Publication date: 2012-09-20
Version: 2.0
Pelizaeus-Merzbacher disease (PMD) is a leukoencephalopathy, one of a group of disorders affecting the white matter of the brain. The condition is inherited and mainly affects boys, although occasionally girls display mild symptoms.
In 1885 Friedrich Pelizaeus described a large family in which the boys developed neurological symptoms at an early age. In 1910 Ludwig Merzbacher noted that while myelin, the white matter of the brain, was generally lacking in the brains of boys with the disease, the myelin which covered nerve fibres outside the brain was normal. Islands of myelin enveloped the blood vessels of the brain, producing a spotted (tigroid) white matter pattern. He also noted that the nerve cells in the brain showed no changes and that there were no signs of inflammation.
In some diseases affecting the white matter of the brain, such as the leukodystrophies, myelin in the nervous system degenerates (demyelinisation). However, in Pelizaeus-Merzbacher disease myelinisation in the brain (the formation of the myelin sheath around a nerve fibre) is disrupted or abnormal (hypomyelinisation / dysmyelinisation). Symptoms may vary, even within the same family, but everyone with the disease has some degree of motor dysfunction. A closely related disorder is hereditary spastic paraplegia, SPG2 (see separate material in the Rare Disease Database of the Swedish Board of Health and Welfare).
Approximately one child per 100,000 is born with Pelizaeus-Merzbacher disease, meaning that approximately one child per year is born with the condition in Sweden. To date, only a few children have been diagnosed. It is likely that a number of children and adults have the disease but have not been accurately diagnosed.
Pelizaeus-Merzbacher disease is caused by a mutation in a gene known as PLP, located on the long arm of the X chromosome (Xq22). PLP governs the production of proteolipid protein 1 (PLP 1), which is one of the main constituents of myelin. The mutation either causes PLP 1 deficiency, as it is produced in insufficient quantities, or the composition of the protein is altered. This stops the myelination process prematurely, at an early stage in brain development.
When the whole gene is absent (a null mutation), no PLP 1 is produced. Contrary to what might be expected, the associated symptoms are relatively mild in these cases. Other mutations cause changes to the structure of PLP 1, thereby preventing the transport of this protein through the oligodendrocytes (the brain cells that constitute the myelin sheath), which damages them and causes cell death. Symptoms range from mild to severe. The most common mutation causes a duplication of the PLP gene and is associated with the classic form of the disease.
PLP 1 normally constitutes 50 per cent of the total amount of protein in the central nervous system, but only one per cent of the amount in the peripheral nerves. PLP 1 and a similar protein, DM20, are formed by oligodendrocytes in the central nervous system, and these proteins are then transported to their destinations so that they may envelop the long, slender projections of nerve cells (axons). This process is very important, not only for the survival and functionality of oligodendrocytes and axons, but also for the calcium balance in myelin. In exceptional cases, myelin in the peripheral nerves is also affected by the disorder.
Similar disorders with other inheritance patterns may be caused by mutations in other genes (GJA12 and MCT8). The term Pelizaeus-Merzbacher-like disease (PMLD) is used to describe these disorders.
Pelizaeus-Merzbacker disease is caused by a mutated gene located on the X chromosome, which is one of the chromosomes determining sex. Men have one X chromosome and one Y chromosome, while women have two X chromosomes. Inherited X-linked recessive disorders usually occur only in men, being passed down via a healthy female carrier who has one normal and one mutated gene. Sons of female carriers of a mutated gene run a 50 per cent risk of inheriting the disease and daughters run the same risk of being healthy carriers of a mutated gene. A man with an inherited X-linked recessive disease cannot pass it on to his sons, but all his daughters will be carriers of the mutated gene.
In rare cases, girls display symptoms similar to those of Pelizaeus-Merzbacher disease. Female carriers have the mutation on one of their two X chromosomes, and their symptoms depend on which of the X chromosomes is most active in each cell.
As more PLP mutations are identified it becomes increasingly clear that Pelizaeus-Merzbacher disease is only one of a spectrum of disorders, distinguished by widely varying symptoms. Severe forms may cause serious motor impairment and intellectual disability while the symptoms of milder forms of the disorder may be limited to spastic paralysis of the leg muscles. The condition is usually divided into four forms:
In classic Pelizaeus-Merzbacher disease the first symptoms present early, usually before the age of five. Low muscle tone (hypotonia) is an early sign of the condition, often noticed in neonates. The head grows slowly and remains small. Most individuals with the disease have involuntary eye movements (nystagmus), and eyesight may be impaired. Noisy breathing (stridor) may also occur. Other common symptoms include periodic bouts of head-shaking, and spastic paralysis in the legs or all the limbs. Difficulties with balance (ataxia), shaking arms (intention tremor) and other uncontrolled movements (chorea and atetosis) make it difficult for people with the condition to feed themselves. Epileptic seizures may occur but are rare.
From the early years, spasticity in arms and legs may be notable. The development of motor skills is delayed. Some individuals learn to walk with support, but for many children mobility is severely impaired.
These children have moderate to severe intellectual disability. Individuals with intellectual disability require more time to understand and learn new skills. They have difficulties processing information and dealing with new situations. It may also be hard to generalize information or to see interconnections between details and broader patterns. Under these circumstances it may take a little longer to express one’s wishes, thoughts, and feelings. If the intellectual disability is moderate to severe, language development will also be impaired. It is therefore important that people interacting with the child are familiar with their non-verbal means of communication such as gestures and mimics.
In severe cases of Pelizaeus-Merzbacher disease life expectancy is shortened.
Congenital Pelizaeus-Merzbacher disease causes severe symptoms from birth, including low muscle tone, nystagmus, noisy breathing and epileptic seizures. These children develop spasticity and do not learn to walk, and they have intellectual disability ranging from moderate to severe. Many die early although some children reach adulthood.
PLP null syndrome, which develops during the first year of life and causes impaired function of the peripheral nerves (peripheral neuropathy), usually gives milder symptoms. Despite the neuropathy, children with this condition usually have better mobility than those with the classic form of the disorder. Life expectancy is not affected as in the classic form of the disease.
X-linked spastic paraplegia (SPG2) may be regarded as the least severe form of the disease. However, walking is difficult because of spasticity in the legs. Nystagmus and loss of bladder control are other symptoms. Individuals with this form of the disease have a normal life span and may have normal cognitive abilities.
A combination of clinical signs and an X-linked recessive inheritance pattern can indicate a diagnosis of Pelizaeus-Merzbacher disease or spastic paraplegia. A diagnosis of PMD may be made after an MRI scan of the brain, which shows that myelination has stopped at a stage comparable to a few months of age. However, it is important to note that other diseases of the brain may show a similar picture. An examination of the eyegrounds (fundoscopy) may indicate that the optic nerve is not fully developed.
A neurophysiological examination usually shows the peripheral nerves conducting impulses normally, but indicates delayed responses in the central nervous system.
It is possible to establish mutations in the PLP gene in up to 95 per cent of all males with Pelizaeus-Merzbacher disease or X-linked spastic paraplegia (SPG2).
When the diagnosis is made the family should be offered genetic counselling. Prenatal diagnosis and pre-implantation genetic diagnosis (PGD) are possible if the mutation in the family has been identified.
There is currently no cure for Pelizaeus-Merzbacher disease. Treatment focuses on alleviating symptoms and compensating as far as possible for disabilities.
Spasticity may be alleviated with medications such as baklofen and botulism toxin. In combination with physiotherapy, the use of orthotic devices, such as braces, and orthopaedic surgery can prevent deformities of the joints (contractures).
In the case of recurrent epileptic seizures, medication is prescribed.
Early vision tests are important. Children with impaired sight require low-vision aids.
Individuals with the disorder may have severe eating problems as a result of their disabilities. Their nutritional requirements may therefore have to be met in other ways, for example by inserting a feeding tube through the nose, or into the stomach through the abdominal wall, a procedure known as percutaneous endoscopic gastrostomy (PEG).
Habilitation should be initiated early. A habilitation team includes professionals with special expertise in how disability affects everyday life, health and development. Support and treatment are offered within the medical, educational, psychological, social and technical fields. Help includes assessment, treatment, the provision of aids, information on the specific disability, and counselling. It also includes information on all available support offered in the community, as well as advice on adjustments to the home environment and other places where the child spends time. The family may also need help in coordinating different measures.
The measures focus on the needs of the child and family, may vary over time, and are always implemented in collaboration with individuals close to the child. The objective is that a young person or adult should be able to participate in community life on his or her own terms. It is important to stimulate speech development from a young age by means including augmentative and alternative communication (AAC), so that the child develops communication skills. Training of motor skills to manage activities of daily living should be adapted to the capacities and limitations of the individual child. Aids to help compensate for impaired mobility are important in making leisure-time activities and everyday life at home, day-care and school easier. The social environment and the way the child/young person is treated are just as important as the physical environment.
There should be close contact with the local authority, where different kinds of help including personal assistance, a contact family or short-term accommodation, to make daily life easier are available.
Adults with the disease may also require continued individual habilitation and support in their daily lives. They may, for example, need housing offering special services and daily activities.
The parents may need psychological support, both at the time of diagnosis and later. Children and young people with the syndrome should also be offered psychological support, adapted to the needs of the individual.
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A group of paediatric neurologists, neuroradiologists, neurochemists and neurologists with a special interest in and knowledge of diseases of the white matter of the brain (the “white matter group”), meets regularly. Clinical information and MRI scans may be sent to the group for examination and discussion (see under the heading “Resource Personnel”). The work of the group does not include clinical examinations of individual patients.
Special expertise in the examination and treatment of children with progressive diseases of the brain can be found at The Queen Silvia Children’s Hospital in Gothenburg. Contacts are Professor Paul Uvebrant and Dr Ragnhildur Kristjánsdottir.
Every university hospital in Sweden has specialists in paediatric neurology and neuroradiology who can examine and assess children and young people with suspected Pelizaeus-Merzbacher disease.
The list below primarily includes physicians in the Swedish “White Matter Group”:
Professor Paul Uvebrant and Dr Ragnhildur Kristjánsdottir, The Queen Silvia Children’s Hospital, SE-416 85 Gothenburg, Sweden. Tel: +46 31 343 40 00.
Professor Oluf Andersen, Neurology Clinic, Sahlgrenska University Hospital/Sahlgrenska, SE-413 45 Gothenburg, Sweden. Tel: +46 31 342 10 00.
Professor Olof Flodmark, Department of Clinical Genetics, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden. Tel: +46 8 517 700 00.
Associate senior physician Karin Naess, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Huddinge, SE-141 86 Stockholm, Sweden. Tel: +46 8 585 800 00.
International
Odile Boespflug-Tanguy, Inserm U384, Faculté de Médecine, 28 Place Henri-Dunant BP 38-63001, Clermont-Ferrand Cedex, France. Tel: +33 473 178179, or 473 448657, fax: +33 473 276132, email: odile.boespflug@inserm.u-clermont1.fr.
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Pelizaeus-Merzbacher disease is represented in patient associations for leukodystrophies. The Swedish Leukodystrophy Association is part of Rare Diseases Sweden, a federation of rare disease organizations. The address is: Box 1386, SE-172 27 Sundbyberg, Sweden. Tel: +46 8 764 49 99, email: info@sallsyntadiagnoser.se, www.sallsyntadiagnoser.se.
In the UK there is a Pelizaeus-Merzbacher Support Group, c/o Contact a Family, 209-211 City Road, London EC1V 1JN, England. Tel: +44 0808 808 3555, email: pmd@dsl.pipex.com.
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Research is ongoing in the fields of medicine, neurochemistry, neuroradiology and neuro-ophthalmology at the Sahlgrenska Academy, University of Gothenburg.
Genetic research is being carried out in many places in the world. For information, contact Odile Boespflug-Tanguy, Clermont-Ferrand Cedex, France. (See address under “Resource Personnel.”)
An information leaflet on Pelizaeus-Merzbacher disease summarising the information in this database text is available free of charge from the customer service department of the Swedish National Board of Health and Welfare (in Swedish only, article number 2012-4-6). Address: SE-120 88 Stockholm, Sweden. Tel: +46 75 247 38 80, fax: +46 35 19 75 29, email: publikationsservice@socialstyrelsen.se. Postage will be charged for bulk orders.
7 besteforeldre (pages 30-35, in Norwegian only), Frambu och Handikappade Barns Foreldreforening (2010). Frambu, Senter for sjeldne funksjonshemninger, Sandbakkveien 18, NO-1404 Siggerud, Norway. Tel: +47 64 85 60 00, fax: +47 64 85 60 99, email: info@frambu.no, www.frambu.no.
Grossi S, Regis S, Briancheri R, Mort M, Lualdi S, Bertini E et al. Molecular genetic analysis of the PLP1 gene in 38 families with PLP1-related disorders: identification and functional characterization of 11 novel PLP1 mutations. Orphanet J Rare Dis 2011; 6: 40.
Henneke M, Combes P, Diekmann S, Bertini E, Brockmann K, Burlina AP et al. GJA12 mutations are a rare cause of Pelizaeus-Merzbacher-like disease. Neurology 2008; 70: 748-754.
Inoue K. PLP1-related inherited dysmyelinating disorders: Pelizaeus-Merzbacher disease and spastic paraplegia type 2. Neurogenetics 2005; 6: 1-16.
Koeppen AH, Robitaille Y. Pelizaeus-Merzbacher disease. J Neuropath Exp Neurol 2002; 61: 747-759.
Plecko B, Stockler-Ipsiroglu S, Gruber S, Mlynarik V, Moser E, Simbrunner J et al. Degree of hypomyelination and magnetic resonance spextroscopy findings in patients with Pelizaeus-Merzbacher phenotype. Neuropediatrics 2003; 34: 127-136.
Shimojima K, Inoue T, Hoshino A, Kakiuchi S, Watanabe Y, Sasaki M et al. Comprehensive genetic analyses of PLP1 in patients with Pelizaeus-Merzbacher disease applied by array-CGH and fiber-FISH analyses identified new mutations and variable sizes of duplications. Brain Dev 2010; 32: 171-179.
Steenweg ME, Vanderver A, Blaser S, Bizzi A, de Koning TJ Mancini GM et al. Magnetic resonance imaging pattern recognition in hypomyelinating disorders. Brain 2010; 133: 2971-2982.
Vaurs-Barrière C, Deviulle M, Sarret C, Giraud G, Des Portes V, Prats-Viñas JM et al. Pelizaeus-Merzbacher-like disease presentation of MCT8 mutated male subjects. Ann Neurol 2009; 65: 114-118.
Woodward KJ. The molecular and cellular defects underlying Pelizaeus-Merzbacher disease. Expert Rev Mol Med 2008; 10: e14.
OMIM (Online Mendelian Inheritance in Man)
www.ncbi.nlm.nih.gov/omim
Search: Pelizaeus-Merzbacher disease
GeneReviews (University of Washington)
www.genetests.org (find GeneReviews, then Titles)
Search: PLP1-related disorders
The Swedish Information Centre for Rare Diseases produced and edited this information material.
The medical experts who wrote the draft of this information material are Associate Professor Mårten Kyllerman and Professor Paul Uvebrant, The Queen Silvia Children’s Hospital, Gothenburg, and Ragnhildur Kristjánsdóttir, Örebro University Hospital.
The material has been revised by Associate Professor Mårten Kyllerman, The Queen Silvia Children’s Hospital, Gothenburg, Sweden.
An expert group on rare diseases, affiliated with the University of Gothenburg, approved the material prior to publication.
Publication date: 2012-09-20
Version: 2.0
Publication date of the Swedish version: 2012-06-14
For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 400, SE-405 30 Gothenburg, Sweden. Tel: + 46 31 786 55 90, email: ovanligadiagnoser@gu.se.