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Disease Profile

Sepiapterin reductase deficiency

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.
<1 / 1 000 000

< 331

US Estimated

< 514

Europe Estimated

Age of onset

Infancy

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ICD-10

G24.1

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

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Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

SPR deficiency; DYT/PARK-SPR; Dopa-responsive dystonia due to sepiapterin reductase deficiency;

Categories

Congenital and Genetic Diseases; Metabolic disorders; Musculoskeletal Diseases;

Summary

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]

Symptoms

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)

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
30%-79% of people have these symptoms
Abnormality of the nose
Nasal abnormality
0000366
Bradykinesia
Slow movements
Slowness of movements

[ more ]

0002067
Cognitive impairment
Abnormality of cognition
Cognitive abnormality
Cognitive defects
Cognitive deficits
Intellectual impairment
Mental impairment

[ more ]

0100543
Delayed speech and language development
Deficiency of speech development
Delayed language development
Delayed speech
Delayed speech acquisition
Delayed speech development
Impaired speech and language development
Impaired speech development
Language delay
Language delayed
Language development deficit
Late-onset speech development
Poor language development
Speech and language delay
Speech and language difficulties
Speech delay

[ more ]

0000750
Drowsiness
Sleepy
0002329
Hyperhidrosis
Excessive sweating
Increased sweating
Profuse sweating
Sweating
Sweating profusely
Sweating, increased

[ more ]

0000975
Hyperreflexia
Increased reflexes
0001347
Hypomimic face
Dull facial expression
0000338
Intellectual disability
Mental deficiency
Mental retardation
Mental retardation, nonspecific
Mental-retardation

[ more ]

0001249
Limb hypertonia
Increased muscle tone of arm or leg
0002509
Motor delay
0001270
Muscle weakness
Muscular weakness
0001324
Muscular hypotonia of the trunk
Low muscle tone in trunk
0008936
Oculogyric crisis
0010553
Ptosis
Drooping upper eyelid
0000508
Rigidity
Muscle rigidity
0002063
Sleep disturbance
Difficulty sleeping
Trouble sleeping

[ more ]

0002360
Temperature instability
0005968
Tremor
0001337
5%-29% of people have these symptoms
Cerebral palsy
0100021
Growth delay
Delayed growth
Growth deficiency
Growth failure
Growth retardation
Poor growth
Retarded growth

[ more ]

0001510
Microcephaly
Abnormally small skull
Decreased circumference of cranium
Decreased size of skull
Reduced head circumference
Small head circumference

[ more ]

0000252
Seizure
0001250
Small for gestational age
Birth weight less than 10th percentile
Low birth weight

[ more ]

0001518
Percent of people who have these symptoms is not available through HPO
Aggressive behavior
Aggression
Aggressive behaviour
Aggressiveness

[ more ]

0000718
Ataxia
0001251
Autosomal dominant inheritance
0000006
Autosomal recessive inheritance
0000007
Choreoathetosis
0001266
Dysarthria
Difficulty articulating speech
0001260
Dystonia
0001332
Global developmental delay
0001263
Hyperactivity
More active than typical
0000752
Infantile onset
Onset in first year of life
Onset in infancy

[ more ]

0003593
Oculomotor apraxia
0000657
Spasticity
Involuntary muscle stiffness, contraction, or spasm
0001257
Transient hyperphenylalaninemia
0008297
Variable expressivity
0003828

Cause

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]

Diagnosis

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]

Testing Resources

  • The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.
  • Orphanet lists international laboratories offering diagnostic testing for this condition.

    Treatment

    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]

    Organizations

    Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

    Organizations Supporting this Disease

      Learn more

      These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

      Where to Start

      • Genetics Home Reference (GHR) contains information on Sepiapterin reductase deficiency. This website is maintained by the National Library of Medicine.

        In-Depth Information

        • GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.
        • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
        • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
        • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
        • PubMed is a searchable database of medical literature and lists journal articles that discuss Sepiapterin reductase deficiency. Click on the link to view a sample search on this topic.

          Selected Full-Text Journal Articles

            References

            1. Sepiapterin reductase deficiency. Genetics Home Reference (GHR). June 2011; https://ghr.nlm.nih.gov/condition/sepiapterin-reductase-deficiency.
            2. Kamm C. Dopa-responsive dystonia due to sepiapterin reductase deficiency. Orphanet. November 2013; https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=70594.
            3. Friedman J. Sepiapterin Reductase Deficiency. GeneReviews. July 1, 2015; https://www.ncbi.nlm.nih.gov/books/NBK304122/.
            4. Echenne B et al.,. Sepiapterin reductase deficiency: Clinical presentation and evaluation of long-term therapy. Pediatric Neurology. 2006 Nov; 35(5):308-13. https://www.ncbi.nlm.nih.gov/pubmed/?term=17074599.

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