Autosomal dominant leukodystrophy with autonomic disease

Alternate names

Adult-onset autosomal dominant demyelinating leukodystrophy; Pelizaeus-Merzbacher disease, autosomal dominant or late-onset type; Leukodystrophy, demyelinating, adult-onset, autosomal dominant; Autosomal dominant adult-onset demyelinating leukodystrophy; ADLD; Multiple sclerosis-like disorder; Adult-onset autosomal dominant leukodystrophy

Definition

A rare, slowly progressive neurological disorder involving central nervous system demyelination, leading to autonomic dysfunction, ataxia and mild cognitive impairment.

Summary

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.

Epidemiology

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

Cause

• ADLD is caused by mutations in the LMNB1 gene.
• This gene provides instructions for making the lamin B1 protein.
• Lamin B1 is an essential scaffolding (supporting) component of the nuclear envelope, which is the membrane that surrounds the nucleus, and plays an important role in determining the shape of the nucleus within cells.

Gene mutations

• Lamin B1 also plays a role in the copying (replication) of DNA in preparation for cell division and the activity (expression) of many genes.
• Nearly all cases of ADLD result from an abnormal extra copy (duplication) of the LMNB1 gene.
• As a result of this duplication, more lamin B1 is produced than normal. While lamin B1 is found in cells throughout the body, it appears that cells in the brain are especially sensitive to changes in lamin B1.
• Cells called oligodendrocytes, which help coat nerve cells with myelin, seem to be particularly affected.
• Increased lamin B1 levels lead to decreased expression of genes that play a variety of roles in the cell, including myelin production.
• Additionally, an increase in the amount of lamin B1 leads to a hardening of the nuclear envelope.
• These changes my cause problems with cell function and lead to reduced myelin production and maintenance over time.
• The loss of myelin (demyelination) occurs in the brain and spinal cord (central nervous system) in people with ADLD, often years before movement problems develop.
• Demyelination of the spinal cord likely contributes to the early signs and symptoms of ADLD, including problems with bladder control and orthostatic hypotension, by impairing transmission of nerve signals from the brain to the body.
• The movement problems are probably due to demyelination in the region of the brain involved in coordinating movements (the cerebellum) and of the nerve cells that extend down the spinal cord (corticospinal tracts) and control voluntary muscle movement.

Inheritance

Autosomal dominant pattern, a 50/50 chance.

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In most cases, an affected person has one parent with the condition.

Signs and symptoms

• 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 hypotension anderectile 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.

Clinical presentation

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed.

80%-99% of people have these symptoms

• Ataxia

30%-79% of people have these symptoms

• Abnormal pyramidal sign
• Constipation
• Dilatation of the bladder
• Gait disturbance(Abnormal gait)
• Hyperreflexia(Increased reflexes)
• Hypotension(Low blood pressure)
• Impotence(Difficulty getting a full erection)
• Nystagmus(Involuntary, rapid, rhythmic eye movements)
• Spasticity(Involuntary muscle stiffness, contraction, or spasm)
• Tetraparesis
• Tremor
• Urinary urgency(Overactive bladder)

5%-29% of people have these symptoms

• Atrophy of the spinal cord(Degeneration of the spinal cord)
• Cerebral cortical atrophy(Decrease in size of the outer layer of the brain due to loss of brain cells)
• Corpus callosum atrophy
• Dysarthria(Difficulty articulating speech)
• Dysphagia(Poor swallowing)
• Global developmental delay
• Hearing impairment(Deafness)
• Hypohidrosis(Decreased ability to sweat)
• Intellectual disability, mild(Mental retardation, borderline-mild)
• Visual loss(Loss of vision)

Diagnosis

The diagnosis of ADLD is established with suggestive clinical and MRI findings and either an LMNB1 duplication or a large heterozygous deletion upstream of the LMNB1 promoter.[1].

Treatment

Treatment is symptomatic.[2]. Autonomic dysfunction:

• Neurogenic bladder may require management of urinary retention and/or urgency and recurrent urinary tract infection.
• Constipation may require good hydration, increased dietary fiber, stool softeners, and/or laxatives.
• Hypotensive events can be minimized by pharmacologic intervention, physical therapy, and increased dietary salt.
• Feeding difficulties can be managed with speech therapy and appropriate feeding interventions to assure adequate nutrition while preventing aspiration pneumonia.
• 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.

NIH genetic and rare disease info

• NIH info on Autosomal dominant leukodystrophy with autonomic disease

Autosomal dominant leukodystrophy with autonomic disease is a rare disease.

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