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CONGENITAL MUSCULAR DYSTROPHY(CMD)

INTRODUCTION:

Congenital muscular dystrophy (CMD) is a clinically and genetically heterogeneous group of inherited muscle disorders(autosomal recessive). They are a characterized by muscle weakness which is present at birth and the different changes on muscle biopsy that ranges from myopathic to overtly dystrophic due to the age at which the biopsy takes place. Affected infants typically appear "floppy" with low muscle tone and poor spontaneous movements. Affected children may present with delay or arrest of gross motor development together with joint and/or spinal rigidity. Muscle weakness may improve, worsen, or stabilize in the short term; however, with time progressive weakness and joint contractures, spinal deformities, and respiratory compromise may affect quality of life and life span.

SYMPTOMS/SIGNS:

Most infants with CMD will display some progressive muscle weakness or muscle wasting (atrophy), although there can be different degrees and symptoms of severeness of progression. The weakness is indicated as hypotonia, or lack of muscle tone, which can make an infant seem unstable. Children may be slow with their motor skills; such as rolling over, sitting up or walking, or may not even reach these milestones of life. Some of the more rarer forms of CMD can result in significant learning disabilities.The genetics of congenital muscular dystrophy are autosomal recessive which means two copies of an abnormal gene must be present for the disease or trait to happen.

CLASSIFICATIONS:

The classification scheme for subtypes of CMD is based on the gene in which pathogenic variants occur and organized by the cellular localization of the protein encoded by the gene: structural proteins of the extracellular matrix, defects in glycosylation, proteins of the endoplasmic reticulum, and proteins of the nuclear envelope . Although phenotypic classification has also been proposed, such a classification has its shortcoming because the phenotypes caused by pathogenic variants in different genes can overlap significantly and pathogenic variants in one gene can be associated with a spectrum of clinical phenotypes.

Defects of glycosylation. Rare form of congenital muscular dystrophy (autosomal recessive disorder) causing a lack of normal muscle tone which can delay walking due to being weak ,also paralysis of eye muscles and intellectual disability which affects an individuals way of processing information.

CMD with adducted (drawn inward) thumbs:
A rare form of CMD causing permanent shortening of the toe joints and lack of muscle tone which can delay walking due to the individual being weak. The person with this form of congenital muscular dystrophy might have mild cerebellar hypoplasia in some cases .

Large related CMD:

Present at the beginning of the newborn period, the issues the infant receives are; poor muscle tone and weak motor function; the individual will present with mental retardation and the structure of the brain will likely be abnormal.

CMD with cerebellar atrophy:

Severe cerebellar hypoplasia, poor muscle tone, delayed in motor milestones, lack of coordination in motive skills, difficulty speaking, involuntary movements and some intellectual disability. Furthermore, muscle biopsy does not reveal any deficiency.

Walker–Warburg syndrome:

Caused by defects of glycosylation , at the beginning a progressive weakness and low muscle tone at birth or during early infancy; small muscles; the majority of affected children do not live more than 3 years of age. Eye structure problems are present, with accompanying visual impairment.

CMD/LGMD with MR:

Defect of glycosylation. weakness and deformity and rigidity joints present at birth, poor muscle tone, slowly progressive; individuals may present with cerebellar cysts (or cortical problems), microcephaly may be present as well. Abnormal flexibility might occur, spinal curvature possible.

CDG I (DPM3):

Some of the symptoms at birth and through out the infants life are weakness or poor muscle tone. The individual may present with cardiomyopathy (no outflow obstruction), a rise in serum creatine kinase might be present as well. Some IQ problems may be present, along with weakness in the proximal muscles. Also of note, a reduction of dolichol phosphate mannose .

CDG I (DPM2):

Weak muscle tone starting in first weeks of the infant, the individual may show severe neurologic physical characteristics that result in fatality early in life. Hypotonia and myopathic facies may be present in such individuals, while contractures of joints may also be present. Finally, myoclonic seizures may occur at a very early age (3 months).

CDG Ie (DPM1):

At birth the infant will have weakness with involvement of the respiratory system , as well as, severe mental and psychomotor problems.By age of 3,the individual may be blind with speech problems. Microcephaly may occur in early childhood, as well as seizures.

CMD/LGMD without MR:

First years of a newborn begins with weakness, which affects motive skills, walking can be accomplished in adolescence, deformity and rigidity of joints. The joints, neck and spine; progressive cardiomyopathy at the early ages; cardiac rhythm abnormalities may be present in the individual.

CMD with spinal rigidity:
Present at birth can have poor muscle tone and weakness, reduced respiratory capacity, muscles could be deformed, beginning early ages stabilization or slow decline spinal rigidity, limited mobility to flex the neck and spine, spinal curvature and progressing deformity and rigidity joints, minor cardiac abnormalities, normal intelligence.

CMD with lamin A/C abnormality:

Within the first year, the infant is weak, individual may have problems later lifting arms and head. May need nasogastric tube, limb weakness and elevated serum creatine kinase. Individual may show a diaphragmatic manner when breathing.

Integrin α7:
Weakness which is present at birth, poor muscle tone with late walking, loss of muscle tissue, intellectual disability.Furthermore, the creatine kinase level was elevated.

Fukuyama CMD:

Caused by defects of glycosylation .In western countries this type of CMD is rare but is common in Japan. The effects this disease has on infants is spectrum of severity, weakness in muscle tone within first year, some infants may achieve some walking, have deformity and rigidity joints, spinal curvatures, seizures, eye involvement and intellectual disability.

Merosin-deficient CMD:

Defect of structural protein. Present at birth, weakness in muscle tone, spectrum of severity; may show hypotonia, and poor motot development. Most individuals have periventricular white matter problems. However, mental retardation is rare in most cases.

Merosin-positive CMD:

Some forms of merosin-positive CMD are: Early spinal rigidity, CMD with muscle hypertrophy, CMD with muscle hypertrophy and respiratory failure.

Ullrich congenital muscular dystrophy

Caused by defects of structural protein . present at birth. Infant is weak,have poor muscle tone, will have some deformity and rigidity joints, some joints will have excessive flexibility, spinal rigidity, curvature, respiratory impairment, soft skin, normal cardiac function and normal intelligence.

Cmd of unknown cause:

A number of reports describe individuals with a subtype of CMD which does not resemble the known subtypes and/or is not caused by mutation of the genes currently known to be associated with CMD subtypes.

1. CMD with cerebellar involvement. Cerebellar abnormalities may include cysts or other signs of cerebellar dysplasia or hypoplasia.

2. CMD with intellectual disability and normal MRI. Minimal ventricular dilation or minor white matter changes on MRI are observed .

3. CMD with no intellectual disability and normal MRI. 4. CMD with intellectual disability, microcephaly, cerebellar hypoplasia, feeding difficulties,

TREATMENT:

Unfortunately, there's no cure for congenital muscular dystrophy. However, there are several treatment options that can help reduce its symptoms. One common treatment option is physical therapy, which helps keep strengthen muscles and joints and may increase range of motion.

Occupational therapy is a similar treatment, but it focuses on helping children to perform certain tasks that will be useful in everyday life. Assistive devices like leg braces and wheelchairs may be helpful for improving mobility. In some cases, doctors may recommend surgery to correct joint problems or curvature of the spine that may be caused by congenital muscular dystrophy.

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IDENTIFICATION METHODS

Physical examination:

Muscle pseudo hypertrophy: dystroglycanopathies Diffuse joint contractures: laminin alpha-2 deficiency, collagen VI-deficient CMD Distal hyperlaxity: collagen VI-deficient CMD Hypertrophic scars or keloid formation: collagen VI-deficient CMD Spinal stiffness without limb joint contractures: SEPN1-related CMD Axial hypotonia and weakness (poor trunk control) preceding spinal stiffness: in early laminin alpha-2 deficiency, L-CMD, and collagen VI-deficient CMD . Cardiac involvement: rhythm disturbances in L-CMD; cardiomyopathy in dystroglycanopathies; right heart failure in any CMD subtype if chronic severe respiratory failure is untreated Nocturnal hypoventilation or respiratory failure in a person who is ambulatory:SEPN1-related CMD; occasionally collagen VI-deficient CMD. The type and location of spinal deformity: Thoracic kyphosis: collagen VI-deficient CMD Thoracic lordosis: laminin alpha-2 deficiency, SEPN1-related CMD, and L-CMD; late stage of dystroglycanopathies. Lumbar hyperlordosis is frequently seen in all subtypes.

Neurologic examination:

Occipital-frontal circumference (OFC): may be abnormal in laminin alpha 2 deficiency (macrocephaly) or in dystroglycanopathies (microcephaly or macrocephaly). Muscle pseudohypertrophy (calves and tongue): dystroglycanopathies. Calf pseudohypertrophy may resemble that seen in Duchenne muscular dystrophy CNS malformation and abnormal white matter: may be evident as: Pyramidal signs (hyperreflexia, clonus) and cognitive involvement: dystroglycanopathies Seizures easy to control with routine antiepileptic drugs: typical for laminin alpha-2 deficiency Seizures refractory to polytherapy: often in MEB disease, especially those with POMGNT1 pathogenic variants.Intellectual disability associated with marked behavioral disturbances: suggestive of MEB disease, especially those with POMGNT1 pathogenic variants.

Eye examination by a pediatric ophthalmologist.

Eye examinations are recommended in the presence of signs or symptoms of ocular involvement or if dystroglycanopathy is suspected.

Serum CK concentration:
In general CMD subtypes with no abnormality in merosin expression (collagen VI-deficient CMD, SEPN1-related CMD, L-CMD) show normal or mildly increased serum concentration of CK. While those with primary merosin deficiency (laminin alpha-2 deficiency) or secondary merosin deficiency (dystroglycanopathies) have high serum concentration of CK.

Neuroimaging:

MRI can be used to guide diagnosis. The two CMD subtypes with brain abnormalities visualized on MRI are laminin alpha-2 deficiency and the dystroglycanopathies.

In laminin alpha-2 deficiency abnormal white matter signal after age six months helps establish the diagnosis. White matter changes do not regress with time. In the dystroglycanopathies, structural changes (including hydrocephalus, brain stem hypoplasia, cerebellar cysts) or abnormalities in neuronal migration (lissencephaly or polymicrogyria) are common. White matter changes may regress with time.

Muscle imaging:
Distinct recognizable patterns on muscle MRI in persons with spinal rigidity, normal merosin staining of skin or muscle biopsy, and normal serum CK concentrations can help distinguish between collagen VI-deficient CMD, SEPN1-related CMD, and L-CMD and between the CMDs and the overlapping phenotypes considered in the differential diagnosis that are caused by pathogenic variants in RYR1, GAA (encoding acid maltase) or DNM2. ===

Molecular genetic testing:

With the expanding role of molecular genetic testing in confirming the diagnosis of a CMD subtype, the trend recently has been to perform molecular genetic testing without muscle biopsy when the medical history, physical examination, and neurologic examination support the diagnosis of a CMD.For example, in the past the evaluation of an infant with head lag, hypotonia, and brain white matter abnormalities on MRI who is suspected of having laminin alpha-2 deficiency may have been to perform a skin biopsy first to demonstrate merosin deficiency followed by LAMA2 molecular genetic testing. However, currently the evaluation may proceed directly to molecular genetic testing (without skin biopsy) depending on the level of suspicion, the exclusion of other more common diagnoses, and the confidence of the neurologist in the diagnosis.

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REFERENCES:

https://en.wikipedia.org/wiki/Congenital_muscular_dystrophy#Diagnosis https://www.ncbi.nlm.nih.gov/books/NBK1291/ https://www.sharecare.com/health/muscular-dystrophy/treatment-options-congenital-muscular-dystrophy http://www.sciencedirect.com/science/article/pii/S1071909102800055 http://www.healio.com/pediatrics/journals/pedann/2005-7-34-7/%7B5c411a6c-2fad-4e86-b987-2cead5b58aef%7D/congenital-muscular-dystrophy