Myotonic dystrophy type 2 (MD2), also known as proximal myotonic myopathy, is a very rare genetic multi-system disorder of late childhood or adult-onset characterized by mild myotonia, muscle weakness, and rarely cardiac conduction disorders¹.

Prevalence

2.29 100,000

2.29/100,000²; population specific prevalence³. Most cases have European ancestry, but disease has been reported worldwide³.

Age of Onset

Typical: 28-56⁴; Range: 0-73⁵.

HPO Terms

HP:0000026 Male hypogonadism HP:0000135 Hypogonadism HP:0000407 Sensorineural hearing impairment HP:0000518 Cataract HP:0000798 Oligozoospermia HP:0000975 Hyperhidrosis HP:0001249 Intellectual disability HP:0001262 Excessive daytime somnolence HP:0001265 Hyporeflexia HP:0001348 Brisk reflexes HP:0001638 Cardiomyopathy HP:0001649 Tachycardia HP:0001962 Palpitations HP:0002015 Dysphagia HP:0002019 Constipation HP:0002027 Abdominal pain HP:0002292 Frontal balding HP:0002360 Sleep disturbance HP:0002486 Myotonia HP:0002850 Decreased circulating IgM concentration HP:0002870 Obstructive sleep apnea HP:0002926 Abnormality of thyroid physiology HP:0003077 Hyperlipidemia HP:0003202 Skeletal muscle atrophy HP:0003236 Elevated circulating creatine kinase activity HP:0003326 Myalgia HP:0003327 Axial muscle weakness HP:0003552 Muscle stiffness HP:0003554 Type 2 muscle fiber atrophy HP:0003700 Generalized amyotrophy HP:0003701 Proximal muscle weakness HP:0003722 Neck flexor weakness HP:0004313 Decreased circulating immunoglobulin concentration HP:0004315 Decreased circulating IgG concentration HP:0005978 Type II diabetes mellitus HP:0006682 Premature ventricular contraction HP:0007787 Posterior subcapsular cataract HP:0007889 Iridescent posterior subcapsular cataract HP:0008189 Insulin insensitivity HP:0008232 Elevated circulating follicle stimulating hormone level HP:0008981 Calf muscle hypertrophy HP:0011712 Complete right bundle branch block HP:0012036 Sternocleidomastoid amyotrophy HP:0012378 Fatigue HP:0012452 Restless legs HP:0012899 Handgrip myotonia HP:0030319 Weakness of facial musculature HP:0030891 Periventricular white matter hyperintensities HP:0031546 Cardiac conduction abnormality HP:0100543 Cognitive impairment

Association

Mendelian

Locus

hg19 chr3:128891419-128891499

hg38 chr3:129172576-129172656

t2t chr3:131917482-131917557

Details

≤30 uninterrupted CCTG repeats or 11-26 CCTG repeats with GCTC/TCTG interruptions are considered benign; 27-29 repeats with interruptions have currently unknown significance, ~30-~54 repeats are considered premutations, ~55-74 repeats are premutations with possible reduced penetrance, and >74 repeat alleles are considered pathogenic³. Penetrance is age-dependent and approaches 100%. Locus structure is (TG)n(TCTG)n(CCTG)n. CCTG expansion causes DM2, but the other repeat units are also variable. Interruptions include GCTG/TCTG/GGCT⁶. Many DM2 expansions include a downstream 3' (TCTG)n block after the main array. One cohort found this structure in 88% of DM2 patients⁷.

Mechanism

GoF

Aberrant splicing, RAN translation^8,9. Proposed pathogenesis contributions include nucleolar stress, autophagy dysregulation, and stress granule formation¹⁰.

Detection

Bidirectional RP-PCR and Southern blotting are commonly used for detection³. A downstream 3' (TCTG)n block can cause false negative or unclear results, so TCTG targeted RP-PCR or long-read sequencing has been used to resolve these cases^11,12.

Year

2001¹³

Location in Gene

Intron 1

Gene Strand

Alleles

Ref. Motif

CAGG

Ranges

Benign (ref.)

–

Benign (gene)

–

Pathogenic (ref.)

CAGG

Pathogen. (gene)

CCTG

Unknown (ref.)

ACAG

Unknown (gene)

CTGT

Interruption (ref.)

–

Interrup. (gene)

–

gnomAD

References

Direct supporting references for info on this page.

Ontology Lookup Service (OLS)

mondo:0011266

Global Prevalence of Myotonic Dystrophy: An Updated Systematic Review and Meta-Analysis.

Qiao,Liao, Yihao,Zhang, Jian,He, Kun,Huang

Neuroepidemiology · 2022-04-28

pmid:35483324

Myotonic Dystrophy Type 2

Felix,Kleefeld, Hannes,Erdmann, Benedikt,Schoser

GeneReviews® · 1993-01-01

genereviews:NBK1466

Assessing the influence of age and gender on the phenotype of myotonic dystrophy type 2.

Federica,Montagnese, Stefania,Mondello, Stephan,Wenninger, Wolfram,Kress, Benedikt,Schoser

Journal of neurology · 2017-10-30

pmid:29086017

The DM-scope registry: a rare disease innovative framework bridging the gap between research and medical care.

Marie,De Antonio, Céline,Dogan, Ferroudja,Daidj, Bruno,Eymard, Jack,Puymirat, Jean,Mathieu, Cynthia,Gagnon, Sandrine,Katsahian, Dalil,Hamroun, Guillaume,Bassez

Orphanet journal of rare diseases · 2019-06-03

pmid:31159885

Comprehensive genetic diagnosis of tandem repeat expansion disorders with programmable targeted nanopore sequencing.

Igor,Stevanovski, Sanjog R,Chintalaphani, Hasindu,Gamaarachchi, James M,Ferguson, Sandy S,Pineda, Carolin K,Scriba, Michel,Tchan, Victor,Fung, Karl,Ng, Andrea,Cortese, Henry,Houlden, Carol,Dobson-Stone, Lauren,Fitzpatrick, Glenda,Halliday, Gianina,Ravenscroft, Mark R,Davis, Nigel G,Laing, Avi,Fellner, Marina,Kennerson, Kishore R,Kumar, Ira W,Deveson

Science advances · 2022-03-04

pmid:35245110

Updated Structure of

Martin,Wendlandt, Hannes,Erdmann, Simone,Rost, Morghan C,Lucas, Kerstin,Becker, Stephanie,Kleinle, Manuela,Timmer, Andrea,Bier, Gilbert,Wunderlich, Stephan,Wenninger, Maggie C,Walter, Teresa,Neuhann, Benedikt,Schoser, Elke,Holinski-Feder, Angela,Abicht

Neurology. Genetics · 2024-12-18

pmid:39703464

Muscle weakness in myotonic dystrophy associated with misregulated splicing and altered gating of Ca(V)1.1 calcium channel.

Zhen Zhi,Tang, Viktor,Yarotskyy, Lan,Wei, Krzysztof,Sobczak, Masayuki,Nakamori, Katy,Eichinger, Richard T,Moxley, Robert T,Dirksen, Charles A,Thornton

Human molecular genetics · 2011-12-02

pmid:22140091

Sequence composition changes in short tandem repeats: heterogeneity, detection, mechanisms and clinical implications.

Indhu-Shree,Rajan-Babu, Egor,Dolzhenko, Michael A,Eberle, Jan M,Friedman

Nature reviews. Genetics · 2024-03-11

pmid:38467784

Distinct cellular effects of myotonic dystrophy type 2 repeat-associated non-AUG tetrapeptides.

Marta,Marzullo, Assia,De Simone, Marta,Terribili, Michela,Di Salvio, Degisew Yinur,Mengistu, Maria Patrizia,Somma, Rodrigo,D'Amico, Gianluca,Canettieri, Gianluca,Cestra, Laura,Ciapponi

Disease models & mechanisms · 2026-05-18

pmid:42003432

Characterization of full-length

Massimiliano,Alfano, Luca,De Antoni, Federica,Centofanti, Virginia Veronica,Visconti, Simone,Maestri, Chiara,Degli Esposti, Roberto,Massa, Maria Rosaria,D'Apice, Giuseppe,Novelli, Massimo,Delledonne, Annalisa,Botta, Marzia,Rossato

eLife · 2022-08-26

pmid:36018009

The novel (TCTG)

Federica,Centofanti, Virginia Veronica,Visconti, Maria Rosaria,D'Apice, Marco,Carlomagno, Simone,Maestri, Dario,Ciabini, Mario,Bengala, Enrica,Marchionni, Erica,Frezza, Roberto,Massa, Antonio,Petrucci, Francesca,Lupidi, Elena,Pegoraro, Gabriele,Siciliano, Matteo,Garibaldi, Paola,Origone, Massimo,Delledonne, Marzia,Rossato, Annalisa,Botta, Giuseppe,Novelli

Human genomics · 2026-04-05

pmid:41937177

Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9.

C L,Liquori, K,Ricker, M L,Moseley, J F,Jacobsen, W,Kress, S L,Naylor, J W,Day, L P,Ranum

Science (New York, N.Y.) · 2001-08-03

pmid:11486088

Additional Literature

Additional literature related to this locus.

Raw PubMed search results
(All PubMed results returned by searching for this gene, tandem repeats, and disease, in medline format)

Genome-wide detection and clinical prioritization of tandem repeat outliers using long-read sequencing.

Sophia B,Gibson, Nikhita,Damaraju, J Gus,Gustafson, Elsa V,Balton, Sirisak,Chanprasert, Ian A,Glass, Martha,Horike-Pyne, Runjun D,Kumar, Kathleen A,Leppig, Chris,Lundberg, Jane,Ranchalis, Elisabeth A,Rosenthal, Andrew K,Solomon, Andrew B,Stergachis, Mark,Wener, Gail P,Jarvik, Elizabeth E,Blue, Katrina M,Dipple, Harriet,Dashnow, Lea M,Starita, Danny E,Miller

medRxiv : the preprint server for health sciences · 2026-05-01

pmid:42094143

The novel (TCTG)

Human genomics · 2026-04-05

pmid:41937177

Aberrant skeletal muscle morphogenesis and myofiber differentiation characterize equine myotonic dystrophy.

Stephanie J,Valberg, Zoë J,Williams, Elizabeth G,Ames, James R,Mickelson, Yvette S,Nout-Lomas, Gabriele,Landolt, Macarena,Sanz, Keri,Gardner

PloS one · 2026-01-29

pmid:41610137

Association of Non-Coding Repeat Expansions with Parkinson's Disease Risk: Evidence from a UK Biobank-Based Whole-Genome Sequencing Study.

Zhen,Hu, Qin-Qin,Yan, Jing-Jin,Wan, Yu,Fan, Jun,Liu

Movement disorders : official journal of the Movement Disorder Society · 2025-10-11

pmid:41074692

Optical genome mapping enables accurate testing of large repeat expansions.

Bart,van der Sanden, Kornelia,Neveling, Syukri,Shukor, Michael D,Gallagher, Joyce,Lee, Stephanie L,Burke, Maartje,Pennings, Ronald,van Beek, Michiel,Oorsprong, Ellen,Kater-Baats, Eveline,Kamping, Alide A,Tieleman, Nicol C,Voermans, Ingrid E,Scheffer, Jozef,Gecz, Mark A,Corbett, Lisenka E L M,Vissers, Andy Wing Chun,Pang, Alex,Hastie, Erik-Jan,Kamsteeg, Alexander,Hoischen

Genome research · 2025-04-14

pmid:40113266

High-resolution repeat structure analysis in myotonic dystrophy type 2 diagnostics using short-read whole genome sequencing.

Ingrid,Lojova, Marcel,Kucharik, Andrea,Zatkova, Andrej,Balaz, Zuzana,Pös, Eva Tothova,Tarova, Ludevit,Kadasi, Jaroslav,Budis, Tomas,Szemes, Jan,Radvanszky

Analytical biochemistry · 2025-02-01

pmid:39894140

Life expectancy and causes of death in patients with Myotonic Dystrophy Type 2.

Manon J,Damen, Otto G,Muilwijk, Tom Bg,Olde Dubbelink, Baziel Gm,van Engelen, Nicol C,Voermans, Alide A,Tieleman

Journal of neuromuscular diseases · 2024-11-01

pmid:39240646

Co-occurrence of

Wiktoria,Radziwonik-Frączyk, Ewelina,Elert-Dobkowska, Jolanta,Kubalska, Iwona,Stępniak, Marta,Lipowska, Anna,Potulska-Chromik, Anna,Sułek

Postepy psychiatrii neurologii · 2024-07-24

pmid:39119544

Effects of interrupting residues on DNA dumbbell structures formed by CCTG tetranucleotide repeats associated with myotonic dystrophy type 2.

Yingquan,Yang, Yang,Wang, Zhenzhen,Yan, Zhigang,Li, Pei,Guo