Congenital muscular dystrophy (CMD) is a primary, progressive myopathy with symptoms appearing at birth or within the first few months of life. the first case of CMD was described by Batten in 1903, and since then experts have reported different types of CMD. CMD is uncommon, but is an important cause of floppy children, and to date To date, 15 genes are known to be responsible for CMD.
Clinical presentation and typing
About 50% of CMD patients in Europe and the United States are laminin-a2 negative CMD, which is generally classified into two major groups according to the results of laminin-α2 staining. In Japan, the classification is based on Fukuyama type CMD and non-Fukuyama type CMD. Late onset or mild allelic disease exists in almost all hereditary CMDs, and the relatively common types of CMDs are described as follows.
1. extracellular matrix defects
(1) Laminin-a2 deficiency (MDC1A): Laminin is involved in cell adhesion, differentiation, growth, shaping and migration, and laminin 2 is present in the extracellular matrix of transverse muscle, peripheral nerves, nerve-muscle junctions, skin tissue, etc. MDC1A is associated with a defect in one of the three subunits of laminin 2, the a2 chain (laminin-a2, also called merosin). related. Deficiency of this protein causes disruption of the cytoskeleton-extracellular matrix junctions, leading to degeneration and necrosis of myofibers and the appearance of Merosin-negative myofibers. The gene LAMA2 is localized to 6q22-23.
The disease is prevalent in Europe and the United States, and affects children mostly at birth or within the first 6 months of life, presenting with hypotonia and hypotonia, joint contractures, and involvement of facial and respiratory muscles without ocular symptoms. There is no or only mild mental retardation. Cranial CT showed extensive white matter hypodensity, brain MRI showed abnormal signal in white matter and very mild cortical changes.
(2) CMD with Ullrich congenital muscular dystrophy (UCMD): This disease is caused by defective type VI collagen. type VI collagen has three chains, the genes COL6A1 and COL6A2 encoding the a1 and a2 chains are located at 21q22.3, and COL6A3 encoding the a3 chain is located at 2q37. type VI collagen is found in the basement membrane of skeletal muscle and cardiac muscle cells in the reticular Type VI collagen forms microfilaments in the basement membrane of skeletal and cardiac muscle cells in the form of head-to-tail junctions and binds to other basement membrane components such as type IV collagen, fibronectin, double-glycan chain proteoglycans, basement membrane proteoglycans, core proteoglycans, and also binds to transmembrane receptors such as integrins to mediate signal transduction. Abnormalities in this protein lead to impaired maturation and regeneration of myofibers and the typical pathological changes of myotonic dystrophy, sometimes with myopathy-like or neurogenic pathological changes.
The typical clinical manifestations of the disease are postnatal onset, large joint contractures of the proximal extremities, scoliosis, common congenital slant neck and congenital hip dislocation, progressive generalized muscle weakness and myasthenia, distal joint hyperextension due to low muscle tone, soft skin on the palms of the hands and the soles of the feet, and hyperkeratosis of the skin on the extensor side of the upper and lower extremities, a skin change that is consistent with UCMD. This skin change is consistent with UCMD and is accompanied by a tendency to scar formation. Due to poor chest wall extension and diaphragmatic weakness, patients under 20 years of age tend to suffer from fatal infections leading to respiratory failure. Intelligence is normal. Many children have been found to have dominant de novo mutations in the COL6A1, COL6A2 and COL6A3 genes.
Bethlem myopathy is allelic to UCMD and is autosomal dominant. The disease is relatively mild. Initially thought to be benign, subsequent studies have shown that Bethlem’s myopathy also progresses slowly to contracture after initial hypermobility of the joints, and that more than 2/3 of patients over 50 years of age require an appliance to assist with ambulation and may develop restrictive lung disease.
2. Alpha-dystroglycanopathy (a-DG): Most CMDs in this category have skeletal muscle, brain and eye lesions with overlapping clinical symptoms, and a common feature is hypoglycosylation of a-DG.
(1) Muscle-eye-brain disease (MEB): first discovered in Finland, now reported in several countries. The gene is located at 1p34.1 and the gene product POMGnT1 is an O-linked glycosyltransferase. Immunohistochemical staining for muscle merosin is positive. The main clinical features are CMD with severe myopia, retinal degeneration, optic nerve atrophy, giant cerebral gyrus, multiple cerebellar gyrus, hydrocephalus, hyaline septum and corpus callosum hypoplasia or agenesis.
(2) Walker-Warburg syndrome (WWS): the gene product mannosyltransferase (POMT1/POMT2) is also an O-linked glycosyltransferase. Positive staining for muscle merosin. Clinical features are CMD with type II anencephaly or synencephaly, hydrocephalus, cerebellar and brainstem dysplasia, and extensive cerebral white matter abnormalities. Typical ocular lesions include anterior and posterior chamber dysfunction, macroglossia, bulls-eye or microphthalmia, iris defects, cataracts, optic nerve hypoplasia, and retinal anomalies. The disease is severe, with hypotonia of the facial muscles and extremities present at birth and prominent brain symptoms.
(3) Fukuyama type CMD (FCMD): It occurs in Japanese and is rarely reported in other countries. The gene is located at 9q31 and the gene product Fukutin, whose function is not known yet. It is positively expressed by merosin staining of muscle fibers. The main clinical features are progressive myotonic dystrophy with extensive neurological congenital malformations, including multiple microcephalic gyrus, giant gyrus, and type II anencephaly. Ocular lesions include myopia, ocular motility abnormalities, and also optic nerve hypoplasia and retinal detachment. The onset of the disease is most often within the first 6 months of life, with muscle weakness and hypotonia, delayed head raising and sitting, marked involvement of the facial muscles, often with pseudohypertrophy of the gastrocnemius and joint contractures. Mental retardation and epilepsy.
(4) Congenital muscular dystrophy type 1C (MDC1C): The causative gene is located at 19q13.3 and encodes a Fukutin-related protein, which may be a glycosyltransferase. Mutations in this gene cause a variety of phenotypes, including LGMD2I in mild cases and MDC1C in severe muscle weakness, inability to stand alone, mental retardation, and cerebellar cysts. Recently, some children with mutations in this gene have been found to exhibit severe WWS-like symptoms.
(5) Congenital muscular dystrophy type 1D (MDC1D): the gene is located at 22q12, and the gene product may also be a glycosyltransferase. It is manifested as myotonic dystrophy with mental retardation.
3. Endoplasmic reticulum protein defect: CMD with early spinal ankylosis (RSMD1): the causative gene is located at 1p36-p35 and is caused by a defect in selenoprotein N (SEPN1). Selenoproteins are located in the endoplasmic reticulum and are a family of enzymes containing a single selenium atom that form selenocysteine in the catalytic region and are involved in oxidation-reduction reactions and may be involved in protein translocation, processing, or stabilization of the calcium endotropic environment. Because of the high expression of SEPN1 in the diaphragm, patients with RSMD1 often present with severe respiratory insufficiency.
The disease is characterized by limited lumbar back and cervical flexion and impaired spinal and thoracic mobility in early childhood due to contracture of the spinal extensors, resulting in spinal ankylosis with scoliosis and anterior scoliosis with pelvic tilt with respiratory insufficiency. Muscle CT or MRI revealed selective extensor, suture, biceps femoris, and rectus femoris muscle involvement, resulting in characteristic medial thigh muscle atrophy.
Skeletal muscle pathology was myopathy-like changes.
4, Nuclear membrane protein defects: LMNA-associated congenital muscular dystrophy (L-CMD), one of the spectrum of nuclear laminopathies (laminopathies), manifests as weakness of vertical head and trunk support during the first 6 months of life or progressive loss of head elevation after acquiring solitary sitting or walking alone (drop head syndrome). Patients with this subtype are very severe with congenital onset of symptoms, most can sit, stand or walk, and then tend to regress rapidly. Frequently, axial-cervical hypotonia and muscle weakness progress rapidly, followed by a more gradual progression of proximal upper extremity and distal lower extremity muscle weakness. The facial muscles are rarely involved, and as the disease progresses, the typical presentation is head hypoplasia, thoracolumbar hyperextension, lower extremity contractures, and clubfoot, but no significant upper extremity contractures. Therefore, trunk muscle weakness, spinal ankylosis, head drop, scapulohumeral and distal muscle weakness are characteristic. As muscle weakness progresses, restrictive lung disease can lead to respiratory insufficiency. L-CMD can also be considered as an early onset variant of Emery Dreifuss myotonic dystrophy.
There are several pathological manifestations: myotonic changes (deltoid more than quadriceps); non-specific myopathic manifestations (mainly quadriceps); significant atrophy of myofibers, mostly type 1, which may show inflammatory myopathy-like manifestations, with occasional positive inflammatory markers.
The causative gene LMNA is located at 1q21.2-q21.3 and encodes the nuclear lamin A/C protein, which is a common “gripper” for multiple binding proteins. The mutation in all children is a dominant de novo LMNA mutation.
Ancillary tests
1, serum CK Laminin-a2 deficiency and alpha anti-myasthenia-associated glycoprotein disease can be 20 to 100 times higher than normal, other types of congenital myotonic dystrophy generally have mild to moderate increases in CK, and type VI collagen disease can be normal.
2.Electromyography Generally, the damage is myogenic.
3.Head MRI Laminin-a2 deficiency has abnormal signals in the white matter of the brain. aAnti-myasthenia-associated glycoprotein disease has abnormal brain development.
4.Pathological examination Most of them are myotonic changes, the size of muscle fibers varies, small and round muscle fibers can be seen, interstitial connective tissue hyperplasia, muscle fiber necrosis and regeneration are generally not significant. LMNA-related congenital myotonic dystrophy can appear inflammatory myopathy changes.
Diagnosis and differential diagnosis
The diagnosis of CMD is based on the following: muscle strength, hypotonia and joint contractures present at birth or within the first few months of life; elevated muscle enzymes; myotonic changes seen on muscle pathology; and specific protein defects seen on muscle immunostaining. Confirmation of the diagnosis requires detection of the relevant causative gene.
Differential diagnosis: (1) congenital myopathy: the course of the disease is not progressive, muscle enzymes are normal or near normal, and typical pathological changes of congenital myopathy can be found in muscle histopathology; (2) Prader-Willi syndrome: it is associated with biparent-specific methylation blotting abnormalities in the Prader-Willi critical region (PWCR) of chromosome 15q11. Severe hypotonia and feeding difficulties in early infancy, increased appetite and morbid obesity later in life. It is associated with some degree of cognitive impairment and a specific behavioral abnormal phenotype. Spinal myasthenia gravis: It is caused by mutations in the motor neuron survival gene, with progressive muscle weakness and atrophy, normal intelligence, normal CPK, neurogenic damage on EMG, and neurogenic changes on muscle biopsy. ④ Congenital ankylosing myotonic dystrophy: caused by CTG trinucleotide repeat expansion of the DMPK gene. Severe generalized hypotonia and muscle weakness are present at birth, often with respiratory insufficiency and early death. Tendon reflexes are usually present, CK is normal, and electromyography may show myotonic discharges. Myocardial biopsy shows myotonic changes with more inward migration of the nuclei of the muscle fibers. Pompe disease, a glycogen accumulation disease type II, is caused by a defect in the acid maltase enzyme of the lysosome. The first symptoms are dyspnea and cyanosis, hypotonia and weakness of the skeletal muscles. On examination, a giant tongue, enlarged heart and mildly enlarged liver are seen. The disease progresses rapidly and death often occurs within a few months.
Genetic counseling
Mostly autosomal recessive, but in type VI collagenosis and LMNA-associated congenital myotonic dystrophy, it is due to autosomal dominant de novo mutations.
Treatment
There is no specific treatment, and a comprehensive therapy based on symptomatic and exercise rehabilitation is adopted.
1, rehabilitation training more stretching exercises to improve mobility and prevent joint contracture. Mechanical aids such as wheelchairs to improve the movement ability. Orthopedic surgery to correct skeletal deformities such as scoliosis, foot deformities, joint contractures, etc.
2, feeding problems Infants with feeding difficulties, can be nasal feeding. Anti-epileptic drug therapy to actively control seizures.
Respiratory monitoring Because of the presence of respiratory muscle involvement, respiratory insufficiency may occur to varying degrees as the disease progresses, respiratory function should be monitored regularly and mechanical assisted ventilation should be taken if necessary.
4.Heart Cardiac comorbidities are commonly seen in LMNA and FKRP mutations, and occasionally in LAMA2 mutation. In LMNA-related congenital myotonic dystrophy, early diagnosis, regular monitoring of ECG and timely treatment with pacemaker implantation should be emphasized.
5. Ophthalmologic treatment Symptomatic treatment of ocular abnormalities can be performed in the ophthalmology department.