• Disease Overview
  • Synonyms
  • Signs & Symptoms
  • Causes
  • Affected Populations
  • Disorders with Similar Symptoms
  • Diagnosis
  • Standard Therapies
  • Clinical Trials and Studies
  • References
  • Programs & Resources
  • Complete Report

Segawa Syndrome


Last updated: July 09, 2015
Years published: 2009, 2012, 2015


NORD gratefully acknowledges Jonathan W. Mink, MD, PhD, Professor of Neurology, Neurobiology & Anatomy, and Pediatrics; Chief, Child Neurology, University of Rochester Medical Center, for assistance in the preparation of this report.

Disease Overview

Segawa syndrome is a rare genetic disorder characterized by an uncoordinated or clumsy manner of walking (abnormal gait) and 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). Dystonia in Segawa syndrome usually affects the legs, but some children may first develop dystonia in the arms. In some cases, usually in adolescents and adults, the symptoms of Segawa syndrome may become noticeably worse or more pronounced in the afternoon and evening than in the morning (marked diurnal fluctuation). The symptoms of Segawa syndrome usually become apparent by around six years of age. Intelligence is not affected. Children with Segawa syndrome usually show a dramatic and sustained improvement when treated with levodopa. Levodopa is an amino acid that is converted to dopamine, a brain chemical that serves as a neurotransmitter. Dopamine is deficient in children with Segawa syndrome. The disorder is caused by mutations of the GCH-1 gene. The GCH-1 gene mutation is inherited as an autosomal dominant trait.

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  • autosomal dominant dopa-responsive dystonia (DRD
  • autosomal dominant segawa syndrome
  • DYT5 dystonia
  • GTP cyclohydrolase 1-deficient dopa-responsive dystonia
  • guanosine triphosphate cyclohydrolase I deficiency
  • progressive dystonia with marked diurnal fluctuation
  • Segawa disease
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Signs & Symptoms

The symptoms and severity of Segawa syndrome can vary greatly from one person to another, even among members of the same family. Symptoms usually become apparent by around six years of age. In some cases, symptoms may not become apparent until later in childhood or even as late as adulthood.

The initial symptom of Segawa syndrome is usually an uncoordinated or clumsy manner of walking (abnormal gait) that develops during early childhood because of involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions (dystonia). The legs are usually affected first, typically one foot. Dystonia of the foot may force the foot into a twisted posture that resembles clubfoot. Children with Segawa syndrome may fall frequently and display exaggerated reflexes (hyperreflexia) as well.

When dystonia affects only one part of the body (e.g., a foot), it is referred to as focal dystonia. Dystonia in Segawa syndrome eventually progresses to legs and then the arms (multifocal dystonia), although it usually remains worse in the legs. In some cases, as a result of dystonia, abnormal curvature of the spine (lordosis) may occur. Without treatment, dystonia gradually progresses over time (approximately 10-15 years) and may eventually affect most of the body (generalized dystonia).

The dystonia and associated gait disturbances are usually worse during the afternoon, evening and at night than in the morning, a characteristic finding associated with Segawa syndrome called diurnal fluctuation. In some individuals the symptoms may be less severe in the morning than in the evening; in others the symptoms may be absent in morning and only present during the evening or at night. Although a key finding of Segawa syndrome, diurnal fluctuation does not occur in all cases. It is more lilely to occur in older individuals (adolescents and adults) than in young children. Dystonia and gait disturbances may also worsen following exercise or exertion.

Some affected children also develop stiffness (rigidity) and abnormal slowness of movement of the muscles of the arms and legs. The degree of stiffness and slowness of movement may vary greatly. Affected individuals may rapidly fatigue or require abnormal effort when attempting to perform certain tasks. During adolescence, some affected individuals develop a tremor that occurs when attempting to hold a certain position against gravity (postural tremor). Postural tremor usually affects one hand, although it may spread to all the arms and legs and even the neck. The progression of Segawa syndrome usually stops around the fourth decade.

When the onset of Segawa syndrome is during adolescence rather than childhood, the symptoms tend to be less severe. Generalized dystonia usually does not develop. When the onset of Segawa syndrome is during adulthood, the symptoms may resemble those found in Parkinson’s disease, which is sometimes referred to as parkinsonism. These symptoms include tremors, abnormal slowness of movement and an inability to remain in a stable or balanced position.

In some cases, individuals with Segawa syndrome may develop other forms of dystonia including those affecting the wrist (writer’s cramp), the neck (spasmodic torticollis) or the face and jaw (oromandibular dystonia). Some individuals may develop progressive weakness and increased muscle tone and stiffness (spastic paraplegia) or the spontaneous appearance and disappearance of dystonia and parkinsonism. In rare cases, mood or behavioral symptoms may occur including sleep problems, depression, anxiety or obsessive-compulsive disorder. Some researchers believe that mood and behavioral problems associated with Segawa syndrome are underreported.

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Segawa syndrome is caused by mutations of the guanosine triphosphate cyclohydrolase I (GCH-1) gene. The GCH-1 gene mutation is inherited as an autosomal dominant trait or occurs as a spontaneous genetic change (i.e., new mutation) that occurs sporadically for no apparent reason.

Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.

Investigators have determined that the GCH-1 gene is located on the long arm (q) of chromosome 14 (14q22.1-q22.2. 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 14q22.1-22.2″ refers to band 22.1-22.2 on the long arm of chromosome 14. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

The GCH-1 gene contains instructions for creating (encoding) an enzyme called guanosine triphosphate cyclohydrolase 1 (GTPCH1). This enzyme is an essential part of the chemical processes that contribute to the development of dopamine in the body. Dopamine is a neurotransmitter, a chemical that modifies, amplifies or transmits nerve impulses from one nerve cell (neuron) to another, enabling nerve cells to communicate. Dopamine is also converted into two additional neurotransmitters called norepinephrine and epinephrine (adrenaline). Dopamine is critical for the proper function of certain processes of the brain especially those that control movement. Mutation of the GCH-1 gene results in deficient levels of the GTPCH1 enzyme, which ultimately results in a deficiency of dopamine.

Segawa syndrome is also characterized by variable expressivity and incomplete penetrance. Variable expressivity is when individuals with the same genetic mutation have different symptoms or different severity of symptoms. Incomplete penetrance refers to how some individuals who inherited a mutated gene for a dominant disorder are not affected or are only mildly affected, while others develop the disorder.

Segawa syndrome may be classified as a form of dystonia, an inherited neurotransmitter disorder, and a metabolic disorder. Dystonia is a group neuromuscular disorders in which involuntary muscle contractions force the body into abnormal, sometimes painful, movements and positions (postures).

Pediatric inherited neurotransmitter disorders are an emerging group of rare disorders characterized by defects in the creation (synthesis) and metabolism of one or more neurotransmitters and result in a variety of neurological and neuromuscular symptoms. The disorders are differentiated by the specific neurotransmitter involved.

Segawa syndrome is also be classified as an inborn error of metabolism (metabolic disorder). “Metabolism” refers to all the chemical processes in the body, including the breakdown of complex substances into simpler ones (catabolism), usually with the release of energy, and processes in which complex substances are built up from simpler ones (anabolism), usually resulting in energy consumption. Inborn errors of metabolism result from abnormal functioning of a specific protein or enzyme that accelerates particular chemical activities in the body.

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Affected populations

Segawa syndrome affects girls and women more often than boys and men. In sporadic cases (i.e., new mutations), women are affected four times more often than men. Women are also more likely to have severe symptoms than men are. The exact incidence of Segawa syndrome in the general population is unknown. Researchers believe that the disorder is often misdiagnosed or goes undiagnosed, making it difficult to determine its true frequency in the general population. Segawa syndrome and tyrosine hydroxylase deficiency, which is also known as autosomal recessive dopa-responsive dystonia, account for approximately 5-10 percent of all cases of primary dystonia in childhood. Segawa syndrome was first described in the medical literature in 1971. It was originally called hereditary progressive dystonia with marked diurnal fluctuation.

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A diagnosis of Segawa syndrome is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic findings, and a response to therapy with low doses of levodopa. An examination of cerebrospinal fluid (CSF) can detect certain substances that are byproducts of metabolism (metabolites) specifically pterins. Identification of reduced levels of pterins in CSF can help to confirm a diagnosis of Segawa syndrome and distinguish the disorder from related neurotransmitter disorders. A sample of CSF is obtained through a procedure called a spinal tap (lumbar puncture), in which a needle is inserted into the spinal canal in the lower back.

A diagnosis of Segawa syndrome can be confirmed through molecular genetic testing, which can reveal the characteristic mutation of the GCH-1gene that causes the disorder. Molecular genetic testing is available on a clinical basis.

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Standard Therapies


Segawa syndrome is treated with medications to restore normal dopamine levels in the brain. Affected individuals are initially treated with low levels of an amino acid called levodopa (L-dopa) that is converted to dopamine by enzymes in the blood 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 ca. 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 full reversal of symptoms. In others, the response may take time and improvement is seen gradually over a few months. 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 treat the disorder.

A small number of individuals with Segawa syndrome 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. Other treatment is symptomatic and supportive.

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Clinical Trials and Studies

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:

Tollfree: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:


For information about clinical trials conducted in Europe, contact:

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DeLong MR. Dopa-Responsive Dystonia. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:612.
Scriver CR, Beaudet AL, Sly WS, et al. Eds. The Metabolic Molecular Basis of Inherited Disease. 8th ed. McGraw-Hill Companies. New York, NY; 2001:1757-1759.

Scola RH, Carducci C, Amaral VG, et al. A novel missense mutation pattern of the GCH1 gene in dopa-responsive dystonia. Arq Neurosiquiatr. 2007;65:1224-1227.
Swoboda KJ. Inherited disorders of amine biosynthesis. Future Neurol. 2006;1:605-614.
Pearl PL. Inherited neurotransmitter disorders: a rapidly enlarging field of neurometabolism in children and adults. Future Neurol. 2006;1:589-591.
Van Hove JL, Steyaert J, Matthijs G, et al. Expanded motor and psychiatric phenotype in autosomal dominant Segawa syndrome due to GTP cyclohydrolase deficiency. J Neurol Neurosurg Psychiatry. 2006;77:18-23.
Segawa M, Nomura Y, Nishiyama N. Autosomal dominant guanosine triphosphate cyclohydrolase I deficiency (Segawa disease). Ann Neurol. 2003;54:S32-S45.
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Furukawa Y, Kish SJ. Dopa-responsive dystonia: recent advances and remaining issues to be addressed. Mov Disord. 1999;14:709-715.

Nikhar NK, Mani H. Dopamine-Responsive Dystonia. Medscape. Updated: Oct 16, 2014. Available at: https://emedicine.medscape.com/article/1181084-overview Accessed July 9, 2015.
Furukawa Y. GTP Cyclohydrolase 1-Deficient Dopa-Responsive Dystonia. 2002 Feb 21 [Updated 2015 Mar 5]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015.Available from: https://www.ncbi.nlm.nih.gov/books/NBK1508/ Accessed July 9, 2015.
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:128230; Last Update: 08/30/2013. Available at: https://omim.org/entry/128230 Accessed July 9, 2015.

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