Аutosomal recessive limb-girdle muscular dystrophy type 2A: two cases in Ukraine with different age of onset

The paper reports on two cases of young women from Ukraine with autosomal recessive limb-girdle muscular dystrophy type 2A with different age of symptoms onset and an absence of any family history presented with gradual onset of proximal muscle weakness in four limbs and thinning of shoulders, arms and thighs. Both patients had elevated creatine phosphokinase level and c.550delA mutations in CAPN3 gene. Sequence analysis and deletion/duplication testing of the 159 genes from skeletal muscles disease testing panel of 5-year-old girl identified deletion of exon 8 (heterozygous) and c.550delA (p.Thr184Argfs*36) mutation (heterozygous), were in CAPN3 gene. Magnetic Resonance Imaging of soft tissue of the proximal lower extremities was performed which showed signs of symmetrical atrophic changes in the major adductor muscle, the long and short adductor muscles, the semitendinosus muscle of the thigh, as a manifestations of autosomal recessive limb-girdle muscular dystrophy type 2A. Homozygous, pathogenic variant of the defect in the CAPN3 gene c.550del (p.Thr184Argfs * 36) was identified in a 25-year-old woman. Type 2A is the most common form of limb-girdle muscular dystrophy, accounting for about 30% of cases. The autosomal recessive limb-girdle muscular dystrophy type 2A is on caused by mutations in the CAPN3 gene, and it is characterized by selective atrophy and weakness of proximal limb and girdle muscles. The age of onset of muscle weakness is extremely variable; the most common being between 8 and 15 years, although it can range between 2 and 50 years. The diagnosis can be suspected by findings on a muscle biopsy or when a doctor experienced in muscular dystrophy examines you. A serum creatine kinase blood test may also show raised levels which indicate a problem in the muscles. The diagnosis has to be confirmed by means of identifying a mutation in the CAPN3 gene which is done on a deoxyribonucleic acid sample from a blood test. To date there are no specific treatments for limb-girdle muscular dystrophy, however careful management of the symptoms of the condition can improve a person’s quality of life. Joint contractures (tightening) can occur in limb-girdle muscular dystrophy and therefore regular physiotherapy is recommended.

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A case of pseudodominant inheritance of limb-girdle muscular dystrophy caused by mutations in the CAPN3 gene

Annals of Clinical and Experimental Neurology ◽

10.54101/acen.2021.3.10 ◽

2021 ◽

Vol 15 (3) ◽

pp. 85-91

Author(s):

Inna V. Sharkova ◽

Maria V. Bulakh ◽

Liudmila А. Bessonova ◽

Olga A. Shchagina ◽

Elena L. Dadaly

Keyword(s):

Muscular Dystrophy ◽

Autosomal Recessive ◽

Autosomal Recessive Disease ◽

Disease Onset ◽

Limb Girdle Muscular Dystrophy ◽

Compound Heterozygous ◽

Carrier Status ◽

Heterozygous Carrier ◽

Calpain 3 ◽

Capn3 Gene

Introduction. Limb-girdle muscular dystrophy (LGMD) includes more than 30 forms caused by mutations in genes located on autosomes. The most common form is calpain-3-related LGMD, with autosomal recessive inheritance pattern (OMIM 253600). An autosomal dominant form of LGMD (OMIM 618129) caused by c.643_663del heterozygous mutation in the CAPN3 gene is also supposed to exist. This article describes a family case of LGMD caused by mutations in the CAPN3 gene with pseudodominant inheritance. Materials and methods. Two patients with LGMD were studied: a 59-year-old woman and her 38-year-old daughter. Clinical, genealogical and molecular genetics methods were used: limb girdle muscular dystrophy MPS panel, Sanger sequencing of DNA of the proband, her affected daughter, and six first- and second-degree relatives across four generations. Results. It was found that identical variants of the nucleotide sequence, c.598_612del and c.1746-20CG, identified in the CAPN3 gene of the proband and her daughter, are in the trans position (compound heterozygous state), causing autosomal recessive calpain-3-related LGMD. This is an example of an incredibly rare pseudodominant inheritance of an autosomal recessive disease, established through indirect evidence that the probands husband is a heterozygous carrier of a nucleotide substitution in the CAPN3 gene. Conclusion. It is crucial to examine the marriage partner for heterozygous carrier status of a gene mutation responsible for the disease in family planning and when clarifying the childs prognosis for a patient with an autosomal recessive disease. Considering the existence of a late-onset (after 30 years) LGMD phenotype associated with the CAPN3 gene, differential diagnosis should begin with testing this gene in families with late disease onset.

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LIMB-GIRDLE MUSCULAR DYSTROPHY: CLINICAL MANIFESTATIONS AND DETECTION OF PRECLINICAL DISEASE

PEDIATRICS ◽

10.1542/peds.41.2.495 ◽

1968 ◽

Vol 41 (2) ◽

pp. 495-502

Author(s):

Charles E. Jackson ◽

Don A. Strehler

Keyword(s):

Muscular Dystrophy ◽

Autosomal Recessive ◽

Age Of Onset ◽

Clinical Manifestations ◽

Serum Enzymes ◽

Limb Girdle Muscular Dystrophy ◽

Recessive Type ◽

The Face ◽

Mode Of Inheritance

The clinical picture of limb-girdle muscular dystrophy is described as seen in 37 affected individuals from two large Amish kindreds. The disease is characterized by an autosomal recessive mode of inheritance with as many females as males being affected, and with affected individuals being the product generally of consanguineous matings. The age of onset was observed to be between 4 and 15 years of age (average 8½) with a quite variable age of confinement to a wheelchair (12 to 44 years ). The disease was compatible with a life span in one patient to 67 years of age. The involvement of proximal shoulder and pelvic girdle muscles was similar to that in the X-linked recessive, Duchenne type of muscular dystrophy; however, the zygomaticus muscles of the face are preserved and a normal upturned smile is noted in this type of muscular dystrophy rather than the flat transverse smile noted in the X-linked recessive type. Muscle biopsy abnormalities in two individuals very early in the course of their disease suggest that biopsy would probably be useful in detection of preclinical disease in this type of muscular dystrophy. Gross abnomalities of serum enzymes in 12 younger siblings of affected individuals in these two families suggest that these enzyme determinations are useful in detecting preclinical, limb-girdle muscular dystrophy. When therapy for muscular dystrophy becomes available, the determination of preclinical disease by these techniques will become of greater clinical significance.

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A case report: autosomal recessive limb girdle muscular dystrophy caused by a novel mutation (c. 287A > G) in POMT2 gene of a Chinese Han patient

10.21203/rs.2.483/v1 ◽

2019 ◽

Author(s):

Yanlu Gao ◽

Zhixia Kang ◽

Xiaojing Wei ◽

Jing Miao ◽

Xuefan Yu

Keyword(s):

Creatine Kinase ◽

Cognitive Impairment ◽

Case Report ◽

Muscular Dystrophy ◽

Muscle Weakness ◽

Autosomal Recessive ◽

Limb Girdle Muscular Dystrophy ◽

Compound Heterozygous ◽

Proximal Muscle Weakness ◽

Proximal Muscle

Abstract BACKGROUND Autosomal recessive limb girdle muscular dystrophy 2N is caused by mutations in the POMT2 gene. The disease is characterized by proximal muscle weakness,with minimal progression, with cognitive impairment,a significantly elevated serum level of creatine kinase. CASE PRESENTATION A 9-year-old boy presented with proximal muscle weakness since the last 4 years,with minimal progression.There was no significant family history.Medical examination showed no generalized muscle hypertrophy. Serum creatine kinase level was 52-fold higher than the normal value. Wechsler Intelligence scale for Children (WISC, 4) suggested mild cognitive impairment (IQ =74). DNA sequence analysis identified a novel missense mutation (c. 287A > G) and a known mutation (c. 1261C > T). CONCLUSIONS This case report of autosomal recessive limb girdle muscular dystrophy 2N caused by a novel compound heterozygous mutation expands the genotypic spectrum of POMT2 gene.

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Allosteric Modulation of GSK-3β as a New Therapeutic Approach in Limb Girdle Muscular Dystrophy R1 Calpain 3-Related

International Journal of Molecular Sciences ◽

10.3390/ijms22147367 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7367

Author(s):

Anabel Rico ◽

Garazi Guembelzu ◽

Valle Palomo ◽

Ana Martínez ◽

Ana Aiastui ◽

...

Keyword(s):

Muscular Dystrophy ◽

Autosomal Recessive ◽

Glycogen Synthase ◽

Limb Girdle Muscular Dystrophy ◽

Pathophysiological Mechanism ◽

Calpain 3 ◽

Competitive Inhibitors ◽

Gsk 3Β ◽

Muscle Homeostasis ◽

Capn3 Gene

Limb-girdle muscular dystrophy R1 calpain 3-related (LGMDR1) is an autosomal recessive muscular dystrophy produced by mutations in the CAPN3 gene. It is a rare disease and there is no cure or treatment for the disease while the pathophysiological mechanism by which the absence of calpain 3 provokes the dystrophy in muscles is not clear. However, key proteins implicated in Wnt and mTOR signaling pathways, which regulate muscle homeostasis, showed a considerable reduction in their expression and in their phosphorylation in LGMDR1 patients’ muscles. Finally, the administration of tideglusib and VP0.7, ATP non-competitive inhibitors of glycogen synthase kinase 3β (GSK-3β), restore the expression and phosphorylation of these proteins in LGMDR1 cells, opening the possibility of their use as therapeutic options.

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