Brain Advance Access originally published online on July 27, 2005
Brain 2005 128(10):2291-2296; doi:10.1093/brain/awh603
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Sepiapterin reductase deficiency: a congenital dopa-responsive motor and cognitive disorder
1 Neurosciences Unit, Institute of Child Health (UCL) and 2 Great Ormond Street Hospital, 30 Guilford Street, London, UK, 3 Division of Paediatrics, St Luke's Hospital, G'Mangia, Malta and 4 Laboratory of Molecular Genetics, Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, Msida, Malta
Correspondence to: Professor B. G. R. Neville, The Wolfson Centre, Mecklenburgh Square, London WC1N 2AP, UK E-mail: b.neville{at}ich.ucl.ac.uk
This study presents the clinical findings on seven children from Malta (population 385 000). All of them had early motor delay and a significant degree of cognitive impairment. Diurnal variation of the motor impairments was clear in six out of seven of the subjects and oculogyric crises occurred from an early stage also in six out of the seven. Five out of seven had clear evidence of dystonia but the early picture was dominated by hypotonia in five. Two had early Parkinsonian tremor and chorea was seen in four, although in two this was attributable to the use of L-dopa. Three had early bulbar involvement. In all, although minor motor problems persisted, the response to L-dopa was dramatic and there was a need to balance improvement in dystonia against aggravation of chorea. The majority were not able to walk until they were treated. Increased doses of L-dopa were required in hot weather, to which they were sensitive. Despite a good response of improved motor ability and abolition of oculogyric crises, there was no obvious change in cognitive function with learning remaining in the moderate impairment range. This report widens the phenotype of dopa-responsive motor disorders and the range of young children with primary motor delay (cerebral palsy) who need a clinical trial of L-dopa. All of the subjects had the same novel mutation in the tetrahydrobiopterin pathway involving sepiapterin reductase, and no abnormality in the gene encoding guanosine triphosphate cyclohydrolase 1. Clinically and molecularly the condition shows autosomal recessive inheritance.
Key Words: cognition; dopa responsive; L-dopa; sepiapterin reductase
Abbreviations: ADGTPCH1 = Autosomal dominant guanosine triphosphate cyclohydrolase 1; BH4 = Tetrahydrobiopterin; SR = Sepiapterin reductase
Received September 17, 2004. Revised December 10, 2004. Second revision on June 21, 2005. Accepted June 28, 2005.
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