Distal motor neuropathy is a genetically heterogeneous group of hereditary diseases that combine impaired innervation of limb muscles with the development of atrophy without pathology of sensitive fibers. Symptoms of these conditions are slowly progressive weakness of the muscles of the legs, arms and shoulder girdle, as well as a decrease in muscle mass in these areas. Sometimes a violation of vibration sensitivity may be detected. Diagnosis is carried out on the basis of the patient’s examination data, the study of his anamnesis, electromyography and molecular genetic studies. In some cases, histological examination of muscle tissue is performed. There is no effective treatment for this pathology, vitamin therapy and drugs that improve the trophism of nerve tissues are used to slow the progression of the disease.
Distal motor neuropathy (distal spinal amyotrophy) is a group of genetically determined pathologies of various nature characterized by impaired motor innervation of limb muscles with the development of atrophy. Despite the huge number of varieties, the occurrence of such conditions is quite low – depending on the type, its value ranges from 1-40:1000000. Some forms have been known for a long time. Currently, the achievements of modern genetics have made it possible to differentiate a number of diseases that have the same phenotypic manifestations, but have different genetic background. According to many researchers, the study of this condition has not yet been completed – some genes have not been identified, perhaps there are other, even rarer forms.
Due to the huge variety of forms of distal motor neuropathy, the etiology of disorders in this condition is characterized by great variability. A common feature is the degeneration of motor neurons of the anterior horns of the spinal cord or their processes for one reason or another. For example, the most studied distal motor neuropathy of type 5 in this regard is due to a mutation of the BSCL2 gene, which is localized on the 11th chromosome. The gene encodes a special protein seipin, which is part of the endoplasmic reticulum of motor neurons. Due to the mutation, the resulting protein has a defective structure, which complicates the processes of its glycosylation and utilization, so seipin begins to accumulate in neurons. Distal motor neuropathy of the 5th type develops due to the fact that neurons clogged with seipin complexes undergo dystrophy and die.
Similar processes occur in other forms of distal motor neuropathy. Due to one or another mutation, there is a violation of the metabolism or vital activity of motor neurons, which subsequently causes a disease. Since the development of dystrophy of neurons or their fibers requires different time, with different mutations, manifestations of pathology can be detected soon after birth, in childhood, adolescence, adulthood, or even old age. Thus, the combination of all forms creates a continuous spectrum of diseases that can affect people of all ages. The mechanism of inheritance of these pathologies is also different – it can be both autosomal dominant and recessive. There is at least one form of such neuropathy linked to the X chromosome.
Classification and symptoms
According to many geneticists, the classification of forms of this pathology is far from complete at the moment. For a number of types of distal motor neuropathy, the genes responsible for the development of the pathological condition have not yet been identified. In many cases, its pathogenesis remains unclear. Therefore, at present, all known forms of this disease are divided according to the mechanism of inheritance into autosomal dominant, autosomal recessive and sex-linked. Among these groups, various phenotypic subtypes of distal motor neuropathy are distinguished, differing in clinical course. The names of the subtypes come from the English terms Hereditary motor neuropathy (HMN) or Distal spinal muscular atrophy (DSMA). The most common variants of distal motor neuropathy are presented below.
- HMN is a congenital type of distal motor neuropathy, manifested already in newborn children. It is characterized by a very slow progression, inherited by an autosomal dominant mechanism. It is caused by defects in the TRPV4 gene localized on the 12th chromosome.
- HMN2A is a distal motor neuropathy type 2A with an autosomal dominant nature of inheritance, caused by a mutation of the HSPB8 gene located on the 12th chromosome – its defects are the cause of another type of neuropathy, known as Charcot-Marie-Toute syndrome. Occurs in adults, mainly the upper extremities are affected. It is characterized by a slow increase in symptoms: muscle weakness, atrophy and violations of vibration sensitivity.
- HMN2D – distal motor neuropathy with a predominant lesion of the lower legs. It is caused by a mutation of the FBXO38 gene, which is localized on the 5th chromosome. Most often, the first symptoms occur in adolescence or adulthood. At the onset of the disease, there is weakness in the knees, which then develops into a tremor of the lower extremities. In the later stages of the disease, the musculature of the hands is involved in the pathological process.
- HMN5 is one of the most common (relative to other types of disease) and therefore the most studied form of distal motor neuropathy. It is transmitted autosomally dominant, the cause of the pathology lies in a defect of the BSCL2 gene located on the 11th chromosome. It develops mainly in adolescents or adults, occasionally in children. The distal parts of the hands are mainly affected, the symptoms are reduced to the development of weakness and the appearance of tremor of the fingers and hands. Less than half of the patients eventually develop muscle weakness of the distal parts of the legs.
- DSMA1 – distal spinal amyotrophy type 1 with an autosomal recessive inheritance mechanism. It is caused by a mutation of the IGHMBP2 gene localized on the 11th chromosome. It is often characterized by the intrauterine onset of the disease, the musculature of the upper extremity belt is most severely affected. Sometimes degeneration affects motor neurons innervating the respiratory muscles, which dramatically aggravates the course of distal motor neuropathy and can lead to the death of the patient.
- DSMAX is a form of distal motor neuropathy linked to the X chromosome and caused by a mutation of the ATP7A gene. Due to gender-linked inheritance, it occurs in boys, characterized by early onset with damage to all groups of distal limb muscles.
Along with the listed types, there are many forms of distal motor neuropathy with a wide variety of manifestations – for example, with a predominant lesion of the muscles of the vocal cords. Many of these varieties are either not yet associated with defects in certain genes, or are extremely rare. For example, such types as DSMA2 or DSMA4 are described only within one family.
To diagnose distal motor neuropathy, methods such as the study of the patient’s hereditary history, electroneuromyography and molecular genetic studies are used. When examining a patient with almost any form of this condition, weakness of the muscles of the arms and / or legs is revealed, in some cases areflexia is recorded. If distal motor neuropathy has arisen for a long time, muscle hypotrophy is determined, and in severe cases, atrophy of muscle tissues in the distal parts of the extremities is determined. The study of the hereditary history in some cases confirms similar changes in the parents or other close relatives of the patient.
The pattern of electromyography (or electroneuromyography) may vary depending on the type of distal motor neuropathy and, consequently, the pathogenesis of this condition. For example, the DSMA1 type is characterized by a rather noticeable slowdown in the passage of a nerve impulse through the fibers, and for the HMN5 form, the normal value of this indicator is typical in the absence of the action potential of myocytes. A biopsy of muscle tissue in the affected areas almost always reveals signs of hypotrophy and heterogeneity of myocytes. Molecular genetic diagnostics is used only to determine some forms of distal motor neuropathy (for example, HMN2A, HMN, DSMA1). At the same time, it is possible to conduct prenatal diagnostics of such conditions, the material for the study is obtained by biopsy of chorionic villi.
Treatment and prevention
There is currently no specific treatment for any form of distal motor neuropathy. Supportive therapy involves the use of nootropic drugs, drugs that improve tissue trophism, and vitamins, but the effectiveness of such measures is extremely low. Given that most forms of distal motor neuropathy are characterized by mild symptoms and extremely slow progression, some specialists prefer only to observe and control the development of symptoms without prescribing therapy. Physical exercise, contrary to popular belief, often not only does not contribute to slowing down the development of the disease, but also further accelerates the degeneration of neurons or motor fibers. Prevention of distal motor neuropathy is possible only within the framework of prenatal diagnosis and medical and genetic consultation of parents before conception of a child.
The prognosis of the disease varies depending on the form of neuropathy. Congenital and juvenile varieties, as a rule, are more severe and can cause disability at an early age. In addition, in these forms, respiratory muscles are sometimes involved in the process, which significantly aggravates the course of distal motor neuropathy. The varieties of the disease that first appear in adulthood are usually much easier to proceed and progress more slowly. However, even in this case, there is always a risk of a significant deterioration in the quality of life of patients due to hypotrophy and weakness of the muscles of the upper and lower extremities.