Sepiapterin Reductase (SR) Deficiency via the SPR Gene

Inborn errors of tetrahydrobiopterin (BH4) synthesis can result in disruption of phenylalanine homeostasis and dopamine and serotonin biosynthesis. These disorders are caused by pathogenic variants in genes encoding enzymes involved in biosynthesis or regeneration of BH4. The phenylalanine, tyrosine, and tryptophan hydroxylases all require BH4 as a cofactor, and lack of this cofactor often results in secondary hyperphenylalaninemia and depletion of the neurotransmitters dopamine and serotonin. Early detection and treatment can reduce or prevent neurologic symptoms (Blau et al. 2014).

Unlike other disorders of BH4 synthesis, patients with sepiapterin reductase (SR) deficiency do not present with hyperphenylalaninemia and are thus not detected by routine newborn screening. Alternative enzymes are able to compensate for the loss of SR activity in the peripheral tissues, but not in the brain, which explains why patients present with neurological symptoms, but no change in day-to-day phenylalanine homeostasis (Arrabal et al. 2011). Diagnosis of SR deficient patients is therefore based initially on clinical features, the most common of which are psychomotor and growth retardation, microcephaly, L-dopa responsive dystonia, spasticity, tremor, ataxia, behavioral anomalies, and oculogyric crises. Such symptoms often occur with marked diurnal fluctuations, with noticeable improvement after sleep (Bonafé et al. 2001; Steinberger et al. 2004; Friedman 2015).

Biochemically, SR deficient patients have low levels of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA), high levels of dihydrobiopterin (BH2), and slightly increased levels of neopterin and sepiapterin. If measured, SR activity in fibroblasts is decreased or absent, and patients will have normal levels of phenylalanine unless a phenylalanine loading test is performed, in which a greatly increased phenylalanine/tyrosine ratio is observed (Bonafé et al. 2001; Steinberger et al. 2004; Friedman 2015). Most SR deficient patients present in the early years of life, although diagnosis may be delayed if sepiapterin reductase (SR) deficiency is not considered early in testing (Arrabal et al. 2011). Once diagnosed, patients are typically treated with L-dopa or 5-hydroxytryptophan (5-HTP), potentially in combination with carbidopa. Treatment is often able to correct motor abnormalities, but cognitive difficulties may remain (Friedman 2015).

Sepiapterin reductase (SR) deficiency is inherited in an autosomal recessive manner. The SPR gene (chromosome 11q22.3, 3 exons) encodes the SR enzyme, which is involved in the de novo biosynthesis of tetrahydrobiopterin. More specifically, SR converts 6-pyruvoyl tetrahydropterin to tetrahydrobiopterin (Blau et al. 2014). To date, fewer than 20 pathogenic variants have been reported in the SR gene. These variants include a mix of missense, nonsense, splicing, and small deletions and insertions (Human Gene Mutation Database). Pathogenic variants are spread along the coding sequence with no obvious hot spots.

Clinical sensitivity is difficult to estimate because only a small number of affected individuals have been reported. Analytical sensitivity should be high because all variants reported are detectable by direct sequencing.

This test provides full coverage of all coding exons of the SPR gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).