Genotype–phenotype correlations in sepiapterin reductase deficiency. A splicing defect accounts for a new phenotypic variant

Abstract

Sepiapterin reductase (SR) catalyzes the final step in the de novo synthesis of tetrahydrobiopterin, essential cofactor for phenylalanine, tyrosine, and tryptophan hydroxylases. SR deficiency is a very rare disease resulting in monoamine neurotransmitter depletion. Most patients present with clinical symptoms before the first year of age corresponding to a dopa-responsive dystonia phenotype with diurnal fluctuations, although some patients exhibit more complex motor and neurological phenotypes. Herein, we describe four new cases from Spain, their clinical phenotype and the biochemical and genetic analyses. Two mutations in the SPR gene were functionally expressed to provide a basis to establish genotype-phenotype correlations. Mutation c.751A>T is functionally null, correlating with the severe phenotype observed. The novel mutation c.304G>T was identified in three siblings with a strikingly mild phenotype without cognitive delay and close to asymptomatic in the eldest sister. Minigene analysis demonstrated that this mutation located in the last nucleotide of exon 1 affects splicing although some normal transcripts can be produced, resulting in the missense mutant p.G102C that retains partial activity. These results may account for the mild phenotype and the variable clinical presentations observed, which could depend on interindividual differences in relative abundance of correctly spliced and aberrant transcripts.

Dopa-responsive dystonia—clinical and genetic heterogeneity

“…[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.…”

“…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. 84 The severity of the condition varies according to the nature of the genetic defect and consequent enzymatic defect, but symptoms improve with levodopa treatment.…”

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

“…Prolactin levels can also help in monitoring the medication (2,8,12,(15)(16)(17)(18)(19)(20)(21)(22)(23)25).…”

“…This disorder is classified as a neurotransmitter disorder (3,4,13,14). The clinical hallmarks of this rare, but probably underdiagnosed disorder are disease onset most often before 1 year of age with paroxysmal stiffening, upward gaze, and hypotonia (2,8,12,(15)(16)(17)(18)(19)(20)(21)(22)(23). Cognitive symptoms, speech disturbances, motoric delay, and dystonic movements with diurnal fluctuations are frequently seen, but normally occur later in the disease course.…”

Diagnosing dopamine-responsive dystonias

“…Deficiency of any of these three enzymes (GTPCH, SR or TH) leads to dopamine depletion at the synaptic terminals within the basal ganglia, causing both motor and non-motor dysfunction (mood swings, depression, verbal memory deficits and concentration problems) 7 8. There is pathological and biochemical evidence of striatal dopamine deficiency in DRDs to support this hypothesis 9 10…”