Clinical characteristics: LMNB1-related autosomal dominant leukodystrophy (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 by pyramidal and cerebellar abnormalities resulting in spasticity, ataxia, and tremor. Autonomic dysfunction can include bladder dysfunction, constipation, postural hypotension, erectile dysfunction, and (less often) impaired sweating. Pyramidal signs are often more prominent in the lower extremities (e.g., 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 include gait ataxia, dysdiadochokinesia, intention tremor, dysmetria, and nystagmus. Many individuals have sensory deficits starting in the lower limbs. Pseudobulbar palsy with dysarthria, dysphagia, and forced crying and laughing may appear in the seventh or eighth decade. 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 LMNB1-related ADLD is established in a proband with suggestive clinical and MRI findings and either an LMNB1 duplication or (more rarely) a heterozygous deletion upstream of the LMNB1 promoter identified by molecular genetic testing.

Management: Treatment of manifestations: Treatment is symptomatic. For autonomic dysfunction:

1. Neurogenic bladder may require management of urinary retention and/or urgency and recurrent urinary tract infection.

2. Constipation may require good hydration, increased dietary fiber, stool softeners, and/or laxatives.

3. Orthostatic hypotension can be minimized by pharmacologic intervention, compression stockings, physical therapy, and increased dietary salt.

4. Erectile dysfunction is treated medically.

5. Impaired sweating is managed with cool environment and attention to fever during infection.

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. Feeding difficulties can be managed with speech therapy and appropriate feeding interventions to assure adequate nutrition while preventing aspiration pneumonia.

Surveillance: Routine assessment of: weight, nutrition, and feeding; pulmonary status (re possible recurrent pneumonia); bladder and erectile function; psychosocial well-being; and medications/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: LMNB1-related ADLD is inherited in an autosomal dominant manner. To date, all individuals diagnosed with LMNB1-related ADLD whose parents have undergone molecular genetic testing have the disorder as the result of a large LMNB1 duplication (or a deletion upstream of LMNB1) inherited from an affected parent. Each child of an individual with LMNB1-related ADLD has a 50% chance of inheriting the LMNB1 duplication (or deletion upstream of LMNB1). Once the causative pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for LMNB1-related ADLD are possible.