Novel mutations in the tyrosine hydroxylase gene in the first Czech patient with tyrosine hydroxylase deficiency.

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.

[1]  L. Puelles,et al.  Cerebrospinal fluid alterations of the serotonin product, 5-hydroxyindolacetic acid, in neurological disorders , 2010, Journal of Inherited Metabolic Disease.

[2]  D. Zafeiriou,et al.  Tyrosine hydroxylase deficiency: a treatable disorder of brain catecholamine biosynthesis. , 2010, Brain : a journal of neurology.

[3]  Ulrich Müller,et al.  The monogenic primary dystonias. , 2009, Brain : a journal of neurology.

[4]  I. Krägeloh-Mann,et al.  Dyskinetic cerebral palsy in Europe: trends in prevalence and severity , 2009, Archives of Disease in Childhood.

[5]  A. Ormazabal,et al.  Biochemical diagnosis of dopaminergic disturbances in paediatric patients: analysis of cerebrospinal fluid homovanillic acid and other biogenic amines. , 2008, Clinical biochemistry.

[6]  S. Duarte,et al.  Mitochondrial diseases mimicking neurotransmitter defects. , 2008, Mitochondrion.

[7]  K. Hyland Clinical utility of monoamine neurotransmitter metabolite analysis in cerebrospinal fluid. , 2008, Clinical chemistry.

[8]  A. Ormazabal,et al.  Secondary abnormalities of neurotransmitters in infants with neurological disorders , 2007, Developmental medicine and child neurology.

[9]  P. Pearl,et al.  The Pediatric Neurotransmitter Disorders , 2007, Journal of child neurology.

[10]  L. Wiklund,et al.  Dyskinetic cerebral palsy: a population‐based study of children born between 1991 and 1998 , 2007, Developmental medicine and child neurology.

[11]  D. Murphy,et al.  Cerebrospinal fluid monoamine metabolite levels in human newborn infants born in winter differ from those born in summer , 2006, Psychiatry Research.

[12]  P. Verstreken,et al.  Mitochondria at the Synapse , 2006, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[13]  I. Reynolds,et al.  Mitochondrial Trafficking to Synapses in Cultured Primary Cortical Neurons , 2006, The Journal of Neuroscience.

[14]  A. Albanese,et al.  A systematic review on the diagnosis and treatment of primary (idiopathic) dystonia and dystonia plus syndromes: report of an EFNS/MDS‐ES Task Force , 2006, European journal of neurology.

[15]  G. Hoffmann,et al.  Tyrosine Hydroxylase Deficiency , 2006 .

[16]  A. Ormazabal,et al.  HPLC with electrochemical and fluorescence detection procedures for the diagnosis of inborn errors of biogenic amines and pterins , 2005, Journal of Neuroscience Methods.

[17]  M. Naumann,et al.  Tyrosine hydroxylase deficiency causes progressive encephalopathy and dopa‐nonresponsive dystonia , 2003, Annals of neurology.

[18]  R. Wevers,et al.  Decreased homovanillic acid concentrations in cerebrospinal fluid in children without a known defect in dopamine metabolism. , 2003, European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society.

[19]  V. Fung,et al.  Tyrosine hydroxylase deficiency: Clinical manifestations of catecholamine insufficiency in infancy , 2002, Movement disorders : official journal of the Movement Disorder Society.

[20]  Ann Johnson Prevalence and characteristics of children with cerebral palsy in Europe. , 2002, Developmental medicine and child neurology.

[21]  J. Strawn,et al.  In-use stability of monoamine metabolites in human cerebrospinal fluid. , 2001, Journal of chromatography. B, Biomedical sciences and applications.

[22]  S Rozen,et al.  Primer3 on the WWW for general users and for biologist programmers. , 2000, Methods in molecular biology.

[23]  K. Hyland Presentation, diagnosis, and treatment of the disorders of monoamine neurotransmitter metabolism. , 1999, Seminars in perinatology.

[24]  F. Gabreëls,et al.  Biochemical hallmarks of tyrosine hydroxylase deficiency. , 1998, Clinical chemistry.

[25]  A. Nemeth,et al.  Clinical and molecular genetics of primary dystonias , 1998, Neurogenetics.

[26]  R. Surtees,et al.  Recessively inherited L-DOPA-responsive parkinsonism in infancy caused by a point mutation (L205P) in the tyrosine hydroxylase gene. , 1996, Human molecular genetics.

[27]  M. Candito,et al.  High-performance liquid chromatographic measurement of cerebrospinal fluid tetrahydrobiopterin, neopterin, homovanillic acid and 5-hydroxindoleacetic acid in neurological diseases. , 1994, Journal of chromatography. B, Biomedical applications.

[28]  D. Howells,et al.  Cerebrospinal Fluid Concentrations of Pterins and Metabolites of Serotonin and Dopamine in a Pediatric Reference Population , 1993, Pediatric Research.

[29]  M. Åsberg,et al.  Amine metabolites in the cerebrospinal fluid as a measure of central neurotransmitter function: methodological aspects. , 1984, Advances in biochemical psychopharmacology.