Glycine encephalopathy
Glycine encephalopathy (non-ketotic hyperglycinemia) | |
---|---|
Other names | Non-ketotic hyperglycinemia or NKH |
Glycine | |
Specialty | Neurology, medical genetics, endocrinology |
Glycine encephalopathy is a rare
Glycine encephalopathy is sometimes referred to as "nonketotic hyperglycinemia" (NKH), as a reference to the biochemical findings seen in patients with the disorder, and to distinguish it from the disorders that cause "ketotic hyperglycinemia" (seen in propionic acidemia and several other inherited metabolic disorders). To avoid confusion, the term "glycine encephalopathy" is often used, as this term more accurately describes the clinical symptoms of the disorder.
Signs and symptoms
It typically presents as a severe encephalopathy with myoclonic seizures, is rapidly progressive and eventually results in respiratory arrest. Standard evaluation for inborn errors of metabolism and other causes of this presentation does not reveal any abnormality (no acidosis, no hypoglycaemia, or hyperammonaemia and no other organ affected). Pronounced and sustained hiccups in an encephalopathic infant have been described as a typical observation in non-ketotic hyperglycinaemia.[citation needed]
Genetics
Glycine encephalopathy has an estimated incidence of 1 in 60,000, making it the second most common disorder of amino acid metabolism, after phenylketonuria. It is caused by a defect in the glycine cleavage system (GCS), which is made up of four protein subunits. Each of these four subunits is encoded by a separate gene. Defects in three of these four genes have been linked to glycine encephalopathy.[1]: 790
Gene | Name | Percent |
---|---|---|
GLDC
|
encodes the "glycine dehydrogenase" subunit, also called "glycine decarboxylase" | About 70-75% of cases of glycine encephalopathy result from mutations in the GLDC gene. |
GCST or AMT | encoding the "aminomethyltransferase" subunit | About 20% of cases are caused by mutations in the AMT gene. |
GCSH | encoding the subunit "glycine cleavage system protein H" | Mutations in the GCSH gene account for less than 1% of cases. |
There is a fourth unit in the GCS: dihydrolipoamide dehydrogenase or GCSL. However, to date there have been no mutations in GCSL found to be associated with glycine encephalopathy.
A small percentage of affected individuals do not have detectable mutations in any of the three genes (listed above) that are typically associated with the disease. However, they still show defective glycine-cleavage enzymatic activity. It is thought that these patients may have mutations in the genes encoding one of the cofactors associated with the GCS complex.[citation needed]
Defects in the GCS proteins can prevent the complex from functioning properly or can prevent the GCS complex from forming entirely. When the complex is unable to metabolize glycine properly, this causes excess glycine to build up to toxic levels in the body's organs and tissues. Damage caused by elevated levels of glycine in the brain and
This disorder is inherited in an
Pathophysiology
Glycine is the simplest amino acid, having no
All forms of glycine encephalopathy show elevated levels of glycine in the plasma, as well as in cerebral spinal fluid (CSF).
Glycine encephalopathy (nonketotic hyperglycinemia, or NKH) should not be confused with other metabolic disorders that can produce elevated glycine levels. For example, certain inherited 'organic acidurias' (aka '
Glycine metabolism
Glycine is metabolized in the body's cells to end products of
Diagnosis
Classification
There are several different forms of glycine encephalopathy, which can be distinguished by the age of onset, as well as the types and severity of symptoms. All forms of glycine encephalopathy present with only neurological symptoms, including intellectual disability (
With the classical, or neonatal presentation of glycine encephalopathy, the infant is born after an unremarkable pregnancy, but presents with
Transient neonatal hyperglycinemia has been described in a very small number of cases. Initially, these patients present with the same symptoms and laboratory results that are seen in the classical presentation. However, levels of glycine in plasma and cerebrospinal fluid typically normalize within eight weeks, and in five of six cases there were no neurological issues detected at follow-up times up to thirteen years. A single patient was severely retarded at nine months. The suspected cause of transient neonatal hyperglicinemia is attributed to low activity of the glycine cleavage system in the immature brain and liver of the neonate.[3]
Treatment
A treatment of
Prognosis
The prognosis is very poor. Two studies reported typical age of deaths in infancy or early childhood, with the first reporting a median age of death of 2.6 for boys and less than 1 month for girls.[8][5]
Research
Response to treatment is variable and the long-term and functional outcome is unknown. To provide a basis for improving the understanding of the epidemiology, genotype/phenotype correlation and outcome of these diseases their impact on the quality of life of patients, and for evaluating diagnostic and therapeutic strategies a patient registry was established by the noncommercial International Working Group on Neurotransmitter Related Disorders (iNTD).[9]
Support
NKH is a rare disease but maintains a very active community presence for educating parents with newly diagnosed children and fundraising for genetic therapy. Leaders in the space include the Jack Richard Urban Foundation and the NKH Crusaders.
See also
- List of amino acid metabolism disorders
- inborn errors of metabolism
References
- ^ a b c d e f Sarafoglou, Kyriakie; Hoffmann, Georg F.; Roth, Karl S. (eds.). Pediatric Endocrinology and Inborn Errors of Metabolism. New York: McGraw Hill Medical. p. 811.
- ^ "Autosomal recessive: MedlinePlus Medical Encyclopedia".
- ^ a b c "Nonketotic hyperglycinemia". McGraw Hill. Retrieved 2011-09-22.
- ^ "The Organic Acidemias: An Overview -- GeneReviews -- NCBI Bookshelf". Archived from the original on 2010-05-27.
- ^ S2CID 25206831.
- ^ PMID 20301531. Retrieved 2011-09-22.
- ^ PMID 26749113.
- S2CID 23783707.
- ^ "Patient registry".