Sepiapterin reductase deficiency

The signs and symptoms of sepiapterin reductase deficiency vary from significant motor and cognitive delays to only minor findings. The condition often starts with nonspecific features in infancy, including developmental delay and hypotonia, with other features developing over time. The majority of affected individuals have the following features, which show diurnal fluctuation and sleep benefit (being worse at night and better in the morning after sleeping):^[1][2][3]

• motor and speech delay
• hypotonia affecting the trunk and limbs (axial hypotonia)
• dystonia (unusual body posturing or twisting movements that are caused by uncontrolled muscle contractions)
• weakness
• oculogyric crises (abnormal rotation of the eyeballs; extreme irritability and agitation; and pain, muscle spasms, and uncontrolled movements, especially of the head and neck) 

Other common features include:^[1][2][3]

• parkinsonian signs (tremor, bradykinesia (slowness of mevement), masked facies, rigidity)
• microcephaly
• seizures
• limb hypertonia
• dysarthria
• hyperreflexia
• intellectual disability
• psychiatric and/or behavioral abnormalities (anxiety, irritability)
• autonomic dysfunction
• sleep disturbances (hypersomnia, difficulty initiating or maintaining sleep, and drowsiness)

Sepiapterin reductase deficiency is caused by mutations in the SPR gene. This gene provides instructions for making the sepiapterin reductase enzyme, which is involved in the productions of a molecule called tetrahydrobiopterin (also known as BH4).^[1][2][3] Sepiapterin reductase is specifically responsible for the last step in the production of tetrahydrobiopterin. Tetrahydrobiopterin helps process several building blocks of proteins (amino acids), and is involved in the production of chemicals called neurotransmitters, which transmit signals between nerve cells and the brain.^[1]

SPR gene mutations disrupt the production of sepiapterin reductase. This leads to a reduction or absence of tetrahydrobiopterin. Without tetrahydrobiopterin, the brain cannot produce dopamine and serotonin, leading to the symptoms of sepiapterin reductase deficiency.^[1]

Yes. It is thought to be inherited in an autosomal recessive pattern.^[1][2][3] This means that to be affected, a person must have a mutation in both copies of the responsible gene in each cell. Affected people inherit one mutated gene from each parent, who is referred to as a carrier. Carriers of an autosomal recessive condition typically do not have any signs or symptoms (they are unaffected). When 2 carriers of an autosomal recessive condition have children, each child has a: 

• 25% (1 in 4) chance to be affected
• 50% (1 in 2) chance to be an unaffected carrier like each parent
• 25% (1 in 4) chance to be unaffected and not be a carrier

 

Sepiapterin reductase deficiency may be considered in children with characteristic clinical findings, including developmental delays with hypotonia, unexplained cerebral palsy, especially when dystonia is present, and an L-dopa responsive motor disorder.^[3]

Diagnosis is based on characteristic abnormalities of neurotransmitters and pterins in the cerebrospinal fluid.^[3][2][4] More specifically, cerebrospinal fluid findings include low levels of 5-hydroxyindolacetic acid (5-HIAA) and homovanillic acid (HVA); slightly increased levels of neopterin; and elevated total biopterin and dihydrobiopterin (BH2). Sepiapterin reductase activity in fibroblasts is usually reduced or absent. Molecular genetic testing can identify mutations in the SPR gene, confirming the diagnosis.^[3][2] Testing can be done using single-gene testing or a multi-gene panel.^[3]

Treatment of sepiapterin reductase deficiency may involve levodopa (L-dopa), carbidopa and 5-hydroxytryptophan.^[2][3] General information on levodopa and carbidopa can be found on the MedlinePlus Web site by clicking here.  

Treatment should be started as soon as possible in order to avoid irreversible neurological damage and continued for life.^[2] The amounts of L-dopa administered to people with sepiapterin reductase deficiency vary, but, in general, tends to be between 0.1 and 16 mg/kg/day. 5-hydroxytryptophan doses tend to be between 0.14 to 6 mg/kg/day.^[2][3] Combination therapy is introduced slowly and increased by over the course of days or weeks until the final target concentration is reached. People receiving this treatment regimen require careful monitoring because increasing the dose too quickly can cause side-effects. Patients receiving treatment may be monitored with routine evaluations by a pediatric neurologist, video documentation, and follow-up testing looking at cerebral spinal fluid (CSF) metabolite concentrations. Samples of CSF are obtained by lumbar puncture.^[4]

If L-dopa and 5-hydroxytryptophan in combination with carbidopa are not well tolerated or don't achieve the desired results, other medications may be considered. These include monoamine oxidase inhibitors, serotonin reuptake inhibitors, melatonin, dopamine agonists, anticholinergics, and methylphenidate. While these medications address the motor abnormalities of the condition, cognitive delays commonly remain.^[3]

Prognosis depends on disease severity and how quickly treatment can be started.^[2] Children with this condition who are treated with levodopa medications tend to show great improvement in motor skills. The effectiveness of levodopa therapy on cognitive outcome varies. Children often have moderate-to-significant learning disabilities, especially if treatment is delayed.^[2][4]