<%server.execute "isdev.asp"%> A rare case of glycine encephalopathy unveiled by valproate therapy Subramanian V, Kadiyala P, Hariharan P, Neeraj E - J Pediatr Neurosci
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Year : 2015  |  Volume : 10  |  Issue : 2  |  Page : 143-145

A rare case of glycine encephalopathy unveiled by valproate therapy

1 Department of Paediatric Neurology, Institute of Social Paediatrics, Stanley Medical College, Chennai, Tamil Nadu, India
2 Department of Biochemistry, Institute of Child Health, Madras Medical College, Chennai, Tamil Nadu, India
3 Intern, Stanley Medical College, Chennai, Tamil Nadu, India
4 Department of Paediatrics, Institute of Social Paediatrics, Stanley Medical College, Chennai, Tamil Nadu, India

Date of Web Publication22-Jun-2015

Correspondence Address:
Velusamy Subramanian
Department of Paediatric Neurology, Institute of Social Paediatrics, Stanley Medical College, Chennai, Tamil Nadu
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1817-1745.159200

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Glycine encephalopathy (GE) or nonketotic hyperglycinemia is an autosomal recessive disorder due to a primary defect in glycine cleavage enzyme system. It is characterized by elevated levels of glycine in plasma and cerebrospinal fluid usually presenting with seizures, hypotonia, and developmental delay. In our case, paradoxical increase in seizure frequency on starting sodium valproate led us to diagnose GE.

Keywords: Glycine encephalopathy, nonketotic hyperglycinemia, organic acidemia, recurrent seizures, valproate

How to cite this article:
Subramanian V, Kadiyala P, Hariharan P, Neeraj E. A rare case of glycine encephalopathy unveiled by valproate therapy. J Pediatr Neurosci 2015;10:143-5

How to cite this URL:
Subramanian V, Kadiyala P, Hariharan P, Neeraj E. A rare case of glycine encephalopathy unveiled by valproate therapy. J Pediatr Neurosci [serial online] 2015 [cited 2023 Sep 25];10:143-5. Available from: https://www.pediatricneurosciences.com/text.asp?2015/10/2/143/159200

   Introduction Top

Glycine encephalopathy (GE) or nonketotic hyperglycinemia is an autosomal recessive disorder due to defect in various protein components of glycine cleavage enzyme system (GCS). Incidence is 1 in 55,000 in Finland and carrier state is approximately 1:125 in British Columbia, Canada. [1] Most cases present with recurrent seizures and characteristically elevated cerebrospinal fluid (CSF) glycine to plasma glycine ratio. This case is presented for its rarity and to facilitate early recognition and management of this disorder.

   Case Report Top

A 6-year-old girl born to nonconsanguineous parents presented with global developmental delay and recurrent seizures since 6 months of age. Her natal and neonatal period was uneventful. Family history was negative. She had 4 episodes of generalized tonic-clonic seizures (GTCS) till 4 years of age. She was started on phenobarbitone 5 mg/kg/day at 6 months of age following an episode of seizure. At 4 years of age, sodium valproate 15 mg/kg/day was added. Frequency increased to 10-15 episodes of multiple atonic seizures in the next 2 years. Dose of valproate was increased to 25 mg/kg/day after which the child started developing occasional myoclonic jerks.

On examination, the child was well nourished. She had microcephaly with head circumference measuring 46.5 cm. Cranial nerves and fundus were normal. She was able to speak 6-7 words, obey simple commands but she was unable to communicate her basic needs. Bulk and tone of all limbs were normal with power of grade 4/5. Deep tendon reflexes were brisk in lower limbs and plantar reflex was extensor bilaterally. She was able to walk a few steps unsupported.

Dose of valproate was further increased to 30 mg/kg/day. The child had 3 episodes of GTCS in a day following which she developed quadriplegia and was bedridden. Suspecting inborn error of metabolism, Valproate was discontinued. She was started on clobazam 0.7 mg/kg/day and carnitine. Weakness improved over 3 months. On follow-up, the child is seizure free for the past 2 years.

Magnetic resonance imaging (MRI) brain revealed mild thinning of posterior part of the body of corpus callosum. MRI spine was normal. Electroencephalogram (EEG) showed bilateral frequent bursts of sharp wave discharges. Nerve conduction studies of all limbs were normal. Serum lactate, pyruvate, ammonia, and routine investigations were within normal limits. Blood tandem mass spectrometry done during follow-up revealed elevated plasma glycine values of 615 μmol/L (normal: 125-450 μmol/L) and normal levels of other amino acids and organic acids. Simultaneous quantitative chromatography and spectrophotometric estimation of both CSF and plasma revealed elevated plasma glycine of 959.76 μmol/L and CSF glycine of 799.8 μmol/L (normal: <20 μmol/L). Urine examination showed elevated urine glycine - 31.45 mg/dl (normal: 12-106 mg/day). The biochemical hallmark of GE-elevated CSF glycine to plasma glycine ratio of 0.83 (normal < 0.02) was evident. In addition, urine ketone and organic acids were negative. The child is currently on phenobarbitone and clobazam [Figure 1] and [Figure 2].
Figure 1: Coronal T1-weighted image of magnetic resonance imaging of the brain done 2 years later, show thinning of posterior part of the body of corpus callosum

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Figure 2: Proton magnetic resonance spectroscopy showing glycine peak at 3.55 ppm

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   Discussion Top

Glycine encephalopathy is caused by the primary defect in GCS transmitted by autosomal recessive mode of inheritance. As a consequence, high concentrations of glycine accumulate throughout the body including central nervous system. [2]

Elevated glycine in CSF is known to cause neurological manifestations. Glycine is an excitatory neurotransmitter in the cerebral cortex and inhibitory in brainstem and spinal cord. Glycine, a co-agonist of N-methyl-D-aspartate (NMDA)-glutamate receptor enhances the excitotoxic activity of glutamate. [3],[4]

Three genes are known to cause GE, each of which codes for a protein subunit in GCS: Glycine decarboxylase (GLDC) (P-protein component) on chromosome 9p24.1, aminomethyltransferase (AMT) (T-protein component) on 3p21.31 and glycine cleavage system H protein (GCSH) (H-protein component) on chromosome 16q23.2 with GLDC mutation constituting 70-75% of the disease. [1] Use of anti-epileptics like valproate for seizure control can further increase glycine levels in CSF, thereby worsening the condition as in our case.

Majority of the cases present in the neonatal period with 85% suffering severe outcome: Progressive lethargy within first few hours to days of life, hypotonia, hiccups, and myoclonic jerks leading to apnea and death. Infantile form presents with history of hypotonia, developmental delay, and seizures. Atypical cases present late in childhood with spastic diplegia, ataxia, and optic atrophy. [5] Only 20% of the cases carry good prognosis although they suffer from minimal developmental delay. [6]

The illness may be precipitated by fever or high protein diet. [7] Increased CSF/plasma glycine ratio, normal levels of other amino acids and organic acids distinguishes GE from other amino acid metabolism disorders. [8] 13 C-glycine breath is a rapid and reliable method to diagnose GE. [9] The diagnosis can be confirmed by sequence analysis and targeted deletion analysis of GLDC, AMT, and GCSH genes. GCS enzyme activity can also be measured in liver biopsy. [10]

Brain malformations such as agenesis of corpus callosum, gyral malformation, posterior fossa cysts, and ventricular enlargement may be evident in MRI brain. [11],[12] Vacuolating myelinopathy is the pathology behind GE. [13] In our case, MRI brain showed mild thinning of posterior part of the body of corpus callosum and proton MR spectroscopy reveals an abnormal glycine peak at 3.55 ppm in GE which correlates with findings from literature. [14],[15]

Sodium benzoate, a binding agent of glycine, as a treatment of GE has been used with varying success rates. [16],[17],[18] Dextromethorphan, an NMDA antagonist produces clinical and EEG improvement in patients with GE. [19] Since the child is seizure free for the past 2 years, the recommended drugs for GE such as sodium benzoate and NMDA antagonists were not tried. Though sodium benzoate reduces plasma glycine concentration and prevents seizures, it requires careful monitoring of glycine levels, benzoate levels and carnitine levels. NMDA antagonists require vigilant observation as well. As regular monitoring is a hitch in our setup, the child was advised to continue phenobarbitone and clobazam. Patients with GE may respond to glycine-free diet and methionine-rich diet but this may not prevent the development of severe mental retardation. [20],[21] Apart from urea cycle disorders and mitochondrial disorders, one should also consider the possibility of GE if seizures worsen on starting valproate.

   Acknowledgments Top

We acknowledge the Department of Radiology, Stanley Medical College for MR spectroscopy.

   References Top

Ncbi.nlm.nih.gov. Van Hove J, Coughlin C, Scharer G. Glycine encephalopathy. NCBI Initial Posting; 2002. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1357/. [Last update on 2013 Jul 11].  Back to cited text no. 1
Perry TL, Urquhart N, MacLean J, Evans ME, Hansen S, Davidson GF, et al. Nonketotic hyperglycinemia. Glycine accumulation due to absence of glycerine cleavage in brain. N Engl J Med 1975;292:1269-73.  Back to cited text no. 2
McDonald JW, Johnston MV. Excitatory amino acid neurotoxicity in the developing brain. NIDA Res Monogr 1993;133:185-205.  Back to cited text no. 3
McDonald JW, Johnston MV. Physiological and pathophysiological roles of excitatory amino acids during central nervous system development. Brain Res Brain Res Rev 1990;15:41-70.  Back to cited text no. 4
Hennermann JB. Clinical variability in glycine encephalopathy. Future Neurol 2006;1:621-30.  Back to cited text no. 5
Hoover-Fong JE, Shah S, Van Hove JL, Applegarth D, Toone J, Hamosh A. Natural history of nonketotic hyperglycinemia in 65 patients. Neurology 2004;63:1847-53.  Back to cited text no. 6
Steiner RD, Sweetser DA, Rohrbaugh JR, Dowton SB, Toone JR, Applegarth DA. Nonketotic hyperglycinemia: Atypical clinical and biochemical manifestations. J Pediatr 1996;128:243-6.  Back to cited text no. 7
Applegarth DA, Toone JR. Nonketotic hyperglycinemia (glycine encephalopathy): Laboratory diagnosis. Mol Genet Metab 2001;74:139-46.  Back to cited text no. 8
Kure S, Korman SH, Kanno J, Narisawa A, Kubota M, Takayanagi T, et al. Rapid diagnosis of glycine encephalopathy by 13C-glycine breath test. Ann Neurol 2006;59:862-7.  Back to cited text no. 9
Hamosh A, Scharer G, Van Hove J. Glycine encephalopathy. In: Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP, editors. GeneReviews™. Seattle: University of Washington, Seattle; 2002. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1357/. [Last cited 2011 Jan 31].  Back to cited text no. 10
Dobyns WB. Agenesis of the corpus callosum and gyral malformations are frequent manifestations of nonketotic hyperglycinemia. Neurology 1989;39:817-20.  Back to cited text no. 11
Press GA, Barshop BA, Haas RH, Nyhan WL, Glass RF, Hesselink JR. Abnormalities of the brain in nonketotic hyperglycinemia: MR manifestations. AJNR Am J Neuroradiol 1989;10:315-21.  Back to cited text no. 12
Van der Knaap MS, Valk J. Magnetic Resonance of Myelin, Myelination and Myelin Disorders. New York: Springer-Verlag; 1995. p. 209-10.  Back to cited text no. 13
Huisman TA, Thiel T, Steinmann B, Zeilinger G, Martin E. Proton magnetic resonance spectroscopy of the brain of a neonate with nonketotic hyperglycinemia: In vivo-in vitro (ex vivo) correlation. Eur Radiol 2002;12:858-61.  Back to cited text no. 14
Heindel W, Kugel H, Roth B. Noninvasive detection of increased glycine content by proton MR spectroscopy in the brains of two infants with nonketotic hyperglycinemia. AJNR Am J Neuroradiol 1993;14:629-35.  Back to cited text no. 15
Wolff JA, Kulovich S, Yu AL, Qiao CN, Nyhan WL. The effectiveness of benzoate in the management of seizures in nonketotic hyperglycinemia. Am J Dis Child 1986;140:596-602.  Back to cited text no. 16
Zammarchi E, Donati MA, Ciani F, Pasquini E, Pela I, Fiorini P. Failure of early dextromethorphan and sodium benzoate therapy in an infant with nonketotic hyperglycinemia. Neuropediatrics 1994;25:274-6.  Back to cited text no. 17
Chien YH, Hsu CC, Huang A, Chou SP, Lu FL, Lee WT, et al. Poor outcome for neonatal-type nonketotic hyperglycinemia treated with high-dose sodium benzoate and dextromethorphan. J Child Neurol 2004;19:39-42.  Back to cited text no. 18
Schmitt B, Steinmann B, Gitzelmann R, Thun-Hohenstein L, Mascher H, Dumermuth G. Nonketotic hyperglycinemia: Clinical and electrophysiologic effects of dextromethorphan, an antagonist of the NMDA receptor. Neurology 1993;43:421-4.  Back to cited text no. 19
De Groot CJ, Troelstra JA, Hommes FA. Nonketotic hyperglycinemia: An in vitro study of the glycine-serine conversion in liver of three patients and the effect of dietary methionine. Pediatr Res 1970;4:238-43.  Back to cited text no. 20
Krieger I, Hart ZH. Valine-sensitive nonketotic hyperglycinemia. Case report. J Pediatr 1974;85:43-8.  Back to cited text no. 21


  [Figure 1], [Figure 2]

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