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Pelizaeus Merzbacher Disease

OMIM lists 3 variations of Pelizaeus Merzbacher Disease. They are:

• Pelizaeus Merzbacher Disease, PMD, an X-linked recessive with the mutation at Xq22¹
• Pelizaeus Merzbacher Disease,acute infantile type, perinatal sudanophilic leukodystrophy, inheritance uncertain, possibly heterogeneous but boys and girls affected, probably autosomal recessive²
• Pelizaeus-Merzbacher-like-Disease, PMLD, PMLDAR, autosomal recessive with mutation at 1q41-q42³

This article will concentrate on the first of these 3 diseases. Spastic paraplegia type 2, designated SPG2⁴ is due to a mutation at the same allele and so it would seem that the two diseases are each end of a spectrum. The fault is in the proteolipid protein 1 (PLP1 gene) in both.⁵ The protein is an important constituent of myelin and so the result is defective myelination of the central nervous system.

Epidemiology: This is a rare disease with an international incidence that is probably between 0.1 and 1 per 100,000 population.

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.

Presentation:

• The most severe variant of the disease is called the connatal form. Spastic paraplegia is at the milder end of the spectrum.
• Typically the disease begins in infancy but milder variations may not present until childhood.
• Classical PMD in boys presents within the first 2 months of life. There is nystagmus and weakness, followed by development of ataxia, cognitive delay, and spasticity. Titubation is described. This may mean either a staggering gait or tremor or shaking of the head of cerebellar origin but in this context it is more likely to be the latter as most never learn to walk properly. Those that do tend to be milder cases but lose the ability in adolescence.
• In the severe connatal form there is nystagmus from birth or the first few weeks of life. They often have stridor, respiratory difficulty and hypotonia. Seizures may occur. They have limited language, never walk, and develop severe spasticity with little voluntary movement. They usually die before the third decade of life.
• Most cases are less severe and achieve some language skills but fluency is slow and may suggest a more severe degree of mental retardation than is present. These patients may survive to the sixth decade of life or longer.
• In the least severe form, bordering on SPG2, 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.

Other general observations may be made:

• Although the disease is associated with spasticity, there may be hypotonia in early life.
• There is cognitive delay but this may seem more severe than it is because of severe limitation of speech. Comprehension may be rather better than phonation. Developmental milestones are either markedly delayed or never achieved.
• They are small for age.
• As the child grows, spasticity replaces hypotonia but head control remains poor and in more severe cases there may be convulsions. In severe cases the child is unable to sit unsupported and is certainly unable to walk.
• Milder cases may be able to walk but this is lost in adolescence. There is gross spasticity, hyperreflexia and extensor plantar response.
• Milder cases show nystagmus, ataxia and spasticity is worse in the legs. The ataxia affects their speech.
• Over 95% have nystagmus but the age of onset does not predict clinical severity. The nystagmus is usually pendular but can have horizontal or rotor components.
• Voluntary movements are almost invariably complicated by ataxia.
• In severe cases the neonatal hypotonia may resemble spinal muscular atrophy but over 90% of cases develop spasticity although possibly not until the second year of life.

Investigations:

• MRI is a very useful investigation as it shows poor myelination although this may not be apparently abnormal until about 1 year old. It also shows reduced brain volume. This is most marked in the connate variety and is not very obvious in SPG2.
• Nerve conduction studies show normal conduction in peripheral nerves whereas other leukodystrophies show a slowing of peripheral nerve conduction.
• Molecular diagnostic testing is the definitive test.⁶ There will be some variation according to the type of mutation present.

Differential diagnosis:

• Pelizaeus Merzbacher Disease,acute infantile type² appears to be very rare and the precise clinical features are poorly defined
• Pelizaeus-Merzbacher-like-Disease³ is an autosomal recessive that seems more likely to affect consanguinous couples. Features are similar.
• Spinal muscular atrophy
• Autosomal dominant cerebellar ataxia
• Cerebral autosomal dominant arteriopathy (CADSIL)
• Severe cerebral palsy

Management: There is no cure for the disease. Management is purely supportive and this will include genetic counselling and telling the parents of the prognosis. Clonazepam and baclofen may help spasticity. Physiotherapy may help prevent contractures.

Prognosis:

• Those with connatal PMD often die of respiratory complications during childhood, but otherwise they can live into their 20s.
• Those with the classical form often live into their 40s or 50s.
• If the phenotype is predominantly spastic paraplegia, they can have a normal life expectancy.
• There may appear to be periods of stability but the prognosis is for gradual deterioration.

Female carriers: Females have random inactivation of the X-chromosome and so a heterozygous female begins life with roughly half the oligodendrocytes manifesting the normal and half the mutated X chromosome. Females heterozygous for severe mutations show transient neurological abnormalities during childhood but are neurologically normal as adults. This is probably because the abnormal oligodendrocytes die and are replaced by healthy ones. Females heterozygous for less severe mutations that do not result in oligodendrocyte apoptosis (programmed cell death) continue to have oligodendrocytes that have the defective PLP1 and therefore will continue to have abnormal neurological signs. Carrier girls are usually asymptomatic but some develop a classical picture that then regresses and they are normal as adults. 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.⁷

References:

1. OMIM
2. OMIM
3. OMIM
4. OMIM
5. Griffiths I, Klugmann M, Anderson T, et al; Current concepts of PLP and its role in the nervous system.;Microsc Res Tech. 1998 Jun 1;41(5):344-58.[abstract]
6. Boulloche J, Aicardi J; Pelizaeus-Merzbacher disease: clinical and nosological study.;J Child Neurol. 1986 Jul;1(3):233-9.[abstract]
7. Hodes ME, DeMyer WE, Pratt VM, et al; Girl with signs of Pelizaeus-Merzbacher disease heterozygous for a mutation in exon 2 of the proteolipid protein gene.;Am J Med Genet. 1995 Feb 13;55(4):397-401.[abstract]

Internet:

• Garbern JY Pelizaeus Merzbacher Disease; eMedicine; January 2005
• Patient UK The Pelizaeus Merzbacher Disease Support Group

Acknowledgements EMIS is grateful to the Mentor authoring team for writing this article. The final copy has passed peer review of the independent Mentor GP authoring team. ©EMIS 2006.

Last issued 08 May 2006