Autosomal dominant leukodystrophy with autonomic disease

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

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 (dysdiadochokinesia), 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.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

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. 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 and family implications

From: MedlinePlus Genetics, National Library of Medicine

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.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

The exact prevalence of ADLD is unknown. At least 70 affected individuals have been described in the scientific literature, although this condition is likely to be underdiagnosed.

Which doctor should you see?

The suggested department for discussing Autosomal dominant leukodystrophy with autonomic disease is Clinical Genetics, with a clinical geneticist as the relevant type of clinician. Paediatrician (children) or physician (adults), with clinical geneticist referral.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Does the exact genetic or chromosome finding explain the observed features?
• Would a genetic counsellor help the family understand the result?
• Which organ-specific assessments are appropriate for this particular diagnosis?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Autosomal dominant leukodystrophy with autonomic disease. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.