cause of this false-positive result was unknown. Kure et al. (1999) also reported the ability to obtain unambiguous prenatal diagnosis in both Finnish and Israeli Arab families due to prevalent mutations in those populations. The H42R mutation in the T protein (238310.0003) may lead to ambiguous enzymatic activity, suggesting an advantage for DNA analysis.
Most patients with GCE have the neonatal phenotype, presenting in the first few days of life with lethargy, hypotonia, and myoclonic jerks, and progressing to apnea, and often to death. Those who ... - Classic Neonatal Form Most patients with GCE have the neonatal phenotype, presenting in the first few days of life with lethargy, hypotonia, and myoclonic jerks, and progressing to apnea, and often to death. Those who regain spontaneous respiration develop intractable seizures and profound mental retardation. In the infantile form of GCE, patients present with seizures and have various degrees of mental retardation after a symptom-free interval and seemingly normal development for up to 6 months. In the mild-episodic form, patients present in childhood with mild mental retardation and episodes of delirium, chorea, and vertical gaze palsy during febrile illness. In the late-onset form, patients present in childhood with progressive spastic diplegia and optic atrophy, but intellectual function is preserved and seizures have not been reported (Hamosh and Johnston, 2001). See review by Tada and Hayasaka (1987). Unlike glycinemia with ketoacidosis and leukopenia, also known as propionic acidemia (606054), episodic ketoacidosis with vomiting, neutropenia, and thrombocytopenia does not occur in nonketotic hyperglycinemia. Glycine is the only amino acid elevated in serum and urine and the only amino acid harmful to these patients. Some have died in the newborn period after a course characterized by lethargy, weak cry, generalized hypotonia, absent reflexes, and periodic myoclonic jerks (Balfe et al., 1965). The few who attain an older age show severe mental retardation (Mabry and Karam, 1963; Gerritsen et al., 1965). Hayasaka et al. (1983) studied the glycine cleavage system in the liver and brain obtained at autopsy in 2 male infants with the typical form of nonketotic hyperglycinemia. In one a defect in the P protein was found; in the second, T protein was defective. The infant with the P protein defect was born of unrelated parents, was lethargic with a poor suck from birth, developed marked hypotonia, intermittent apnea, and poor responsiveness to stimuli, had mildly elevated blood ammonia and markedly elevated glycine in blood and cerebrospinal fluid, and died at age 12 days. Immunochemical analysis indicated absence of the enzyme P protein itself. The second infant appeared well at birth and nursed well the first day. He was hospitalized on the third day with 'lethargy, bordering on coma.' Despite ventilatory support, 7 exchange transfusions to lower blood glycine, and treatment with sodium benzoate and strychnine, he died on the twentieth day. T protein was undetectable in the brain and extremely low in liver. Autopsy in the first case, with P protein deficiency, showed absence of the corpus callosum and spinal cord hydromelia. The authors stated that they had seen a similar structural defect with deficiency of the pyruvate dehydrogenase complex (see 312170). Schutgens et al. (1986) reported a case with T protein deficiency. Cataltepe et al. (2000) reported 4 patients with nonketotic hyperglycinemia who developed pulmonary hypertension. Two patients had classic neonatal GCE and developed pulmonary hypertension in the newborn period; both died from pulmonary hypertension. The other 2 patients were sibs from Bangladesh with atypical GCE, the first of whom presented with pulmonary hypertension at the age of 6. His brother had documented pulmonary at the age of 4 years, which resolved spontaneously and then recurred in association with thiamine deficiency when he was 21 years old. Van Hove et al. (2000) reported 4 patients with typical neonatal-onset NKH who developed hydrocephalus requiring shunting in early infancy. Brain imaging revealed acute hydrocephalus, a megacisterna magna or posterior fossa cyst, pronounced atrophy of the white matter, and an extremely thin corpus callosum in all. The 3 older patients had profound developmental disabilities. Van Hove et al. (2000) concluded that the development of hydrocephalus in NKH is an additional poor prognostic sign. - Atypical Mild Form Unlike the classic neonatal form of the disorder, atypical or mild glycine encephalopathy is phenotypically heterogeneous and nonspecific, making diagnosis difficult (Flusser et al., 2005). Cole and Meek (1985) emphasized the occurrence of an expressive speech deficit and neurologic abnormalities during intercurrent infections as striking features of the milder form of the disease. The cases of Ando et al. (1978), Frazier et al. (1978), and Flannery et al. (1983) also fall into this category. Hayasaka et al. (1987) cited one patient with atypical GCE and features of progressive degeneration of the central nervous system. Dinopoulos et al. (2005) reported 3 unrelated adults with a mild form of glycine encephalopathy confirmed by genetic analysis (238300.0008; 238300.0009). All 3 patients showed hypotonia as infants and had developmental delay. One patient showed appendicular ataxia and choreoathetoid movements at age 4 years. Between ages 5 and 12 years, he had frequent outbursts of aggressiveness. He attended special education classes and graduated from high school. The second patient was hypotonic at birth and developed seizures during the first week of life. Aggressive behavior was noted at age 12 years; he was fully dependent on his family. The third patient developed hypotonia at age 6 months. He was diagnosed with attention deficit-hyperactivity disorder (ADHD) and had outbursts of aggression and impulsivity. Treatment with dextromethorphan was ineffective. He graduated from school in special education classes. Biochemical analysis showed residual GLDC activity ranging from 6 to 8%, which Dinopoulos et al. (2005) suggested may explain the milder clinical phenotype. The authors emphasized the clinical heterogeneity of the mild form of GCE. Flusser et al. (2005) reported a large consanguineous Israeli Bedouin kindred in which 9 members had atypical GCE confirmed by genetic analysis (238300.0010). Most patients presented during the first months of life with abnormal movements, including mild to moderate generalized hypotonia, lateral head nodding, choreoathetoid hand movements, and pill rolling. Seven patients had seizures with generalized spike and slow wave abnormalities in EEG; 2 had infantile spasms with hypsarrhythmia. All had delayed motor development, moderate mental retardation, and limited expressive language. The patients also showed irritability and restlessness as infants and later showed aggressive and destructive behavior. Treatment was ineffective. - Transient Neonatal Hyperglycinemia Transient neonatal hyperglycinemia (TNH) is characterized by elevated plasma and CSF glycine levels at birth that are normalized within 2 to 8 weeks. TNH is clinically and biochemically indistinguishable from typical nonketotic hyperglycinemia at onset. Applegarth and Toone (2001) reviewed 7 cases of transient NKH. Korman et al. (2004) reported 3 sibs from a consanguineous Muslim Palestinian family who had an unusual NKH phenotype. All 3 sibs were diagnosed with NKH within the first 3 days of life with characteristic elevated CSF and plasma glycine levels and elevated CSF-to-plasma glycine ratios. However, none of them developed neurologic symptoms, and all showed appropriate development, including good school performance in the 2 children of school age. The 2 older children showed persistent hyperglycinemia. A patient from a second unrelated family diagnosed with NKH had mild neurologic sequelae. In all 4 patients, Korman et al. (2004) identified a homozygous mutation in the GLDC gene (238300.0006), which was shown to retain 32% residual enzyme activity in vitro. The authors suggested that these patients exhibited a new phenotype of NKH.
A high frequency of glycine encephalopathy has been found in Finland; the incidence has been estimated to be 1 in 55,000 newborns overall, and 1 in 12,000 in northern Finland (von Wendt and Simila, 1980; Boneh et al., ... A high frequency of glycine encephalopathy has been found in Finland; the incidence has been estimated to be 1 in 55,000 newborns overall, and 1 in 12,000 in northern Finland (von Wendt and Simila, 1980; Boneh et al., 2005). High incidences have also been reported in British Columbia and in small Arab villages in Israel (Boneh et al., 2005).