The Invitae Glycine Encephalopathy Panel analyzes the three genes that are associated with glycine encephalopathy (nonketotic hyperglycinemia [NKH]). This test is useful for the diagnosis of patients in whom glycine encephalopathy is suspected due to clinical symptoms or biochemical findings. This test may help distinguish neonatal patients with glycine encephalopathy from those with transient glycine encephalopathy.
AMT GCSH GLDC
AMT GCSH GLDC
Glycine encephalopathy (nonketotic hyperglycinemia [NKH])
Glycine encephalopathy is an inborn error of glycine metabolism that most commonly presents in the neonatal period. Patients with this disorder are not able to metabolize glycine properly due to a defect in the glycine cleavage system. This defect leads to toxic accumulation of glycine, especially in the brain. The age of onset in patients with glycine encephalopathy can range from neonatal to adulthood, with the most severely affected individuals presenting in the neonatal period.
Patients with glycine encephalopathy have hyperglycinemia that is detectable in both plasma and CSF. These patients will also have an elevated CSF-to-plasma glycine ratio (>0.08 in severe patients; note that this value can be lower in late-onset patients). The absence of acidosis and ketosis is important in distinguishing this disorder from other causes of hyperglycinemia (e.g., propionic acidemia, methylmalonic acidemia).
Neonatal glycine encephalopathy
This is the most common clinical subtype of glycine encephalopathy. Most patients are normal at birth but can present as early as a few hours of life. Symptoms include progressive encephalopathy leading to lethargy, muscular hypotonia, apneic attacks, hiccups, seizures, burst suppression pattern on EEG, coma, and early death. The vast majority of patients that do survive the first 15 months of life show severe intellectual impairment (IQ<20) and motor disability (inability to sit or grasp objects).
Late-onset glycine encephalopathy
This phenotype presents anytime from infancy to adulthood and has a heterogeneous clinical picture. The late-onset form may include features such as intellectual disability, hypotonia, choreic movement disorder, aggressiveness, attention deficit hyperactivity disorder (ADHD), confusion triggered by fever, and, although rarely, seizures.
Transient glycine encephalopathy
This phenotype has been reported in a few patients. These patients may present with symptoms similar to neonatal glycine encephalopathy, though the biochemical elevations typically normalize by the third month of life. Differentiating neonatal glycine encephalopathy from transient glycine encephalopathy based on biochemical findings alone is difficult. Transient glycine encephalopathy may be due to delayed maturation of the glycine cleavage system, high residual activity of the glycine cleavage system in the presence of two pathogenic variants, or a heterozygous individual.
For patients with a biochemical diagnosis of glycine encephalopathy (elevated plasma and CSF glycine with an increased CSF-to-plasma glycine ratio), approximately 90%–95% will have two pathogenic variants in one of these three genes. GLDC is the most commonly mutated gene in glycine encephalopathy patients (70%–75%), followed by AMT (20%) and GCSH (<1%).
Glycine encephalopathy is inherited in an autosomal recessive manner.
Glycine encephalopathy is a fully penetrant disorder. Patients with little or no residual enzyme activity typically have the severe neonatal presentation, and patients with higher residual enzyme activity have the attenuated, late-onset form. Phenotypic expression in the late-onset form is heterogeneous, ranging from mild language delay, intellectual disability, and chorea to pulmonary hypertension with rapid neurological deterioration.
The general prevalence of glycine encephalopathy is unknown. The birth incidence in several subpopulations have been estimated as follows:
Some small, consanguineous Arab villages in Israel have a higher incidence of glycine encephalopathy.
Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).
Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.
Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.
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