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Diseases

Genetic and Rare Diseases Information Center (GARD)

Sepiapterin reductase deficiency


Other Names for this Disease
  • SPR deficiency
Related Diseases
See Disclaimer regarding information on this site. Some links on this page may take you to organizations outside of the National Institutes of Health.

Your Question

My child has been diagnosed with sepiapterin reductase deficiency. What is this condition? How is it treated? How long does it take for the effects of treatment with levodopa to become noticeable?

Our Answer

We have identified the following information that we hope you find helpful. If you still have questions, please contact us.

What is sepiapterin reductase deficiency?

Sepiapterin reductase deficiency is a neurometabolic disorder characterized by a pattern of involuntary sustained muscle contractions known as dystonia. Other common features include axial hypotonia , oculogyric crises, and delays in motor and cognitive development. The condition is caused by mutations in the SPR gene. It is inherited in an autosomal recessive fashion.[1][2] Treatment with levodopa (L-dopa) in combination with carbidopa has shown much success causing drastic improvements in motor functioning.[2][3]
Last updated: 4/19/2016

What are inborn errors of metabolism?

Our bodies get the energy they need from food through metabolism, the chemical reactions in the body's cells that convert the fuel from food into the energy needed to do everything from moving to thinking to growing. Specific proteins in the body control the chemical reactions of metabolism, and each chemical reaction is coordinated with other body functions.[4]

In a broad sense, a metabolic disorder is any disease that is caused by an abnormal chemical reaction in the body's cells. Most disorders of metabolism involve either abnormal levels of enzymes or hormones or problems with the functioning of those enzymes or hormones. When the metabolism of body chemicals is blocked or defective, it can cause a buildup of toxic substances in the body or a deficiency of substances needed for normal body function, either of which can lead to serious symptoms.[4] Some metabolic diseases are inherited and these conditions are called inborn errors of metabolism.[4]
Last updated: 2/18/2009

What causes sepiapterin reductase deficiency?

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]
Last updated: 4/19/2016

What are the symptoms of 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]
Last updated: 4/20/2016

Is sepiapterin reductase deficiency genetic?

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
 
Last updated: 4/19/2016

What is autosomal recessive inheritance?

Autosomal recessive inheritance refers to the inheritance pattern in which two mutated copies of the gene that causes a disorder are present in each cell. An affected person usually has unaffected parents who each carry a single copy of the mutated gene (and are referred to as carriers). Autosomal recessive disorders are typically not seen in every generation of an affected family. When two people who are carriers of an autosomal recessive condition have a child, there is a 25% (1 in 4) chance that the child will be affected.[5]
Last updated: 12/28/2015

How is sepiapterin reductase deficiency diagnosed?

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][6] 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]
Last updated: 4/20/2016

How might sepiapterin reductase deficiency be treated?

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.[6]

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]
Last updated: 4/20/2016

Does it take a while for levodopa medications to become effective?

Not typically. Levodopa therapy may result in noticeable improvements (particularly in motor skills) days and in some cases hours following treatment.[6]
Last updated: 2/18/2009

What is the long-term outlook (prognosis) for people with sepiapterin reductase deficiency?

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][6]
Last updated: 4/20/2016

Are there any clinical trials enrolling people with sepiapterin reductase deficiency?

The National Institutes of Health, through the National Library of Medicine, developed ClinicalTrials.gov to provide patients, family members, and members of the public with current information on clinical research studies. Although no studies involving sepiapterin reductase deficiency are listed at this time, there is a study, entitled "Studies of Children with Metabolic and Other Genetic Diseases", which is evaluating individuals with known or suspected genetic or metabolic diseases. Despite its title, this study is enrolling individuals of all ages. To read about this study, click on the link below. After you click on the study, review its 'eligibility' criteria to determine its appropriateness.
http://www.clinicaltrials.gov/ct/show/NCT00025870?order=1
 
You can also contact the Patient Recruitment and Public Liaison (PRPL) Office at the National Institutes of Health (NIH). We recommend calling the toll-free number listed below to speak with a specialist, who can help you identify appropriate studies.

Patient Recruitment and Public Liaison Office (PRPL)
NIH Clinical Center
Bethesda, Maryland 20892-2655
Toll-free: 800-411-1222
Fax: 301-480-9793
Email: prpl@mail.cc.nih.gov
Web site: http://clinicalcenter.nih.gov/  

You can find information about participating in a clinical trials, as well as learn about resources for travel and lodging assistance, through the Get Involved in Research section of our website.
Last updated: 4/20/2016

References
Other Names for this Disease
  • SPR deficiency
Related Diseases
See Disclaimer regarding information on this site. Some links on this page may take you to organizations outside of the National Institutes of Health.