Autosomal Dominant Leukodystrophy with Autonomic Disease

Clinical characteristics Autosomal dominant leukodystrophy with autonomic disease (ADLD) is a slowly progressive disorder of central nervous system white matter characterized by onset of autonomic dysfunction in the fourth to fifth decade, followed in months to years by pyramidal and cerebellar involvement. Autonomic dysfunction can include bladder dysfunction, constipation, postural hypotension, feeding difficulties, erectile dysfunction, and (less often) impaired sweating. Pyramidal signs are often more prominent in the lower extremities (i.e., spastic weakness, hypertonia, clonus, brisk deep tendon reflexes, and bilateral Babinski signs). Cerebellar signs typically appear at the same time as the pyramidal signs and can include gait ataxia, dysdiadochokinesia, intention tremor, dysmetria, and nystagmus. Although cognitive function is usually preserved or only mildly impaired early in the disease course, dementia and psychiatric manifestations can occur as late manifestations. Affected individuals may survive for decades after onset. Diagnosis/testing The diagnosis of ADLD is established in a proband with suggestive clinical and MRI findings and either an LMNB1 duplication or (more rarely) a large heterozygous deletion upstream of the LMNB1 promoter. Management Treatment of manifestations: Treatment is symptomatic. Autonomic dysfunction: Spasticity may be treated with medications and physical therapy. Ataxia can be managed with strategies to minimize falls and increase strength, and adaptive equipment such as walkers or wheelchairs. Surveillance: Routine assessment of: weight, nutrition, and feeding; pulmonary status (re possible recurrent pneumonia); bladder and erectile function; psychosocial well-being; and medications and their doses to avoid iatrogenic polypharmacy. At least yearly assessment: by a neurologist for disease manifestations and progression; and by a physiatrist, orthopedist, physical therapist, and occupational therapist to address orthopedic, equipment, and functional needs. Genetic counseling ADLD is inherited in an autosomal dominant manner. To date all individuals with ADLD have inherited a large LMNB1 duplication (or large deletion upstream of LMNB) from an affected parent. Each child of an individual with ADLD has a 50% chance of inheriting the ADLD-related LMNB1 pathogenic variant. When the ADLD-related LMNB1 pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk is possible.