-Related Disorders

CLINICAL CHARACTERISTICS

related disorders include -related dystonia (DYT-), reported in 93% families, and -related neurodevelopmental disorder (NDD) that is non-dystonic, reported in 7% of families. DYT- is a complex childhood-onset progressive movement disorder (median age of onset: 6 years; range: 0-43 years) typically evolving from lower-limb focal dystonia into generalized dystonia with prominent cervical, cranial, and laryngeal involvement. Communication difficulties secondary to articulation difficulties (dysarthria) and low speech volume (hypophonia) are common. Bulbar dysfunction can lead to impaired swallowing with an increased risk of aspiration and need for gastrostomy tube placement in some. Most individuals have additional neurologic or systemic manifestations including intellectual disability (ID) / developmental delay (DD), other movement disorders (myoclonus, spasticity, tremor, ataxia, eye movement abnormalities), and neurobehavioral/psychiatric manifestations (e.g., attention-deficit/hyperactivity disorder, anxiety, depression, and obsessive-compulsive disorder.) Life expectancy is not known; however, individuals in the seventh decade of life have been reported. -related NDD, sometimes described in family members of individuals with DYT-, is characterized by DD and ID ranging from mild to severe. Additional findings can include bulbar dysfunction and neurobehavioral/psychiatric manifestations Life expectancy is not known; to date, too few individuals have been reported.

DIAGNOSIS/TESTING: The diagnosis of a -related disorder is established in a proband with suggestive findings and either of the following identified by molecular genetic testing: a heterozygous pathogenic variant involving (88% of affected individuals) or a heterozygous deletion of 19q13.11-19q13.12 involving (12% of affected individuals).

MANAGEMENT

A movement disorder specialist should be involved early on to discuss pharmacologic and surgical treatment options. Although use of anti-dystonic agents (levodopa and other agents) has not resulted in long-term benefit for most individuals, a trial of these agents would be considered reasonable. Antimuscarinic (anticholinergic) agents have significantly improved motor manifestations in about 50% of individuals and should be considered a first-line pharmacologic treatment in individuals with a -related disorder. Bilateral globus pallidus pars interna deep brain stimulation, performed in about 80 individuals to date, has resulted in substantial clinical and functional improvement. Treatment of DD/ID, neurobehavioral/psychiatric manifestations, communication difficulties, feeding difficulties, and other movement disorders should follow standard practice. Assess for progression of known features and to identify new manifestations such as changes in tone and movement disorders with regularly scheduled follow up; at each visit, assess safety of oral intake, communication needs, mobility, self-help skills, features neurobehavioral/psychiatric manifestations, and family need for social work support (e.g., palliative/respite care, home nursing, other local resources), care coordination, or follow-up genetic counseling if new questions arise (e.g., family planning); assess developmental progress and educational needs throughout childhood and adolescence; full psychoeducational evaluation for children who have difficulty with school or behavioral changes.

GENETIC COUNSELING

DYT- and -related NDD are autosomal dominant disorders. The majority of individuals reported to date with a -related disorder whose parents have undergone molecular genetic testing have the disorder as a result of a genetic alteration. Some individuals diagnosed with a -related disorder inherited a genetic alteration from a parent (a parent with a pathogenic variant may be affected or clinically asymptomatic). Each child of an individual with a -related disorder has a 50% chance of inheriting the genetic alteration. Once the pathogenic variant or deletion of 19q13.12 involving has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.