SNP Shot: Genomic Insights

Dopa-responsive dystonia (DRD) is a condition characterized by involuntary muscle contractions (dystonia), tremors, and other uncontrolled movements. The severity of these symptoms varies from mild to severe. This specific type of dystonia responds well to treatment with L-Dopa, a medication that helps manage the signs and symptoms.

Typically, DRD symptoms begin in childhood, often around the age of 6. Initial signs may include clubfoot (inward and upward turning of the feet) and dystonia in the legs. The dystonia gradually spreads to the arms, and by adolescence, it usually affects the entire body. Individuals with DRD may exhibit unusual limb positions and experience coordination difficulties when walking or running. Sleep disturbances and increased episodes of depression can also occur in some patients.

Over time, individuals with DRD frequently develop parkinsonism, a collection of movement-related abnormalities. These include unusually slow movement (bradykinesia), muscle stiffness (rigidity), tremors, and difficulty maintaining balance and an upright posture (postural instability).

The movement problems associated with DRD tend to worsen with age, but generally stabilize around age 30. A distinguishing characteristic of DRD is diurnal fluctuation, where symptoms worsen later in the day and improve in the morning after sleep.

In rare instances, DRD symptoms do not appear until adulthood. In these adult-onset cases, parkinsonism usually precedes dystonia, and the progression of movement problems is slow, without the typical diurnal fluctuations.

Inheritance:

DRD caused by mutations in the GCH1 gene follows an autosomal dominant inheritance pattern. This means that only one copy of the mutated gene in each cell is sufficient to cause the disorder. An affected individual may inherit the mutation from an affected parent, or the mutation may arise spontaneously in the individual with no prior family history of the condition. Notably, some individuals who inherit the mutated GCH1 gene never develop symptoms of DRD, a phenomenon known as reduced penetrance. The reasons behind this variability are currently unknown. Interestingly, DRD due to GCH1 mutations is two to four times more common in females than in males. DRD caused by TH gene mutations follows an autosomal recessive inheritance pattern. This requires both copies of the gene in each cell to carry mutations. In such cases, each parent carries one copy of the mutated gene but typically does not exhibit symptoms of DRD. When mutations in the SPR gene cause dopa-responsive dystonia, it can be inherited in either an autosomal recessive pattern, or, less frequently, an autosomal dominant pattern.