Nonketotic hyperglycinemia, also known as glycine encephalopathy, is a genetic disorder distinguished by the accumulation of glycine in body tissues. The condition is either fatal or presents with several mental and neurological disability in early life. Only a minority of patients develop a milder clinical form. Seizures, hypotonia, lethargy, and hiccups are the principal symptoms, and many neonates/infants rapidly progress to coma. The diagnosis rests on clinical criteria, identification of high glycine levels in cerebrospinal fluid or in the breath, and genetic studies.
Nonketotic hyperglycinemia is a metabolic disorder of glycine, a neurotransmitter possessing both excitatory and inhibitory effects in the central nervous system (CNS)  . For this reason, the term glycine encephalopathy (GE) is often used in the literature to describe this condition    . The pathogenesis stems from mutations in genes that regulate the synthesis and activity of proteins involved in the glycine cleavage system (GCS), which is responsible for degradation of glycine    . But because of these mutations, abnormal concentrations of glycine accumulate in the CNS and the rest of the body, exerting severely toxic effects that arise soon after birth   . In up to 85% of cases with nonketotic hyperglycinemia, symptoms such as lethargy, myoclonic jerks, seizures, microcephaly hiccups, and generalized hypotonia appear in the early neonatal period    . Fatal outcomes in the first week of life are observed in up to 50% of cases . Those who survive through the neonatal manifestations of nonketotic hyperglycinemia suffer from serious retardation and failure to reach developmental milestones, whereas seizures, ataxia, and spastic diplegia are less frequently reported  . A somewhat delayed form of nonketotic hyperglycinemia is seen in about 20% of patients, in whom typical features do not start before 6 months of age, with a less severe symptomatology and minor developmental delay   . Some studies determined that the complaints may be aggravated by fever and a high protein diet .
Entire Body System
Progressive Mental Retardation
A 13-year-old girl with early-onset, mild, slowly progressive mental retardation caused by nonketotic hyperglycinemia is described. [ncbi.nlm.nih.gov]
Death in Infancy
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. [en.wikipedia.org]
Failure to Thrive
Amino acid analysis presents diagnostic values for classic nonketotic hyperglycinemia, but it also should be performed in suspected cases of atypical nonketotic hyperglycinemia and in children with seizures, failure to thrive, behavior problems, and uncoordinated [ncbi.nlm.nih.gov]
[…] glycine metabolism, due to a deficiency of glycine dicarboxylase P protein (GCSP), a component of glycine cleavage system; characteristically overwhelming disease in the newborn period, with coma, seizures, and death, or, less often, gradual onset with failure [medical-dictionary.thefreedictionary.com]
At eight months of age she was admitted to the hospital with the diagnosis of "failure to thrive." On examination the patient was a poorly developed white female who weighed 28.4 kg. She was unable to raise her head, sit, or roll over. [healio.com]
[…] to thrive 非器質性成長障害 nonparalytic poliomyelitis 非麻痺型ポリオ nonpathologic proteinuria 非病理的タンパク尿 nonselective proteinuria 非選択性タンパク尿 nonsteroidal anti-inflammatory drug 非ステロイド性抗炎症薬 NSAID nontraumatic medical problem in sports 内科的スポーツ障害 nontypable Haemophilus [jpeds.or.jp]
The third patient, with the slowest development, had intractable seizures for nearly a month before diagnosis, and although seizure-free for 30 months, now has grand-mal seizures. One patient died of intractable seizures at 3 months. [ncbi.nlm.nih.gov]
An attenuated outcome was significantly associated with hyperactivity and choreiform movement disorders. We describe a severity score which facilitates the prediction of the outcome in patients with GE. [ncbi.nlm.nih.gov]
They often have hyperactivity and behavioral problems. The clinical picture of individuals with variant NKH is rapidly evolving. Presentation varies depending upon what gene is mutated and the specific mutation itself. [rarediseases.org]
These patients also tended to be hyperactive. Interestingly, patients with choreic movements tended to fare better. Atypical forms range from mild disease, with onset anytime from infancy to adulthood, to severe unrelenting disease with later onset. [cancertherapyadvisor.com]
This report describes a patient with mild language delay and mental retardation, who was found to have nonketotic hyperglycinemia following her presentation with acute encephalopathy and chorea shortly after initiation of valproate therapy. [ncbi.nlm.nih.gov]
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. [invitae.com]
After normal development for 6 months, this patient lost all milestones, became lethargic, hypotonic, irritable, and developed seizures, dying at 15 months of age. [brain.oxfordjournals.org]
Alteration of Consciousness
We describe a girl with late-onset nonketotic hyperglycinemia presenting at 5 years of age with hypotonia, chorea, ataxia, and alterations in consciousness in the setting of febrile illness. [ncbi.nlm.nih.gov]
The diagnosis of nonketotic hyperglycinemia is rarely made in practice, as incidence rates in isolated reports established its occurrence in approximately 1 in 55,000 individuals . Nevertheless, the physician must obtain a detailed history from the parents about the course and progression of signs, and perform a thorough physical examination that would confirm their presence. To make a diagnosis of nonketotic hyperglycinemia, specific tests that evaluate the concentrations of glycine in cerebrospinal fluid (CSF) should be performed  . The CSF/plasma ratio of glycine is highly suggestive of nonketotic hyperglycinemia  . In addition, the 13C-glycine breath test is regarded as a very useful exam for the identification of nonketotic hyperglycinemia, primarily because of its non-invasiveness  The ailment can be confirmed through enzyme assays and genetic testing that determine the exact mutations responsible for the disorder. Some authors recommend a biopsy of the liver as the optimal tissue for conducting these studies because the expression of these defects is not seen in fibroblast or lymphocytes   . A thorough family history might be an important tool in the assessment of patients, given the autosomal recessive pattern of inheritance.
No effective treatment has been consistently reported. [ncbi.nlm.nih.gov]
Nonketotic hyperglycinemia has variable phenotypic expressions and a poor prognosis. We report a case of severe neonatal nonketotic hyperglycinemia, who started convulsing immediately after birth. [ncbi.nlm.nih.gov]
Biochemical and molecular predictors for prognosis in nonketotic hyperglycinemia. Ann Neurol. 2015 Oct;78(4):606-18. [connectingthegrowingbrain.com]
Early myoclonic encephalopathy is an epileptic syndrome with different etiologies. Nonketotic hyperglycinemia is one cause. [ncbi.nlm.nih.gov]
Ongoing controversies regarding etiology, diagnosis, treatment There is debate over treatment and if it should be initiated at all given the poor outcome of patients with NKH. [cancertherapyadvisor.com]
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 [en.wikipedia.org]
This aims to provide a basis for improving our 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. [intd-online.org]
Epidemiologic studies have revealed the incidence of glycine encephalopathy in Finland is 1/55,000 newborns and a similar study in British Columbia, Canada revealed the incidence to be 1/63,000. [cancertherapyadvisor.com]
I will review the pathophysiology of NKH, methods of diagnosis, and the differential diagnosis. There are a variety of different pharmacologic and alternative therapies for NKH. [ncbi.nlm.nih.gov]
The exact pathophysiology of the disorder is not known, but it is considered likely that buildup of glycine in the brain is responsible for the symptoms.All forms of glycine encephalopathy show elevated levels of glycine in the plasma, as well as in cerebral [en.wikipedia.org]
The pathophysiology of NKH has been attributed to an overstimulation of the excitatory N- methyl-d-aspartate receptors in the cerebral cortex (1, 2). [nature.com]
Those who survive are severely handicapped. 6 A late-onset form has also been described in which patients develop neurological symptoms of varying degrees after the neonatal period. 7 The pathophysiologic effects of hyperglycinemia were attributed to [annsaudimed.net]
雑誌 Mol Genet Metab 74:139-46 (2001) DOI: 10.1006/mgme.2001.3224 文献 PMID: 8412015 著者 Tada K, Kure S タイトル Non-ketotic hyperglycinaemia: molecular lesion, diagnosis and pathophysiology. 雑誌 J Inherit Metab Dis 16:691-703 (1993) DOI: 10.1007/BF00711901 [genome.jp]
Prospective treatment with oral sodium benzoate, the N-methyl-d-aspartate receptor antagonist ketamine, and dextromethorphan can favorably modify the early neonatal course of severe nonketotic hyperglycinemia, but does not prevent poor long-term outcomes [ncbi.nlm.nih.gov]
Nonketotic Hyperglycinemia (NKH) is a metabolic disorder in children which prevents their little bodies from processing glycine. NKH usually affects infants and children, appearing shortly after birth. [foundationnkh.org]
- Van Hove J, Coughlin C II, Scharer G. Glycine Encephalopathy. 2002 Nov 14 [Updated 2013 Jul 11]. In: Pagon RA, Adam MP, Ardinger HH, et al, eds. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.
- Subramanian V, Kadiyala P, Hariharan P, Neeraj E. A rare case of glycine encephalopathy unveiled by valproate therapy. J Pediatr Neurosci. 2015;10(2):143-145.
- Iqbal M, Prasad M, Mordekar SR. Nonketotic hyperglycinemia case series. J Pediatr Neurosci. 2015;10(4):355-358.
- Hoover-Fong JE, Shah S, Van Hove JL, Applegarth D, Toone J, Hamosh A. Natural history of nonketotic hyperglycinemia in 65 patients. Neurology. 2004;63:1847–1853.
- Applegarth DA, Toone JR. Nonketotic hyperglycinemia (glycine encephalopathy): laboratory diagnosis. Mol Genet Metab. 2001;74(1-2):139-146.
- Lang TF, Parr JR, Matthews EE, Gray RG, Bonham JR, Kay JD. Practical difficulties in the diagnosis of transient non-ketotic hyperglycinaemia. Dev Med Child Neurol. 2008;50(2):157-159.
- Korman SH, Gutman A. Pitfalls in the diagnosis of glycine encephalopathy (non-ketotic hyperglycinemia). Dev Med Child Neurol. 2002;44(10):712-720.