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Hereditary Myopathies
Essentials
- The majority of patients with myopathies have an inherited disease.
- Symptoms alone are not usually enough to diagnose myopathy, but they warrant further neurological examinations that are performed in larger hospitals and in special outpatient clinics for neuromuscular disorders.
- National or regional centre(s) with special expertise may be available. See also ERN EURO-NMD http://ern-euro-nmd.eu/.
Suspicion of a myopathy
- Typical symptoms include
- slowly progressive muscle weakness
- muscular atrophy
- muscle weakness, pain or cramps associated with exercise
- ptosis
- dysphagia
- speech impairment.
- Positive family history supports the suspicion.
- Symptoms alone are not usually enough to diagnose myopathy, but they warrant further neurological examinations.
Examination
- History of presenting complaint, thorough family history, physical examination and laboratory investigations
- Plasma creatine kinase is increased in many myopathies.
- Normal values do not exclude the possibility of a myopathy.
- Note that the CK concentration is also increased by traumas, intramuscular injections, and previous ENMG.
- Electroneuromyography (ENMG)
- Muscle biopsy
- Suitable for differential diagnosis between myositis, myopathy and neurogenic muscular problems. Due to the specialist techniques required, biopsies should only be carried out in facilities with relevant experience.
- Imaging of the muscles (primarily MRI)
- Very useful method in assessing the degree and extent of muscle damage
- Often required in order to define the right point for biopsy
- DNA studies
- The primary method if the clinician has a clear suspicion: a child with SMA I-II, dystrophia myotonica (both type 1 and type 2), Duchenne's and Becker's muscular dystrophy, tibial muscle dystrophy, facio-scapulo-humeral (FSH) dystrophy
- Suitable for further investigation when other investigations have raised the suspicion of a specific disease: primary neuropathies, motoneuron diseases, myotonies, hereditary myopathies, dystrophies, mitochondrial myopathies, etc.
- Treatment should be provided under the supervision of a specialist unit.
- There is no treatment that would affect the clinical course for the majority of genetic myopathies.
- Many myopathies hinder mobilisation and coping with daily activities. Physiotherapy, alterations to the patient's home and various aids and equipment are often necessary. Patients may also benefit from adaptation training and occasional rehabilitation at an appropriate facility.
- The patient should also be provided with information about the heritability of the disease. If appropriate, the patient should be referred for genetic counselling for further tests and information.
Myopathies in early childhood
- Symptoms include
- muscle hypotonia, flaccidity or weakness in a neonate or infant, presenting as difficulty in holding the head upright, lack of facial expressions, immobility, difficulty suckling or breathing, or recurrent respiratory tract infections
- dislocation of the hip joint, joint contractures and scoliosis, as well as arthrogryposes, i.e. permanent joint contractures, are findings that may be associated with congenital myopathies.
- E.g. nemaline myopathy appears at this age. Dystrophia myotonica and myasthenia may also be congenital.
Myodystrophies with nervous origin and spinal muscular atrophies
- The early-onset disease forms are usually inherited as an autosomal recessive trait. The progressive lesion is located in the anterior horn of the spinal cord.
- Symptoms include muscular hypotonia, flaccidity, weakness and atrophy. Tongue fasciculations and tremor are a part of the clinical picture.
- SMA (spinal muscular atrophy) I-III are caused by a defect in the SMN1 gene and a direct DNA test can be used for diagnosis. There are also other, more rare spinal muscle atrophies and motor neuropathies.
- There are numerous subcategories of adult-onset spinal muscle atrophies or motor neuropathies that are inherited either recessively (e.g. the X-chromosomal Kennedy's disease, i.e. spinal bulbar muscle atrophy, SBMA) or dominantly (e.g. late-onset lower motor neuronopathy, LOSMoN, that has recently been described in Finland). The most common motor neurone disease is amyotrophic lateral sclerosis (ALS) Amyotrophic Lateral Sclerosis (ALS), which in a significant number of cases is of genetic origin.
SMA I, Werdnig-Hoffmann's disease
SMA II, intermediate form
- OMIM http://www.ncbi.nlm.nih.gov/omim/253550
- There is also an intermediate form of the disease with less severe symptoms and with disease onset at around 12 months of age. It causes considerable disability but life expectancy may be over 50 years.
SMA III, Kugelberg-Welander's disease
- OMIM http://www.ncbi.nlm.nih.gov/omim/253400
- A very rare form of the disease with onset in childhood after the age of 18 months or in young adulthood. The severity and rate of progression of this disease vary.
Amyotrophic lateral sclerosis (ALS)
Inherited polyneuropathies and disorders of the neuromuscular junction
- Inherited polyneuropathies Polyneuropathies and disorders of the neuromuscular junction, such as myasthenia gravis and the myasthenic syndromes Myasthenia Gravis, also cause weakness of the muscles; in myasthenias, muscles tire during repetitive exercise. A small share of myasthenias are hereditary.
Progressive muscular dystrophies
- There are various forms of dystrophies that differ in their clinical picture and the way in which they are inherited. In muscle biopsy the diameter of muscle fibres shows great variability. Some of the fibres are atrophying, some are regenerating and the muscle fibres are replaced by fibrous tissue and fat cells. ENMG is applicable for these myopathies. In the active stage, plasma creatine kinase is often increased up to 50- or 100-fold.
Duchenne's muscular dystrophy
- OMIM http://www.ncbi.nlm.nih.gov/omim/310200
- One of the most severe muscular dystrophies; the pattern of inheritance is X-chromosomal recessive. About one third of the cases are new mutations. The disease occurs in 1/3 500 of newborn boys.
- The underlying cause is dystrophin deficiency in the surface membrane of skeletal muscle cells, which may be apparent in muscle biopsy. A DNA test will give a confirmed result in more than two thirds of the cases.
- The patients are boys whose symptoms appear around the age of 4-5 years.
- Initial symptoms include gait dysfunction and weakness in the proximal muscles (difficulty in getting up from a squat).
- Calves are thick (pseudohypertrophy).
- The muscle weakness increases and the patient is confined to a wheelchair at around 12 years of age.
- Other disease manifestations include joint contractures and deformity of the back (scoliosis) as well as breathing difficulties and cardiomyopathy that predispose the patient to infections.
- About 15% of the carrier women will show symptoms of myopathy in varying extents.
Becker's muscular dystrophy
- OMIM http://www.ncbi.nlm.nih.gov/omim/300376
- Inheritance is X-chromosomal recessive.
- The dystrophin level is reduced, but not as much as in Duchenne's dystrophy.
- Severity is variable.
- Time of onset varies from childhood to adulthood.
- Cardiomyopathy may be the problem that is most difficult to manage.
Limb-girdle dystrophy (LGMD)
- The muscle weakness is localised to the proximal muscles of the extremities (difficulty in ascending stairs and holding arms raised).
- Onset in childhood, in adolescence or in adulthood; prevalence 5/100 000
- Inheritance is usually autosomal recessive, rarely autosomal dominant.
- More than 30 different genes causing the disease are known; they may be differentiated in specialized genetic laboratories.
Facioscapulohumeral muscular dystrophy
- OMIM http://www.ncbi.nlm.nih.gov/omim/158900
- Usually causes muscular atrophy in the affected regions but there is great variability in the clinical picture.
- The progress of the disorder is fairly slow. The prevalence is 3/100 000.
- Inheritance is autosomal dominant; there are, however, also a high number of new mutations without previous family history.
- Diseases with autosomal dominant inheritance
- Belong to the most common dystrophies, with variable clinical expression and severity. The occurrence of type 1 and type 2 varies from region to region; in Finland, the prevalence of both is over 10/100 000.
- Diagnosis is based on DNA study.
Dystrophia myotonica type I
- OMIM http://www.ncbi.nlm.nih.gov/omim/160900
- Age of symptom onset ranges from neonate to old age.
- Clinical manifestations include
- muscular atrophy and weakness especially distally in the extremities, facial muscles and eyelids (ptosis)
- myotonia, e.g. difficulty in relaxation of muscle contraction when the patient is attempting to open his/her fist, evident in electromyography
- endocrine disturbances, e.g. insulin resistance and in men hypogonadism
- cardiac arrhythmias
- cataracts.
- Congenital forms of the disease may include mental retardation.
- If the onset is in the school age the disease may present as difficulties in the school without muscular symptoms.
Dystrophia myotonica type II
- OMIM http://www.ncbi.nlm.nih.gov/omim/602668
- Usually milder than type I
- The onset may be after 25 years of age but often not before the age of 50 years.
- Vague muscular pain and stiffness that may be confused with fibromyalgia
- Progressive proximal muscular weakness
- To various extent: cataract, arrhythmias, endocrinologic disturbances, increased liver enzyme concentrations, tremor, hypertrophy of the calves
- Even EMG may not always reveal myotonia, and creatine kinase concentration is not necessarily increased.
Congenital myotonias and periodic paralyses
- OMIM http://www.ncbi.nlm.nih.gov/omim/160800
- Diseases caused by genetic defects in the ion channels, with dominant or recessive inheritance, but not progressive like myotonic dystrophies
- Characteristic feature: rigidity in clinical examination and/or myotonia in EMG but without findings indicating muscular damage
- Recessive mutations of the chloride channels are among the most common causes. The carrier frequency of such mutations is high, e.g. in Finland about 3%. DNA diagnostics are available.
Distal myopathies
- Myopathies with weakness symptoms predominantly in fingers and ankles
- The diagnosis is based on DNA study performed in a specialized laboratory.
- In 1993 a new phenotype of distal myopathy, tibial muscular dystrophy (TMD, OMIM http://www.ncbi.nlm.nih.gov/omim/600334) was described in Finland, where over 500 cases have been confirmed so far. The true prevalence is estimated to be around 1 000 patients which makes this condition the most common myopathy in the country.
- The symptoms emerge in middle age; the patient develops a slapping and unsteady gait. Electromyography will show characteristic changes of muscle damage and CT/MRI will reveal a highly selective muscle damage in the pretibial muscles.
- The disease progresses slowly. There is no pain or sensory loss. Patients with a considerable foot drop will benefit from supportive walking aids.
- Welander distal myopathy is an autosomal dominant myopathy that belongs to the Swedish disease heritage but is quite common also in Finland. Symptom onset is around the age of 40.
- Several other forms of distal myopathies have been identified in the recent years.
Mitochondrial myopathies
- OMIM http://www.ncbi.nlm.nih.gov/omim/251900
- Myopathies with various clinical expressions: chronic ophthalmoplegia, progressive proximal weakness or the clinical picture of a metabolic myopathy (see below)
- In children often associated with encephalopathy or hepatopathy, but in adults the condition is isolated.
- Lactate concentration may be increased in the childhood.
- The suspicion is confirmed by muscle biopsy and the final diagnosis is settled by DNA methods.
Metabolic myopathies
- These are rare myopathies that manifest themselves as reduced musclular endurance, muscle pain on exertion and increased tendency for cramps, rarely as severe muscle cell damage, rhabdomyolysis, that requires readiness to intensive care because of the risk for acute renal damage. The underlying cause is an enzyme defect in the energy metabolism of the muscles.
- Also mitochondrial myopathies, either isolated or as part of a multi-organ problem, can be counted among metabolic myopathies. Most cases are revealed in basic muscle biopsy investigations.
Secondary myopathies
- A disorder of muscle tissue may be associated with a systemic disease.
- Muscle damage caused by statin therapy
- Hyperthyroidism
- Hypothyroidism
- Hyperparathyroidism, hypercalcaemia
- Cushing's disease
- Alcoholism