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

Abstract

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.

Dopamine-Responsive Growth-Hormone Deficiency and Central Hypothyroidism in Sepiapterin Reductase Deficiency

“…The phenotype of SR deficiency is mainly characterized by an affection of the motor and cognitive system. Patients exhibit psychomotor retardation and neurologic symptoms dominated by axial muscular hypotonia, dystonic movements, spasticity, and parkinsonism with diurnal fluctuation (Abeling et al 2006;Dill et al 2012;Neville et al 2005). In infancy, muscular hypotonia and developmental delay are usually the only clinical findings.…”

Levodopa Response Reveals Sepiapterin Reductase Deficiency in a Female Heterozygote with Adrenoleukodystrophy

“…Patients exhibit psychomotor retardation, inconsolable crying, neurological abnormalities (hypotonia, dystonic posturing, oculogyric crises, spasticity, tremor, ataxia, gait disorder, chorea, Parkinsonism, seizure-like movements), psychiatric symptoms (depressed affect, aggressive behavior, hypersomnolence), and occasional physical findings (microcephaly, growth deficiency) (Abeling et al 2006, Neville et al 2005. As with other dopa-responsive disorders, symptoms are characteristically worse in the evenings, so-called diurnal variation.…”

“…Collectively, the disorders that respond to levodopa are termed dopa-responsive dystonias (DRD), the best known being GTP cyclohydrolase deficiency (Segawa's disease). In addition, defects in tyrosine hydroxylase, aromatic L-amino acid decarboxylase and sepiapterin reductase (SR) can also lead to DRD (Zorzi et al 2002;Friedman et al 2006; Th€ ony and Blau 2006; Abeling et al 2006;Neville et al 2005). No association with peroxisomal disorders has ever been described.…”

Dystonia and Dopaminergic Therapy: Rationale Derived from Pediatric Neurotransmitter Diseases

“…(Bonafé et al, 2001) Many of patients were reported around Mediterranean. (Neville et al, 2005) Sepiapterin reductase is one of enzymes to covert sepiapterin into BH4. (See Fig.2) Patients from Malta showed early motor delay and a significant degree of cognitive impairment.…”

“…Initial dose of L-dopa was 1.5 to 4 mg/kg/day (12.5 to 50 mg/day). (Neville et al, 2005) In these patients, 100 mg L-dopa and 10 mg Carbidopa tablets were used. One case report described incomplete response to treatment during short-term follow-up.…”