Sepiapterin reductase deficiency: a congenital dopa-responsive motor and cognitive disorder

• Published in: Brain (London, England : 1878) Vol. 128; no. 10; pp. 2291 - 2296
• Main Authors: Neville, B. G. R., Parascandalo, R., Farrugia, R., Felice, A.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.10.2005; Oxford Publishing Limited (England)
• Subjects: ADGTPCH1 = Autosomal dominant guanosine triphosphate cyclohydrolase 1; Adolescent; Alcohol Oxidoreductases - deficiency; BH4 = Tetrahydrobiopterin; Biological and medical sciences; Cerebral Palsy - drug therapy; Cerebral Palsy - enzymology; Cerebral Palsy - physiopathology; Child; Child, Preschool; Circadian Rhythm - physiology; cognition; Cognition Disorders - enzymology; Cognition Disorders - physiopathology; Developmental Disabilities - drug therapy; Developmental Disabilities - enzymology; Developmental Disabilities - physiopathology; Diseases of striated muscles. Neuromuscular diseases; dopa responsive; Dopamine Agents - therapeutic use; Dyskinesias - drug therapy; Dyskinesias - enzymology; Dyskinesias - physiopathology; Female; Genotype; Humans; l-dopa; Levodopa - therapeutic use; Male; Medical sciences; Motor Activity - physiology; Movement Disorders - drug therapy; Movement Disorders - enzymology; Movement Disorders - physiopathology; Nervous system (semeiology, syndromes); Nervous system as a whole; Neurology; sepiapterin reductase; SR = Sepiapterin reductase; Nervous system diseases; Cognitive disorder; dopa responsive; Congenital; L-dopa; Enzyme; Motor system disorder; Deficiency; Cognition; Sepiapterin reductase; Oxidoreductases; Levodopa; Neurological disorder; Dopa
• ISSN: 0006-8950; 1460-2156; 1460-2156
• DOI: 10.1093/brain/awh603

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.