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Muscular dystrophy, limb-girdle, autosomal recessive 23(LGMDR23)

MedGen UID:
1648462
Concept ID:
C4748327
Disease or Syndrome
Synonyms: LGMDR23; MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 23
 
Gene (location): LAMA2 (6q22.33)
 
Monarch Initiative: MONDO:0029136
OMIM®: 618138
Orphanet: ORPHA565837

Disease characteristics

Excerpted from the GeneReview: LAMA2 Muscular Dystrophy
The clinical manifestations of LAMA2 muscular dystrophy (LAMA2-MD) comprise a continuous spectrum ranging from severe congenital muscular dystrophy type 1A (MDC1A) to milder late-onset LAMA2-MD. MDC1A is typically characterized by neonatal profound hypotonia, poor spontaneous movements, and respiratory failure. Failure to thrive, gastroesophageal reflux, aspiration, and recurrent chest infections necessitating frequent hospitalizations are common. As disease progresses, facial muscle weakness, temporomandibular joint contractures, and macroglossia may further impair feeding and can affect speech. In late-onset LAMA2-MD onset of manifestations range from early childhood to adulthood. Affected individuals may show muscle hypertrophy and develop a rigid spine syndrome with joint contractures, usually most prominent in the elbows. Progressive respiratory insufficiency, scoliosis, and cardiomyopathy can occur. [from GeneReviews]
Authors:
Jorge Oliveira  |  João Parente Freixo  |  Manuela Santos, et. al.   view full author information

Additional description

From OMIM
Autosomal recessive limb-girdle muscular dystrophy-23 is characterized by slowly progressive proximal muscle weakness primarily affecting the lower limbs and resulting in gait difficulties. Age at onset generally ranges from childhood to mid-adulthood. Additional features include white matter abnormalities on brain imaging, increased serum creatine kinase, and dystrophic features, with partial LAMA2 deficiency on muscle biopsy. Some patients may have additional neurologic features, including executive deficits, seizures, and peripheral neuropathy. Patients remain ambulatory well into adulthood (summary by Gavassini et al., 2011 and Chan et al., 2014). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive limb-girdle muscular dystrophy, see LGMDR1 (253600).  http://www.omim.org/entry/618138

Clinical features

From HPO
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.
Waddling gait
MedGen UID:
66667
Concept ID:
C0231712
Finding
Weakness of the hip girdle and upper thigh muscles, for instance in myopathies, leads to an instability of the pelvis on standing and walking. If the muscles extending the hip joint are affected, the posture in that joint becomes flexed and lumbar lordosis increases. The patients usually have difficulties standing up from a sitting position. Due to weakness in the gluteus medius muscle, the hip on the side of the swinging leg drops with each step (referred to as Trendelenburg sign). The gait appears waddling. The patients frequently attempt to counteract the dropping of the hip on the swinging side by bending the trunk towards the side which is in the stance phase (in the German language literature this is referred to as Duchenne sign). Similar gait patterns can be caused by orthopedic conditions when the origin and the insertion site of the gluteus medius muscle are closer to each other than normal, for instance due to a posttraumatic elevation of the trochanter or pseudarthrosis of the femoral neck.
Areflexia
MedGen UID:
115943
Concept ID:
C0234146
Finding
Absence of neurologic reflexes such as the knee-jerk reaction.
Delayed ability to walk
MedGen UID:
66034
Concept ID:
C0241726
Finding
A failure to achieve the ability to walk at an appropriate developmental stage. Most children learn to walk in a series of stages, and learn to walk short distances independently between 12 and 15 months.
Abnormal cerebral white matter morphology
MedGen UID:
181756
Concept ID:
C0948163
Pathologic Function
An abnormality of the cerebral white matter.
Sensorimotor neuropathy
MedGen UID:
207266
Concept ID:
C1112256
Disease or Syndrome
Axonal degeneration
MedGen UID:
332464
Concept ID:
C1837496
Finding
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Decreased nerve conduction velocity
MedGen UID:
347509
Concept ID:
C1857640
Finding
A reduction in the speed at which electrical signals propagate along the axon of a neuron.
Kyphosis
MedGen UID:
44042
Concept ID:
C0022821
Anatomical Abnormality
Exaggerated anterior convexity of the thoracic vertebral column.
Gowers sign
MedGen UID:
65865
Concept ID:
C0234182
Finding
A phenomenon whereby patients are not able to stand up without the use of the hands owing to weakness of the proximal muscles of the lower limbs.
Difficulty climbing stairs
MedGen UID:
68676
Concept ID:
C0239067
Finding
Reduced ability to climb stairs.
Elbow flexion contracture
MedGen UID:
98367
Concept ID:
C0409338
Acquired Abnormality
An elbow contracture that limits the ability of the elbow joint to be extended (straightened), meaning that the elbow is fixed in an flexed (bent) position.
Difficulty running
MedGen UID:
108251
Concept ID:
C0560346
Finding
Reduced ability to run.
Calf muscle hypertrophy
MedGen UID:
335868
Concept ID:
C1843057
Finding
Muscle hypertrophy affecting the calf muscles.
Neck flexor weakness
MedGen UID:
334801
Concept ID:
C1843637
Finding
Weakness of the muscles involved in neck flexion (sternocleidomastoid, longus capitus, longus colli, and scalenus anterior).
Increased variability in muscle fiber diameter
MedGen UID:
336019
Concept ID:
C1843700
Finding
An abnormally high degree of muscle fiber size variation. This phenotypic feature can be observed upon muscle biopsy.
Exercise-induced muscle cramps
MedGen UID:
383715
Concept ID:
C1855578
Finding
Sudden and involuntary contractions of one or more muscles brought on by physical exertion.
Proximal muscle weakness in lower limbs
MedGen UID:
356423
Concept ID:
C1866010
Finding
A lack of strength of the proximal muscles of the legs.
Proximal muscle weakness in upper limbs
MedGen UID:
356424
Concept ID:
C1866012
Finding
A lack of strength of the proximal muscles of the arms.
Internally nucleated skeletal muscle fibers
MedGen UID:
1623054
Concept ID:
C4531255
Anatomical Abnormality
An abnormally increased proportion of nuclei of sarcomeres with an internal localization. Individual muscle fibers are syncytia, formed by embryonic fusion of many myoblasts or later, myosatellite cells. Each muscle fiber contains many nuclei, peripherally positioned immediately adjacent to the sarcolemmal membrane. In healthy muscle only 3-5% of fibers contain nuclei that are located internally, within the cell, but many disease processes lead to internal nuclei.
Elevated muscle fiber laminin alpha 5 expression
MedGen UID:
1052712
Concept ID:
CN377489
Finding
A decreased amount of laminin alpha-5 in muscle tissue. This feature can be shown by immunohistochemistry or Western blotting of muscle tissue. Laminin subunit alpha-5 is a protein encoded by the LAMA5 gene.
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.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVMuscular dystrophy, limb-girdle, autosomal recessive 23

Recent clinical studies

Etiology

Lorenzoni PJ, Kay CSK, Ducci RD, Fustes OJH, Rodrigues PRDVP, Hrysay NMC, Arndt RC, Werneck LC, Scola RH
Arq Neuropsiquiatr 2023 Oct;81(10):922-933. Epub 2023 Oct 18 doi: 10.1055/s-0043-1772833. PMID: 37852290Free PMC Article
Alonso-Pérez J, González-Quereda L, Bruno C, Panicucci C, Alavi A, Nafissi S, Nilipour Y, Zanoteli E, Isihi LMA, Melegh B, Hadzsiev K, Muelas N, Vílchez JJ, Dourado ME, Kadem N, Kutluk G, Umair M, Younus M, Pegorano E, Bello L, Crawford TO, Suárez-Calvet X, Töpf A, Guglieri M, Marini-Bettolo C, Gallano P, Straub V, Díaz-Manera J
Brain 2022 Apr 18;145(2):596-606. doi: 10.1093/brain/awab301. PMID: 34515763Free PMC Article
Deconinck N, Richard P, Allamand V, Behin A, Lafôret P, Ferreiro A, de Becdelievre A, Ledeuil C, Gartioux C, Nelson I, Carlier RY, Carlier P, Wahbi K, Romero N, Zabot MT, Bouhour F, Tiffreau V, Lacour A, Eymard B, Stojkovic T
J Neurol Neurosurg Psychiatry 2015 Dec;86(12):1337-46. Epub 2014 Dec 22 doi: 10.1136/jnnp-2013-307245. PMID: 25535305
Nigro V, Savarese M
Acta Myol 2014 May;33(1):1-12. PMID: 24843229Free PMC Article
Nalini A, Gayathri N, Thaha F, Das S, Shylashree S
Neurol India 2010 Sep-Oct;58(5):691-6. doi: 10.4103/0028-3886.72164. PMID: 21045489

Diagnosis

Alonso-Pérez J, González-Quereda L, Bruno C, Panicucci C, Alavi A, Nafissi S, Nilipour Y, Zanoteli E, Isihi LMA, Melegh B, Hadzsiev K, Muelas N, Vílchez JJ, Dourado ME, Kadem N, Kutluk G, Umair M, Younus M, Pegorano E, Bello L, Crawford TO, Suárez-Calvet X, Töpf A, Guglieri M, Marini-Bettolo C, Gallano P, Straub V, Díaz-Manera J
Brain 2022 Apr 18;145(2):596-606. doi: 10.1093/brain/awab301. PMID: 34515763Free PMC Article
Zhang C, Zheng X, Lu D, Xu L, Che F, Liu S
Mol Med Rep 2021 Jun;23(6) Epub 2021 Apr 26 doi: 10.3892/mmr.2021.12119. PMID: 33899113Free PMC Article
Løkken N, Born AP, Duno M, Vissing J
Muscle Nerve 2015 Oct;52(4):547-53. Epub 2015 Aug 13 doi: 10.1002/mus.24588. PMID: 25663498
Orrell RW
Practitioner 2012 Sep;256(1754):21-4, 2-3. PMID: 23252132
Angelini C
Acta Myol 2004 Dec;23(3):130-6. PMID: 15938568

Therapy

Audhya IF, Cheung A, Szabo SM, Flint E, Weihl CC, Gooch KL
J Neuromuscul Dis 2022;9(4):477-492. doi: 10.3233/JND-210771. PMID: 35527561Free PMC Article

Prognosis

Cheung A, Audhya IF, Szabo SM, Friesen M, Weihl CC, Gooch KL
J Clin Neuromuscul Dis 2023 Dec 1;25(2):65-80. doi: 10.1097/CND.0000000000000461. PMID: 37962193
Alonso-Pérez J, González-Quereda L, Bruno C, Panicucci C, Alavi A, Nafissi S, Nilipour Y, Zanoteli E, Isihi LMA, Melegh B, Hadzsiev K, Muelas N, Vílchez JJ, Dourado ME, Kadem N, Kutluk G, Umair M, Younus M, Pegorano E, Bello L, Crawford TO, Suárez-Calvet X, Töpf A, Guglieri M, Marini-Bettolo C, Gallano P, Straub V, Díaz-Manera J
Brain 2022 Apr 18;145(2):596-606. doi: 10.1093/brain/awab301. PMID: 34515763Free PMC Article
Deconinck N, Richard P, Allamand V, Behin A, Lafôret P, Ferreiro A, de Becdelievre A, Ledeuil C, Gartioux C, Nelson I, Carlier RY, Carlier P, Wahbi K, Romero N, Zabot MT, Bouhour F, Tiffreau V, Lacour A, Eymard B, Stojkovic T
J Neurol Neurosurg Psychiatry 2015 Dec;86(12):1337-46. Epub 2014 Dec 22 doi: 10.1136/jnnp-2013-307245. PMID: 25535305
Rosales XQ, Moser SJ, Tran T, McCarthy B, Dunn N, Habib P, Simonetti OP, Mendell JR, Raman SV
J Cardiovasc Magn Reson 2011 Aug 4;13(1):39. doi: 10.1186/1532-429X-13-39. PMID: 21816046Free PMC Article
Angelini C
Acta Myol 2004 Dec;23(3):130-6. PMID: 15938568

Clinical prediction guides

Alonso-Pérez J, González-Quereda L, Bruno C, Panicucci C, Alavi A, Nafissi S, Nilipour Y, Zanoteli E, Isihi LMA, Melegh B, Hadzsiev K, Muelas N, Vílchez JJ, Dourado ME, Kadem N, Kutluk G, Umair M, Younus M, Pegorano E, Bello L, Crawford TO, Suárez-Calvet X, Töpf A, Guglieri M, Marini-Bettolo C, Gallano P, Straub V, Díaz-Manera J
Brain 2022 Apr 18;145(2):596-606. doi: 10.1093/brain/awab301. PMID: 34515763Free PMC Article
Tan D, Ge L, Fan Y, Wei C, Yang H, Liu A, Xiao J, Xiong H, Zhu Y
Neuromuscul Disord 2021 Nov;31(11):1144-1153. Epub 2021 Sep 23 doi: 10.1016/j.nmd.2021.09.006. PMID: 34702656
Deconinck N, Richard P, Allamand V, Behin A, Lafôret P, Ferreiro A, de Becdelievre A, Ledeuil C, Gartioux C, Nelson I, Carlier RY, Carlier P, Wahbi K, Romero N, Zabot MT, Bouhour F, Tiffreau V, Lacour A, Eymard B, Stojkovic T
J Neurol Neurosurg Psychiatry 2015 Dec;86(12):1337-46. Epub 2014 Dec 22 doi: 10.1136/jnnp-2013-307245. PMID: 25535305
Rosales XQ, Moser SJ, Tran T, McCarthy B, Dunn N, Habib P, Simonetti OP, Mendell JR, Raman SV
J Cardiovasc Magn Reson 2011 Aug 4;13(1):39. doi: 10.1186/1532-429X-13-39. PMID: 21816046Free PMC Article
Franczak MB, Ulmer JL, Jaradeh S, McDaniel JD, Mark LP, Prost RW
J Neuroimaging 2000 Apr;10(2):73-7. doi: 10.1111/jon200010273. PMID: 10800259

Recent systematic reviews

Cheung A, Audhya IF, Szabo SM, Friesen M, Weihl CC, Gooch KL
J Clin Neuromuscul Dis 2023 Dec 1;25(2):65-80. doi: 10.1097/CND.0000000000000461. PMID: 37962193
Audhya IF, Cheung A, Szabo SM, Flint E, Weihl CC, Gooch KL
J Neuromuscul Dis 2022;9(4):477-492. doi: 10.3233/JND-210771. PMID: 35527561Free PMC Article

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