DCTN1-Related Neurodegeneration

Excerpt

Clinical characteristics: The spectrum of DCTN1-related neurodegeneration includes Perry syndrome, distal hereditary motor neuronopathy type 7B (dHMN7B), frontotemporal dementia (FTD), motor neuron disease / amyotrophic lateral sclerosis (ALS), and progressive supranuclear palsy. Some individuals present with overlapping phenotypes (e.g., FTD-ALS, Perry syndrome-dHMN7B).

Perry syndrome (the most common of the phenotypes associated with DCTN1) is characterized by parkinsonism, neuropsychiatric symptoms, hypoventilation, and weight loss. The mean age of onset in those with Perry syndrome is 49 years (range: 35-70 years), and the mean disease duration is five years (range: 2-14 years). In most affected persons, the reported cause/circumstance of death relates to sudden death/hypoventilation or suicide.

Diagnosis/testing: The diagnosis of DCTN1-related neurodegeneration is established in a proband by identification of a heterozygous DCTN1 pathogenic variant on molecular genetic testing.

Management: Treatment of manifestations: Dopaminergic therapy in individuals with significant parkinsonism; ventilation support; anti depressants and psychiatric care for depression; high caloric intake for weight loss; feeding tube when needed to prevent aspiration pneumonia and provide adequate caloric intake; arytenoidectomy for vocal cord paralysis to provide a larger airway for respiration; orthosis for neuropathic foot.

Surveillance: Evaluation of weight and calorie intake, respiratory function (particularly at night or during sleep), motor function, and mood/personality changes annually or more frequently as needed.

Agents/circumstances to avoid: Central respiratory depressants (e.g., benzodiazepines, alcohol, narcotics).

Genetic counseling: DCTN1-related neurodegeneration is inherited in an autosomal dominant manner. Most individuals diagnosed with DCTN1-related neurodegeneration have an affected parent. Less commonly, individuals diagnosed with DCTN1-related neurodegeneration have the disorder as the result of a de novo pathogenic variant. Each child of an individual with DCTN1-related neurodegeneration has a 50% chance of inheriting the pathogenic variant. Once the DCTN1 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for DCTN1-related neurodegeneration are possible.