Glycine Encephalopathy (GCE), also known as nonketotic hyperglycinemia, is an autosomal recessive defect of glycine metabolism, characterized by an accumulation of the amino acid in body tissues, especially in the brain. The classical form of GCE manifests itself soon after birth and is typified by hypotonia, feeding and breathing difficulties, and lethargy. The condition can be fatal at this stage, if not properly managed. Infant who do survive, develop further complications, including mental retardation and recalcitrant seizures. Apart from the classical form, other atypical forms of GCE also exist. These include the infantile form, which presents itself only about six months after birth, as well as childhood or adult-onset forms. In general, the later the onset, the milder are the symptoms. Another rare variant of the disease is the transient neonatal form, which presents as a typical case of classical GCE at birth. However, the glycine levels in this case, return to normal with time and, usually, no long-term complications remain.
Infants who present with the above-mentioned symptoms along with elevated glycine levels are suspected to have GCE. An increased CSF:plasma concentration of glycine is a strong indicator of the condition. Confirmation is, however, done only on the basis of molecular genetic testing of mutations in either the GLDC, AMT, or GCSH genes. Management of the disease is difficult. Standard anticonvulsant drugs cannot be administered, since they either tend to raise the glycine levels, or have only limited efficacy in controlling the seizures. Instead, benzoate is recommended. No treatment is available for GCE.
Glycine is metabolized in the body via the glycine cleavage enzyme complex, a multi-enzyme complex that carries out the degradation of glycine. GCE can occur from mutations in genes coding for any one of three enzymes in this complex: Glycine Decarboxylase (GLDC), Aminomethyltransferase (AMT), or Glycine Cleavage System H Protein (GCSH). Approximately 80% of cases of GCE are due to mutations in the GLDC gene, whereas mutations in the AMT gene account for 10-15% of GCE cases. Only one cases of GCE due to mutation in the GCSH gene has been described thus far.
Joshi et al. (2002) carried out a retrospective analysis of all patients born with inborn errors of metabolism in Oman between June 1998 and December 2000. Among the 82 patients, one was diagnosed with non-ketotic hyperglycinemia [CTGA Database Editor's note: Computed annual incidence rate is 0.8/100,000]. Few years later, Joshi and Venugopalan (2007) conducted a study over a seven year period (1998-2005) to evaluate the clinical profiles of 166 neonates at high risk of having inborn errors of metabolism using Tandem Mass Spectrometry (TMS). Out of a total of 38 neonates with positive TMS results, a one-day old baby boy, born to consanguineous parents, was diagnosed with nonketotic hyperglycinemia. There was no family history of the condition. The infant presented with acute neonatal encephalopathy.
Al-Riyami et al. (2012) reported on the types and patterns of IEMs encountered in a sample of 1100 high-risk neonates referred to SQU Hospital in Oman over a 10-year period (1998-2002). MS/MS was used to analyze blood samples from heel pricks. A total of 119 of these neonates were found to test positive for an IEM. Non Ketotic Hyperglycinemia was detected in three neonates (two females, one male), belonging to two families. Both patients had a family history of the condition as well as consanguineous parents.
A high frequency of glycine encephalopathy has been found in small Arab villages (Boneh et al., 2005). In eight patients from six extended families, all from a small suburban village, a novel mutation causing GE was described. A methionine to threonine change in the initiation codon of the glycine decarboxylase gene led to markedly reduced glycine decarboxylase mRNA levels and abolished glycine cleavage system activity.
Flusser et al. (2005) reported a large consanguineous Bedouin kindred in which nine members had atypical GCE confirmed by genetic analysis. 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.
Roy et al. (2004) descried three Saudis with classical nonketotic hyperglycinemia, two of whom were from the same family. The first patient was a 5-day-old girl, born to first cousin parents, who presented with a weak cry, progressive lethargy, poor feeding and hiccough for three days. She was hypotonic, unable to open her eyes, her pupils were equal and reactive to light, and she had a very weak cry on painful stimuli. She had very shallow breathing and became apneic. She also developed multifocal clonic seizures. MRI revealed generalized brain atrophy and a hypoplastic corpus callosum. EEG revealed generalized epilepsy. Her 1-year-old sister presented with developmental delay and seizures. At 4-days of age she had poor feeding and lethargy. At 1-month of age she developed seizures. Brain MRI showed agenesis of the corpus callosum. Neurological examination showed severe head lag, generalized hypotonia, subnormal muscle power and brisk tendon reflexes. The third patient was a 4-month-old boy presented with hypoactivity and sleepiness since birth. He had generalized clonic seizures. Brain CT scan and ultrasound showed brain atrophy.
Moammar et al. (2010) reviewed all patients diagnosed with inborn errors of metabolism (IEM) from 1983 to 2008 at Saudi Aramco medical facilities in the Eastern province of Saudi Arabia. During the study period, 165530 Saudi infants were born, of whom a total of 248 newborns were diagnosed with 55 IEM. Affected patients were evaluated based on clinical manifestations or family history of similar illness and/or unexplained neonatal deaths. Almost all patients were born to consanguineous parents. Aminoacidopathies were diagnosed in 38 out of 248 cases (16%). Among them, only one case was found to have Glycine encephalopathies. The estimated incidence is 1 in 100,000 live births. The authors concluded that data obtained from this study underestimate the true figures of various IEM in the region. Therefore, there is an urgent need for centralized newborn screening program that utilizes tandem mass spectrometry, and offers genetic counseling for these families.
Al-Shamsi et al. (2014) undertook a study to calculate the birth prevalence of IEMs among Emiratis in the UAE by taking into consideration all neonates born with an inherited metabolic condition at Tawam Hospital between 1995 and 2012. A total of 37 distinct IEMs were found in Emirati neonates in this study, providing an estimated IEM birth prevalence of 75.24 per 100,000 live births. Glycine Encephalopathy was found to have a birth prevalence of less that 0.98 per 100,000. One novel mutation was identified in the GLDC gene among the affected patients.
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