Pelizaeus-Merzbacher disease

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Pelizaeus-Merzbacher disease is an inherited condition involving the brain and spinal cord (central nervous system) that primarily affects males. This disease is one of a group of genetic disorders called leukodystrophies. Leukodystrophies are conditions that involve abnormalities of the nervous system's white matter, which consists of nerve fibers covered by a fatty substance called myelin. Myelin insulates nerve fibers and promotes the rapid transmission of nerve impulses. In particular, Pelizaeus-Merzbacher disease involves hypomyelination, which means that the nervous system has a reduced ability to form myelin. As a result, overall neurological function is reduced.

Pelizaeus-Merzbacher disease is divided into classic and connatal (present from birth) types. Although these two types differ in severity, their features can overlap.

Classic Pelizaeus-Merzbacher disease is the more common type. Within the first year of life, those affected with classic Pelizaeus-Merzbacher disease typically experience weak muscle tone (hypotonia), involuntary movements of the eyes (nystagmus), and delayed development of motor skills, such as sitting or grasping objects. Some individuals are able to walk with assistance. Despite these neurological problems, intellectual and motor skills develop throughout childhood, but development usually stops around adolescence, and these skills are slowly lost (developmental regression). As the condition worsens, nystagmus usually goes away but other movement disorders develop, including muscle stiffness (spasticity), problems with movement and balance (ataxia), head and neck tremors (titubation), involuntary tensing of the muscles (dystonia), and jerking (choreiform) movements.

Connatal Pelizaeus-Merzbacher disease is the more severe of the two types. Symptoms can begin in infancy and include problems with feeding, poor weight gain and slow growth, high-pitched breathing caused by an obstructed airway (stridor), nystagmus, progressive speech difficulties (dysarthria), severe ataxia, hypotonia, and seizures. As the condition worsens, affected children develop spasticity leading to joint deformities (contractures) that restrict movement. Individuals with connatal Pelizaeus-Merzbacher disease are never able to walk, and many are not able to purposefully use their arms. They also have problems producing speech (expressive language) but can generally understand speech (receptive language).

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Mutations in the PLP1 gene cause Pelizaeus-Merzbacher disease. The PLP1 gene provides instructions for making proteolipid protein 1 and a modified version (isoform) of that protein called DM20. Proteolipid protein 1 is found primarily in nerves in the central nervous system and DM20 is produced mainly in nerves that connect the brain and spinal cord to muscles (peripheral nervous system). These two proteins are found within the cell membrane of nerve cells, where they make up the majority of myelin and anchor it to the cells.

Most mutations that cause Pelizaeus-Merzbacher disease copy (duplicate) the PLP1 gene, which results in increased production of proteolipid protein 1 and DM20. Other mutations lead to production of abnormal proteins that are often misfolded. Excess or abnormal proteins become trapped within cell structures and cannot travel to the cell membrane. As a result, proteolipid protein 1 and DM20 are not available to form myelin. The accumulation of excess proteins leads to swelling and breakdown of nerve fibers. Still other mutations delete the PLP1 gene, which prevents proteolipid protein 1 and DM20 protein production and results in a lack of these proteins in the cell membrane, which causes any myelin that is formed to be unstable and quickly broken down. All of these PLP1 gene mutations lead to hypomyelination, nerve fiber damage, and impairment of nervous system function, resulting in the signs and symptoms of Pelizaeus-Merzbacher disease.

It is estimated that 5 to 20 percent of people with Pelizaeus-Merzbacher disease do not have identified mutations in the PLP1 gene. In these cases, the cause of the condition is unknown.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

Pelizaeus-Merzbacher disease is inherited in an X-linked pattern. A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes in each cell. In males, who have only one X chromosome, a mutation in the only copy of the PLP1 gene in each cell is sufficient to cause the condition. In females, who have two copies of the X chromosome, one altered copy of the PLP1 gene in each cell can lead to less severe features of the condition, such as muscle stiffness or a decrease in intellectual function, or may cause no signs or symptoms at all. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

The prevalence of Pelizaeus-Merzbacher disease is estimated to be 1 in 200,000 to 500,000 males in the United States. This condition rarely affects females.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Abnormality of movement · Very frequent (99-80%)

An abnormality of movement with a neurological basis characterized by changes in coordination and speed of voluntary movements.

Ataxia · Very frequent (99-80%)

Ataxia refers to impaired coordination of voluntary muscle movement. Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).

Atypical behavior · Very frequent (99-80%)

Atypical behavior is an abnormality in a person's actions that can be controlled or modulated by the will of the individual. While abnormal behaviors can be difficult to control, they are distinct from other abnormal actions that cannot be affected by the individual's will.

Cachexia · Very frequent (99-80%)

Severe weight loss, wasting of muscle, loss of appetite, and general debility related to a chronic disease.

Cerebral cortical atrophy · Very frequent (99-80%)

Atrophy of the cortex of the cerebrum.

Developmental regression · Very frequent (99-80%)

Loss of developmental skills, as manifested by loss of developmental milestones.

Gait disturbance · Very frequent (99-80%)

The term gait disturbance can refer to any disruption of the ability to walk.

Hypotonia · Very frequent (99-80%)

Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.

Other findings in the same source

From: Orphanet

Additional reported features include Joint stiffness (Very frequent (99-80%)); Kyphosis (Very frequent (99-80%)); Nystagmus (Very frequent (99-80%)); Optic atrophy (Very frequent (99-80%)); Premature birth (Very frequent (99-80%)); Scoliosis (Very frequent (99-80%)); Spasticity (Very frequent (99-80%)); Visual impairment (Very frequent (99-80%)); Failure to thrive in infancy (Very frequent (99-80%)); Abnormality of speech or vocalization (Frequent (79-30%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Pelizaeus-Merzbacher disease is Neurology, with a neurologist as the relevant type of clinician. General physician / Family Medicine; paediatrician for children. Referral depends on symptoms.

Additional services that may be relevant, depending on the findings, include: Clinical Genetics.

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.

• Which nervous-system findings help explain the symptoms?
• Would an assessment of walking, communication or daily function be helpful?
• Are rehabilitation or other specialist services relevant?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Pelizaeus-Merzbacher 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.