Paula and Bobby
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Glycine Encephalopathy; GCE
What is Glycine Encephalopathy; GCE?
Glycine Encephalopathy; GCE is a rare disease. It is also known as GLDC Glycine encephalopathy Hyperglycinemia, Nonketotic; Nkh.
There is a mild and severe form of this condition. In the severe infantile form the onset is in the first few days of life with hypotonia, lethargy, myoclonic and generalized convulsions. Those who do survive are likely to be mentally handicapped. The patient reported by Van Hove et al., (2000) developed an acute hydrocephalus at 4 months. The EEG might show bursts of poly-spikes but the definitive biochemical tests are the increased levels of glycine in urine, plasma and CSF. Perhaps the best measurement is the plasma: CSF glycine ratio, which is normally below 0.04, but in this condition is above 0.09. Toone et al., (1992), report prenatal diagnosis by using a CVS glycine cleavage assay followed by amniotic fluid glycine measurement, but in for instance, Finnish and Israeli-Arab populations, where two common mutations occur molecular analysis is much more reliable (Tome et al., 1999). Note too the report by Applegarth et al., (2000) of three false negative prenatals using direct measurement of glycine cleavage enzyme activity in uncultured chorionic villi. Molecular diagnosis is much better (Applegarth etal., 2002).
Note in the next entry, a milder form starting in late-childhood or adulthood and atypical forms
The enzyme (glycine cleavage enzyme) is a mitochondrial multienzyme complex consisting of a P-protein, (glycine carboxylase) an H-protein, a T (AMT) and an L protein. It catalyses the formation of ammonia, carbon dioxide, methylenetetrahydrofolate and NADH+H+ from glycine, tetrahydrofolate, NAD+ and water. The gene has been mapped to 3p21.1-21.2 and most Finnish patients have a common mutation (S5641)) in the P-protein. A Japanese patient has been reported with a T-protein mutation (Nanao et al., 1994), as has a large Israeli-Arab family (Kure et al., 1998). This is a H42R mutation. Heterozygotes might have transient neonatal hyperglycinemia (Kure et al., 2002). Further P-protein or glycine decarboxylase mutations in 4 patients from 2 consanguineous families, were reported by Korman et al., (2004). The first family presented clinically and biochemically with classic disease, but recovered completely (except for the biochemistry) and developed normally (see also next entry). They are now 6 years and 10 years old. The other family was also unusual in that there was also recovery, but then deterioration occurred at 14 months.
The condition is well reviewed by Applegarth and Toone (2004).
Not all patients have a GLDC mutation (18 out of 28) reported by Conter et al., (2006). A patient with a AMT mutation was reported by Belcastro et al., (2016). The presentation was with early myoclonic encephalopathy.
Khraim et al. (2017) described three siblings from a consanguineous family with glycine encephalopathy due to a novel homozygous missense mutation in the GLDC gene. The first sib, a girl, had an infantile onset disease. She presented at the age of six months with intractable seizures, developmental delay, hypotonia, microcephaly, optic atrophy, and multifocal epilepsy on EEG. Her brother developed clinical symptoms at the age of two days including poor sucking, hiccups, and lethargy. The third sib, a boy, presented with speech delay at the age of 20 months. All the patients had an elevated blood glycine, CSF glycine and CSF/plasma glycine ratio.
* This information is courtesy of the L M D.
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What gene changes cause Glycine Encephalopathy; GCE?
The syndrome is inherited in the following inheritance pattern/s:
Autosomal Recessive - Autosomal recessive inheritance means an affected individual receives one copy of a mutated gene from each of their parents, giving them two copies of a mutated gene. Parents, who carry only one copy of the gene mutation will not generally show any symptoms but have a 25% chance of passing the copies of the gene mutations onto each of their children.
In some cases, a genetic syndrome may be the result of a de-novo mutation and the first case in a family. In this case, this is a new gene mutation that occurs during the reproductive process.
OMIM Number - 605899 (please check the OMIM page for updated information)
The syndrome can be caused by mutations in the following gene/s location/s:
AMT - 3p21.31
GCSH - 16q23.2
GLDC - 9p24.1
What are the main symptoms of Glycine Encephalopathy; GCE?
The typical symptoms of the syndrome are:
Intellectual disability, Lethargy, Irritability, Muscular hypotonia, Myoclonus, Impulsivity, Hyperreflexia, Hyperglycinuria, Hyperglycinemia, Hyperactivity, Recurrent singultus, Death in infancy, Aggressive behavior, Autosomal recessive inheritance, Seizure, Restlessness, Encephalopathy, Agenesis of corpus callosum
How does someone get tested for Glycine Encephalopathy; GCE?
The initial testing for Glycine Encephalopathy; GCE can begin with facial genetic analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the type of genetic testing needed. A consultation with a genetic counselor and then a geneticist will follow.
Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.
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