Sepiapterin Reductase Deficiency

Clinical characteristics: The phenotypic spectrum of sepiapterin reductase deficiency (SRD), which ranges from significant motor and cognitive deficits to only minimal findings, has not been completely elucidated. Clinical features in the majority of affected individuals include motor and speech delay, axial hypotonia, dystonia, weakness, and oculogyric crises; symptoms show diurnal fluctuation and sleep benefit. Other common features include parkinsonian signs (tremor, bradykinesia, masked facies, rigidity), limb hypertonia, hyperreflexia, intellectual disability, psychiatric and/or behavioral abnormalities, autonomic dysfunction, and sleep disturbances (hypersomnolence, difficulty initiating or maintaining sleep, and drowsiness). Most affected individuals have nonspecific features in infancy including developmental delays and axial hypotonia; other features develop over time.

Diagnosis/testing: The diagnosis of sepiapterin reductase deficiency is established in a proband by detection of biallelic pathogenic variants in SPR on molecular genetic testing or characteristic abnormalities of CSF neurotransmitters and pterins.

Management: Treatment of manifestations: L-dopa in combination with carbidopa (or another peripheral decarboxylase inhibitor) is the main therapy used to correct CNS dopamine deficiency; 5-hydroxytryptophan (5-HTP), also in combination with carbidopa, has shown additional clinical benefit in some. When L-dopa/5HTP/carbidopa are not tolerated or sufficiently effective some individuals may benefit from use of other agents such as monoamine oxidase inhibitors, serotonin reuptake inhibitors, melatonin, dopamine agonists, anticholinergics, and methylphenidate. These medications most consistently correct motor abnormalities; however, in some individuals cognitive manifestations remain more refractory.

Prevention of secondary complications: Physical, occupational, and speech therapy may improve or maintain motor function.

Surveillance: Data are insufficient to determine how frequently CSF levels of dopamine and serotonin metabolites should be evaluated and whether these levels should be used to adjust medication doses.

Agents/circumstances to avoid: Although adverse events with specific agents have not been reported in persons with SRD, the following should be avoided on a theoretic basis: sulfa drugs, methotrexate, nitrous oxide, neuroleptics, and other dopamine antagonists (e.g., metoclopramide).

Evaluation of relatives at risk: Although no data on outcomes are available, it is appropriate to use molecular genetic testing for the SPR pathogenic variants identified in the proband and/or analysis of CSF neurotransmitter metabolites and pterins to clarify the genetic status of apparently asymptomatic older and younger sibs of an affected individual in order to identify as soon as possible those who would benefit from early initiation of treatment to correct CNS dopamine and serotonin deficiency.

Genetic counseling: SRD is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the SPR pathogenic variants in the family are known.