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Merosin deficient congenital muscular dystrophy(MDC1A)

MedGen UID:
224728
Concept ID:
C1263858
Disease or Syndrome
Synonyms: LAMA2-Related Muscular Dystrophy; MDC1A; Muscular dystrophy congenital, merosin negative; Muscular dystrophy, congenital, merosin-deficient 1A
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: HPO
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 homozygotes. In the context of medical genetics, autosomal recessive disorders manifest in homozygotes (with two copies of the mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
SNOMED CT: Merosin deficient congenital muscular dystrophy (111503008)
 
Gene (location): LAMA2 (6q22.33)
OMIM®: 607855
Orphanet: ORPHA258

Definition

Congenital muscular dystrophy (CMD) is a clinically and genetically heterogeneous group of inherited muscle disorders. Muscle weakness typically presents from birth to early infancy. 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. The main CMD subtypes, grouped by involved protein function and gene in which causative allelic variants occur, are laminin alpha-2 (merosin) deficiency (MDC1A), collagen VI-deficient CMD, the dystroglycanopathies (caused by mutation of POMT1, POMT2, FKTN, FKRP, LARGE1, POMGNT1, and ISPD), SEPN1-related CMD (previously known as rigid spine syndrome, RSMD1) and LMNA-related CMD (L-CMD). Several less known CMD subtypes have been reported in a limited number of individuals. Cognitive impairment ranging from intellectual disability to mild cognitive delay, structural brain and/or eye abnormalities, and seizures are found almost exclusively in the dystroglycanopathies while white matter abnormalities without major cognitive involvement tend to be seen in the laminin alpha-2-deficient subtype. [from GeneReviews]

Additional descriptions

From OMIM
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).  http://www.omim.org/entry/607855
From GHR
LAMA2-related muscular dystrophy is a disorder that causes weakness and wasting (atrophy) of muscles used for movement (skeletal muscles). This condition generally appears in one of two ways: as a severe, early-onset type or 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 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 (failure to thrive). Hypotonia also affects the muscles used for breathing, which causes a weak cry and breathing problems that can lead to frequent, potentially life-threatening lung infections.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 usually do not learn to walk unassisted. Speech problems may result from weakness of the facial muscles and tongue, but intelligence is usually normal. Heart problems and seizures occasionally occur in early-onset LAMA2-related muscular dystrophy. Because of the serious health problems that occur in this form of the disorder, many affected individuals do not survive past adolescence.Late-onset LAMA2-related muscular dystrophy occurs later in childhood or in adulthood. Signs and symptoms of this form of the disorder are milder than in the early-onset type 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, and life expectancy and intelligence are usually not affected in late-onset LAMA2-related muscular dystrophy.  http://ghr.nlm.nih.gov/condition/lama2-related-muscular-dystrophy

Clinical features

Ophthalmoplegia
MedGen UID:
45205
Concept ID:
C0029089
Sign or Symptom
Paralysis of one or more extraocular muscles that are responsible for eye movements.
Seizure Disorders
MedGen UID:
4506
Concept ID:
C0014544
Disease or Syndrome
Epilepsy is a brain disorder that causes people to have recurring seizures. The seizures happen when clusters of nerve cells, or neurons, in the brain send out the wrong signals. People may have strange sensations and emotions or behave strangely. They may have violent muscle spasms or lose consciousness. Epilepsy has many possible causes, including illness, brain injury, and abnormal brain development. In many cases, the cause is unknown. Doctors use brain scans and other tests to diagnose epilepsy. It is important to start treatment right away. There is no cure for epilepsy, but medicines can control seizures for most people. When medicines are not working well, surgery or implanted devices such as vagus nerve stimulators may help. Special diets can help some children with epilepsy. NIH: National Institute of Neurological Disorders and Stroke.
Intellectual functioning disability
MedGen UID:
7544
Concept ID:
C0025362
Mental or Behavioral Dysfunction
Subnormal intellectual functioning which originates during the developmental period. Intellectual disability, previously referred to as mental retardation, has been defined as an IQ score below 70.
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
Finding
An abnormality of the gyri (i.e., the ridges) of the cerebral cortex of the brain.
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.
Respiratory insufficiency due to muscle weakness
MedGen UID:
812797
Concept ID:
C3806467
Finding
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.
Contracture
MedGen UID:
3227
Concept ID:
C0009917
Acquired 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.
Muscular hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
A diminution of the skeletal muscle tone marked by a diminished resistance to passive stretching.
Muscular dystrophy
MedGen UID:
44527
Concept ID:
C0026850
Congenital Abnormality
Muscular dystrophy (MD) is a group of more than 30 inherited diseases. They all cause muscle weakness and muscle loss. Some forms of MD appear in infancy or childhood. Others may not appear until middle age or later. The different types can vary in whom they affect, which muscles they affect, and what the symptoms are. All forms of MD grow worse as the person's muscles get weaker. Most people with MD eventually lose the ability to walk. There is no cure for muscular dystrophy. Treatments can help with the symptoms and prevent complications. They include physical and speech therapy, orthopedic devices, surgery, and medications. Some people with MD have mild cases that worsen slowly. Others cases are disabling and severe. NIH: National Institute of Neurological Disorders and Stroke.
Congenital muscular dystrophy
MedGen UID:
147063
Concept ID:
C0699743
Disease or Syndrome
Congenital muscular dystrophy (CMD) is a clinically and genetically heterogeneous group of inherited muscle disorders. Muscle weakness typically presents from birth to early infancy. 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. The main CMD subtypes, grouped by involved protein function and gene in which causative allelic variants occur, are laminin alpha-2 (merosin) deficiency (MDC1A), collagen VI-deficient CMD, the dystroglycanopathies (caused by mutation of POMT1, POMT2, FKTN, FKRP, LARGE1, POMGNT1, and ISPD), SEPN1-related CMD (previously known as rigid spine syndrome, RSMD1) and LMNA-related CMD (L-CMD). Several less known CMD subtypes have been reported in a limited number of individuals. Cognitive impairment ranging from intellectual disability to mild cognitive delay, structural brain and/or eye abnormalities, and seizures are found almost exclusively in the dystroglycanopathies while white matter abnormalities without major cognitive involvement tend to be seen in the laminin alpha-2-deficient subtype.
Respiratory insufficiency due to muscle weakness
MedGen UID:
812797
Concept ID:
C3806467
Finding
CREATINE PHOSPHOKINASE INCREASED
MedGen UID:
57470
Concept ID:
C0151576
Finding
A laboratory test result which indicates increased levels of creatine phosphokinase in a biological specimen.
Contracture
MedGen UID:
3227
Concept ID:
C0009917
Acquired 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.
Contracture
MedGen UID:
3227
Concept ID:
C0009917
Acquired 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.

Term Hierarchy

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

Professional guidelines

PubMed

Wang CH, Bonnemann CG, Rutkowski A, Sejersen T, Bellini J, Battista V, Florence JM, Schara U, Schuler PM, Wahbi K, Aloysius A, Bash RO, Béroud C, Bertini E, Bushby K, Cohn RD, Connolly AM, Deconinck N, Desguerre I, Eagle M, Estournet-Mathiaud B, Ferreiro A, Fujak A, Goemans N, Iannaccone ST, Jouinot P, Main M, Melacini P, Mueller-Felber W, Muntoni F, Nelson LL, Rahbek J, Quijano-Roy S, Sewry C, Storhaug K, Simonds A, Tseng B, Vajsar J, Vianello A, Zeller R; International Standard of Care Committee for Congenital Muscular Dystrophy
J Child Neurol 2010 Dec;25(12):1559-81. Epub 2010 Nov 15 doi: 10.1177/0883073810381924. [Epub ahead of print] PMID: 21078917

Recent clinical studies

Etiology

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
Jones LC, Waite PD
J Oral Maxillofac Surg 2012 Feb;70(2):e141-6. doi: 10.1016/j.joms.2011.10.011. PMID: 22260916
Fujii Y, Sugiura C, Fukuda C, Maegaki Y, Ohno K
Brain Dev 2011 Feb;33(2):140-4. Epub 2010 Mar 19 doi: 10.1016/j.braindev.2010.02.003. [Epub ahead of print] PMID: 20303224
Mercuri E, Pennock J, Goodwin F, Sewry C, Cowan F, Dubowitz L, Dubowitz V, Muntoni F
Neuromuscul Disord 1996 Dec;6(6):425-9. PMID: 9027850
Shorer Z, Philpot J, Muntoni F, Sewry C, Dubowitz V
J Child Neurol 1995 Nov;10(6):472-5. PMID: 8576559

Diagnosis

Andrade RC, Nevado J, de Faria Domingues de Lima MA, Saad T, Moraes L, Chimelli L, Lapunzina P, Vargas FR
Am J Med Genet A 2014 Nov;164A(11):2908-13. Epub 2014 Aug 14 doi: 10.1002/ajmg.a.36716. [Epub ahead of print] PMID: 25124546
Kumar S, Aroor S, Mundkur S, Kumar M
BMJ Case Rep 2014 Mar 6;2014 doi: 10.1136/bcr-2013-202684. PMID: 24604798Free PMC Article
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
Fujii Y, Sugiura C, Fukuda C, Maegaki Y, Ohno K
Brain Dev 2011 Feb;33(2):140-4. Epub 2010 Mar 19 doi: 10.1016/j.braindev.2010.02.003. [Epub ahead of print] PMID: 20303224
Yuan J, Takashima H, Higuchi I, Arimura K, Li N, Zhao Z, Shen H, Hu J
Neuropediatrics 2008 Oct;39(5):264-7. Epub 2009 Mar 17 doi: 10.1055/s-0029-1202288. PMID: 19294599

Therapy

Aoki Y, Nagata T, Yokota T, Nakamura A, Wood MJ, Partridge T, Takeda S
Hum Mol Genet 2013 Dec 15;22(24):4914-28. Epub 2013 Jul 23 doi: 10.1093/hmg/ddt341. [Epub ahead of print] PMID: 23882132
Yamauchi J, Kumar A, Duarte L, Mehuron T, Girgenrath M
Hum Mol Genet 2013 Nov 1;22(21):4306-17. Epub 2013 Jun 16 doi: 10.1093/hmg/ddt280. [Epub ahead of print] PMID: 23773998
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. [Epub ahead of print] 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. [Epub ahead of print] PMID: 19015158
Philpot J, Cowan F, Pennock J, Sewry C, Dubowitz V, Bydder G, Muntoni F
Neuromuscul Disord 1999 Mar;9(2):81-5. PMID: 10220862

Prognosis

Andrade RC, Nevado J, de Faria Domingues de Lima MA, Saad T, Moraes L, Chimelli L, Lapunzina P, Vargas FR
Am J Med Genet A 2014 Nov;164A(11):2908-13. Epub 2014 Aug 14 doi: 10.1002/ajmg.a.36716. [Epub ahead of print] PMID: 25124546
Jones LC, Waite PD
J Oral Maxillofac Surg 2012 Feb;70(2):e141-6. doi: 10.1016/j.joms.2011.10.011. PMID: 22260916
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. [Epub ahead of print] 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
Mercuri E, Pennock J, Goodwin F, Sewry C, Cowan F, Dubowitz L, Dubowitz V, Muntoni F
Neuromuscul Disord 1996 Dec;6(6):425-9. PMID: 9027850

Clinical prediction guides

Andrade RC, Nevado J, de Faria Domingues de Lima MA, Saad T, Moraes L, Chimelli L, Lapunzina P, Vargas FR
Am J Med Genet A 2014 Nov;164A(11):2908-13. Epub 2014 Aug 14 doi: 10.1002/ajmg.a.36716. [Epub ahead of print] PMID: 25124546
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
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
Hayashi YK, Tezak Z, Momoi T, Nonaka I, Garcia CA, Hoffman EP, Arahata K
Neuromuscul Disord 2001 May;11(4):350-9. PMID: 11369186
Naom IS, D'Alessandro M, Topaloglu H, Sewry C, Ferlini A, Helbling-Leclerc A, Guicheney P, Weissenbach J, Schwartz K, Bushby K, Philpot J, Dubowitz V, Muntoni F
J Med Genet 1997 Feb;34(2):99-104. PMID: 9039983Free PMC Article

Recent systematic reviews

Clement EM, Feng L, Mein R, Sewry CA, Robb SA, Manzur AY, Mercuri E, Godfrey C, Cullup T, Abbs S, Muntoni F
Neuromuscul Disord 2012 Jun;22(6):522-7. Epub 2012 Apr 3 doi: 10.1016/j.nmd.2012.01.010. [Epub ahead of print] PMID: 22480491

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