Sepiapterin reductase deficiency is a condition characterized by movement problems, most often a pattern of involuntary, sustained muscle contractions known as dystonia. Other movement problems can include muscle stiffness (spasticity), tremors, problems with coordination and balance (ataxia), and involuntary jerking movements (chorea). People with sepiapterin reductase deficiency can experience episodes called oculogyric crises. These episodes involve abnormal rotation of the eyeballs; extreme irritability and agitation; and pain, muscle spasms, and uncontrolled movements, especially of the head and neck. Movement abnormalities are often worse late in the day. Most affected individuals have delayed development of motor skills such as sitting and crawling, and they typically are not able to walk unassisted. The problems with movement tend to worsen over time.

People with sepiapterin reductase deficiency may have additional signs and symptoms including an unusually small head size (microcephaly), intellectual disability, seizures, excessive sleeping, and mood swings.

Sepiapterin reductase deficiency appears to be a rare condition. At least 30 cases have been described in the scientific literature.

Mutations in the SPR gene cause sepiapterin reductase deficiency. The SPR gene provides instructions for making the sepiapterin reductase enzyme. This enzyme is involved in the production of a molecule called tetrahydrobiopterin (also known as BH4). Specifically, sepiapterin reductase is 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 in the brain.

SPR gene mutations disrupt the production of sepiapterin reductase. Most SPR gene mutations result in an enzyme with little or no function. A nonfunctional sepiapterin reductase leads to a lack of tetrahydrobiopterin. In most parts of the body, there are alternate pathways that do not use sepiapterin reductase for the production of tetrahydrobiopterin, but these pathways are not found in the brain. Therefore, people with sepiapterin reductase deficiency have a lack of tetrahydrobiopterin in the brain. When no tetrahydrobiopterin is produced in the brain, production of dopamine and serotonin is greatly reduced. Among their many functions, dopamine transmits signals within the brain to produce smooth physical movements, and serotonin regulates mood, emotion, sleep, and appetite. The lack of these two neurotransmitters causes the problems with movement and other features of sepiapterin reductase deficiency.

Genetic Testing Information

• Genetic Testing Registry: Dopa-responsive dystonia due to sepiapterin reductase deficiency

Genetic and Rare Diseases Information Center

• Dopa-responsive dystonia due to sepiapterin reductase deficiency

Patient Support and Advocacy Resources

• National Organization for Rare Disorders (NORD)

Clinical Trials

• ClinicalTrials.gov

Catalog of Genes and Diseases from OMIM

• DYSTONIA, DOPA-RESPONSIVE, DUE TO SEPIAPTERIN REDUCTASE DEFICIENCY

Scientific Articles on PubMed

• PubMed

• Abeling NG, Duran M, Bakker HD, Stroomer L, Thony B, Blau N, Booij J, Poll-The BT. Sepiapterin reductase deficiency an autosomal recessive DOPA-responsive dystonia. Mol Genet Metab. 2006 Sep-Oct;89(1-2):116-20. doi: 10.1016/j.ymgme.2006.03.010. Epub 2006 May 2. Citation on PubMed
• Arrabal L, Teresa L, Sanchez-Alcudia R, Castro M, Medrano C, Gutierrez-Solana L, Roldan S, Ormazabal A, Perez-Cerda C, Merinero B, Perez B, Artuch R, Ugarte M, Desviat LR. Genotype-phenotype correlations in sepiapterin reductase deficiency. A splicing defect accounts for a new phenotypic variant. Neurogenetics. 2011 Aug;12(3):183-91. doi: 10.1007/s10048-011-0279-4. Epub 2011 Mar 24. Citation on PubMed
• Blau N, Bonafe L, Thony B. Tetrahydrobiopterin deficiencies without hyperphenylalaninemia: diagnosis and genetics of dopa-responsive dystonia and sepiapterin reductase deficiency. Mol Genet Metab. 2001 Sep-Oct;74(1-2):172-85. doi: 10.1006/mgme.2001.3213. Citation on PubMed
• Echenne B, Roubertie A, Assmann B, Lutz T, Penzien JM, Thony B, Blau N, Hoffmann GF. Sepiapterin reductase deficiency: clinical presentation and evaluation of long-term therapy. Pediatr Neurol. 2006 Nov;35(5):308-13. doi: 10.1016/j.pediatrneurol.2006.05.006. Citation on PubMed
• Longo N. Disorders of biopterin metabolism. J Inherit Metab Dis. 2009 Jun;32(3):333-42. doi: 10.1007/s10545-009-1067-2. Epub 2009 Feb 9. Citation on PubMed
• Neville BG, Parascandalo R, Farrugia R, Felice A. Sepiapterin reductase deficiency: a congenital dopa-responsive motor and cognitive disorder. Brain. 2005 Oct;128(Pt 10):2291-6. doi: 10.1093/brain/awh603. Epub 2005 Jul 27. Citation on PubMed
• Verbeek MM, Willemsen MAAP, Wevers RA, Lagerwerf AJ, Abeling NGGM, Blau N, Thony B, Vargiami E, Zafeiriou DI. Two Greek siblings with sepiapterin reductase deficiency. Mol Genet Metab. 2008 Aug;94(4):403-409. doi: 10.1016/j.ymgme.2008.04.003. Epub 2008 May 27. Citation on PubMed
• Zorzi G, Redweik U, Trippe H, Penzien JM, Thony B, Blau N. Detection of sepiapterin in CSF of patients with sepiapterin reductase deficiency. Mol Genet Metab. 2002 Feb;75(2):174-7. doi: 10.1006/mgme.2001.3273. Citation on PubMed