The portal for rare diseases and orphan drugs

More than 20 families in different ethnic groups have been reported to date. Exact prevalence and incidence data are however lacking.

Unlike most forms of leukodystrophy which appear in childhood, ADLD occurs in the 4th to 6th decade of life. ADLD may clinically resemble multiple sclerosis in the initial phase. In most patients, the initial manifestation of the disease is autonomic dysfunction resulting in micturition urgency, bladder retention, constipation, postural hypotension and erectile dysfunction in affected males. Decreased sweating is reported in some cases. Some patients develop autonomic dysfunction later in the disease course. The other features are cerebellar dysfunction (gait ataxia, nystagmus, dysmetria, loss of fine motor control, and action tremors), pyramidal signs (spasticity, weakness of both upper and lower extremities, hyperreflexia), and cognitive impairment possibly with personality changes. These manifestations may not develop for years following initial presentation. Neuroradiological characteristics include extensive symmetrical white matter changes, corpus callosum atrophy, and brain stem and spinal cord atrophy. The disease follows a slow progressive course with an eventual loss of walking ability and slightly shortened lifespan.

ADLD is caused by chromosomal rearrangements with duplications of the LMNB1 gene (5q23.2) or a ''position effect'' due to a genomic deletion upstream of the gene causing its upregulation. Overexpression of LMNB1 causes myelin disruption in the central nervous system for which the precise underlying pathogenic mechanisms have not been elucidated. Alteration of splicing patterns suggests that ADLD is a spliceopathy.

Genetic counseling should be provided to affected families indicating the autosomal dominant pattern of inheritance.