Clinical and genetic studies in a family with a novel mutation in the sepiapterin reductase gene

Abstract

Objectives -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. Materials and 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.

Dopa-responsive dystonia—clinical and genetic heterogeneity

“…115 Sepiapterin reductase deficiency Most patients with sepiapterin reductase deficiency exhibit a dramatic response to low doses of levodopa, which improves dystonia, spasticity, pyramidal signs, oculogyric crisis, concentration and overall cognitive function. 83,84,87 One study reported a marked improvement in cognitive ability-especially use of language and performance at school-with levodopa treatment in two patients with sepiapterin reductase deficiency, although these children still did not reach normal academic performance for their age. 87 Doses of levodopa (usually in combination with carbidopa) used for treatment of sepiapterin reductase deficiency range from 0.1 mg/kg to 16.0 mg/kg daily; on average, the most effective dose is 3.9 mg/kg daily.…”

“…The condition is usually autosomal recessive and results from mutations in SPR, which is located at chromosome 2p14-2p12. [80][81][82][83][84] Sepiapterin reductase deficiency is characterized by axial hypotonia, delays in the development of motor function and language, oculogyric crises, muscle weakness, and dystonia. 81,[82][83][84][85][86][87] Patients with mutations in SPR are commonly misdiagnosed with cerebral palsy.…”

“…[80][81][82][83][84] Sepiapterin reductase deficiency is characterized by axial hypotonia, delays in the development of motor function and language, oculogyric crises, muscle weakness, and dystonia. 81,[82][83][84][85][86][87] Patients with mutations in SPR are commonly misdiagnosed with cerebral palsy. 84 As in GTP-CH-I deficiency, the symptoms can fluctuate diurnally; 81,86,87 in one review of published cases, marked diurnal variation of motor abnormalities was observed in nine of 11 patients, 87 although diurnal variation might be difficult to identify in infants.…”

“…87 Other signs of sepiapterin reductase deficiency that are observed in some patients include parkinsonism, tremor, dysarthria, limb hypertonia, hyperreflexia, psychiatric disorders, autonomic dysfunction, and sleep disturbances. 83,84,87 The deficiency is also associated with intellectual disability. 80 Differential diagnoses At the initial presentation, DRD is frequently misdiagnosed as conditions such as cerebral palsy, juvenile parkinsonism, hereditary spastic paraplegia, foot drop and psychogenic gait disorders.…”

Combined Sepiapterin Reductase and Methylmalonyl-CoA Epimerase Deficiency in a Second Patient: Cerebrospinal Fluid Polyunsaturated Fatty Acid Level and Follow-Up Under l-DOPA, 5-HTP and BH4 Trials

“…Sleep disorders and marked hypersomnolence are also described (Friedman et al 2006). To date, 13 different mutations for 44 subjects have been reported in the database (http://www.biopku.org) (Koht et al 2014). SRD is a potentially treatable inborn error of pterin metabolism with a response to L-DOPA/carbidopa and 5-hydroxytryptophan (5-HTP).…”