Novel Mutations in the Tyrosine Hydroxylase Gene in the First Czech Patient with Tyrosine Hydroxylase Deficiency

K Szentiványi,Tomáš Honzík,J Zeman,M Tesařová,P Klement,K Vinšová,E Rozsypalová,J Krijt,H Hansíková

doi:10.14712/23362936.2015.28

Abstract

Tyrosine hydroxylase deficiency manifests mainly in early childhood and includes two clinical phenotypes: an infantile progressive hypokinetic-rigid syndrome with dystonia (type A) and a neonatal complex encephalopathy (type B). The biochemical diagnostics is exclusively based on the quantitative determination of the neurotransmitters or their metabolites in cerebrospinal fluid (CSF). The implementation of neurotransmitter analysis in clinical praxis is necessary for early diagnosis and adequate treatment. Neurotransmitter metabolites in CSF were analyzed in 82 children (at the age 1 month to 17 years) with clinical suspicion for neurometabolic disorders using high performance liquid chromatography (HPLC) with electrochemical detection. The CSF level of homovanillic acid (HVA) was markedly decreased in three children (64, 79 and 94 nmol/l) in comparison to age related controls (lower limit 218-450 nmol/l). Neurological findings including severe psychomotor retardation, quadruspasticity and microcephaly accompanied with marked dystonia, excessive sweating in the first patient was compatible with the diagnosis of tyrosine hydroxylase (TH) deficiency (type B) and subsequent molecular analysis revealed two novel heterozygous mutations c.636A>C and c.1124G>C in the TH gene. The treatment with L-DOPA/carbidopa resulted in the improvement of dystonia. Magnetic resonance imaging studies in two other patients with microcephaly revealed postischaemic brain damage, therefore secondary HVA deficit was considered in these children. Diagnostic work-up in patients with neurometabolic disorders should include analysis of neurotransmitter metabolites in CSF.

Highlights

Paediatric neurotransmitter disorders refer to an inherited group of neurometabolic syndromes attributable to a disturbance of neurotransmitter metabolism
Magnetic resonance imaging studies in two other patients with microcephaly revealed postischaemic brain damage, secondary homovanillic acid (HVA) deficit was considered in these children
The boy presented in newborn period after complicated perinatal history with hypotonia progressing into infantile encephalopathy dominated by severe psychomotor retardation, hypokinesia, facial hypomimia, generalized dystonia, ptosis, disturbed autonomic functions and oculogyric crisis

Summary

Introduction

Paediatric neurotransmitter disorders refer to an inherited group of neurometabolic syndromes attributable to a disturbance of neurotransmitter metabolism. The enzyme tyrosine hydroxylase (TH; EC 1.14.162) catalyzes the conversion of L-tyrosine to L-dihydroxyphenylalanine (L-dopa), which is the rate-limiting step in the biosynthesis of the catecholamines dopamine, norepinephrine and epinephrine. Human tyrosine hydroxylase deficiency (THD; OMIM 191290) is an autosomal recessive neurometabolic disorder due to mutations in the TH gene on chromosome 11p15.5 (Lüdecke et al, 1996). Many different features of THD (hypokinesia, bradykinesia, rigidity, dystonia, chorea, tremor, oculogyric crises, ptosis and hypersalivation, among others) are caused by cerebral dopamine and norepinephrine deficiency (Grattan-Smith et al, 2002). After careful evaluation of the detailed case histories in the literature, it was possible to class the different phenotypes at presentation into two major groups: an infantile progressive hypokinetic-rigid syndrome with dystonia (type A) and a neonatal complex encephalopathy (type B). In type B, L-dopa treatment does not improve all signs and it may take months before all effects of treatment become clear (Willemsen et al, 2010)

Methods

Results

Discussion

Conclusion