Machado-Joseph disease is a neurodegenerative disorder belonging to the spinocerebellar ataxia group. The cause of the disease is a genetic mutation that is passed on in an autosomal dominant inheritance. To date, only supportive treatments such as physical and occupational therapy are available.
What is Machado-Joseph disease?
Neurodegenerative diseases are characterized by pathologic processes in the nervous system that cause loss of function of nerve cells. The group of neurodegenerative diseases consists of different subgroups. One of them is spinocerebellar ataxia 3, a group of diseases with degenerations of the central nervous system. Spinocerebellar ataxia 3 corresponds to Machado-Joseph disease (MJD). During the course of the disease, there is progressive loss of Purkinje cells. These are the largest neurons of the cerebellum with localization in the stratum ganglionare of the cerebellar cortex. Purkinje cells are equipped with metabotropic glutamate receptors that serve to modulate and integrate motor efferents, thus enabling motor learning. The prevalence of spinocerebellar ataxias is reported to be one to nine cases per 100,000 people. Machado-Joseph disease is the most common form in Germany.
Causes
Machado-Joseph disease is a hereditary disease. As for all other hereditary diseases, the primary cause of spinocerebellar ataxia 3 is in the genes. Machado-Joseph disease is considered to have an autosomal dominant mode of inheritance. Familial clustering has therefore been observed in the cases documented to date. Sporadic occurrence without familial clustering is rather rare. Inherited in Machado-Joseph disease is a genetic mutation. This change in genetic material affects the gene located on chromosome 14 in gene locus q24.3-32.1. The gene located there no longer fulfills its physiologically intended coding and, as a result of the mutation, extends the polyglutamine region. More than a dozen different genes have been identified to date as mutation loci for spinocerebellar ataxias. In the course of MJD, unlike other forms of spinocerebellar ataxia, the mutation causes progressive degeneration of the defective Purkinje cells, leading predominantly to movement disorders.
Symptoms, complaints, and signs
Patients with Machado-Joseph disease suffer from disorders of the motor coordination center. This motor center is located in the cerebellum and is associated with Purkinje cells, which in a healthy organism control the integration of motor movement signals through their metabotropic glutamate receptors. As the Purkinje cells of patients with Machado-Joseph disease progressively degenerate, it is mainly the motor function of the affected persons that is disturbed. In middle age, nonspecific movement disorders increasingly occur. Affected individuals perform seemingly nonsensical movement patterns because their control center no longer integrates motor efferents in a meaningful way, making movement planning difficult. MJD initially manifests itself mostly in eye movements without a logical pattern. Fixation appears to be impeded by the movements. The more the disease progresses, the more the sense of orientation is impaired. Severe disturbances of perception are added to the symptomatology. Although the symptomatology in individual cases depends on the severity of the progression, there is usually at least a moderate disability after a certain point.
Diagnosis and course of the disease
The diagnosis of Machado-Joseph disease is made on the basis of clinical symptoms, with characteristic eye movements being most diagnostic in early stages. Family history is a crucial point in the diagnostic process. The differential diagnostic differentiation of the disease from other spinocerebellar ataxias is not readily apparent at first glance. Imaging of the brain shows typical changes within the cerebellum. Molecular genetic analysis, which provides evidence of the associated mutation, can confirm the diagnosis and aid in differential diagnosis. The prognosis for patients with Machado-Joseph disease depends on the symptoms and the course in each individual case. Life expectancy of affected individuals is usually not affected.However, multiple disabilities are to be expected for particularly severe courses, associated with more or less high levels of care. Mild cases with moderate impairment in daily living have also been documented.
Complications
As a result of Machado-Joseph disease, affected individuals primarily suffer from various disorders of coordination or concentration. The daily life of the affected persons is considerably restricted by this disease, so that in some cases they are dependent on the help of other people. Furthermore, the general condition of the patient deteriorates in the course of the disease, so that movement disorders continue to occur. The patient’s motor skills are also reduced and there is discomfort with movement planning. Not infrequently, orientation also suffers from Machado-Joseph disease, so that those affected are often confused and do not know where they are. However, the exact symptoms and complications depend very much on the severity and general condition of the patient. As a rule, Machado-Joseph disease leads to mental disability of the patient. It is not possible to treat Machado-Joseph disease causally. For this reason, only the symptoms and discomfort can be limited, although it will not result in a completely positive course of the disease. However, the life expectancy of those affected is not reduced by the disease. Patients are then dependent on various therapies that can facilitate their daily lives.
When should one go to the doctor?
If a newborn child shows mobility disorders, a medical examination is needed. In many cases, pediatricians or nurses can detect initial movement irregularities immediately after delivery. They independently initiate the necessary steps for medical care in a routine procedure. If the first abnormalities occur within the child’s growth process, a pediatrician should be consulted. If movement patterns are unusual or interpreted by the parents as nonsensical, the observations should be presented to a physician. If eye movements are perceived to be off the norm, there is cause for concern. As soon as they do not make sense and continue for several days or weeks, a medical examination is advised. If the child has visible difficulty with movement planning or if orientation problems are apparent, medical attention is needed. If children show problems with fixation of objects and at the same time their own movement patterns in reaching the target, a disorder is present. A visit to the doctor is necessary so that the cause of the complaints can be determined. If there is a disturbance in perception, learning problems or a developmental delay, a follow-up visit to a doctor is necessary. If severe differences in memory or locomotion can be observed in direct comparison to children of the same age, a physician should be consulted.
Treatment and therapy
Machado-Joseph disease is among the incurable diseases. Thus, causal therapy is not available for patients with the movement disorders. Causal therapies resolve the cause of a disorder to make all symptoms disappear. Since the cause of spinocerebellar ataxias lies in the genes, only gene therapy approaches could hold out the prospect of causal treatment and associated cure. Gene therapy is currently a focus of medical research. However, approaches have not yet reached the clinical phase. Therefore, patients with Machado-Joseph disease have so far received only supportive care. Symptomatic treatment approaches are severely limited, due in large part to the rarity of the disease in the U.S. and central European regions. Supportive treatment measures primarily include physiotherapy and occupational therapy. Occupational therapy in particular teaches patients how to cope with the disease in everyday life. The use of various aids and other compensatory strategies makes everyday life easier for them and improves their quality of life. In addition, those affected are usually offered psychotherapy. Together with an experienced therapist, they come to terms with their illness and come to terms with the diagnosis. For relatives, too, psychotherapeutic support can be a useful step in coming to terms with the disease.Genetic counseling is equally important for affected families. Drug treatment approaches to delay the course of the disease do not yet exist. However, regular physical therapy may delay progression, according to speculation.
Outlook and prognosis
The outlook for people with Machado-Joseph disease is considered intermediate. The courses of Machado-Joseph disease vary from individual to individual. This disease is caused genetically. So far, the symptoms of Machado-Joseph disease can only be alleviated in a supportive way. In addition, the hereditary disease progresses over the years. Machado-Joseph disease causes significant disability and increasing mobility limitations by midlife at the latest. With aging, the prospects for a symptom-free life therefore increasingly worsen. However, the outlook regarding the course of the disease depends on the symptoms present. In most cases, the life expectancy of affected individuals is not affected by Machado-Joseph disease. However, it is problematic that there are affected persons with particularly severe courses. These patients suffer from multiple disabilities. These result in a need for care, which can be of varying degrees. The reason for this is a more or less severe disorder of movement coordination. Despite an overall moderate prognosis, milder cases of Machado-Joseph disease have also been documented in patients with moderate to moderately severe impairment in everyday life due to motor disturbances. The sense of direction is also increasingly impaired as Machado-Joseph disease progresses. As the condition of affected individuals worsens, the degree of disability or need for care often increases as they progress. As a minimum, a moderately severe degree of disability can be assumed in older affected individuals.
Prevention
Like all other hereditary diseases, Machado-Joseph disease can so far only be prevented by genetic counseling during the family planning phase. Couples at increased risk may choose not to have their own children and to adopt.
Follow-up
Because treatment of Machado-Joseph disease is complex and lengthy, there is no aftercare in the strict sense. Rather, it manifests as concomitant measures to gain confidence in dealing with the disease. Those affected should try to build up a positive attitude despite the difficult circumstances. Relaxation exercises and meditation can help to calm and focus the mind. Sufferers are usually permanently dependent on the help of relatives, as everyday life is considerably restricted by the disease. The treating physicians try to limit the symptoms so that leading a normal life becomes easier for the affected person. Machado-Joseph disease cannot be cured. Sufferers must permanently undergo various therapies so that a normal life can be led. To better cope with the hardships, it may help to seek psychological support.
This is what you can do yourself
Machado-Joseph disease is a genetic disorder that has no cure. It is progressive and leads to ataxia of the affected person, the movement patterns are impaired. This impairment can be at least partially counteracted with physiotherapy. It has already been shown that the progression of the disease could be slowed down by physiotherapy. In general, it is important that the patient does not give up and continues to move as much as possible. In some cases, the brain is also affected by the disease. If speech is impaired, logopedic measures can lead to improvement. Unfortunately, the progression of Machado-Joseph disease is not possible with the measures available today. Physical and mental disabilities often occur due to the progression of the disease. This can lead to emotional stress for the affected person. The social environment consisting of partner, family and friends can be a psychological support for the affected person and help him to cope with everyday life. In addition, the support of a psychotherapist is helpful, as he or she can provide the affected person with professional care during the ongoing illness.If the affected person has a family, it is significant that the family undergoes genetic testing and counseling, as the disease can be genetically inherited.
