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Muscular dystrophy, limb-girdle, autosomal recessive 28(MYPLG; LGMDR28)

MedGen UID:
1841154
Concept ID:
C5830518
Disease or Syndrome
Synonym: Myopathy, limb-girdle, adult-onset
 
Gene (location): HMGCR (5q13.3)
 
Monarch Initiative: MONDO:0957270
OMIM®: 620375

Definition

Autosomal recessive limb-girdle muscular dystrophy-28 (LGMDR28) is characterized by progressive muscle weakness affecting the proximal and axial muscles of the upper and lower limbs. The age at onset is highly variable, usually in the first decade, although onset in the fourth decade has also been reported. The disorder can be rapidly progressive or show a slower course. Most patients have limited ambulation or become wheelchair-bound within a few decades, and respiratory insufficiency commonly occurs. Laboratory studies show increased serum creatine kinase and elevated fasting blood glucose levels, although cholesterol is normal. EMG shows a myopathic pattern; muscle biopsy is generally unremarkable, but can show nonspecific myopathic or dystrophic features (Yogev et al., 2023; Morales-Rosado et al., 2023). For a discussion of genetic heterogeneity of autosomal recessive limb-girdle muscular dystrophy, see LGMDR1 (253600). [from OMIM]

Clinical features

From HPO
Myalgia
MedGen UID:
68541
Concept ID:
C0231528
Sign or Symptom
Pain in muscle.
Exercise-induced myalgia
MedGen UID:
340638
Concept ID:
C1850830
Sign or Symptom
The occurrence of an unusually high amount of muscle pain following exercise.
Left ventricular diastolic dysfunction
MedGen UID:
696562
Concept ID:
C1273070
Disease or Syndrome
Abnormal function of the left ventricule during left ventricular relaxation and filling.
Increased circulating troponin T concentration
MedGen UID:
1634809
Concept ID:
C4703661
Finding
An increased concentration of tropnin T in the blood, which is a cardiac regulatory protein that controls the calcium mediated interaction between actin and myosin. Raised cardiac troponin concentrations are now accepted as the standard biochemical marker for the diagnosis of myocardial infarction.
Dysphagia
MedGen UID:
41440
Concept ID:
C0011168
Disease or Syndrome
Difficulty in swallowing.
Areflexia
MedGen UID:
115943
Concept ID:
C0234146
Finding
Absence of neurologic reflexes such as the knee-jerk reaction.
Hyporeflexia
MedGen UID:
195967
Concept ID:
C0700078
Finding
Reduction of neurologic reflexes such as the knee-jerk reaction.
Loss of ambulation
MedGen UID:
332305
Concept ID:
C1836843
Finding
Inability to walk in a person who previous had the ability to walk.
Reduced tendon reflexes
MedGen UID:
356648
Concept ID:
C1866934
Finding
Diminution of tendon reflexes, which is an invariable sign of peripheral nerve disease.
Brain imaging abnormality
MedGen UID:
751376
Concept ID:
C2711610
Finding
An anomaly of metabolism or structure of the brain identified by imaging.
Proximal muscle weakness
MedGen UID:
113169
Concept ID:
C0221629
Finding
A lack of strength of the proximal muscles.
Centrally nucleated skeletal muscle fibers
MedGen UID:
330782
Concept ID:
C1842170
Finding
An abnormality in which the nuclei of sarcomeres take on an abnormally central localization (or in which this feature is found in an increased proportion of muscle cells).
Calf muscle hypertrophy
MedGen UID:
335868
Concept ID:
C1843057
Finding
Muscle hypertrophy affecting the calf muscles.
Axial muscle weakness
MedGen UID:
334472
Concept ID:
C1843697
Finding
Reduced strength of the axial musculature (i.e., of the muscles of the head and neck, spine, and ribs).
Type 1 muscle fiber predominance
MedGen UID:
344274
Concept ID:
C1854387
Finding
An abnormal predominance of type I muscle fibers (in general, this feature can only be observed on muscle biopsy).
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.
Type 2 muscle fiber predominance
MedGen UID:
478817
Concept ID:
C3277187
Finding
An abnormal predominance of type II muscle fibers (in general, this feature can only be observed on muscle biopsy).
Upper limb amyotrophy
MedGen UID:
867165
Concept ID:
C4021523
Disease or Syndrome
Muscular atrophy involving the muscles of the upper limbs.
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.
Reduced muscle fiber alpha dystroglycan
MedGen UID:
868254
Concept ID:
C4022646
Finding
Immunohistochemistry reveals reduced alpha dystroglycan protein in the muscle biopsy. Alpha-dystroglycan is a heavily glycosylated peripheral-membrane component of the dystrophin-associated glycoprotein complex (DAPC), which, in addition to laminin alpha2, binds perlecan and agrin in the extracellular matrix, whereas beta-dystroglycan, derived from the same gene, is a transmembrane protein that links to dystrophin intracellularly.
Lower limb amyotrophy
MedGen UID:
870475
Concept ID:
C4024921
Finding
Muscular atrophy affecting the lower limb.
Respiratory insufficiency
MedGen UID:
11197
Concept ID:
C0035229
Pathologic Function
Impairment of gas exchange within the lungs secondary to a disease process, neoplasm, or trauma, possibly resulting in hypoxia, hypercarbia, or both, but not requiring intubation or mechanical ventilation. Patients are normally managed with pharmaceutical therapy, supplemental oxygen, or both.
Respiratory distress
MedGen UID:
96907
Concept ID:
C0476273
Sign or Symptom
Respiratory distress is objectively observable as the physical or emotional consequences from the experience of dyspnea. The physical presentation of respiratory distress is generally referred to as labored breathing, while the sensation of respiratory distress is called shortness of breath or dyspnea.
Respiratory insufficiency due to muscle weakness
MedGen UID:
812797
Concept ID:
C3806467
Finding
Respiratory failure requiring assisted ventilation
MedGen UID:
870821
Concept ID:
C4025279
Finding
A state of respiratory distress that requires a life saving intervention in the form of gaining airway access and instituting positive pressure ventilation.
Elevated circulating aspartate aminotransferase concentration
MedGen UID:
57497
Concept ID:
C0151904
Finding
The concentration of aspartate aminotransferase (AST) in the blood circulation is above the upper limit of normal.
Elevated circulating alanine aminotransferase concentration
MedGen UID:
57740
Concept ID:
C0151905
Finding
An abnormally high concentration in the circulation of alanine aminotransferase (ALT).
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.
Elevated circulating alkaline phosphatase concentration
MedGen UID:
727252
Concept ID:
C1314665
Finding
Abnormally increased serum levels of alkaline phosphatase activity.
Increased intramyocellular lipid droplets
MedGen UID:
866481
Concept ID:
C4020730
Finding
An abnormal increase in intracellular lipid droplets In a muscle. The number and size of these drops can increase with somd disorders of lipid metabolism affecting muscle. See PMID 20691590 for histological images.
Abnormal circulating creatine kinase concentration
MedGen UID:
868058
Concept ID:
C4022449
Finding
Any deviation from the normal circulating creatine kinase concentration.
Abnormality of alkaline phosphatase level
MedGen UID:
892397
Concept ID:
C4025328
Finding
An abnormality of alkaline phosphatase level.

Professional guidelines

PubMed

Alcántara-Ortigoza MA, Reyna-Fabián ME, González-Del Angel A, Estandia-Ortega B, Bermúdez-López C, Cruz-Miranda GM, Ruíz-García M
Genes (Basel) 2019 Oct 29;10(11) doi: 10.3390/genes10110856. PMID: 31671740Free PMC Article

Recent clinical studies

Etiology

Johnson NE, Statland JM
Continuum (Minneap Minn) 2022 Dec 1;28(6):1698-1714. doi: 10.1212/CON.0000000000001178. PMID: 36537976
Ten Dam L, Frankhuizen WS, Linssen WHJP, Straathof CS, Niks EH, Faber K, Fock A, Kuks JB, Brusse E, de Coo R, Voermans N, Verrips A, Hoogendijk JE, van der Pol L, Westra D, de Visser M, van der Kooi AJ, Ginjaar I
Clin Genet 2019 Aug;96(2):126-133. Epub 2019 May 6 doi: 10.1111/cge.13544. PMID: 30919934
Chamova T, Bichev S, Todorov T, Gospodinova M, Taneva A, Kastreva K, Zlatareva D, Krupev M, Hadjiivanov R, Guergueltcheva V, Grozdanova L, Tzoneva D, Huebner A, V der Hagen M, Schoser B, Lochmüller H, Todorova A, Tournev I
Neuromuscul Disord 2018 Aug;28(8):625-632. Epub 2018 May 17 doi: 10.1016/j.nmd.2018.05.005. PMID: 29935994
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
Meena AK, Sreenivas D, Sundaram C, Rajasekhar R, Sita JS, Borgohain R, Suvarna A, Kaul S
Neurol India 2007 Apr-Jun;55(2):117-21. doi: 10.4103/0028-3886.32781. PMID: 17558114

Diagnosis

Johnson NE, Statland JM
Continuum (Minneap Minn) 2022 Dec 1;28(6):1698-1714. doi: 10.1212/CON.0000000000001178. PMID: 36537976
Ten Dam L, Frankhuizen WS, Linssen WHJP, Straathof CS, Niks EH, Faber K, Fock A, Kuks JB, Brusse E, de Coo R, Voermans N, Verrips A, Hoogendijk JE, van der Pol L, Westra D, de Visser M, van der Kooi AJ, Ginjaar I
Clin Genet 2019 Aug;96(2):126-133. Epub 2019 May 6 doi: 10.1111/cge.13544. PMID: 30919934
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
Stehlíková K, Skálová D, Zídková J, Mrázová L, Vondráček P, Mazanec R, Voháňka S, Haberlová J, Hermanová M, Zámečník J, Souček O, Ošlejšková H, Dvořáčková N, Solařová P, Fajkusová L
BMC Neurol 2014 Aug 19;14:154. doi: 10.1186/s12883-014-0154-7. PMID: 25135358Free PMC Article
Blázquez L, Azpitarte M, Sáenz A, Goicoechea M, Otaegui D, Ferrer X, Illa I, Gutierrez-Rivas E, Vilchez JJ, López de Munain A
Neurogenetics 2008 Jul;9(3):173-82. Epub 2008 Jun 19 doi: 10.1007/s10048-008-0129-1. PMID: 18563459

Therapy

Allen T, Maguire S
Int J Obstet Anesth 2007 Oct;16(4):370-4. Epub 2007 Jul 20 doi: 10.1016/j.ijoa.2007.03.003. PMID: 17643284

Prognosis

Belhassen I, Laroussi S, Sakka S, Rekik S, Lahkim L, Dammak M, Authier FJ, Mhiri C
Neuromuscul Disord 2023 Oct;33(10):718-727. Epub 2023 Aug 18 doi: 10.1016/j.nmd.2023.08.007. PMID: 37716854
Johnson NE, Statland JM
Continuum (Minneap Minn) 2022 Dec 1;28(6):1698-1714. doi: 10.1212/CON.0000000000001178. PMID: 36537976
Chamova T, Bichev S, Todorov T, Gospodinova M, Taneva A, Kastreva K, Zlatareva D, Krupev M, Hadjiivanov R, Guergueltcheva V, Grozdanova L, Tzoneva D, Huebner A, V der Hagen M, Schoser B, Lochmüller H, Todorova A, Tournev I
Neuromuscul Disord 2018 Aug;28(8):625-632. Epub 2018 May 17 doi: 10.1016/j.nmd.2018.05.005. PMID: 29935994
Guglieri M, Magri F, D'Angelo MG, Prelle A, Morandi L, Rodolico C, Cagliani R, Mora M, Fortunato F, Bordoni A, Del Bo R, Ghezzi S, Pagliarani S, Lucchiari S, Salani S, Zecca C, Lamperti C, Ronchi D, Aguennouz M, Ciscato P, Di Blasi C, Ruggieri A, Moroni I, Turconi A, Toscano A, Moggio M, Bresolin N, Comi GP
Hum Mutat 2008 Feb;29(2):258-66. doi: 10.1002/humu.20642. PMID: 17994539
Allen T, Maguire S
Int J Obstet Anesth 2007 Oct;16(4):370-4. Epub 2007 Jul 20 doi: 10.1016/j.ijoa.2007.03.003. PMID: 17643284

Clinical prediction guides

Belhassen I, Laroussi S, Sakka S, Rekik S, Lahkim L, Dammak M, Authier FJ, Mhiri C
Neuromuscul Disord 2023 Oct;33(10):718-727. Epub 2023 Aug 18 doi: 10.1016/j.nmd.2023.08.007. PMID: 37716854
Argyropoulou Z, Liu L, Ozoemena L, Branco CC, Senra R, Reis-Rego Â, Mota-Vieira L
BMC Dermatol 2018 Jan 20;18(1):1. doi: 10.1186/s12895-018-0069-x. PMID: 29352809Free PMC Article
Alavi A, Esmaeili S, Nilipour Y, Nafissi S, Tonekaboni SH, Zamani G, Ashrafi MR, Kahrizi K, Najmabadi H, Jazayeri F
J Neurogenet 2017 Sep;31(3):161-169. Epub 2017 Jul 7 doi: 10.1080/01677063.2017.1346093. PMID: 28687063
Hermanová M, Zapletalová E, Sedlácková J, Chrobáková T, Letocha O, Kroupová I, Zámecník J, Vondrácek P, Mazanec R, Maríková T, Vohánka S, Fajkusová L
Muscle Nerve 2006 Mar;33(3):424-32. doi: 10.1002/mus.20480. PMID: 16372320

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