What is Pelizaeus-Merzbacher Disease?

Pelizaeus-Merzbacher disease (PMD) is a rare genetic condition affecting the central nervous system. It is estimated that PMD affects approximately 1 in 500,000 people internationally.

It is one of a group of gene-linked disorders known as the leukodystrophies, which are all characterised by abnormalities in the myelin sheath (the fatty tissue which surrounds the brain and nerves). These abnormalities are caused by a mutation in the Proteolipid Protein1 (PLP1) gene that controls the production of the myelin protein.

The exact type of PLP1 mutation dictates the onset and severity of PMD.

There are four levels of severity described which, in order of decreasing severity are:

  • Connatal PMD - the most severe type: involves delayed mental and physical development and severe neurological symptoms.

  • Classic PMD - the early symptoms include muscle weakness, involuntary movements of the eyes (nystagmus) and delays in motor development within the first year of life.

  • Complicated SPG2 - features motor development problems and brain involvement.

  • Pure SPG2 - includes cases of PMD that do not have neurological complications.



Generally, the clinical picture is one of:

  • Nystagmus (uncontrolled movement/wobbly eyes)
  • Spastic quadriplegia (stiffness of limbs)
  • Ataxia (involuntary movements)
  • Developmental delay

Parents have also highlighted the following symptoms:

  • Poor sleeping habits

  • Failure to Thrive (poor weight gain)

  • Eating difficulties (issues with chewing/swallowing and aspiration)

  • Hearing Impairment

Typically, the disease begins in the first two months of life, but milder variations may not present until childhood.

Connatal PMD - usually there is nystagmus from birth, they often have stridor, respiratory difficulties and hypotonia(decreased muscle tone). Boys with connatal PMD can also suffer from seizures, have limited language, inability to walk and develop severe spasticity (stiffness) with little voluntary movement. It is believed that most boys with this variation of PMD die during infancy or early childhood.

Classical PMD - boys usually present within the first 2 months of life. Again the first sign tends to be nystagmus, followed by development of ataxia, cognitive delay and spasticity. Nodding or a tremor of the head is often noted, and those who learn to walk, will often do so in a staggering fashion. Those that do walk tend to be milder cases but it is noted that they tend to lose the ability when the reach adolescence. Most cases achieve some language skills but fluency is slow and may suggest a more severe degree of learning difficulty than is present. These patients may survive to the sixth decade of life or longer.

SPG2-like disease - there is spastic paraplegia from childhood, mild cognitive impairment, ataxia and athetosis (continual slow movements, especially of the extremities). They usually live to the sixth decade or beyond. Neurological signs progress gradually with periods of relative stability. If they learn to walk they tend to lose it during adolescence (occasionally adulthood).

Other general observations may be made:

  • Developmental milestones are either markedly delayed or sometimes never achieved.
  • Many individuals are small for their age. 
  • Over 95% have nystagmus but the age of onset does not predict clinical severity. The nystagmus is usually pendular (wave pattern) but can have horizontal or rotor components.
  • As the child grows and spasticity replaces hypotonia, head control remains poor.
  • In more severe cases there may be convulsions. 
  • Milder cases may be able to walk but this is lost in adolescence, as the spasticity tends to be worse in the legs.
  • In severe cases, the child is unable to sit unsupported and is certainly unable to walk.
  • Ataxia is evident once voluntary movements are acquired and affects virtually all patients.
  • In milder cases, the ataxia affects their speech. Therefore, although there is cognitive delay, this may seem more severe than it is because of severe limitation of speech. Comprehension may be rather better than phonation.
  • Voluntary movements are almost invariably complicated by ataxia.

Differential diagnosis

We believe that PMDs rarity is partly down to misdiagnosis over the years. It is now better understood and therefore more correct diagnoses are being made. 

PMD has features similar to many conditions, including:

  • Spinal muscular atrophy.
  • Autosomal dominant cerebellar ataxia .
  • Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).
  • Severe cerebral palsy.​
  • Multiple sclerosis.


MRI scan is a very useful investigation as it shows poor myelination, although this may not be apparently abnormal until about 1 year of age. It may also show reduced brain volume in those with the connatal form. 

Nerve conduction studies show normal conduction in peripheral nerves whereas other leukodystrophies show a slowing of peripheral nerve conduction. Genetic diagnostic testing is the definite test, and will be used to confirm PMD once an MRI scan shows myelination issues. Genetic testing will also show whether there is a point mutation or a duplication of the PLP1 gene. 


There is currently no cure for the disease and, currently, there are no treatment.

Managing the symptoms is therefore the only way to 'treat' the patient.

Management options include:

  • Genetic counselling and telling the parents the prognosis.
  • Physiotherapy
  • Occupational therapy - providing equipment
  • Muscle relaxant medicines
  • Surgery (often on bones, joints and tendons. Operations for severe stridor is also possible)
  • Dietary supplements
  • Sleep Aids

Severely affected individuals may also require airway protection (tracheostomy), management of gastro-oesophageal reflux, and anticonvulsant medicines to help with seizures.


Connatal PMD - these individuals often die of respiratory complications during infancy or early childhood. If they get through this early period of life, they can live into their third decade of life.

Classic PMD - if these individuals survive past adolescence, they may live into their 40s or 50s.[6] This depends on the predominant phenotype - if this is predominantly spastic paraplegia, they can have a normal life expectancy.

SPG2 - these patients tend to have a normal lifespan.

There may appear to be periods of stability but the prognosis is for gradual deterioration.


As an X-linked disease it would be natural to expect that males are affected and females are carriers but females do have features of the disease.

Females have random inactivation of the X-chromosome, some females begin life with roughly half the normal and half the mutated X chromosome (heterozygous).

Females heterozygous for severe mutations show impermanent neurological abnormalities during childhood but symptoms regress (presumably as defective cells die and are replaced by healthy ones) and these individuals are neurologically normal as they reach adulthood.

Females heterozygous for less severe mutations, where the defective cells are not replaced with healthy ones will continue to have the defective PLP1 and will therefore have abnormal nuerologcial signs throughout thier life.

Carrier girls usually show no symptoms, however some may show some classical signs of PMD during their childhood. This symptoms will regress with age and the carrier female will be 'normal' as an adult. 

Female carriers of less severe variations are usually normal in childhood but may develop symptoms in adulthood, including dementia.

Female carriers have a 1 in 2 chance of passing on the abnormal chromosome to a child, giving a 1 in 4 chance of having an affected son, a 1 in 4 chance of having a carrier daughter and a 1 in 2 chance of having a normal child, boy or girl. Molecular genetic analysis is the best technique for carrier detection.

Further reading & references.

information sourced from patient.info