title: Clinical and genetic studies in a family with a novel mutation in the sepiapterin reductase gene.
abstract: OBJECTIVE
  Sepiapterin reductase deficiency is a rare, but treatable inherited disorder of tetrahydrobiopterin and neurotransmitter metabolism. This disorder is most probably underdiagnosed. To date, only 44 cases have been described in the literature. We present the clinical and genetic investigations in a family with a complex movement disorder.
  
  
  METHODS
  We examined two affected sisters and three healthy family members. The cerebrospinal fluid was analyzed for neurotransmitter and pterins, and the sepiapterin reductase gene (SPR) was sequenced.
  
  
  RESULTS
  The sisters had a complex movement disorders with dystonia and diurnal fluctuations. Both had oculogyric crises, and the older sister also hypersomnia. Both sisters had raised prolactin levels twice above the reference level. One sister had a dramatic response to levodopa, the other responded, but developed dyskinesia despite low doses. Both patients improved dramatically over time with levodopa (2.3 and 1.5 mg/kg/day). Very low levels of homovanillic acid and 5-hydroxyindoleacetic acid and increased levels of sepiapterin and dihydrobiopterin were measured in the cerebrospinal fluid before treatment. DNA analyses revealed a novel homozygous mutation in exon 2 in the SPR gene, c.364A>G/p.(Tyr123Cys), located in a highly conserved region in the gene. Both parents and the healthy sister were carriers for the same mutation.
  
  
  CONCLUSIONS
  A new homozygous mutation in the SPR gene was found in two sisters with dopa-responsive dystonia. This important and treatable neurotransmitter disorder must be considered in patients with a complex movement disorder with diurnal fluctuations with or without intellectual impairment. Patients with these symptoms should undergo levodopa trial, cerebrospinal fluid investigations, and genetic analyses.
authors.affiliation: Department of Neurology, Drammen Hospital, Vestre Viken Health Trust, Drammen, Norway.
authors.forename: J
authors.initials: J
authors.lastname: Koht
authors.forename: A
authors.initials: A
authors.lastname: Rengmark
authors.forename: T
authors.initials: T
authors.lastname: Opladen
authors.forename: K A
authors.initials: KA
authors.lastname: Bjørnarå
authors.forename: T
authors.initials: T
authors.lastname: Selberg
authors.forename: C M E
authors.initials: CM
authors.lastname: Tallaksen
authors.forename: N
authors.initials: N
authors.lastname: Blau
authors.forename: M
authors.initials: M
authors.lastname: Toft
mesh_terms: D000293:Adolescent; D000429:Alcohol Oxidoreductases / Q000235:genetics*; D002648:Child; D020821:Dystonic Disorders / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007980:Levodopa / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D011622:Pterins / Q000378:metabolism
chemical_list: D011622:Pterins; D007980:Levodopa; C016727:sepiapterin; D000429:Alcohol Oxidoreductases; C022630:sepiapterin reductase
keywords: dopa-responsive dystonia; dystonia; sepiapterin reductase deficiency