The Invitae Glycine Encephalopathy Panel analyzes 6 genes associated with glycine encephalopathy, also referred to as nonketotic hyperglycinemia (NKH). This test is useful for the diagnosis of individuals in whom glycine encephalopathy is suspected due to clinical symptoms or biochemical findings. This test may help distinguish neonatal glycine encephalopathy from transient glycine encephalopathy. Identification of disease-causing variants provides accurate risk assessment and carrier status for at-risk relatives.
AMT GCSH GLDC LIAS NFU1 SLC6A9
AMT GCSH GLDC LIAS NFU1 SLC6A9
For a broader analysis of the genetics of metabolic conditions:
Glycine encephalopathy – also known as nonketotic hyperglycinemia (NKH)
|AMT||Glycine encephalopathy (GCE)||Autosomal recessive|
|LIAS||Hyperglycinemia, lactic acidosis, and seizures (HGCLAS), also known as pyruvate dehydrogenase lipoic acid synthetase deficiency (PDHLD)|
|NFU1||multiple mitochondrial dysfunctions syndrome 1 (MMDS1)|
|SLC6A9||Glycine encephalopathy with normal serum glycine|
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.
Hyperglycinemia, lactic acidosis, and seizures (HGCLAS)
Caused by pathogenic variants in the LIAS gene, is a severe disorder characterized by a clinical picture similar to that of neonatal glycine encephalopathy. It represents a distinct, ‘variant’ form of nonketotic hyperglycinemia. Individuals typically present with hypotonia, seizures, and increased serum glycine and lactate within the first days of life, followed by development of encephalopathy and/or severe psychomotor delays, which may result in childhood death. Unlike classic glycine encephalopathy, HGCLAS appears to be caused by mitochondrial lipoate biosynthesis defects.
Multiple mitochondrial dysfunctions syndrome 1 (MMDS1)
Caused by pathogenic variants in the NFU1 gene, is another ‘variant’ form of glycine encephalopathy, characterized by infantile-onset neuronal deterioration, vacuolating leukoencephalopathy, lactic acidosis, and pulmonary hypertension. Biochemical studies show increased levels of plasma, urinary, and CSF glycine. The disorder is typically fatal by early childhood.
Glycine encephalopathy with normal serum glycine
Caused by pathogenic variants in the SLC6A9 gene, is characterized by features of severe neonatal glycine encephalopathy along with arthrogryposis multiplex congenita, joint hyperlaxity, and respiratory issues. Biochemical studies show increased CSF glycine and normal to mildly increased serum glycine, which differs from classic forms of glycine encephalopathy. The disorder is typically fatal in infancy.
In individuals 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 the AMT, GCSH, or GLDC gene. Pathogenic variants in GLDC are the most commonly identified in individuals with glycine encephalopathy (70%–75%), followed by AMT (20%) and GCSH (<1%). Approximately 5% of individuals with an enzymatically confirmed diagnosis of glycine encephalopathy do not have a pathogenic variant in any of the aforementioned genes, and may have a variant form of glycine encephalopathy.
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 in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|