Abstract
BackgroundMyotonia congenita is a rare neuromuscular disease, which is characterized by a delay in muscle relaxation after evoked or voluntary contraction. Myotonia congenita can be inherited in a dominant (Thomsen disease) and recessive form (Becker disease) and both are caused by pathogenic variants in the CLCN1 gene. Noncanonical splice site variants are often classified as variants of uncertain significance, due to insufficient accuracy of splice-predicting tools. Functional analysis using minigene plasmids is widely used in such cases. Moreover, functional analysis is very useful in investigation of the disease pathogenesis, which is necessary for development of future therapeutic approaches. To our knowledge only one noncanonical splice site variant in the CLCN1 gene was functionally characterized to date. We further contribute to this field by evaluation the molecular mechanism of splicing alteration caused by the c.1582 + 5G > A in a homozygous state.Case presentationWe report a clinical case of an affected 6-y.o boy with athletic appearance due to muscle hypertrophy, calf muscle stiffness, cramping and various myotonic signs in a consanguineous family with no history of neuromuscular disorders. The neurological examination showed percussion-activated myotonia in the hands and legs. Plasma creatine kinase enzyme and transaminases levels were normal. Electromyography at the time of examination shows myotonic runs in the upper and lower extremities.ConclusionsFunctional analysis of the variant in a minigene system showed alteration of splicing leading to loss of function, thereby confirming that the variant is pathogenic.
Highlights
Myotonia congenita is a rare neuromuscular disease, which is characterized by a delay in muscle relaxation after evoked or voluntary contraction
Functional analysis of the variant in a minigene system showed alteration of splicing leading to loss of function, thereby confirming that the variant is pathogenic
Myotonia congenita (MC) is associated with pathogenic variants in the Chloride voltage-gated channel 1 (CLCN1) gene, which encode for the skeletal muscle chloride channel CLC-1 and can be inherited in a dominant or recessive trait
Summary
Myotonia congenita is a rare neuromuscular disease, which is characterized by a delay in muscle relaxation after evoked or voluntary contraction. Conclusions: Functional analysis of the variant in a minigene system showed alteration of splicing leading to loss of function, thereby confirming that the variant is pathogenic. MC is associated with pathogenic variants in the CLCN1 gene, which encode for the skeletal muscle chloride channel CLC-1 and can be inherited in a dominant or recessive trait.
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