Dyskinesia, Familial, With Facial Myokymia

A number sign (#) is used with this entry because familial dyskinesia with facial myokymia (FDFM) is caused by heterozygous mutation in the ADCY5 gene (600293) on chromosome 3q21.

Description

Familial dyskinesia with facial myokymia is an autosomal dominant movement disorder characterized by childhood onset of involuntary choreiform or dystonic movements that involve the limb and facial muscles. The severity is variable, but can result in difficulty walking and talking (summary by Chen et al., 2014).

Clinical Features

Fernandez et al. (2001) reported a 5-generation German family segregating an autosomal dominant syndrome of familial dyskinesia and facial myokymia (FDFM). The disorder was characterized by adventitious movements that sometimes appeared to be choreiform and were associated with perioral and periorbital myokymia. The same family had been reported by Bird and Hall (1978) as a possible variant of familial essential chorea (118700) before the recognition of myokymia as a feature. Eighteen members of the family, including 10 males and 8 females, were affected, and all had onset in early childhood or adolescence. The involuntary movements were paroxysmal at early ages, increased in frequency and severity, and in some became constant in the third decade. Thereafter, there was no further deterioration. The adventitious movements were worsened by anxiety but not by voluntary movement, startle, caffeine, or alcohol. The disease was socially disabling, but had no effect on intellect or life span.

Chen et al. (2012) provided follow-up of the family reported by Fernandez et al. (2001). The age at onset ranged from 2.5 to 19 years. Reexamination of 1 affected individual at age 50 years showed some improvement of the neurologic manifestations. However, he had developed severe dilated cardiomyopathy at age 46 years, and family history revealed that 4 neurologically affected individuals also developed congestive heart failure. Chen et al. (2012) suggested that heart disease may be a component of FDFM.

Chen et al. (2014) reported 2 unrelated teenaged girls of European descent with a movement disorder since childhood. A 15-year-old girl presented with axial hypotonia and weakness, limb hypertonia, hyperreflexia, intermittent tremors and paroxysmal dyskinesia, dystonia, and myoclonus both at rest and with activity. She had poor neck support, extreme difficulty walking, dysarthria, and subtle signs of perioral and periorbital dyskinesia. The abnormal movements also caused significant sleep disruption. The patient had had mildly delayed motor development in infancy, with the first appearance of paroxysmal choreic movements at age 19 months. An 18-year-old girl was less severely affected. She had onset of choreiform movements at age 5 years. Choreoathetosis and dystonia were most prominent at rest and were alleviated by physical activity. The abnormal movements progressed to include facial twitches and mild dysarthria, but frank myokymia was not present. Treatments were ineffective.

Inheritance

The transmission pattern of dyskinesia with facial myokymia in the family reported by Fernandez et al. (2001) was consistent with autosomal dominant inheritance.

Mapping

Fernandez et al. (2001) performed a candidate gene and haplotype analysis in 9 affected and 3 unaffected members from 3 generations of the German family segregating FDFM and excluded linkage to 11 chromosomal regions containing genes associated with chorea and myokymia.

Molecular Genetics

In affected members of a large German family with autosomal dominant familial dyskinesia with facial myokymia, Chen et al. (2012) identified a heterozygous mutation in the ADCY5 gene (A726T; 600293.0001). Chen et al. (2012) noted that Adcy5-null mice develop a movement disorder that is worsened by stress (Kim et al., 2006), supporting the pathogenicity of the A726T mutation.

In 2 unrelated teenaged girls of European ancestry with FDFM, Chen et al. (2014) identified a de novo heterozygous mutation in the ADCY5 gene (R418W; 600293.0002). The mutations were found by whole-exome sequencing. In vitro functional expression studies showed that both mutant A726T and R418W ADCY5 caused a significant increase in cAMP production in response to beta-adrenergic stimulation compared to wildtype, consistent with a gain of function. One of the girls with a more severe phenotype also carried a de novo heterozygous N1882S variant in the DOCK3 gene (603123), which may have a role in neuronal activity and could have possibly contributed to the phenotype. In addition, sequence reads suggested that the girl with the less severe phenotype may have been somatic mosaic for the R418W mutation. Chen et al. (2014) postulated that these findings may have played a role in the phenotypic variability observed in the 2 patients.