Abstract Nonketotic hyperglycinemia (NKH) is an autosomal recessive hereditary disease caused by a defect in the glycine cleavage system and is classified into typical and atypical NKH. Atypical NKH has complex manifestations and is difficult to diagnose in clinical practice. This article reports a family of NKH. The parents had normal phenotypes, and the older brother and the younger sister developed this disease in the neonatal period. The older brother manifested as intractable epilepsy, severe spastic diplegia, intellectual disability, an increased level of glycine in blood and cerebrospinal fluid, an increased glycine/creatinine ratio in urine, and an increased ratio of glycine concentration in cerebrospinal fluid and blood. The younger sister manifested as delayed language development, ataxia, chorea, mental and behavior disorders induced by pyrexia, hypotonia, an increased level of glycine in cerebrospinal fluid, and an increased ratio of glycine concentration in cerebrospinal fluid and blood. High-throughput sequencing found a maternal missense mutation, c.3006C > G (p.C1002W), and a paternal nonsense mutation, c.1256C > G (p.S419X), in the GLDC gene in both patients. These two mutations were thought to be pathogenic mutations by a biological software. H293T cells transfected with these two mutants of the GLDC gene had a down-regulated activity of glycine decarboxylase. NKH has various phenotypes, and high-throughput sequencing helps to make a confirmed diagnosis. Atypical NKH is associated with the downregulated activity of glycine decarboxylase caused by gene mutations.
JIANG Tie-Jia,JIANG Jing-Jing,XU Jia-Lu et al. Clinical and genetic analyses of a family with atypical nonketotic hyperglycinemia caused by compound heterozygous mutations in the GLDC gene[J]. CJCP, 2017, 19(10): 1087-1091.
JIANG Tie-Jia,JIANG Jing-Jing,XU Jia-Lu et al. Clinical and genetic analyses of a family with atypical nonketotic hyperglycinemia caused by compound heterozygous mutations in the GLDC gene[J]. CJCP, 2017, 19(10): 1087-1091.
Coughlin CR 2nd, Swanson MA, Kronquist K, et al. The genetic basis of classic nonketotic hyperglycinemia due to mutations in GLDC and AMT[J]. Genet Med, 2017, 19(1):104-111.
[2]
Perry TL, Urquhart N, Maclean J, et al. Nonketotic hyperglycinemia. Glycine accumulation due to absence of glycerine cleavage in brain[J]. N Engl J Med, 1975, 292(24):1269-1273.
[3]
Baker PR 2nd, Friederich MW, Swanson MA, et al. Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5[J]. Brain, 2014, 137(Pt 2):366-379.
[4]
Brenton JN, Rust RS. Late-onset nonketotic hyperglycinemia with a heterozygous novel point mutation of the GLDC gene[J]. Pediatr Neurol, 2014, 50(5):536-538.
[5]
Dinopoulos A, Matsubara Y, Kure S, et al. Atypical variants of nonketotic hyperglycinemia[J]. Mol Genet Metab, 2005, 86(1-2):61-69.
Rahman S, Footitt EJ, Varadkar S, et al. Inborn errors of metabolism causing epilepsy[J]. Dev Med Child Neurol, 2013, 55(1):23-36.
[9]
Ezgu F, Çiftci B, Topçu B, et al. Diagnosis of glycine encephalopathy in a pediatric patient by detection of a GLDC mutation during initial next generation DNA sequencing[J]. Metab Brain Dis, 2014, 29(1):211-213.
[10]
Korman SH, Boneh A, Ichinohe A, et al. Persistent NKH with transient or absent symptoms and a homozygous GLDC mutation[J]. Ann Neurol, 2004, 56(1):139-143.
[11]
Swanson MA, Coughlin CR, Scharer GH, et al. Biochemical and molecular predictors for prognosis in nonketotic hyperglycinemia[J]. Ann Neurol, 2015, 78(4):606-618.
[12]
Van Hove JL, Vande KK, Hennermann JB, et al. Benzoate treatment and the glycine index in nonketotic hyperglycinaemia[J]. J Inherit Metab Dis, 2005, 28(5):651-663.
[13]
Suzuki Y, Kure S, Oota M, et al. Nonketotic hyperglycinemia:proposal of a diagnostic and treatment strategy[J]. Pediatr Neurol, 2010, 43(3):221-224.
[14]
Deutsch SI, Rosse RB, Mastropaolo J. Current status of NMDA antagonist interventions in the treatment of nonketotic hyperglycinemia[J]. Clin Neuropharmacol, 1998, 21(2):71-79.
[15]
Chien YH, Hsu CC, Huang A, et al. Poor outcome for neonatal-type nonketotic hyperglycinemia treated with high-dose sodium benzoate and dextromethorphan[J]. J Child Neurol, 2004, 19(1):39-42.
[16]
Korman SH, Wexler ID, Gutman A, et al. Treatment from birth of nonketotic hyperglycinemia due to a novel GLDC mutation[J]. Ann Neurol, 2006, 59(2):411-415.
[17]
Bjoraker KJ, Swanson MA, Christodoulou J, et al. Neurodevelopmental outcome and treatment efficacy of benzoate and dextromethorphan in siblings with attenuated nonketotic hyperglycinemia[J]. J Pediatr, 2016, 170:234-239.
[18]
Subramanian V, Kadiyala P, Hariharan P, et al. A rare case of glycine encephalopathy unveiled by valproate therapy[J]. J Pediatr Neurosci, 2015, 10(2):143-145.
