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Merosin deficient congenital muscular dystrophy(MDC1A)

MedGen UID:
224728
Concept ID:
C1263858
Disease or Syndrome
Synonyms: Congenital merosin-deficient muscular dystrophy 1A; MDC1A; Muscular dystrophy congenital, merosin negative
SNOMED CT: Merosin deficient congenital muscular dystrophy (111503008); Merosin-negative congenital muscular dystrophy (787037000); Congenital muscular dystrophy type 1A (787037000); CMD1A - congenital muscular dystrophy type 1A (787037000); Congenital muscular dystrophy due to laminin alpha2 deficiency (787037000); MCD1A - muscular congenital dystrophy type 1A (787037000)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): LAMA2 (6q22.33)
 
Monarch Initiative: MONDO:0011925
OMIM®: 607855
Orphanet: ORPHA258

Definition

Merosin-deficient congenital muscular dystrophy is an autosomal recessive form of muscular dystrophy characterized by muscle weakness apparent at birth or in the first 6 months of life. Patients show hypotonia, poor suck and cry, and delayed motor development; most never achieve independent ambulation. Most patients also have periventricular white matter abnormalities on brain imaging, but mental retardation and/or seizures occur only rarely (summary by Xiong et al., 2015). [from OMIM]

Additional descriptions

From GeneReviews
The cartilage-hair hypoplasia – anauxetic dysplasia (CHH-AD) spectrum disorders are a continuum that includes the following phenotypes: Metaphyseal dysplasia without hypotrichosis (MDWH). Cartilage-hair hypoplasia (CHH). Anauxetic dysplasia (AD). CHH-AD spectrum disorders are characterized by severe disproportionate (short-limb) short stature that is usually recognized in the newborn, and occasionally prenatally because of the short extremities. Other findings include joint hypermobility, fine silky hair, immunodeficiency, anemia, increased risk for malignancy, gastrointestinal dysfunction, and impaired spermatogenesis. The most severe phenotype, AD, has the most pronounced skeletal phenotype, may be associated with atlantoaxial subluxation in the newborn, and may include cognitive deficiency. The clinical manifestations of the CHH-AD spectrum disorders are variable, even within the same family.
From MedlinePlus Genetics
As affected children grow, they often develop an abnormal, gradually worsening side-to-side curvature of the spine (scoliosis) and inward curvature of the back (lordosis). Children with early-onset LAMA2-related muscular dystrophy often do not develop the ability to walk. Difficulty with speech may result from weakness of the facial muscles and an enlarged tongue. Seizures occur in about a third of individuals with early-onset LAMA2-related muscular dystrophy; rarely, heart complications occur in this form of the disorder.

LAMA2-related muscular dystrophy is a disorder that causes weakness and wasting (atrophy) of muscles used for movement (skeletal muscles). This condition varies in severity, from a severe, early-onset type to a milder, late-onset form.

Early-onset LAMA2-related muscular dystrophy is apparent at birth or within the first few months of life. It is considered part of a class of muscle disorders called congenital muscular dystrophies and is sometimes called congenital muscular dystrophy type 1A. Affected infants may have severe muscle weakness, lack of muscle tone (hypotonia), little spontaneous movement, and joint deformities (contractures). Weakness of the muscles in the face and throat can result in feeding difficulties and an inability to grow and gain weight at the expected rate. Respiratory insufficiency, which occurs when muscles in the chest are weakened, causes a weak cry and breathing problems that can lead to frequent, potentially life-threatening lung infections.

Symptoms of late-onset LAMA2-related muscular dystrophy become evident later in childhood or adulthood, and are similar to those of a group of muscle disorders classified as limb-girdle muscular dystrophies. In late-onset LAMA2-related muscular dystrophy, the muscles most affected are those closest to the body (proximal muscles), specifically the muscles of the shoulders, upper arms, pelvic area, and thighs. Children with late-onset LAMA2-related muscular dystrophy sometimes have delayed development of motor skills such as walking, but generally achieve the ability to walk without assistance. Over time, they may develop rigidity of the back, joint contractures, scoliosis, and breathing problems. However, most affected individuals retain the ability to walk and climb stairs.  https://medlineplus.gov/genetics/condition/lama2-related-muscular-dystrophy

Clinical features

From HPO
Feeding difficulties in infancy
MedGen UID:
436211
Concept ID:
C2674608
Finding
Impaired feeding performance of an infant as manifested by difficulties such as weak and ineffective sucking, brief bursts of sucking, and falling asleep during sucking. There may be difficulties with chewing or maintaining attention.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Areflexia
MedGen UID:
115943
Concept ID:
C0234146
Finding
Absence of neurologic reflexes such as the knee-jerk reaction.
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Abnormal cortical gyration
MedGen UID:
343457
Concept ID:
C1856019
Anatomical Abnormality
An abnormality of the gyri (i.e., the ridges) of the cerebral cortex of the brain.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Hypointensity of cerebral white matter on MRI
MedGen UID:
866563
Concept ID:
C4020908
Finding
A darker than expected signal on magnetic resonance imaging emanating from the cerebral white matter.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Muscular dystrophy
MedGen UID:
44527
Concept ID:
C0026850
Disease or Syndrome
The term dystrophy means abnormal growth. However, muscular dystrophy is used to describe primary myopathies with a genetic basis and a progressive course characterized by progressive skeletal muscle weakness and wasting, defects in muscle proteins, and histological features of muscle fiber degeneration (necrosis) and regeneration. If possible, it is preferred to use other HPO terms to describe the precise phenotypic abnormalities.
Muscle weakness
MedGen UID:
57735
Concept ID:
C0151786
Finding
Reduced strength of muscles.
Flexion contracture
MedGen UID:
83069
Concept ID:
C0333068
Anatomical Abnormality
A flexion contracture is a bent (flexed) joint that cannot be straightened actively or passively. It is thus a chronic loss of joint motion due to structural changes in muscle, tendons, ligaments, or skin that prevents normal movement of joints.
Kyphoscoliosis
MedGen UID:
154361
Concept ID:
C0575158
Anatomical Abnormality
An abnormal curvature of the spine in both a coronal (lateral) and sagittal (back-to-front) plane.
Increased endomysial connective tissue
MedGen UID:
867771
Concept ID:
C4022161
Finding
An increased volume of the endomysium, which is a connective tissue sheath that surrounds each muscule fiber. Together, bundles of muscle fibers form a fasciculus, surrounded by another layer of connective tissue called the perimysium.
Respiratory insufficiency due to muscle weakness
MedGen UID:
812797
Concept ID:
C3806467
Finding
Elevated circulating creatine kinase concentration
MedGen UID:
69128
Concept ID:
C0241005
Finding
An elevation of the level of the enzyme creatine kinase (also known as creatine phosphokinase (CK; EC 2.7.3.2) in the blood. CK levels can be elevated in a number of clinical disorders such as myocardial infarction, rhabdomyolysis, and muscular dystrophy.
Ophthalmoplegia
MedGen UID:
45205
Concept ID:
C0029089
Sign or Symptom
Paralysis of one or more extraocular muscles that are responsible for eye movements.

Term Hierarchy

Follow this link to review classifications for Merosin deficient congenital muscular dystrophy in Orphanet.

Professional guidelines

PubMed

Geranmayeh F, Clement E, Feng LH, Sewry C, Pagan J, Mein R, Abbs S, Brueton L, Childs AM, Jungbluth H, De Goede CG, Lynch B, Lin JP, Chow G, Sousa Cd, O'Mahony O, Majumdar A, Straub V, Bushby K, Muntoni F
Neuromuscul Disord 2010 Apr;20(4):241-50. Epub 2010 Mar 6 doi: 10.1016/j.nmd.2010.02.001. PMID: 20207543
Vainzof M, Richard P, Herrmann R, Jimenez-Mallebrera C, Talim B, Yamamoto LU, Ledeuil C, Mein R, Abbs S, Brockington M, Romero NB, Zatz M, Topaloglu H, Voit T, Sewry C, Muntoni F, Guicheney P, Tomé FM
Neuromuscul Disord 2005 Oct;15(9-10):588-94. doi: 10.1016/j.nmd.2005.04.009. PMID: 16084089
Naom I, Sewry C, D'Alessandro M, Topaloglu H, Ferlini A, Wilson L, Dubowitz V, Muntoni F
Neuromuscul Disord 1997 May;7(3):176-9. doi: 10.1016/s0960-8966(97)00448-3. PMID: 9185181

Recent clinical studies

Etiology

Nouri Z, Sarmadi A, Narrei S, Sehhati M, Tabatabaiefar MA
Neuromuscul Disord 2022 Sep;32(9):776-784. Epub 2022 Jul 23 doi: 10.1016/j.nmd.2022.07.400. PMID: 35989179
Sakr HM, Fahmy N, Elsayed NS, Abdulhady H, El-Sobky TA, Saadawy AM, Beroud C, Udd B
Neuromuscul Disord 2021 Sep;31(9):814-823. Epub 2021 Jul 1 doi: 10.1016/j.nmd.2021.06.012. PMID: 34481707
Ip JJ, Hui PK, Chau MT, Lam WW
J Radiol Case Rep 2012 Aug;6(8):1-7. Epub 2012 Aug 1 doi: 10.3941/jrcr.v6i8.997. PMID: 23365711Free PMC Article
Chae JH, Lee JS, Hwang H, Kim KJ, Hwang YS, Park JD, Cheon JE, Kim IO, Choe GY, Park SH
Brain Dev 2009 May;31(5):341-6. Epub 2008 Aug 23 doi: 10.1016/j.braindev.2008.06.009. PMID: 18723302
Shorer Z, Philpot J, Muntoni F, Sewry C, Dubowitz V
J Child Neurol 1995 Nov;10(6):472-5. doi: 10.1177/088307389501000610. PMID: 8576559

Diagnosis

Nouri Z, Sarmadi A, Narrei S, Sehhati M, Tabatabaiefar MA
Neuromuscul Disord 2022 Sep;32(9):776-784. Epub 2022 Jul 23 doi: 10.1016/j.nmd.2022.07.400. PMID: 35989179
Hashemi-Gorji F, Yassaee VR, Dashti P, Miryounesi M
Iran Biomed J 2018 Nov;22(6):408-14. Epub 2018 Apr 30 doi: 10.29252/.22.6.408. PMID: 29707938Free PMC Article
Buteică E, Roşulescu E, Burada F, Stănoiu B, Zăvăleanu M
Rom J Morphol Embryol 2008;49(2):229-33. PMID: 18516331
Naom I, Sewry C, D'Alessandro M, Topaloglu H, Ferlini A, Wilson L, Dubowitz V, Muntoni F
Neuromuscul Disord 1997 May;7(3):176-9. doi: 10.1016/s0960-8966(97)00448-3. PMID: 9185181
Wewer UM, Engvall E
Neuromuscul Disord 1996 Dec;6(6):409-18. doi: 10.1016/s0960-8966(96)00384-7. PMID: 9027848

Therapy

Bouman K, Groothuis JT, Doorduin J, van Alfen N, Udink Ten Cate FEA, van den Heuvel FMA, Nijveldt R, van Tilburg WCM, Buckens SCFM, Dittrich ATM, Draaisma JMT, Janssen MCH, Kamsteeg EJ, van Kleef ESB, Koene S, Smeitink JAM, Küsters B, van Tienen FHJ, Smeets HJM, van Engelen BGM, Erasmus CE, Voermans NC
BMC Neurol 2021 Aug 12;21(1):313. doi: 10.1186/s12883-021-02336-z. PMID: 34384384Free PMC Article
Maruyama R, Yokota T
Methods Mol Biol 2018;1828:79-90. doi: 10.1007/978-1-4939-8651-4_5. PMID: 30171536
Rooney JE, Knapp JR, Hodges BL, Wuebbles RD, Burkin DJ
Am J Pathol 2012 Apr;180(4):1593-602. Epub 2012 Feb 6 doi: 10.1016/j.ajpath.2011.12.019. PMID: 22322301Free PMC Article
Hicks D, Lampe AK, Laval SH, Allamand V, Jimenez-Mallebrera C, Walter MC, Muntoni F, Quijano-Roy S, Richard P, Straub V, Lochmüller H, Bushby KM
Brain 2009 Jan;132(Pt 1):147-55. Epub 2008 Nov 16 doi: 10.1093/brain/awn289. PMID: 19015158
Philpot J, Cowan F, Pennock J, Sewry C, Dubowitz V, Bydder G, Muntoni F
Neuromuscul Disord 1999 Mar;9(2):81-5. doi: 10.1016/s0960-8966(98)00110-2. PMID: 10220862

Prognosis

Nouri Z, Sarmadi A, Narrei S, Sehhati M, Tabatabaiefar MA
Neuromuscul Disord 2022 Sep;32(9):776-784. Epub 2022 Jul 23 doi: 10.1016/j.nmd.2022.07.400. PMID: 35989179
Khorrami A, Goleij P, Karamad V, Taheri E, Shadman B, Emami P, Jahangirzadeh G, Hajazimian S, Isazadeh A, Baradaran B, Heidari M
J Clin Lab Anal 2021 Nov;35(11):e23930. Epub 2021 Sep 16 doi: 10.1002/jcla.23930. PMID: 34528292Free PMC Article
Geranmayeh F, Clement E, Feng LH, Sewry C, Pagan J, Mein R, Abbs S, Brueton L, Childs AM, Jungbluth H, De Goede CG, Lynch B, Lin JP, Chow G, Sousa Cd, O'Mahony O, Majumdar A, Straub V, Bushby K, Muntoni F
Neuromuscul Disord 2010 Apr;20(4):241-50. Epub 2010 Mar 6 doi: 10.1016/j.nmd.2010.02.001. PMID: 20207543
Chae JH, Lee JS, Hwang H, Kim KJ, Hwang YS, Park JD, Cheon JE, Kim IO, Choe GY, Park SH
Brain Dev 2009 May;31(5):341-6. Epub 2008 Aug 23 doi: 10.1016/j.braindev.2008.06.009. PMID: 18723302
Vainzof M, Richard P, Herrmann R, Jimenez-Mallebrera C, Talim B, Yamamoto LU, Ledeuil C, Mein R, Abbs S, Brockington M, Romero NB, Zatz M, Topaloglu H, Voit T, Sewry C, Muntoni F, Guicheney P, Tomé FM
Neuromuscul Disord 2005 Oct;15(9-10):588-94. doi: 10.1016/j.nmd.2005.04.009. PMID: 16084089

Clinical prediction guides

Nouri Z, Sarmadi A, Narrei S, Sehhati M, Tabatabaiefar MA
Neuromuscul Disord 2022 Sep;32(9):776-784. Epub 2022 Jul 23 doi: 10.1016/j.nmd.2022.07.400. PMID: 35989179
Ip JJ, Hui PK, Chau MT, Lam WW
J Radiol Case Rep 2012 Aug;6(8):1-7. Epub 2012 Aug 1 doi: 10.3941/jrcr.v6i8.997. PMID: 23365711Free PMC Article
Feltri ML, Wrabetz L
J Peripher Nerv Syst 2005 Jun;10(2):128-43. doi: 10.1111/j.1085-9489.2005.0010204.x. PMID: 15958125
Leite CC, Reed UC, Otaduy MC, Lacerda MT, Costa MO, Ferreira LG, Carvalho MS, Resende MB, Marie SK, Cerri GG
Radiology 2005 Apr;235(1):190-6. Epub 2005 Feb 9 doi: 10.1148/radiol.2351031963. PMID: 15703311
Mercuri E, Anker S, Philpot J, Sewry C, Dubowitz V, Muntoni F
Pediatr Neurol 1998 May;18(5):399-401. doi: 10.1016/s0887-8994(97)00222-1. PMID: 9650678

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