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Nonketotic Hyperglycinemia

NKA

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.


Presentation

Nonketotic hyperglycinemia is a metabolic disorder of glycine, a neurotransmitter possessing both excitatory and inhibitory effects in the central nervous system (CNS) [1] [2]. For this reason, the term glycine encephalopathy (GE) is often used in the literature to describe this condition [1] [3] [4] [5]. 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 [1] [2] [5] [6]. 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 [1] [2] [3]. 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 [1] [2] [3] [4]. Fatal outcomes in the first week of life are observed in up to 50% of cases [1]. 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 [1] [2]. 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 [1] [2] [6]. Some studies determined that the complaints may be aggravated by fever and a high protein diet [2].

Precocious Puberty
  • Precocious puberty was observed in an 11-month-old girl with nonketotic hyperglycinemia.[ncbi.nlm.nih.gov]
Aspiration
  • Clinical suspicion of neonatal encephalopathy should be considered in any infant exhibiting an abnormal level of consciousness, seizures, tone and reflex abnormalities, apnea, aspiration, and feeding difficulties.[ncbi.nlm.nih.gov]
Hiccup
  • Seizures, hypotonia, lethargy, and hiccups are the principal symptoms, and many neonates/infants rapidly progress to coma.[symptoma.com]
  • A neonate with nonketotic hyperglycinemia who experienced apnea, hiccups and tonic-clonic seizures on the first day of life is reported. The physical findings and laboratory tests including arterial blood gases were normal.[ncbi.nlm.nih.gov]
  • We describe a male neonate with hypotonia, hiccups, and persistent apnea, but without seizures.[ncbi.nlm.nih.gov]
  • The neonatal form presents in the first days after birth with encephalopathy, seizures. and characteristic "hiccups." Rapid progression can lead to intractable seizures, coma, and respiratory failure.[ncbi.nlm.nih.gov]
  • A severe outcome was significantly associated with early onset of spasticity, frequent hiccupping, EEG burst-suppression or hypsarrhythmia patterns, microcephaly, and congenital or cerebral malformations, e.g. corpus callosum hypoplasia.[ncbi.nlm.nih.gov]
Short Arm
  • Seizures are rarely reported in association with deletion or duplication syndromes of the short arm of chromosome 5, or with chromosome 5 rings.[ncbi.nlm.nih.gov]
  • This unusual occurrence may not have been coincidental and suggests that there may be a gene for nonketotic hyperglycinemia located on the short arm of chromosome 9.[ncbi.nlm.nih.gov]
  • The AMT gene, located on the short arm of chromosome 3 (3p21.31), and GLDC gene, located on the short arm of chromosome 9 (9p22), encoding enzymes and dehydrogenase aminomethyltransferase respectively glycine.[ivami.com]
Alopecia
  • Acrodermatitis enteropathica is a rare inherited disorder characterized by zinc deficiency and a triad of dermatitis, diarrhea, and alopecia.[ncbi.nlm.nih.gov]
Eruptions
  • In addition to zinc, deficiencies of other nutrients such as branched chain amino acids have induced an acrodermatitis enteropathica-like eruption.[ncbi.nlm.nih.gov]
Seizure
  • 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]
  • The second infant had seizures, hypotonia, and respiratory distress shortly after birth. She was treated with phenobarbital and diphenylhydantoin, which had no effect on her seizures.[ncbi.nlm.nih.gov]
  • […] to no seizures, or only occasional minor ones, after treatment.[ncbi.nlm.nih.gov]
  • The efficacy in seizure reduction persists for at least 3 years in both children.[ncbi.nlm.nih.gov]
  • Most patients present soon after birth with seizures and hypotonia, and infants that survive the newborn period often have profound intellectual disability and intractable seizures.[ncbi.nlm.nih.gov]
Hyperactivity
  • 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.[clinicaladvisor.com]

Workup

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 [2]. 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 [1] [5]. The CSF/plasma ratio of glycine is highly suggestive of nonketotic hyperglycinemia [1] [5]. 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 [2] 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 [1] [5] [7]. A thorough family history might be an important tool in the assessment of patients, given the autosomal recessive pattern of inheritance.

Left Ventricular Hypertrophy
  • In this article, the authors report an infant with nonketotic hyperglycinemia, who was found to have progressive left ventricular hypertrophy and dysfunction.[ncbi.nlm.nih.gov]
Ventricular Hypertrophy
  • In this article, the authors report an infant with nonketotic hyperglycinemia, who was found to have progressive left ventricular hypertrophy and dysfunction.[ncbi.nlm.nih.gov]

Treatment

  • No effective treatment has been consistently reported.[ncbi.nlm.nih.gov]
  • Abstract Neonatal-type nonketotic hyperglycinemia treatment remains unsatisfactory, even if started early. A review of six patients who underwent treatment for neonatal-type nonketotic hyperglycinemia in our hospital is presented.[ncbi.nlm.nih.gov]
  • […] as treatment with sodium benzoate.[ncbi.nlm.nih.gov]
  • Treatment with low-dose DM needs further evaluation.[ncbi.nlm.nih.gov]
  • This contrasts with the favorable outcome with early treatment in variant NKH with mild GCS deficiency (Ann Neuol 2004;56:139-143).[ncbi.nlm.nih.gov]

Prognosis

  • 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]
  • Despite these treatments, the prognosis for infants with NKH is poor, with severe neurologic impairment, intractable seizures, and death common before 5 years of age.[ncbi.nlm.nih.gov]
  • The prognosis of neonatal nonketotic hyperglycinemia remains poor with current treatment. Genetic counseling helps parents cope with this devastating genetic disease.[ncbi.nlm.nih.gov]
  • The charts of six children treated in our department since 1991 were reviewed for details that might contribute to the prediction of prognosis.[ncbi.nlm.nih.gov]
  • Nonketotic hyperglycinemia (NKH) is an inborn error of glycine degradation causing muscular hypotonia, seizures, apnea, and lethargy; it has a poor prognosis.[ncbi.nlm.nih.gov]

Etiology

  • Early myoclonic encephalopathy is an epileptic syndrome with different etiologies. Nonketotic hyperglycinemia is one cause.[ncbi.nlm.nih.gov]
  • Acquired zinc deficiency due to a variety of etiologies may produce a similar clinical picture. These causes include inadequate supply, malabsorption, and low zinc stores.[ncbi.nlm.nih.gov]
  • Since the feasibility of determining glycine transport parameters in postmortem tissue has been established, we think it would be of interest to investigate such systems in cases where the etiology of hyperglycinemia is not clear.[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.[clinicaladvisor.com]

Epidemiology

  • 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.[clinicaladvisor.com]
Sex distribution
Age distribution

Pathophysiology

  • 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]
  • 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]
  • Tada K, Kure S (1993) Non-ketotic hyperglycinaemia: molecular lesion, diagnosis and pathophysiology. J Inherit Metab Dis 16:691–703 PubMed CrossRef Google Scholar 2.[link.springer.com]

Prevention

  • 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]
  • Previous therapies which have been directed toward reducing the glycine concentration in plasma and CSF have not been successful in preventing neurological deterioration, which may be the result of the role of glycine as an inhibitory neurotransmitter[ncbi.nlm.nih.gov]
  • INTERPRETATION: Prospective treatment with this regimen can favorably modify the early neonatal course of severe NKH but does not prevent the poor long-term outcome, suggesting glycine-induced prenatal injury and/or ongoing postnatal damage.[ncbi.nlm.nih.gov]
  • This acceleration was prevented by 7-chlorokynurenic acid, a glycine antagonist at the NMDA receptor complex, and by the GABA agonist loreclezole.[ncbi.nlm.nih.gov]

References

Article

  1. 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.
  2. 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.
  3. Iqbal M, Prasad M, Mordekar SR. Nonketotic hyperglycinemia case series. J Pediatr Neurosci. 2015;10(4):355-358.
  4. 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.
  5. Applegarth DA, Toone JR. Nonketotic hyperglycinemia (glycine encephalopathy): laboratory diagnosis. Mol Genet Metab. 2001;74(1-2):139-146.
  6. 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.
  7. Korman SH, Gutman A. Pitfalls in the diagnosis of glycine encephalopathy (non-ketotic hyperglycinemia). Dev Med Child Neurol. 2002;44(10):712-720.

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Last updated: 2019-07-11 20:25