Leaky splicing variant in sepiapterin reductase deficiency: Are milder cases escaping diagnosis?

Abstract

Sepiapterin reductase deficiency (SRD), an extremely rare but treatable neurotransmitter disease, is an enzyme defect in the final step of tetrahydrobiopterin (BH4) synthesis.1 Unlike other forms of BH4-deficient dopa-responsive dystonia, SRD uniquely does not manifest hyperphenylalaninemia and thus slips through detection by newborn screening. Owing to its variable presenting features and need for a sensitive method of CSF analysis, diagnosis of SRD may be compromised in mild phenotypes.2. We describe a novel splice site variant leading to leaky splicing control of the SPR gene. Our observation adds evidence to the notion that leaky splicing may take part in SRD heterogeneity and evokes the image of an iceberg beneath the water: patients at the milder end of the spectrum escaping recognition.