Pelizaeus-Merzbacher disease is a hereditary leukodystrophy with degeneration of the nerve substance. Affected individuals suffer from a mutation-related disorder of myelination that results primarily in motor and intellectual deficits. Therapy of the disease has been limited to supportive measures of physiotherapy and psychotherapy.
What is Pelizaeus-Merzbacher disease?
Leukodystrophies are genetic metabolic diseases in which the white matter of the nervous system progressively degenerates due to deficiency symptoms. Myelin, which surrounds the nerves, is degraded in particular. Myelin represents an insulation in the human organism. Like in a plastic cable, the bioelectrical action potential of nerve excitation is protected in myelinated nerve tracts against loss to the environment. Without myelin, the function of a nerve is massively impaired. Excitation losses occur. Conduction of excitation is impeded. Patients with leukodystrophies therefore suffer from neurological deficits. Leukodystrophies are particularly noticeable in the area of motor function. Pelizaeus-Merzbacher disease is a leukodystrophy whose first description goes back to the German neurologist F. C. Pelizaeus and the psychiatrist L. Merzbacher. The disease is characterized by a disorder in myelin sheath formation, which can manifest itself in a variety of different symptoms. All age groups can be affected. The prevalence is estimated at approximately one to nine cases per 1000,000 people. Different literature also refers to leukodystrophy as cerebral sclerosis, diffuse familial leukodystrophy, or Pelizaeus-Merzbacher cerebral sclerosis.
Causes
Like all leukodystrophies, Pelizaeus-Merzbacher disease is caused by degeneration of the white matter of the nerves. In the case of the disease, this degeneration corresponds to a genetically determined disorder in the formation of myelin sheaths. The myelin formation disorder is due to a multiple mutation, which has now been localized to that of the PLP1 gene. This gene encodes proteolipid protein 1 and is located in gene locus Xq22 of the X chromosome. The type of mutation that occurs in the PLP gene can vary from case to case. For example, the mutations may correspond to deletions. However, duplications of the gene have also been detected in patients with Pelizaeus-Merzbacher disease. Due to the mutations, there is a defective production of proteolipid proteins. The defective proteins in turn result in defective myelin, since they play an essential role in myelin synthesis. This results in non-functional myelin sheaths, which cause loss of potential in the nerves. The disease is inherited in an X-linked recessive manner. For this reason, only the male sex usually suffers from the disease. Females are usually silent carriers.
Symptoms, complaints, and signs
The leading symptom of Pelizaeus-Merzbacher disease is a delay in mental as well as motor development. In addition to uncontrollable twitching of the eyes in the form of nystagmus, the leading symptoms of the disease include spastic and flaccid paralysis of the muscles as well as loss of tone with ataxic unsteadiness of stance and gait. Initial symptoms usually manifest in infancy or childhood. However, manifestation in adulthood is also conceivable. In principle, the congenital form is usually the most severe. Dyspnea or stridor often occur in addition to the above-mentioned symptoms. Spastic tetraparesis is often part of the clinical picture. In the classic form with manifestation in the first months of life, nystagmus and muscle hypotonia progressively turn into spasticity. Besides the classic and congenital form, there is a transitional form with a degree of impairment between the classic and the congenital variant. In principle, therefore, different degrees of severity are conceivable. The symptoms can be relatively wide-ranging, so that the clinical picture of patients often differs greatly.
Diagnosis and course of the disease
Initial clues to Pelizaeus-Merzbacher disease are provided by neurologic examination and history. Because no biochemical markers are available for the disease, imaging plays the most important role in the diagnostic process. Magnetic resonance imaging of the brain reveals disturbances in myelination.Since such disorders are not specific for Pelizaeus-Merzbacher disease, a differential diagnostic differentiation from other demyelinating diseases must be made. Magnetic resonance spectroscopy can be helpful in this process. The final confirmation of the suspected diagnosis usually takes the form of molecular genetic analysis. A detected mutation of the PLP1 gene is considered diagnostic. In principle, prenatal diagnosis is possible. The prognosis of patients depends on the severity of the disease and the type of PLP mutation. Mild courses are just as conceivable as severe forms with a fatal course in childhood.
Complications
Because of Pelizaeus-Merzbacher disease, affected individuals suffer from a number of different limitations and symptoms. In most cases, only a few of the ailments can be completely cured, leaving the affected person dependent on the help of others in his or her life. First and foremost, patients with this disease suffer from significantly delayed development. The motor development of the patient is also considerably restricted in this disease and there are also severe mental deficits. Likewise, in Pelizaeus-Merzbacher disease, patients suffer from gait instability and various paralyses and other disorders of sensitivity. Occasionally, signs of spasticity become apparent. In many cases, bullying or teasing may occur, especially in children, so that patients also suffer from psychological complaints and depression as a result of Pelizaeus-Merzbacher disease. There is no causal treatment for Pelizaeus-Merzbacher disease. Especially for the parents and for the relatives the disease represents a strong psychological burden. Furthermore, some complaints can be limited with the help of therapies. However, there is no complete cure for this disease. Possibly, the life expectancy of the patient is also reduced in the process.
When should one go to the doctor?
Since Pelizaeus-Merzbacher disease leads to severe delays in child development, this disease must always be examined and treated by a doctor. This is the only way to prevent further complications. The earlier treatment of Pelizaeus-Merzbacher disease is initiated, the higher the chances of complete recovery. A doctor should be consulted if the child suffers from paralysis or an unsteady gait. The paralyses can affect different parts of the body. Likewise, the child’s motor or even mental development may be significantly limited and delayed. If parents notice these delays, seek immediate medical attention. Some children also exhibit spasticity due to Pelizaeus-Merzbacher disease. Usually, Pelizaeus-Merzbacher disease is diagnosed by a pediatrician or by a general practitioner. However, further treatment takes place at different specialists and depends on the exact manifestation of the symptoms. Often, Pelizaeus-Merzbacher disease also requires psychological treatment, in which both the parents and the children can participate. The life expectancy of the affected person is usually not negatively reduced by Pelizaeus-Merzbacher disease.
Treatment and therapy
Pelizaeus-Merzbacher disease has its cause in the genes. For this reason, no causal therapy exists for patients with the disease to date. Causal therapies could at most be opened up by gene therapy. Gene therapy approaches are currently a focus of medical research. However, the approaches have not yet reached the clinical phase. Therefore, patients with Pelizaeus-Merzbacher disease are treated purely symptomatically and supportively at the present time. The individual therapy steps depend on the symptoms present in each individual case. The focus of therapy is on supportive measures that are intended to delay the progression of the disease and thus improve the quality of life of those affected. These measures include, above all, occupational therapy and physiotherapy. Mental development can be supported by means of early intervention. In addition, the relatives of those affected receive emotional support. Often, for example, parents are assisted by a psychologist or psychotherapist. Contacts are established with the European Association against Leukodystrophies. Special consultation hours are also offered by various university hospitals.
Outlook and prognosis
Pelizaeus-Merzbacher disease is chromosomal in origin. It occurs in three different forms. These are decided by the age of onset and the expression of the disease or its severity. These parameters then also influence the prognosis. This very rare disease mainly affects male patients. In the congenital variant of the disease, the most serious symptoms are observed. If Pelizaeus-Merzbacher disease first breaks out after birth, the symptoms gradually develop in varying degrees. The prognosis of the transitional form is intermediate between connatal and classic Pelizaeus-Merzbacher disease. However, milder courses of Pelizaeus-Merzbacher disease also occur. Depending on the type present, the prognosis for this disease varies. Without interdisciplinary treatment by neurologists, orthopedists, physiotherapists, gastroenterologists and pulmonologists, patients cannot be helped sufficiently. The progressive course of the disease varies depending on the phenotype. Life expectancy may not necessarily be limited in the presence of Pelizaeus-Merzbacher disease. At least in the milder courses it is relatively normal. Often there is a slower progression of the disease in youth. How high the quality of life can be depends on the clinical picture. The prognosis for severely affected people is different. These usually die before the age of twenty. Until then, those affected can only be given relief by means of symptomatic treatment.
Prevention
To date, Pelizaeus-Merzbacher disease can only be prevented by genetic counseling during the family planning phase. Depending on one’s risk of inheriting the disease, the decision may be made not to have a child of one’s own. In addition, prenatal diagnostics can take place if necessary.
Follow-up
Affected individuals usually have few measures and options for aftercare in Pelizaeus-Merzbacher disease. In this disease, first and foremost, rapid and especially early detection of the disease is very important to prevent further complications or symptoms. Those affected should consult a doctor at the first signs and symptoms of the disease in order to prevent a further worsening of the symptoms or even further complications. As a rule, those affected by Pelizaeus-Merzbacher disease are dependent on measures of physiotherapy or physical therapy, although self-healing cannot occur. Many of the exercises from these therapies can be repeated at home. Since this is a genetic disease, those affected should undergo genetic testing and counseling if they wish to have children to prevent Pelizaeus-Merzbacher disease from recurring in their children and descendants. Since the disease can also lead to depression and other psychological upsets, help and support from one’s own family and friends is often very important in this process. Pelizaeus-Merzbacher disease does not usually reduce the life expectancy of the affected person.
What you can do yourself
Because Pelizaeus-Merzbacher disease is genetic, no self-help measures exist to combat the disorder causally. In most cases, the disease manifests in childhood, so it is up to the parents and families of patients to initiate appropriate measures in a timely manner. Affected parents should first ensure that their child is treated by a physician who has experience with this relatively rare disorder. If the family doctor cannot recommend an expert, the medical association can help. Many university hospitals maintain special consultation hours where patients and their relatives can obtain comprehensive information about the disease and its course. For young parents, it is important to get to grips with what is in store for them and their sick child at an early stage. For well-informed parents, it is easier to find a place in childcare in good time and, later, a school that will guarantee their child the best education within his or her means. In addition, caring for and living with a disabled child is also a great challenge for family members. Those affected should therefore not be afraid to seek help for themselves as well.Often the exchange with other affected persons already helps. The European Association Against Leukodystrophies is helpful in establishing contact.
