Oculopharyngeal muscular dystrophy is a hereditary disease that has both an autosomal dominant and an autosomal recessive variant of inheritance, characterized by a predominant lesion of the muscles of the face and head. Symptoms of this condition are swallowing disorders (dysphagia), ptosis of the eyelids, weakness of facial muscles and ophthalmoparesis. Sometimes general muscle weakness develops. Diagnosis of oculopharyngeal muscular dystrophy is based on the data of the patient’s current status, electromyography, molecular genetic studies. There is no specific treatment of pathology, palliative and symptomatic measures are used.
Oculopharyngeal muscular dystrophy (OMD) is a genetic pathology that manifests itself as a lesion of the muscles of the head and partly of the extremities and has a special character of the mutation that causes it. Historically, the autosomal dominant form of the disease was discovered first – in 1962, Viktor and a team of colleagues observed an unusual combination of dysphagia with ptosis of the eyelids in representatives of three families, the symptoms progressed over time and led to weakness of the upper and lower extremity belts. The study of the hereditary history of patients proved the autosomal dominant mechanism of inheritance of oculopharyngeal muscular dystrophy. Then in 1975, Japanese researchers Satoyoshi and Kinoshita described similar symptoms of myopathy in a girl with healthy parents – this fact, as well as the earlier development of manifestations, indicated an autosomal recessive type of OMD. To date, the exact numbers of the occurrence of the disease have not been clarified, only more frequent occurrence in some national groups (French-speaking Canadians, Bukharian Jews) has been noted. According to modern genetics, oculopharyngeal muscular dystrophy affects both men and women with the same frequency.
The uniqueness of oculopharyngeal muscular dystrophy is the nature of the mutation that causes the development of this hereditary disease. The defect is detected in the PABPN1 gene, which is localized on the 14th chromosome. It encodes polyadenylate-binding protein belonging to the group of proteins of the cell nucleus, which is responsible for the stabilization of matrix RNA molecules formed in the nucleus due to their polyadenylation. In the structure of the gene there is a sequence of repeated GCG triplets, the number of their repeats in a healthy person in 98% of cases is six. It is the change in the number of repetitions of this triplet that causes the development of all forms of oculopharyngeal muscular dystrophy.
In the presence of seven GCG repeats in the PABPN1 gene, especially in the homozygous state, an autosomal recessive form of oculopharyngeal muscular dystrophy develops. However, this does not always happen – approximately 2% of phenotypically healthy people have seven repeats in this gene, both in a heterozygous and homozygous state. The reasons why such persons do not develop OMD have not been reliably studied. In the case of a more pronounced violation of the structure of the PABPN1 gene, in which more than ten GCG repeats are observed, an autosomal dominant type of oculopharyngeal muscular dystrophy occurs. At the same time, in homozygotes with such a disorder (the presence of such a number of repeats in both alleles), the pathology is generally more severe and is diagnosed on average 15-20 years earlier.
Thus, the peculiarity of oculopharyngeal muscular dystrophy is the fact that this disorder is caused by an “overdose” of a certain genetic material. At the same time, the form of pathology in terms of the mechanism of its inheritance and symptoms depends on the scale of the above-mentioned “overdose”. The presence of a genetic defect leads to the appearance of an abnormal “tail” of the residues of the amino acid alanine in the polyadenylate-binding protein, which disrupts the functions of this protein. It is the presence of a polyalanine sequence in the structure of this protein that is associated with the appearance of filamentous inclusions in cell nuclei, which is one of the signs of oculopharyngeal muscular dystrophy.
The clinical picture of oculopharyngeal muscular dystrophy depends on the form of the disease. The most severe and early manifestations are characterized by an autosomal recessive type of this pathology – often the first symptoms appear in childhood. First, general muscle weakness, decreased activity of facial muscles, minor ptosis of the eyelids are recorded. In the autosomal recessive form of oculopharyngeal muscular dystrophy, swallowing disorders develop quite quickly – dysphagia, which often makes the nutrition process simply impossible. In the future, ophthalmoparesis and increasing muscular dystrophy of the upper and lower extremities occur.
The autosomal dominant variant of oculopharyngeal muscular dystrophy is characterized by a more benign course and late onset of symptoms. Usually, the first signs of the disease are noted at the age of 40-50 years, occasionally appear at 15-20 years (in homozygotes according to the mutant form of the PABPN1 gene). One of the first symptoms of this pathology is ptosis of the eyelids, which is soon joined by dysphagia, decreased activity of facial expressions, weakness of other muscles of the face and neck. As autosomal dominant oculopharyngeal muscular dystrophy progresses, weakness of the muscles of the distal extremities and, in some cases, the anal sphincter occurs, which causes encopresis. The course of the disease is long, according to various sources, it can take from 5 to 15 years.
To diagnose oculopharyngeal muscular dystrophy, methods of pathohistological study of muscle tissues, electromyography and study of the patient’s hereditary history, as well as molecular genetic methods are used. During examination, ptosis of the eyelids, swallowing disorders, general muscle weakness, decreased facial activity are detected. The age of patients varies depending on the form of the disease – in the autosomal recessive variety, patients are mainly children, in the case of the dominant type – adults 40-50 years old (less often 15-25 years old). A thorough analysis of the hereditary history allows us to determine the mechanism of inheritance of oculopharyngeal muscular dystrophy.
During electromyography, a decrease in the amplitude of muscle impulses, their elongation and polyphase are detected. A muscle tissue biopsy followed by histological examination usually reveals the presence of filamentous inclusions in the cell nuclei, which sometimes acquire a branched character. With oculopharyngeal muscular dystrophy, violations in the structure of type 1 fibers often occur, with a long-term current disease, signs of muscle atrophy are added. Molecular genetic diagnosis of this pathology is the most reliable and relatively simple (due to the nature of the mutation) method of determination. To this end, the geneticist performs amplification of a section of the GCG sequence followed by electrophoresis to determine its size – an increase in the number of GCG repeats indicates the presence of oculopharyngeal muscular dystrophy. Prenatal diagnosis of this condition by genetic methods is also possible, the material for the study is obtained by amniocentesis or biopsy of chorionic villi.
There is no specific treatment for oculopharyngeal muscular dystrophy, various therapeutic and surgical measures are used to reduce the symptoms of the disease. Prednisone, creatine and other similar drugs are used to slow the progression of pathology, but their effectiveness varies in different patients. Patients with oculopharyngeal muscular dystrophy are prescribed a variety of physical exercises that reduce the rate of increase in muscle weakness. With pronounced ptosis of the eyelids and associated visual impairment, you can use a special adhesive tape to support or, with relatively preserved activity of facial muscles, perform surgical correction (blepharoplasty).
The most severe complication of oculopharyngeal muscular dystrophy requiring medical intervention is dysphagia, which in severe cases leads to complete inability to swallow. In such a situation, nasogastric or other probes are used to feed the patient, sometimes a stoma is applied. Surgical methods of relieving symptoms of dysphagia (for example, dissection of the ring-pharyngeal muscle) can lead to temporary relief, but at the moment most specialists try not to use such techniques.
Prognosis and prevention
The prognosis of oculopharyngeal muscular dystrophy of any type (both autosomal dominant and recessive) is unfavorable, since the disease almost always causes severe eating disorders due to dysphagia. In addition, progressive muscle weakness of the extremities may eventually lead to disability of the patient. Due to swallowing disorders, food particles or saliva from the oral cavity often enter the respiratory tract, bringing with them an infection and provoking quite severe aspiration pneumonia. It is this defeat of the respiratory system, as well as its complications, that most often cause the death of patients with oculopharyngeal muscular dystrophy. Prevention of this condition is possible only within the framework of medical and genetic counseling of parents before conception of a child and prenatal diagnosis in case of the presence of such a disease in close relatives.