Draft:LAMA2 related congenital muscular dystrophy

{{Infobox medical condition (new)
 * name           = LAMA2-related muscular dystrophy or Laminin subunit alpha-2 muscular dystrophy
 * synonyms       = LAMA2-related congenital muscular dystrophy type 1A or MDC1A or Merosin-deficient congenital muscular dystrophy

LAMA2 muscular dystrophy (LAMA2-MD) is a genetically determined muscle disease caused by pathogenic mutations in the LAMA2 gene. The clinical presentation of LAMA2-MD varies according to the age at presentation. The severe forms present at birth and are known as early onset LAMA2 congenital muscular dystrophy type 1A or MDC1A. The mild forms are known as late onset LAMA2 muscular dystrophy or late onset LAMA2-MD. The nomenclature LGMDR23 can be used interchangeably with late onset LAMA2-MD.

Suggestive clinical features include, muscular hyperlaxity or hypotonia, growth retardation progressive spine and joint contractures, and cardiac and respiratory failure. Generally, the term congenital muscular dystrophy refers to inherited or genetically determined childhood onset muscle diseases.

Symptoms and signs
There are two types of LAMA2 muscular dystrophy (LAMA2-MD). The first type is the congenital type known as early onset LAMA2 congenital muscular dystrophy type 1A or MDC1A. It presents at birth and has a relatively severe clinical presentation. Characteristically it manifests in muscular hyperlaxity or hypotonia, respiratory difficulties and growth retardation.

The second type is the late onset LAMA2 muscular dystrophy or late onset LAMA2-MD. The age of presentation of late onset LAMA2-MD ranges from early childhood to adulthood. It usually has a mild clinical presentation in the form of progressive spine and joint contractures, and cardiac and respiratory failure.
 * Delayed development of motor milestones usually more severe in the congenital type or MDC1A.
 * Scoliosis Scoliosis is a side curvature or abnormal deviation of the spine with an element of rotation. Scoliosis is usually rigid and progressive. It may be accompanied by lordosis.
 * Joint contractures Muscle contractures limit the range of motion in the adjoining joints and lead to fixed deformities. The clinical orthopedic features of LAMA2-MD in terms of type, distribution, laterality, deformity progression, chronological order of muscle involvement etc., has shown a fairly characteristic pattern. This is important to the differential diagnosis of LAMA2-MD and other subtypes of congenital muscular dystrophies among others. LAMA2-MD usually manifests in progressive contractures of large joints like knees, ankles, elbow and hips. Contractures tend to be bilateral. That is involving both the left and right sides.
 * Muscle rigidity or stiffness leads to difficulties in ambulation and activities of daily living.
 * Hperlaxity or hypotonia is one the presenting features in the congenital type 1A or MDC1A.
 * Respiratory insufficiency can occur in both types of LAMA2-MD.
 * Cardiac manifestations Cardiac screening is important in LAMA2-MD.
 * Cerebral manifestations Epilepsy is a fairly common manifestation of both types of LAMA2-MD. However, the age at occurrence of first epileptic fit is earlier in the congenital type 1A or MDC1A. Screening for epilepsy should be included in the workup. Intelligence is usually normal.
 * Gastrointestinal manifestations feeding difficulties and failure to thrive especially in the congenital type 1A or MDC1A.

Causative factors
LAMA2-MD is caused by pathogenic variants or mutations in the LAMA2 gene that encodes α2 chain of laminin-211 or laminin-α2, previously known as laminin type 2 or merosin. laminin-211 is important to the function and integrity of the sarcolemma of muscle fibers. Pathogenic variants of the LAMA2 gene which lead to loss of function are accompanied by complete deficiency of laminin-α2 (merosin) and result in a severe clinical picture or phenotype namely early onset LAMA2 congenital muscular dystrophy type 1A or MDC1A. Pathogenic variants of the LAMA2 gene accompanied by partial deficiency of laminin-α2 result in a milder clinical picture namely late onset LAMA2 muscular dystrophy or late onset LAMA2-MD. The disease is inherited through an autosomal recessive mode.

Diagnosis
Correlating the characteristic clinical picture with the varying specific imaging, laboratory and muscle biopsy findings is essential to the diagnosis of LAMA2-MD. The presence of pathogenic variants in LAMA2 gene by Genetic testing, -DNA testing- of the affected individual confirms the diagnosis of LAMA2-MD.

However, these muscle MRI features may overlap with other subtypes of congenital muscular dystrophy. Additionally, some inconsistencies between the above muscle imaging studies can be noted. Thus, more longitudinal studies with larger cohorts and standardized methodologies are needed to arrive at a more uniform and consistent muscle MRI signature in LAMA2-MD. It is therefore paramount to correlate muscle imaging findings with clinical, neuro-imaging, laboratory and genetic testing findings.
 * Serum creatine kinase (CK) concentration is usually highly elevated early in the course of the disease. it tends to decrease or become mildly elevated in adulthood.
 * Brain MRI Brain MRI shows abnormal white matter signals is a near universal sign in patients with LAMA2-MD. Other Structural brain abnormalities may present on brain MRI.
 * Whole body muscle MRI Muscle MRI especially Whole-body muscle MRI can provide important diagnostic clues. Some studies have shown a reasonably characteristic pattern of muscle involvement on whole-body muscle MRI in LAMA2-MD patients. This relates to muscles or group of muscles involvement versus sparing. For example, sparing of the gracilis, sartorius muscles, and the adductor longus muscle has been linked to LAMA2-MD. On the other hand, studies showed a specific predilection to involve the gluteus maximus and anterior thigh muscles  , adductor magnus muscle  , serratus anterior muscle  in LAMA2-MD, and so forth. Abnormal muscle texture or geometry on muscle MRI as presence of granular pattern of involvement in a muscle has been suggested to be a diagnostic clue. Similarly, a homogenous pattern of involvement of group of muscle e.g., anterior compartment of thigh, could be used to support diagnosis. Homogenous pattern refers to involvement of all individual muscles of a muscle compartment to the same extent. Moreover, Whole body muscle MRI could be indicative of clinical disease severity and duration of LAMA2-MD. It can also help establish phenotype genotype correlations


 * Muscle immunostaining

Treatment
Currently, there is no definite cure available for LAMA2-MD. However, preclinical studies on experimental animal modes of iatrogenic induced LAMA2-MD are showing favorable yet early results. Generally, these preclinical studies are geared toward combating substances that regulate and promote muscle fibrosis in the pathogenesis of LAMA2-MD e.g., TGF-β. This may reduce muscle fibrosis and enhance healthy muscle architecture subsequently.

Treatment is mainly supportive and palliative. It is directed at anticipating and preventing or alleviating the systemic complications associated disease progression. This refers to management of respiratory, cardiac, orthopedic and rehabilitative, central nervous system e.g., epilepsy, gastrointestinal and so forth.