Submission Details

The relationship between SPR and dopa-responsive dystonia, an autosomal recessive disorder of tetrahydrobiopterin (BH4) synthesis, was evaluated using the ClinGen Clinical Validity Framework as of May 17, 2021. SPR encodes sepiapterin reductase (SR), an enzyme that converts 6-pyruvoyl-tetrahydropterin to BH4. BH4 is a cofactor required for the activity of phenylalanine hydroxylase, tyrosine hydroxylase, and tryptophan hydroxylase. As a result, individuals with SR deficiency have low levels of monoamines (due to lack of tyrosine and tryptophan hydroxylase activities) which results in the neurological symptoms typical of dopa-responsive dystonia, including motor and speech delay, axial hypotonia, dystonia, weakness, and oculogyric crises; symptoms show diurnal fluctuation and sleep benefit (Friedman et al, 2015, PMID 26131547). Of note, these individuals do not typically have hyperphenylalaninemia, presumably because sufficient BH4 is generated in the liver, by other pathways, for normal function of PAH (Longo 2009, PMID 19234759; Himmelreich et al, 2021, PMID 33903016). Biallelic variants in SPR were first reported in patients with dopa-responsive dystonia in 2001 (Bonafé et al, PMID 11443547). Since then, over 100 variants in SPR in patients with dopa-responsive dystonia have now been reported (Himmelreich et al, 2021, PMID 33903016). In this curation, data from 6 probands, who are homozygous or compound heterozygous for SPR variants were collected including six unique variants (missense, frameshift, nonsense, splice site) from 5 publications (Bonafé et al, 2001, PMID 11443547; Farrugia et al, 2007, PMID 17188538; Verbeek et al, 2008, PMID 18502672; Lohmann et al, 2012, PMID 22018912; Froukh et al, 2019, PMID 31777525). One variant, c.596-2A>G, is common in affected individuals from Malta, suggesting a possible founder effect (Farrugia et al, 2015, PMID 17188538; Friedman et al, 2015, PMID 26131547). More data is available in the literature but the maximum points for genetic evidence (12 points) has been reached. The gene-disease relationship is supported by the biochemical function of the product of SPR, sepiapterin reductase, which is consistent with the biochemical findings and clinical features in patients with biallelic variants in the gene (Citron et al, 1990, PMID 2201030; Levine et al, 1990, PMID 2179471; Longo, 2009, PMID 19234759; Himmelreich et al, 2021, PMID 33903016); and the characteristics reported in a null mouse model (Yang et al, 2006, PMID 16532389) and silkworm mutants (Meng et al, 2009, PMID 19246455; Jiang et al, 2020, PMID 32269807). In summary, SPR is definitively associated with dopa-responsive dystonia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This clinical validity classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel on June 1st 2021 (SOP v7).