Glycine Encephalopathy Panel

Glycine encephalopathy, also known as nonketotic hyperglycinemia (NKH), is an inborn error of glycine metabolism caused by defects in the glycine cleavage multi-enzyme system (GCS) (Van Hove et al. 2019. PubMed ID: 20301531). Affected children have a large accumulation of glycine in the body (including hyperglycinemia in the blood) resulting in various neurological symptoms. The majority of patients with glycine encephalopathy present in the neonatal period, while some patients can develop the disease in infancy. Regardless of age at onset, 20% of all affected children present with atypical, less severe phenotypes.

The majority of affected neonates develop severe symptoms such as progressive lethargy, feeding difficulties, central hypotonia, and generalized myoclonic seizures/myoclonic jerks, and breathing problems such as apnea that may lead to death. These patients often will have abnormal metabolic brain imaging by MRS, EEG with burst suppression, hypoplasia of the corpus callosum, and recurrent singultus (recurrent hiccup). Surviving infants have hypotonia, profound intellectual disability, developmental delay and intractable seizures. The atypical form has disease onset from late infancy to adulthood and the clinical outcomes range from milder features to rapidly progressive severe disease (Van Hove et al. 2019. PubMed ID: 20301531; GARD: Genetic and Rare Diseases Information Center).

The worldwide prevalence of NKH has been estimated at 1:76,000, although it has been reported with increased frequency in specific populations (for example, 1:12,000 in Northern Finland)(Van Hove et al. 2019. PubMed ID: 20301531).

In addition to the genes responsible for the majority of cases of NKH, we have included additional genes on this panel that may also be associated with hyperglycinemia. Those genes are also associated with the following disorders: multiple mitochondrial dysfunctions syndrome 2 with hyperglycinemia (BOLA3), pyridoxine-refractory sideroblastic anemia 3 (GLRX5), multiple mitochondrial dysfunctions syndrome 3 (IBA57), multiple mitochondrial dysfunctions syndrome 4 (ISCA2), hyperglycinemia, lactic acidosis, and seizures (LIAS), severe neonatal encephalopathy with lactic acidosis and brain abnormalities (LIPT2), multiple mitochondrial dysfunctions syndrome 1 (NFU1), glycine encephalopathy with normal serum glycine (SLC6A9). Patients with pathogenic variants in these genes may exhibit some different phenotypic features, such as optic atrophy, pulmonary hypertension, and cardiomyopathy, and testing may also reveal deficient pyruvate dehydrogenase enzyme deficiency (Van Hove et al. 2019. PubMed ID: 20301531).

Molecular testing can be useful for confirmation of a genetic cause of NKH. Molecular diagnosis for a patient with suspected NKH may help with determining appropriate treatment measures, assessment of recurrence risks, and allow for appropriate screening for potential future symptoms. 

Glycine encephalopathy is an autosomal recessive disorder. The vast majority of pathogenic variants are inherited, although de novo pathogenic variants have been reported to occur in ~1% of affected individuals (Van Hove et al. 2019. PubMed ID: 20301531). GLDC, AMT and GCSH are the three known genes associated with the disease (Kure et al. 2006. PubMed ID: 16450403). These three genes encode the P, T and H proteins of the glycine cleavage multi-enzyme system (GCS), respectively.

Genetic defects in GLDC account for approximately 70-80% of glycine encephalopathy cases. Documented pathogenic GLDC variants include missense, various types of truncating variant and large deletions. Large deletions within GLDC have been reported as a major cause of the disease (Kanno et al. 2007. PubMed ID: 17361008). Although pathogenic GLDC variants have been found across the whole coding region of the gene, a clustering of missense pathogenic variants in exon 19, which encodes the cofactor-binding site, has been reported (Kure et al. 2006. PubMed ID: 16450403; Van Hove et al. 2019. PubMed ID: 20301531).

Genetic defects of AMT account for approximately 20% of glycine encephalopathy cases. Documented pathogenic AMT variants include missense and various types of truncating variants. Large deletions and duplications within AMT have not been reported (Van Hove et al. 2019. PubMed ID: 20301531; Human Gene Mutation Database).

Genetic defects of GCSH are an extremely rare cause of glycine encephalopathy. To date, only one conclusively pathogenic GCSH variant affecting splicing has been documented for a transient form of glycine encephalopathy (Van Hove et al. 2019. PubMed ID: 20301531; Human Gene Mutation Database).

The LIAS gene encodes lipoic acid synthase, LIPT2 encodes lipoyl(octanoyl) transferase 2, and BOLA3, GLRX5, IBA57, ISCA2, and NFU1 encode proteins involved in the synthesis of the iron-sulfur cluster necessary for the function of lipoic acid synthase. Lipoate is required for the function of the glycine cleavage multi-enzyme system (GCS) (Kikuchi et al. 2008. PubMed ID: 18941301). Pathogenic variants in these genes cause lipoate deficiency and are associated with a variety of clinical disorders, which may be associated with hyperglycinemia (Baker et al. 2014. PubMed ID: 24334290; Van Hove et al. 2019. PubMed ID: 20301531). Documented pathogenic variants in these genes include missense and various types of truncating variants. Large deletions have only been reported in NFU1 (Human Gene Mutation Database).

The SLC6A9 gene encodes the glycine transporter 1 protein, which is located mainly on astrocytes and is essential in clearance of glycine from the extracellular space, terminating glycinergic transmission (Alfallaj and Alfadhel. 2019. PubMed ID: 30815509). To date, missense, nonsense, and small deletion variants have been reported in SLC6A9 (Human Gene Mutation Database).

See individual gene summaries for more information about molecular biology of gene products and spectra of pathogenic variants.

Genetic defects in GLDC account for 70-80% of glycine encephalopathy (Van Hove et al. 2019. PubMed ID: 20301531) and approximately 20% of GLDC pathogenic alleles are large deletions (Kanno et al. 2007. PubMed ID: 17361008; Van Hove et al. 2019. PubMed ID: 20301531). 

Genetic defects in AMT account for approximately 20% of glycine encephalopathy (Van Hove et al. 2019. PubMed ID: 20301531). Large deletions/duplications within AMT have not been reported (Human Gene Mutation Database).

Genetic defects of GCSH are an extremely rare cause of glycine encephalopathy. In two large studies of families with glycine encephalopathy, no pathogenic GCSH variants were found (Kure et al. 2006. PubMed ID: 16450403; Coughlin et al. 2017. PubMed ID: 27362913).

For the disorders associated with the BOLA3, GLRX5, IBA57, ISCA2, LIAS, LIPT2, NFU1, and SLC6A9 genes, clinical sensitivity cannot be estimated because only a small number of patients with pathogenic variants have been reported.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).