Glycine Encephalopathy

Alternative Names

  • GCE
  • Hyperglycinemia, Nonketotic
  • NKH
  • Hyperglycinemia, Transient Neonatal
  • TNH

Associated Genes

Glycine Decarboxylase
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WHO-ICD-10 version:2010

Endocrine, nutritional and metabolic diseases

Metabolic disorders

OMIM Number

605899

Mode of Inheritance

Autosomal recessive

Gene Map Locus

3p21.2-p21.1,9p22,16q24

Description

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.

Molecular Genetics

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.

Epidemiology in the Arab World

View Map
Subject IDCountrySexFamily HistoryParental ConsanguinityHPO TermsVariantZygosityMode of InheritanceReferenceRemarks
605899.2.1LebanonMaleYesYes Intellectual disability; Hyperammonemia;... NM_000170.3:c.52G>THomozygousAutosomal, RecessiveJalkh et al. 2019
605899.2.2LebanonMaleYesYes Intellectual disability; Hyperammonemia... NM_000170.3:c.52G>THomozygousAutosomal, RecessiveJalkh et al. 2019 Sibling of 605899.2....
605899.1United Arab EmiratesUnknown NM_000170.3:c.919G>THomozygousAutosomal, RecessiveAl-Shamsi et al. 2014

Other Reports

Oman

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). 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.

Palestine

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.

Saudi Arabia

Roy et al. (2004) descried three Saudis with classical nonketotic hyperglycinemia, two of whom were from the same family.  

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.Only one case was found to have Glycine encephalopathies. The estimated incidence is 1 in 100,000 live births.

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