NORD gratefully acknowledges Jennifer Friedman, MD, Clinical Professor Neurosciences and Pediatrics, UCSD/Rady Children's Hospital San Diego, for assistance in the preparation of this report.
Sepiapterin reductase deficiency (SRD) is a rare genetic disorder that is characterized by abnormally low levels of certain neurotransmitters. Neurotransmitters are chemicals that modify, amplify or transmit nerve impulses from one nerve cell to another, enabling nerve cells to communicate. The severity of sepiapterin reductase deficiency can range from a mild movement disorder at one end to severe, progressive neurological disease at the other. Common symptoms include lack of muscle tone (hypotonia), drooling, loss of coordination, abnormal movements, delayed motor and language development (i.e. delays in reaching developmental milestones), and/or dystonia. Dystonia is a general term for a group of muscle disorders, generally characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions (postures). The specific symptoms can vary dramatically from one person to another. Prompt diagnosis and treatment can reduce or potentially prevent severe, irreversible neurological damage. Children with sepiapterin reductase deficiency may show a dramatic response and sustained improvement when treated with levodopa. Levodopa is a chemical that is converted to dopamine, a brain chemical that serves as a neurotransmitter. Some individuals show benefit with treatment with addition of 5-HTP, a neurotransmitter precursor that is converted to serotonin. Sepiapterin reductase deficiency is caused by mutations in the SPR gene and is inherited as an autosomal recessive disorder.
Sepiapterin reductase deficiency can be classified as a form of dystonia, a pediatric neurotransmitter disorder or a disorder of tetrahydrobiopterin deficiency. The disorder is sometimes referred to as a form of dopa-responsive dystonia. However, dystonia is not always present in infancy and may not be a universal symptom so that term may not apply to all cases. The non-specific symptoms of this condition may be misdiagnosed as cerebral palsy.
Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about sepiapterin reductase deficiency is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes influencing the disorder prevent physicians from developing an accurate picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis.
The specific symptoms and severity associated with sepiapterin reductase deficiency can vary greatly from one person to another. Some individuals develop severe, disabling motor and cognitive deficits; others only experience mild symptoms that can go unnoticed, and may only be diagnosed after the disorder is identified in a more severely affected family member. Prompt diagnosis and early treatment of sepiapterin reductase deficiency is essential to reduce or potentially prevent progressive neurological damage.
Symptoms usually become apparent within the first year of life. Some infants may exhibit microcephaly, a condition defined as having a head circumference smaller than normally would be expected based on age and gender. Common symptoms include dystonia, delays in attaining developmental milestones (developmental delays) including delays in motor and speech development, reduced muscle tone (axial hypotonia), and abnormal movements of the eyes that can range from brief upward rolling of the eyes to oculogyric crises, in which the eyes roll upward for a sustained period of time.
In some cases, certain symptoms may become noticeably worse or more pronounced in the afternoon and evening than in the morning (diurnal fluctuation). Dystonia is not always present during infancy and may develop later in childhood. Some individuals may not develop dystonia or only experience mild dystonia that can go unnoticed in infancy. Generally, the most common symptoms in infancy are nonspecific and can occur in many different neurological disorders, making it difficult to obtain a proper diagnosis.
Some affected children develop intellectual disability while others develop mild or moderate learning disabilities. Sleep disturbances particularly excessive daytime sleepiness (hypersomnia), drooling, and psychological symptoms including anxiety, irritability, and hyperactivity may also occur.
Exaggerated reflexes (hyperreflexia) and excess muscle tone of the arms and legs so that they may be stiff and difficult to move (limb hypertonia) are also relatively common findings. Less common symptoms include difficulty speaking (dysarthria), abnormal tongue movements, and abnormalities of the autonomic nervous system. The autonomic nervous system controls involuntary or automatic body processes. Excessive sweating would be an example of an autonomic sign of the disorder.
Some individuals develop symptoms that resemble those seen in Parkinson’s disease, which is sometimes referred to as parkinsonism. These symptoms include tremors, abnormal slowness of movement (bradykinesia), muscle stiffness or rigidity, and an inability to use facial muscles to express emotions (masked facies).
Sepiapterin reductase deficiency is caused by mutations in the SPR gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.
Investigators have determined that the SPR gene is located on the short arm (p) of chromosome 2 (2p13.2). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 2p13.2” refers to band 13.2 on the short arm of chromosome 2.
In most cases, mutations in the SPR gene are inherited as autosomal recessive traits. Recessive genetic disorders occur when an individual inherits an abnormality in the same gene from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
The SPR gene contains instructions for creating (encoding) the enzyme sepiapterin reductase, which is the third (and last) enzyme required for the creation (synthesis) of tetrahydrobiopterin. Mutations in the SPR gene results in deficient levels of functional sepiapterin reductase enzyme and, consequently, improper or deficient production of tetrahydrobiopterin, a naturally-occurring compound that acts as a cofactor. A cofactor is a non-protein substance in the body that enhances or is necessary for the proper function of certain enzymes. When tetrahydrobiopterin is deficient, the chemical balance within the body is upset. Tetrahydrobiopterin has several functions within the body including assisting in the breaking down or processing certain amino acids. Tetrahydrobiopterin is also necessary for the proper development of amine neurotransmitters such as catecholamines (i.e. dopamine, norepinephrine, or epinephrine) and serotonin. Catecholamines are essential for the proper function of certain processes of the brain especially those that control movement. Serotonin helps to regulate mood, appetite, memory, sleep cycles, and certain muscular function.
Sepiapterin reductase deficiency is an extremely rare disorder that affects males and females in equal numbers. More than 40 cases have been described in the medical literature. The exact incidence or prevalence is unknown. Because cases can go undiagnosed or misdiagnosed, determining the true frequency of the disorder in the general population is difficult.
A diagnosis of sepiapterin reductase deficiency is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Unlike other disorders of tetrahydrobiopterin deficiency, sepiapterin reductase deficiency is not associated with elevated phenylalanine levels and, consequently, will not be detected upon newborn screening.
Clinical Testing and Workup
A diagnosis may be made after the evaluation of cerebrospinal fluid (CSF), which can demonstrate low levels byproducts (metabolites) of the breakdown (metabolism) of neurotransmitter such as 5-hydroxyindoleacetic (5-HIAA) and homovanilic acid (HVA). In individuals with sepiapterin reductase deficiency, CSF study will also demonstrate elevated levels of biopterin and dihydrobiopterin, which are pterins. Pterins are the byproducts of the metabolism of tetrahydrobiopterin.
Another rarely used test that can indicate the disorder is an enzyme assay, which is a test that can demonstrate low activity of the sepiapterin reductase enzyme in specialized cells known as fibroblasts.
Molecular genetic testing can confirm a diagnosis. Molecular genetic testing can detect mutations in the SPR gene known to cause sepiapterin reductase deficiency, but is available only as a diagnostic service at specialized laboratories.
Prompt recognition and early treatment of sepiapterin reductase deficiency is critical in reducing or preventing the potentially severe, irreversible neurologic damage that can occur in severe cases. The focus of treatment is to restore the proper balance of neurotransmitters in the brain. Affected individuals are initially treated with low levels of a chemical or neurotransmitter precursor called levodopa (L-dopa) that is converted to the neurotransmitter, dopamine, by enzymes in the liver and brain. Dopamine cannot cross the blood-brain barrier, so affected individuals also receive a second medication (usually carbidopa) to prevent conversion of L-dopa to dopamine before it can cross the blood-brain barrier. The blood-brain barrier is a protective network of blood vessels and cells that allow some materials to enter the brain, while keeping other materials out.
The response to L-dopa therapy varies among affected individuals. Some people respond quickly and completely to L-dopa therapy seeing a significant improvement of symptoms. In others, the response may take time and improvement is seen gradually over a few months. L-dopa is particularly effective in treatment of movement disorders associated with sepiapterin reductase deficiency, with symptomatic improvement occurring within hours of treatment in some cases. The impact on cognitive issues is less consistent. In some cases, the dosage of L-dopa used to treat an affected individual may need to be adjusted until a dosage can be achieved that effectively treats the disorder. In individuals who do not respond to this therapy, another neurotransmitter precursor such as 5-hydroxytryptophan may be added to the treatment regimen (combination therapy). In most cases, supplemental therapy with neurotransmitter precursors is required for life.
Some individuals may develop a side effect of L-dopa therapy called dyskinesia, which refers to abnormal involuntary movements when performing voluntary movements (dyskinesia). Dyskinesia goes away if the dose of L-dopa is lowered; when the dose is gradually increased later on, dyskinesia usually does not reappear.
Genetic counseling may be of benefit for affected individuals and their families. Psychosocial support for the entire family is essential as well.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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For information about clinical trials sponsored by private sources, in the main, contact:
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder.
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