Sepiapterin reductase deficiency

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Disease Profile

<1 / 1 000 000

US Estimated

Europe Estimated

Age of onset

Infancy

ICD-10

G24.1

Inheritance

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

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

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.

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.

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

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.

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.

Not applicable

Other names (AKA)

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

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

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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]

Related diseases

Related diseases are conditions that have similar signs and symptoms. A health care provider may consider these conditions in the table below when making a diagnosis. Please note that the table may not include all the possible conditions related to this disease.

Conditions with similar signs and symptoms from Orphanet
Differential diagnoses include other forms of DRD such as autosomal recessive DRD and autosomal dominant DRD, infantile dystonia-parkinsonism, infantile-onset spastic paraplegia, some forms of epilepsy and cerebral palsy. Visit the Orphanet disease page for more information.

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

Metabolic Support UK
5 Hilliards Court
Sandpiper Way
Chester Business Park
Chester, CH4 9QP United Kingdom
Toll-free: 0800 652 3181
Telephone: 0845 241 2173
E-mail: https://www.metabolicsupportuk.org/contact-us
Website: https://www.metabolicsupportuk.org
Pediatric Neurotransmitter Disease Association
28 Prescott Place
Old Bethpage, NY 11804
Telephone: 603-733-8409
E-mail: pnd@pndassociation.org
Website: https://www.pndassoc.org/

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

B. G. R. Neville, R. Parascandalo, R. Farrugia and A. Felice, Sepiapterin reductase deficiency: a congenital dopa-responsive motor and cognitive disorder, Brain (2005) 128(10):2291-2296.

References

Sepiapterin reductase deficiency. Genetics Home Reference (GHR). June 2011; https://ghr.nlm.nih.gov/condition/sepiapterin-reductase-deficiency.
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.
Friedman J. Sepiapterin Reductase Deficiency. GeneReviews. July 1, 2015; https://www.ncbi.nlm.nih.gov/books/NBK304122/.
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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Infancy

G24.1

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

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.

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.

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

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.

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.

Not applicable

Other names (AKA)

Categories

Summary

Symptoms

Cause

Diagnosis

Testing Resources

Treatment

Related diseases

Organizations

Organizations Supporting this Disease

Learn more

Where to Start

In-Depth Information

Selected Full-Text Journal Articles

References

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.

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