What are the other Names for this Condition? (Also known as/Synonyms)

• Dystonia 5 (DYT5)
• Hereditary Progressive Dystonia with Diurnal Fluctuation
• Progressive Dystonia with Diurnal Variation

What is Dopa-Responsive Dystonia? (Definition/Background Information)

• Dopa-Responsive Dystonia (DRD) describes a group of neurometabolic disorders characterized by dystonia that typically shows diurnal fluctuations, that responds excellently to levodopa (L-dopa) and that is comprised of
  • Autosomal Dominant Dopa-Responsive Dystonia (DYT5a)
  • Autosomal Recessive Dopa-Responsive Dystonia (DYT5b)
  • Dopa-Responsive Dystonia due to sepiapterin reductase (SR) deficiency
• DRD usually has a pediatric onset, typically with lower limb dystonia that leads to gait disturbances and that usually worsens during the course of the day and is improved in the morning after sleeping. Parkinsonism can develop at a later age in some patients
• Anxiety, depression, sleep disturbances and obsessive-compulsive disorders have also been reported in a few patients with DYT5a
• Rarer subtypes which are inherited in an autosomal recessive manner typically show a much more severe phenotype, with onset in the first year of life with additional manifestations of global developmental delay, axial hypotonia, oculogyric crises and encephalopathy
• DRD responds dramatically and continuously to L-dopa therapy, and patients usually experience a significant improvement of symptoms once treatment is initiated. If untreated, patients can become wheelchair bound
• Dopa-Responsive Dystonia can be inherited in an autosomal dominant or autosomal recessive manner, depending on the subtype. It can also occur due to de novo mutations

(Source: Dopa-Responsive Dystonia; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

Who gets Dopa-Responsive Dystonia? (Age and Sex Distribution)

• Dopa-Responsive Dystonia is a rare congenital disorder, with an estimated prevalence of 1-9 cases per million individuals
• The age of onset of symptoms is determined by the type of mutation an individual inherits. It may range from between the first year of life to sometime later in childhood (when the child is about 6 years of age). However, some adult-onset cases have been reported as well
• Both males and females may be affected
• Worldwide, individuals of all racial and ethnic groups may be affected

What are the Risk Factors for Dopa-Responsive Dystonia? (Predisposing Factors)

• A positive family history may be an important risk factor, since Dopa-Responsive Dystonia can be inherited
• Currently, no other risk factors have been clearly identified for DRD

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Dopa-Responsive Dystonia? (Etiology)

• Dopa-Responsive Dystonia is caused by mutations in genes that encode proteins essential for the biosynthesis of dopamine
• The causative gene mutation(s) for the different subtypes are given below:
  • DYT5a is due to mutations in the GTP cyclohydrolase 1 (GCH1) gene, which encodes an enzyme needed for the biosynthesis of tetrahydrobiopterin, the essential co-factor for tyrosine hydroxylase
  • DYT5b is caused by mutations in the tyrosine hydroxylase TH gene encoding tyrosine hydroxylase, the enzyme responsible for catalyzing the conversion of tyrosine to L-dopa, the precursor of dopamine
  • DRD due to an SRD is caused by mutations in the SPR gene encoding the enzyme sepiapterin reductase (SR), which is also required for the biosynthesis of tetrahydrobiopterin
• DYT5a is inherited in an autosomal dominant manner, whereas the DYT5b subtype is inherited in an autosomal recessive pattern

(Source: Dopa-Responsive Dystonia; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

• Sepiapterin reductase (SR) deficiency is inherited in an autosomal recessive manner as well

Autosomal dominant inheritance: Autosomal dominant conditions are traits or disorders that are present when only one copy of the mutation is inherited on a non-sex chromosome. In these types of conditions, the individual has one normal copy and one mutant copy of the gene. The abnormal gene dominates, masking the effects of the correctly function gene. If an individual has an autosomal dominant condition, the chance of passing the abnormal gene on to their offspring is 50%. Children, who do not inherit the abnormal gene, will not develop the condition or pass it on to their offspring.

Autosomal recessive type of transmission: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected).

What are the Signs and Symptoms of Dopa-Responsive Dystonia?

The signs and symptoms of Dopa-Responsive Dystonia may be determined by the subtype of the disorder, and may include the following:

Signs and symptoms of DYT5a:

• Lower limb dystonia
• Gait disturbances
• Anxiety
• Depression
• Sleep disturbances 
• Obsessive-compulsive disorders

Signs and symptoms of DYT5b and DRD due to sepiapterin reductase deficiency:

• Lower limb dystonia
• Gait disturbances
• Global developmental delay
• Axial hypotonia
• Oculogyric crises 
• Encephalopathy

(Source: Dopa-Responsive Dystonia; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

The following additional signs and symptoms may be present in affected individuals:

• Tremors
• Stiffness of muscles
• Uncoordinated movements
• Jerky movements, specifically of the head and neck
• An inability to hold body upright (postural instability)
• Pain
• Excessive sleeping
• Small head size
• Seizures
• Intellectual deficiency
• Irritability
• Mood swings

How is Dopa-Responsive Dystonia Diagnosed?

Dopa-Responsive Dystonia is diagnosed on the basis of the following information:

• Complete physical examination
• Thorough medical history evaluation
• Assessment of signs and symptoms
• Laboratory tests
• Imaging studies
• Biopsy studies, if necessary
• Molecular genetic testing to check for or confirm causative gene mutation(s)

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Dopa-Responsive Dystonia?

The complications of Dopa-Responsive Dystonia may include:

• Progressive worsening of condition without treatment such that a wheelchair may become necessary
• Risk of falls and injury, due to ataxia or if seizures occur

Complications may occur with or without treatment, and in some cases, due to treatment also.

How is Dopa-Responsive Dystonia Treated?

• Dopa-Responsive Dystonia is a genetic disorder, and there is no cure. The treatment methods are aimed at addressing the signs and symptoms, and any complication that develops
• Treatment with L-dopa is reported to be successful in offering significant relief from signs and symptoms in affected individuals

How can Dopa-Responsive Dystonia be Prevented?

Dopa-Responsive Dystonia may not be preventable, since it is a genetic disorder.

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy), if available, may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of genetic disorders such as Dopa-Responsive Dystonia
• Regular medical screening at periodic intervals with tests and physical examinations are recommended

What is the Prognosis of Dopa-Responsive Dystonia? (Outcomes/Resolutions)

• The prognosis of Dopa-Responsive Dystonia is dependent upon the severity of the signs and symptoms and associated complications, if any
• L-dopa therapy is reported to significantly and continually improve the condition of affected individuals
• An individual with DRD may become wheelchair bound without proper treatment

Additional and Relevant Useful Information for Dopa-Responsive Dystonia:

Additional synonyms for Dopa-Responsive Dystonia are:

• Dystonia-Parkinsonism with Diurnal Fluctuation
• DYT-GCH1 (subtype)
• DYT-SPR (subtype)
• DYT-TH (subtype)
• HPD with Diurnal Fluctuation

The following DoveMed website link is a useful resource for additional information:

http://www.dovemed.com/diseases-conditions/rare-disorders/