Autosomal Dominant Leukodystrophy with Autonomic Disease (ADLD)

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UMLS 71 C1868512 C3164344

NIH Rare Diseases : ⁵² The following summary is from Orphanet , a European reference portal for information on rare diseases and orphan drugs. Orpha Number: 99027 Definition A rare, slowly progressive neurological disorder involving centralnervous systemdemyelination, leading to autonomic dysfunction, ataxia and mild cognitive impairment. Epidemiology More than 20 families in different ethnic groups have been reported to date. Exact prevalence and incidence data are however lacking. Clinical description Unlike mostforms 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 micturitionurgency, bladder retention, constipation, postural hypotensionanderectile 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 cerebellardysfunction (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. Neuroradiologicalcharacteristics 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. Etiology 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 disruptionin 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 Genetic counseling should be provided to affected families indicating the autosomal dominant pattern of inheritance. Visit the Orphanet disease page for more resources.

MalaCards based summary : Autosomal Dominant Leukodystrophy with Autonomic Disease, also known as autosomal dominant adult-onset demyelinating leukodystrophy, is related to demyelinating disease and pure autonomic failure, and has symptoms including personality changes, muscle spasticity and cerebellar ataxia. An important gene associated with Autosomal Dominant Leukodystrophy with Autonomic Disease is LMNB1 (Lamin B1). Affiliated tissues include spinal cord, brain and medulla oblongata.

Genetics Home Reference : ²⁵ Autosomal dominant leukodystrophy with autonomic disease (ADLD) is one of a group of genetic disorders called leukodystrophies. Leukodystrophies are characterized by abnormalities of the nervous system's white matter, which consists of nerve fibers covered by a fatty substance called myelin. Myelin insulates and protects nerve fibers and promotes the rapid transmission of nerve impulses. People with ADLD develop signs and symptoms of the condition in adulthood, typically in their forties or fifties. The first signs of the condition often involve problems with the autonomic nervous system, which controls involuntary body processes such as the regulation of blood pressure and body temperature. These problems include difficulty with bowel and bladder function, a sharp drop in blood pressure upon standing (orthostatic hypotension), and erectile dysfunction in men. Rarely, people experience an inability to sweat (anhidrosis), which can lead to a dangerously high body temperature. In ADLD, movement difficulties often develop after the autonomic nervous system problems. Affected individuals can have muscle stiffness (spasticity) or weakness and involuntary rhythmic shaking, called intention tremor because it worsens during movement. People with ADLD often have difficulty coordinating movements (ataxia), including movements that involve judging distance or scale (dysmetria), such as picking up a distant object, and rapidly alternating movements (dysdiadochokinesis), including hand clapping or foot stomping. These movement problems usually first affect the legs, but as the condition worsens, the arms and eventually the face become involved. In some people with ADLD, the symptoms worsen during episodes of fever, infection, or exposure to heat. Due to difficulty walking and an unsteady gait, many affected individuals need a cane, walker, or wheelchair for assistance. Intelligence is usually unaffected; however, people who have had ADLD for a long time may have a decline in intellectual function (dementia). ADLD worsens slowly, and affected individuals usually survive 10 to 20 years after the onset of symptoms.

GeneReviews: NBK338165

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