Sepiapterin Reductase Deficiency

Excerpt

Clinical characteristics: The phenotypic spectrum of sepiapterin reductase deficiency (SRD) is broad, ranging from significant motor and cognitive deficits to isolated movement disorder. Many individuals have developmental delay / intellectual disability, with a minority of individuals having mild learning disabilities or normal cognition. The movement disorder phenotype can include axial hypotonia, levodopa-responsive dystonia (often presenting as oculogyric crises), parkinsonian signs (tremor, bradykinesia, and/or rigidity), and limb hypertonia and hyperreflexia that can be associated with clonus and may be misdiagnosed as cerebral palsy. Autonomic dysfunction is typically present in half of individuals. Epilepsy is rare and mostly characterized as febrile seizures. Neurologic symptoms typically demonstrate diurnal fluctuation. Affected individuals can also experience behavioral and psychiatric symptoms (inattention, irritability, depression, anxiety); endocrinologic abnormalities (growth hormone deficiency, hypothyroidism, reduced levels of IGF-1, IGFBP-3, T₃, free T₃, and T₄) due to dopamine depletion; and sleep disturbances (hypersomnolence, drowsiness, narcolepsy/cataplexy, and/or difficulty initiating or maintaining sleep related to alteration of the sleep-wake circadian rhythm). Treatment may result in improvement or resolution of symptoms over time, depending on the severity of the symptom and the timing and response to treatment.

Diagnosis/testing: The analyte pattern consistent with a diagnosis of SRD includes decreased levels of homovanillic acid (HVA) and 5-hyroxyindolacetic acid (5-HIAA) in cerebrospinal fluid (CSF) with normal to slightly increased levels of neopterin and elevated levels of total biopterin, dihydrobiopterin (BH2), and sepiapterin in CSF and urine. The molecular diagnosis is established in a proband with consistent analyte findings and/or suggestive clinical features by identification of biallelic pathogenic variants in SPR by molecular genetic testing.

Management: Targeted therapies: Levodopa (0.1-16 mg/kg/day) in combination with 10%-25% carbidopa or benserazide, with the most common ratio of levodopa to dopamine decarboxylase (DC) inhibitor being 4:1. In combination with levodopa, 1-6 mg/kg/day of 5-hydroxytryptophan (5-HTP) may provide additional clinical benefit. These medications may reduce manifestations of SRD, although the response can range from complete resolution to partial improvement. They most consistently correct motor abnormalities, while cognitive manifestations remain more refractory in some individuals. The initiation of treatment with levodopa with or without 5-HTP in the first year of life reverses the developmental delay and could prevent cognitive impairment. Other agents used when levodopa/5-HTP/carbidopa are not tolerated or sufficiently effective include monoamine oxidase inhibitors, serotonin reuptake inhibitors, melatonin, dopamine agonists, anticholinergics, and methylphenidate.

Supportive care: Feeding therapy; gastrostomy tube placement may be required for persistent feeding issues; standard treatment for developmental delay / intellectual disability, epilepsy, and spasticity.

Surveillance: Evaluation of CSF neurotransmitter metabolites should be performed as needed during drug dose titration if the clinical response is not satisfactory, and during clinical follow up to clarify otherwise unexplainable discrepancies. This is particularly important for children under two years old, since neurologic symptoms can be difficult to evaluate in this age group. At each visit, monitor those with seizures as clinically indicated; assess for new manifestations (seizures, changes in tone, movement disorders); measure growth parameters and evaluate nutritional status and safety of oral intake; monitor developmental progress and educational needs; and assess for behavioral issues (inattention, anxiety, depression and/or irritability) and sleep disturbances.

Agents/circumstances to avoid: Although adverse events with specific agents have not been reported in persons with SRD, several should be avoided on a theoretic basis, including sulfa drugs (which impair BH4 biosynthesis); methotrexate (which inhibits dihydropteridine reductase); nitrous oxide (which may impair folate metabolism); neuroleptics and other dopamine antagonists.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk sibs of an affected individual via molecular genetic testing (if the pathogenic variants in the family are known) or urine sepiapterin concentration (if the pathogenic variants in the family are not known).

Pregnancy management: No pregnancies have been reported to date in women with SRD; however, it would seem prudent for women with SRD to continue levodopa therapy during pregnancy.

Genetic counseling: SRD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an SPR pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. Once the SPR pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.