Akademik Veri Yönetim Sistemi
INTERNATIONAL INBORN ERRORS OF METABOLISM AND NUTRITION CONGRESS, İstanbul, Türkiye, 10 - 14 Nisan 2019, ss.299-301
INTRODUCTION: Nonketotic hyperglycinemia (NKH) (glycine encephalopathy,
OMIM#605899) is an autosomal recessive disorder caused by defective glycine cleavage
enzyme system (GCS) activity. The enzyme system consists of four subunits: P-protein
(pyridoxal containing), H-protein (hydrogen carrier), T-protein (requires tetrahydrofolate)
and L-protein. Classic form of the disease is caused by the mutations in genes which affect
the protein components of the main catabolic enzyme (GLDC (80%) and AMT (%20)
genes) and based on the clinical severity the condition is divided into severe or attenuated
forms. Variant NKH is a different kind of phenotype caused by the mutations affecting the
main cofactor lipoate which is not only cofactor for GCS but also some dehydrogenase
enzymes (e.g pyruvate dehydrogenase and branched chained ketoacid dehydrogenase).
Patients in the classic form present with lethargy, hypotonia, myoclonic jerks, transient
respiratory depression in the first week of life and often progress to death. Surviving infants
have profound psychomotor retardation, refractory epilepsy and poor quality of life. Variant
form of the disease includes the combination of clinical finding observed in the severe NKH
and mitochondriopathies (leukoencephalopathy, cardiomyopathy, optic atrophy and lactic
acidosis episodes) The biochemical diagnosis of the disease is established by detecting high
glycine levels in the blood and cerebrospinal fluid in the presence of clinical suspicion.
Definitive diagnosis is confirmed by mutation analysis of the genes involved in the GCS.
Treatment options involves low glycine and/or ketogenic diet, sodium benzoate,
dextromethorphan and folinic acid. The effect of these treatments on the outcome is still
unclear, so we evaluated the outcome and response to therapy in our patients.
RESULTS: Patients (n:22) followed between July 2001-March 2019 in İstanbul Medical
Faculty, Department of Pediatric Nutrition and Metabolism, were enrolled in the study.
59%(13/22) were female and 41% were male. Seven patients are currently on follow-up due
to death or other reasons. All patients except one, were term with normal birth weights and
delivery. The rate of consanguineous marriage was 59%(13/22). Clinical findings were
hypotonia, poor feeding and intractable seizures beginning on the second day of life (1-14
days) and hiccup episodes. Electroencephalography (EEG) (15/22) at the time of the
diagnosis showed burst suppression pattern. Median plasma glycine was 1130
μmmo/L(range:233-3784) and CSF 185 μmmo/L(range:58-539). The median CSFGly/
Plasma-Gly ratio was 0.137. Cranial MRI in 12 patients showed restricted diffusion in
the posterior limb of the internal capsule, anterior brainstem, posterior tegmental tracts in
four. Five patients had absent corpus callosum or gyral malformation. Low glycine diet,
sodium benzoate and dekstrometorphan were started in all patients. The current age of the
seven surviving patients ranged from 1.5-months to13-years. In four of these patients, the
diagnosis was genetically confirmed (GLDC gene mutations in 3 and AMT gene mutations
in 1). The clinic of the surviving patients is summarized in the Table 1.
DISCUSSION
Despite the progress in the management of patients with NKH, the long-term outcome
remains poor. High CSF glycine levels with early onset of the disease, presence of brain
malformations, EEG patterns of burst-supression and frequent hiccups refers to severe
clinical course, whereas late onset of the disease (<4 months) or low CSF/plasma Gly levels
(>0,08) indicates attenuated form of the disease. It is important to recognize the condition
early as genetic counseling, and prenatal diagnosis can be offered at the subsequent
pregnancy. Early diagnosis of the disease is also important because the disease has a
heterogeneous course and genetic diagnosis is necessary to predict clinical outcomes
depending on the mutation type. Since the genotype-phenotype correlation is present in the
classical form of the disease; it can be predicted that patients with a mutation leading to a
residual activity will have a better clinical course.