The Unstable CCTG Repeat Responsible for Myotonic Dystrophy Type 2 Originates from an AluSx Element Insertion into an Early Primate Genome

Myotonic dystrophy type 2 (DM2) is an autosomal dominant muscular dystrophy caused by the expansion of an intronic tetranucleotide CCTG repeat in CNBP on chromosome 3. As DM1, DM2 is a multisystem disorder affecting, beside the skeletal muscle, various other tissues, including peripheral nerves. Indeed, a subclinical involvement of peripheral nervous system has been described in several cohorts of DM2 patients, whereas DM2 patients manifesting clinical signs and/or symptoms of neuropathy have been only rarely reported. Here, we describe 2 related DM2 patients both of whom displayed an atypical disease onset characterized by dysautonomic symptoms, possibly secondary to peripheral neuropathy.

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Characterisation of Non-Pathogenic Premutation-Range Myotonic Dystrophy Type 2 Alleles

Journal of Clinical Medicine ◽

10.3390/jcm10173934 ◽

2021 ◽

Vol 10 (17) ◽

pp. 3934

Author(s):

Jan Radvanszky ◽

Michaela Hyblova ◽

Eva Radvanska ◽

Peter Spalek ◽

Alica Valachova ◽

...

Keyword(s):

Myotonic Dystrophy ◽

Intergenerational Transmission ◽

Grey Zone ◽

Myotonic Dystrophy Type ◽

Nucleic Acid Binding ◽

Pathogenic Role ◽

Myotonic Dystrophy Type 2 ◽

Family Structures ◽

Cctg Repeat

Myotonic dystrophy type 2 (DM2) is caused by expansion of a (CCTG)n repeat in the cellular retroviral nucleic acid-binding protein (CNBP) gene. The sequence of the repeat is most commonly interrupted and is stably inherited in the general population. Although expanded alleles, premutation range and, in rare cases, also non-disease associated alleles containing uninterrupted CCTG tracts have been described, the threshold between these categories is poorly characterised. Here, we describe four families with members reporting neuromuscular complaints, in whom we identified altogether nine ambiguous CNBP alleles containing uninterrupted CCTG repeats in the range between 32 and 42 repeats. While these grey-zone alleles are most likely not pathogenic themselves, since other pathogenic mutations were identified and particular family structures did not support their pathogenic role, they were found to be unstable during intergenerational transmission. On the other hand, there was no observable general microsatellite instability in the genome of the carriers of these alleles. Our results further refine the division of CNBP CCTG repeat alleles into two major groups, i.e., interrupted and uninterrupted alleles. Both interrupted and uninterrupted alleles with up to approximately 30 CCTG repeats were shown to be generally stable during intergenerational transmission, while intergenerational as well as somatic instability seems to gradually increase in uninterrupted alleles with tract length growing above this threshold.

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Marathoning with myotonic dystrophy type 2 (proximal myotonic myopathy) and leukopenia

SAGE Open Medical Case Reports ◽

10.1177/2050313x17703021 ◽

2017 ◽

Vol 5 ◽

pp. 2050313X1770302

Author(s):

Josef Finsterer ◽

Georg Safoschnik ◽

Martina Witsch-Baumgartner

Keyword(s):

Myotonic Dystrophy ◽

Sport Activity ◽

Repeat Expansion ◽

Motor Neuropathy ◽

Myotonic Dystrophy Type ◽

Myotonic Dystrophy Type 2 ◽

Continuous Exercise ◽

Proximal Myotonic Myopathy ◽

Cctg Repeat

Objectives: A mild, slowly progressive course of proximal myotonic myopathy, also known as myotonic dystrophy type 2, over years allowing the patient to continue with extreme sport activity, has been only rarely reported. Methods: Case report. Results: The patient is a 54-year-old female sport teacher who developed myotonia of the distal upper limbs at the age of 32 years. Over the following 22 years, myotonia spreaded to the entire musculature. Myotonia did not prevent her from doing her job and from marathoning and improved with continuous exercise. Additionally, she had developed hypothyroidism, ovarial cysts, incipient cataract, motor neuropathy, hepatopathy, leukopenia, and mild hyper-CK-emia. A heterozygous CCTG-repeat expansion of 500–9500 was found in the CNBP/ZNF9 gene. At the age of 54 years, she was still performing sport, without presenting with myotonia on clinical examination or having developed other typical manifestations of proximal myotonic myopathy. Conclusions: This case shows that proximal myotonic myopathy may take a mild course over at least 22 years, that proximal myotonic myopathy with mild myotonia may allow a patient to continue strenuous sport activity, and that continuous physical activity may contribute to the mild course of the disease.

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