Myotonic Dystrophy Type 1 (Steinert Disease) and Type 2

Myotonic dystrophies caused by non-coding repeat expansions: DMPK (CTG) in DM1 and CNBP (CCTG) in DM2, formerly termed proximal myotonic myopathy (PROMM).

Literature and regulatory information updated: 6 October 2026.

0. Initial Reference Table

1. Introduction

Myotonic dystrophies are the most frequent group of hereditary muscular dystrophies in adulthood. The term encompasses two distinct genetic entities, myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2), which share core clinical features — myotonia, progressive muscle weakness, posterior subcapsular cataracts, cardiac conduction disease, insulin resistance and central nervous system involvement — and a common molecular mechanism: expansion of a non-coding nucleotide repeat whose RNA transcript acquires toxicity. Differences between the forms extend beyond severity. DM1 shows marked anticipation, a severe congenital form with almost exclusively maternal transmission and an imperfect correlation between repeat size and severity; DM2 generally begins in adulthood, predominantly affects proximal muscles, frequently involves muscle pain and shows no consistent relationship between expansion size and phenotype [1, 3, 4].

The clinical history of DM1 began in 1909. Hans Gustav Wilhelm Steinert, a neurologist in Leipzig, described six patients with myotonia associated with atrophy and weakness of the face, tongue, masseters, forearm and lower limb muscles, baldness and, in four cases, testicular atrophy; he reviewed 26 cases published by 19 authors and performed the first autopsy, which showed degenerated muscle fibres with internal nuclei and fibrosis, without nerve abnormalities. He described the condition as a dystrophy of patients with myotonia, distinguishing it from non-dystrophic myotonias. In the same year, Batten and Gibb published a description of “myotonia atrophica” in England, and in 1912 Hans Curschmann expanded the concept of multisystem disease, acknowledging Steinert's priority [21, 22].

The molecular basis of DM1 was identified in 1992 by three groups that located an unstable, expanded CTG repeat in patients in the 3' untranslated region of a gene at 19q13.3 encoding a kinase-family protein; Mahadevan's group found the expansion in 253 of 258 affected individuals (98%), and Fu's group observed in one congenital case that the maternal allele was unstable while the paternal allele was transmitted unchanged [23–25]. In 1994, Ricker and colleagues described three German families with myotonia, proximal weakness and cataracts without CTG expansion or linkage to the DM1 locus, naming the condition proximal myotonic myopathy, and Thornton, Griggs and Moxley reported patients with the full multisystem phenotype and a normal CTG repeat [26, 27]. In 2001, Liquori and colleagues demonstrated that this second type resulted from a CCTG expansion in intron 1 of ZNF9, now CNBP [28]. The International Myotonic Dystrophy Consortium (IDMC) established that future multisystem myotonic dystrophies would be numbered sequentially; the family initially proposed as “DM3” proved to have inclusion body myopathy associated with Paget disease and frontotemporal dementia due to a VCP variant [1, 3].

Current clinical practice rests on consensus recommendations because disease rarity and heterogeneity limit trials. The Myotonic Dystrophy Foundation (MDF) published recommendations for adults with DM1 (2018), children with congenital and childhood-onset DM1 (2019), and adults with DM2 (2019), supplemented by recommendations for cardiologists (2020) and European molecular diagnostic best practices (2012) [4, 9, 18, 19, 29]. In France, the Haute Autorité de Santé (HAS) published in December 2024 the PNDS (French National Diagnosis and Care Protocol) for DM1, prepared by the Lille neuromuscular disease reference centre, which adds system-specific surveillance intervals, blood gas criteria for ventilation, a mexiletine dosage for adolescents and children, detailed anaesthetic recommendations and an emergency pathway with a national card [15]. The GeneReviews chapters were revised in November 2024 (DM1) and rewritten in September 2025 (DM2) [1, 3]. Therapeutically, 2026 saw publication of the first trial of an antibody–oligonucleotide conjugate targeting DMPK RNA and a negative primary endpoint result in the first phase 3 trial of this molecular class, making critical appraisal of trial data part of geneticists' training [30, 31].

2. Molecular Genetics and Pathophysiology

2.1. DMPK and the CTG repeat

DMPK has 14 exons spanning approximately 13 kb and encodes an approximately 69 kDa serine–threonine kinase related to cyclic AMP-dependent and Rho-binding kinases; it localises to cardiac and skeletal muscle structures associated with intercellular conduction and interacts with myosin phosphatase [1]. The CTG repeat lies in the 3' untranslated region. DM1 appears to result from a single mutational mechanism, expansion of this repeat: single-nucleotide variants, deletions or insertions in DMPK have not been associated with disease, and GeneReviews identifies no allelic disorders [1]. This specificity has a direct laboratory implication: diagnosis requires repeat-targeted techniques, and exome or genome sequencing interpreted using conventional methods does not exclude disease [4, 6].

2.2. CNBP and the complex intron 1 repeat

CNBP encodes a CCHC-type zinc finger protein binding single-stranded DNA and guanine-rich mRNA. Intron 1 contains a complex (TG)n(TCTG)n(CCTG)n repeat present in all normal and pathogenic alleles; most pathogenic expansions (84% of studied individuals) additionally contain a distal (TCTG')n segment of unknown clinical significance but with technical implications (section 5) [3]. Normal alleles usually contain one or more TCTG or GCTG interruptions within the CCTG segment; these interruptions disappear in pathogenic expansions, suggesting that their loss increases instability and predisposes to germline expansion [3]. No coding sequence variant in CNBP has been associated with disease, and the mechanism is not loss of protein function [3, 6].

2.3. Allelic thresholds and differences between sources

Repeat ranges differ between sources, and reports should specify the criteria used. The table brings together ranges from the consulted sources; discrepancies mainly reflect laboratory conventions and the scarcity of borderline alleles rather than contradictory data about the same allele.

The Brazilian genetic syndromes chapter presents a correlation table with its own values and names the congenital form “Thomsen disease”; in the literature, this designation refers to autosomal dominant myotonia congenita caused by CLCN1 variants, a channelopathy without dystrophy, and is therefore not reproduced [1, 2, 32].

2.4. Variant nomenclature

HGVS repeat nomenclature should specify the versioned transcript. For DMPK, MANE Select is NM_004409.5, and ClinVar records expansions as NM_004409.5:c.*224CTG[n] — for example, VCV000188039, NM_004409.5:c.*224CTG[887], classified as pathogenic; at the GRCh38 genomic coordinate, the same tract appears on the positive strand as NC_000019.10:g.45770205_45770264CAG[n], because the gene lies on the negative strand [8]. GeneReviews uses an alternative transcript and range notation, NM_001081563.1:c.*224_226CTG(5-34) for normal alleles and (50-?) for pathogenic alleles; the two notations describe the same tract and should not be mixed in one report [1, 8]. Interrupted expansions are recorded in ClinVar with their complete structure, for example NM_001081563.2:c.*224_*283CTG[30]CCG[2]CTG[2]CCG[1]CTG[105] (VCV000254213) [8]. For CNBP, MANE Select is NM_003418.5, and the reference pathogenic expansion record is NM_003418.5:c.-14-833_-14-806CCTG[(75_11000)] (VCV000017564), associated with DM2 [8]. Because variability of the TG and TCTG segments precludes directly counting CCTG units without sequencing, laboratories frequently describe expansion in base pairs and estimate CCTG numbers [3].

2.5. RNA toxicity, spliceopathy and other mechanisms

The predominant mechanism in both diseases is toxic RNA gain of function. (CTG)n and (CCTG)n repeats are transcribed into (CUG)n and (CCUG)n RNA forming hairpin structures with affinity for RNA-binding proteins, sequestering them in nuclear foci. Muscleblind-like proteins (MBNL, particularly MBNL1) become functionally depleted, while the CUG-binding protein CELF1 (CUGBP1) increases, especially in DM1. These two regulators have antagonistic effects on a subset of alternative splicing events, resulting in persistence of embryonic isoforms in adult tissues [1, 3]. Relationships between targets and manifestations are established for several genes: abnormal splicing of the chloride channel CLCN1 causes myotonia; insulin receptor splicing is associated with insulin resistance and diabetes; changes in dystrobrevin, dystrophin, BIN1 and RYR1 contribute to atrophy and weakness; cardiac troponin T (TNNT2) and the cardiac sodium channel (SCN5A, with switching from adult exon 6B to fetal exon 6A) are linked to conduction defects; and tau protein (MAPT) is associated with central nervous system manifestations [1, 3, 33]. The cardiogenetics book also describes effects on neighbouring genes, and GeneGuidance reports local chromatin condensation altering SIX5 expression and CpG methylation adjacent to the repeat as a marker more closely associated with congenital disease than repeat size [6, 33].

Molecular differences help explain clinical differences. In DM2, RBFOX protein binds strongly to CCUG repeats and competes with MBNL1, which is not observed in RNA foci; this competition produces less aberrant splicing of MBNL1 targets than in DM1, and increased CELF1 has not been conclusively established. Repeat-associated non-AUG (RAN) translation, occurring in both transcriptional directions, produces the DM2 homopolymers LPAC (Leu-Pro-Ala-Cys) and QAGR (Gln-Ala-Gly-Arg), detected in grey and white matter at autopsy. The fetal TNNT2 isoform is more abundant in the hearts of patients with DM1 than DM2 and is associated with QRS abnormalities, consistent with greater mean cardiac severity in DM1 [3]. DMPK protein predominates in skeletal and cardiac muscle, but its distribution does not explain multisystem involvement; RNA retained in the nucleus accounts for involvement of almost all organs [1, 32].

2.6. Somatic instability, interruptions and genetic modifiers

The CTG repeat is mitotically unstable. Size measured in blood increases with age and varies between tissues, limiting correlation between the number measured in a leucocyte and severity [1]. Estimated progenitor allele length (ePAL), the size at birth corrected for age at sampling, better explains severity: in the OPTIMISTIC trial cohort (250 ambulatory adults), severity depended on ePAL and was modified by age and, in some cases, sex, while patients whose repeat expanded faster somatically had earlier onset than predicted [34]. Between 3% and 8% of expansions contain variant triplet interruptions (CCG, CGG; less than 5% according to European best practices, which also mention GGC and CTC); in OPTIMISTIC, interruptions delayed onset by approximately 13.2 years (95% CI 5.7–20.7), and comparison of six patients with interruptions against patients with pure repeats showed a phenotype intermediate between those patients and controls [1, 4, 34, 35]. Interruptions may also produce aberrant patterns or detection failures in TP-PCR, supporting a second laboratory method [4]. A compound heterozygote carrying alleles with 1260 and 60 repeats and brain abnormalities has been described [1].

In DM2, expansion is even more somatically unstable: it increases with age, more than 25% of patients have two or more differently sized expansions detectable in blood, and long-read sequencing data unpublished at the time of GeneReviews indicate extensive somatic mosaicism in most patients [3]. Patients homozygous for the CCTG expansion with phenotypes comparable to heterozygous siblings and parents reinforce the absence of a dosage effect on severity [3].

2.7. Anticipation and transmission

In DM1, alleles with more than 34 repeats tend to expand during meiosis, and offspring may inherit much larger repeats than their parent, with earlier onset and greater severity — anticipation [1]. Smith's book estimates a 93% probability of expansion when the altered allele is transmitted; in the Saguenay–Lac-Saint-Jean series, 92.1% of children of parents with 50–100 repeats inherited a larger repeat [36, 37]. Congenital disease almost always results from maternal transmission; in 154 pregnancies, mean intergenerational increase was 56 repeats (standard deviation 177) with paternal transmission and 948 (standard deviation 815) with maternal transmission [2]. This relationship reverses when the parent has a small expansion: with 50–100 repeats, children of fathers had greater increases (median 425, range 70–2000) than children of mothers (median 200, range 57–1400), without congenital cases [37]. “Protomutations” of 50–80 repeats may be transmitted stably by women over several generations but frequently expand (70%) beyond 100 when transmitted by men [2]. Repeat contraction occurs in approximately 6% of transmissions [2]. Maternal predominance in congenital disease is incompletely explained; transmission is biased towards larger alleles, and flanking CpG methylation is a possible explanation [1, 6].

In DM2, transmitted expansions are on average smaller than parental expansions (mean difference −17 kb, approximately −4250 CCTG) and subsequently increase with the offspring's age; no parental sex preference is confirmed, and anticipation is unconfirmed [3, 38]. Analysis of 87 patients with known parental origin (26 from two institutions and 61 from the literature) associated maternal inheritance with onset in the first three decades (OR 4.245; 95% CI 1.429–13.820), an association not replicated in the 127 patients in the MDF registry with self-reported onset age [39]. Congenital neuromuscular symptoms have been reported in nine heterozygotes and a three-generation family with congenital pes planovalgus and equinus in the youngest child, all maternally transmitted; since other genetic causes were not excluded, congenital DM2 remains unconfirmed [3, 40].

3. Clinical Spectrum and Manifestations by System

3.1. Clinical forms of DM1

DM1 forms a continuum divided by GeneReviews into three overlapping phenotypes — mild, classic and congenital — to which the paediatric consensus and European best practices add childhood- or juvenile-onset disease [1, 4, 9].

Source: GeneReviews, with data from de Die-Smulders 1998, Mathieu 1999 and IDMC 2000; ranges overlap, and repeat size should not be used to predict individual severity [1].

In mild disease, cataract may be the only manifestation, and many individuals are diagnosed only when a severely affected descendant is born [1, 2]. Classic disease typically begins in the second or third decade, less frequently after 40 years [1, 2]. Childhood-onset disease (after the neonatal period and up to 18 years according to the paediatric consensus) is chiefly associated with learning and socialisation difficulties; it may present with behavioural disorders, school difficulties or constipation, without evident weakness or myotonia for years [2, 4, 9]. Congenital disease probably accounts for 10% to 30% of the DM1 population [9].

The French PNDS distinguishes five forms by age at onset — congenital (neonatal), infantile (1–10 years), juvenile (10–20 years), adult and late-onset — and, on the basis of the DM-Scope registry (De Antonio and colleagues, 2016), assigns them approximately 5%, 19%, 26%, 39% and 11% of the DM1 population, respectively; it acknowledges that the division is artificial, because there is a continuum, and that it serves mainly to prioritise and adapt the frequency of surveillance [15]. The proportion of congenital forms in this registry of patients followed in centres (5%) is lower than the 10% to 30% estimate of the paediatric consensus, reflecting differences in definition and recruitment and precluding a single proportion [9, 15]. In late-onset disease, the signs (baldness or cataract after 50 years) are perceived as physiological and diagnosis arises mainly from family studies, but the PNDS requires the same cardiac and respiratory assessment, because these complications may be asymptomatic. In classic disease, mild symptoms begin at around 20–25 years and diagnosis is usually made at around 40 years, when walking limitation worsens; in the infantile form, approximately one third of children have autistic features, and myotonia and weakness appear after learning difficulties, slowness and hypersomnia [15].

3.2. DM1: skeletal muscle

Weakness predominantly affects facial muscles, levator palpebrae, sternocleidomastoids, finger and wrist flexors and ankle dorsiflexors, causing foot drop, falls and loss of manual dexterity; temporal and masseter atrophy produces an elongated, less expressive face with ptosis and a partly open mouth [1, 2, 32]. Absence of external ophthalmoplegia and blepharospasm is useful in differential examination, although some patients have ophthalmoplegia [1, 2]. Proximal weakness does not exclude diagnosis [2]. Myotonia — delayed relaxation after voluntary contraction or percussion — occurs during grip (difficulty releasing a door handle, tools or steering wheel), worsens with cold and improves with repeated contractions (the “warm-up” phenomenon), which may also improve dysarthria [1, 2]. Weakness progresses slowly in relation to disease duration and repeat size; a nine-year study documented slow progression, falls with fractures are frequent, and approximately half of patients in a Dutch series were partly or fully wheelchair-dependent shortly before death [1, 11]. Fatigue and musculoskeletal pain, particularly in the lower limbs, are frequent; pain has a neuropathic component, with reduced intraepidermal nerve fibre density in 63% of DM1 and 50% of DM2 patients in a quantitative sensory testing study [1, 3]. Biopsy shows chains of internal nuclei, ring fibres, sarcoplasmic masses, predominance and atrophy of type 1 fibres, and markedly increased intrafusal fibres [1].

The PNDS grades motor severity with the MIRS (Muscular Impairment Rating Scale), from 1 (no weakness) to 5 (severe proximal weakness), and reports limitation of mobility or walking in 85% of patients, who generally remain ambulant [15]. Walking aids are rarely needed before 40 years; between 40 and 60 years, the probability of intermittent wheelchair use is 20%, of an ankle–foot orthosis 30%, of a walking frame 40% and of a cane 50%. Falls are seven to eight times more frequent than in the matched general population (approximately 0.2 trips or falls per 5000 steps, ten times more than in healthy volunteers), occur mainly indoors and increase with MIRS ≥4, visual, hearing and cognitive deficits and physical deconditioning; 7% of deaths in patients with DM1 have a fracture as the initial cause. In congenital disease, fewer than 4% of children fail to acquire walking, and in an international population of 74 children the mean age at walking was 24 months; motor function improves in the first decade, stabilises in adolescence and begins to decline in the second decade, particularly foot dorsiflexion [15]. Among follow-up instruments, domain D1 (standing and transfers) of the MFM (Motor Function Measure) is the most sensitive to change, with a loss of 2.32 points per year; the PNDS also proposes grip dynamometry (with strain-gauge dynamometers when strength is below approximately 5 kg), the OMMYD battery (6-minute walk, 30-second sit-to-stand, 10-m walk and run, Nine-Hole Peg Test), the Timed Up and Go (normal <9 s), the Berg scale, DM1-Activ and, for fatigue, the FSS, FDSS and MDHI [15]. Muscle MRI is not systematic; when performed, it shows preferential involvement of the cervical and thoracic erector spinae, multifidus and gluteus minimus, with constant sparing of the iliopsoas, legs more affected than thighs, medial gastrocnemius as the most damaged muscle and tibialis posterior as the most spared, and STIR or fat-suppressed T2 hyperintensity in 84% of patients, around areas of fatty replacement. Electromyography shows myotonic discharges of 20–150 Hz and may show, on the short exercise test, a cold-enhanced type II pattern similar to that of myotonia congenita and DM2 [15].

3.3. DM1: heart

Conduction system disease predominates in cardiac involvement. Approximately 90% of patients have electrocardiographic abnormalities, most often PR and QRS prolongation; sinus node dysfunction, progressive atrioventricular block (AVB), tachycardia, atrial flutter or fibrillation, and ventricular tachycardia or fibrillation may occur [1, 33]. Among 406 adults followed for a mean of 5.7 years (US), there were 81 deaths, including 27 sudden deaths and 32 from neuromuscular respiratory failure; severe electrocardiographic abnormality (non-sinus rhythm, PR ≥240 ms, QRS ≥120 ms or second- or third-degree AVB) and atrial tachyarrhythmia diagnosis were independent risk factors for sudden death, with relative risks of 3.30 (95% CI 1.24–8.78) and 5.18 (95% CI 2.28–11.77) [10]. In a French cohort of 1388 adults followed for a median of 10 years, 253 (18.2%) died, 39 suddenly; age, family history of sudden death and left bundle branch block independently predicted sudden death, severe conduction defects requiring a pacemaker occurred in 19.3%, and sustained ventricular tachyarrhythmia in 2.3%, its sole predictor being non-sustained ventricular tachycardia [41]. The cardiogenetics book attributes approximately 30% of mortality to sudden death [42]. Cardiomyopathy and heart failure are less frequent than conduction disorders; the most common echocardiographic findings are mitral valve prolapse and septal and myocardial fibrosis [33]. The cardiogenetics chapter on left ventricular noncompaction includes DMPK in its table of associated genes and mentions the description of morphological changes resembling noncompaction in myotonic dystrophy [43]. Recommendations for cardiologists estimate left ventricular dysfunction in up to 40% of patients, with symptoms masked by motor limitations; atrial fibrillation increases stroke risk [1, 29].

The French PNDS attributes the cardiac manifestations mainly to aberrant SCN5A splicing, compounded by fibrosis, fatty replacement and cardiomyocyte hypertrophy, and summarises the frequencies: first-degree AVB in 28–34% and complete bundle branch block in 20% of patients; atrial fibrillation in 11–30%, up to 70 times more than in the general population and often asymptomatic; ventricular extrasystoles in 15%, non-sustained ventricular tachycardia in 4% and sustained ventricular arrhythmias in fewer than 3% [15]. Complete AVB, usually with asystole, is the main mechanism of sudden death, and an ECG without conduction abnormalities (PR <200 ms and QRS <100 ms) does not exclude high-grade atrioventricular disease. A severely abnormal ECG (non-sinus rhythm, PR >240 ms, QRS >120 ms, second- or third-degree AVB), left bundle branch block and a family history of sudden death more than triple the risk of sudden death, and a QTc >459 ms is also associated with it; the annual incidence of sudden death, above 3% in natural history, is approximately 0.56% since preventive strategies were introduced, a value within the 0.53–1.16% range cited by the HRS (section 7.4) [15, 44]. Left ventricular dysfunction (LVEF <55%) and dilated cardiomyopathy appear later (median age at symptoms 47 years) and affect 13.8% of patients, a figure that differs from the up-to-40% estimate in the recommendations for cardiologists because of differences in definition and population; global longitudinal strain abnormalities, present in 28%, precede the fall in LVEF and predict cardiovascular events, and late gadolinium enhancement on MRI appears in 12–40%, with no established prognostic value [15, 29]. The PNDS also emphasises the high venous thromboembolic risk (deep vein thrombosis and pulmonary embolism) and hypotensive profiles, which limit titration of heart failure therapy and have an independent negative impact on survival [15].

3.4. DM1: breathing, sleep and swallowing

Pulmonary complications are the leading cause of death. Weakness and myotonia of the diaphragm and intercostals and susceptibility to aspiration contribute to hypoventilation, recurrent infections and respiratory failure, which may require mechanical ventilation [1, 18, 32]. Excessive daytime sleepiness is frequent across all forms and severities, often results from central sleep regulation dysfunction and may be aggravated by apnoea; in one study, 20 of 40 patients had obstructive sleep apnoea [1, 2]. Poor pharyngeal clearance is an early indicator of muscle dysfunction — partial pharyngeal contrast retention after swallowing has been described as a sensitive radiological sign — and oropharyngeal dysphagia and dysarthria with a nasal voice are frequent [1, 32, 36].

According to the PNDS, respiratory failure is the leading cause of death; it affects 41% of children with the congenital form, 23% with the infantile form and 11% with the juvenile form, and in adults a restrictive pattern appears in 30–40% of patients, with a decline of approximately 1.4% predicted per year [15]. Hypoventilation combines diaphragmatic and intercostal weakness with dysfunction of central ventilatory drive (reduced response to CO2, which non-invasive ventilation does not correct), and patients minimise or ignore symptoms. A 15–20% fall in supine vital capacity indicates diaphragmatic weakness and correlates with daytime PaCO2; maximal inspiratory pressure at the mouth (MIP) and sniff nasal inspiratory pressure (SNIP), of which the best value is retained, correlate modestly with PaCO2 (r = −0.33); a peak cough flow below 270 L/min indicates a weak cough and below 160–200 L/min an ineffective cough requiring assistance, and the maximal expiratory pressure needed for an effective cough is 40–45 cmH2O. In children, FVC and FEV1 are obtained in only about half of cases, with a median age of success of 13 years, and a restrictive syndrome is present in 25% [15]. Fatigue affects 50–80% of patients (FSS ≥36) and excessive daytime sleepiness 45–60% (DSS >6), but an objective reduction in sleep latency on multiple sleep latency testing is confirmed in only about 40%; polysomnography shows more deep (N3) and REM sleep, less N2, lower efficiency and more arousals, and there are secondary narcolepsy or hypersomnia, delayed circadian phase (more frequent in adolescents), restless legs syndrome and periodic limb movements [15]. Dysphagia, described in 25–80% of patients and present from fetal life (polyhydramnios), involves the oral, pharyngeal and oesophageal phases, is more frequent with myotonia and is often denied by patients; in the congenital form, 78% have a swallowing disorder, 77% need speech and language therapy, 69% nasogastric tube feeding and 33% prolonged enteral nutrition, and pneumonias, largely due to aspiration, are implicated in 25–31% of deaths. Speech and voice disorders affect about half of patients: flaccid dysarthria with difficulty in bilabial and labiodental consonants, rhinolalia and hypernasality (sometimes the only sign in adults, with difficulty in velar consonants), hoarseness, slow rate and wet voice [15].

3.5. DM1: gastrointestinal tract, liver and gallbladder

Smooth muscle involvement causes dysphagia, reflux, constipation, diarrhoea, irritable bowel syndrome-like symptoms, incontinence and intestinal pseudo-obstruction [1, 2, 18]. Gallstones occur at unusually young ages, attributed to increased gallbladder sphincter tone, and cholecystectomy is sometimes necessary [1, 2]. Mild, persistent elevation of transaminases and gamma-glutamyltransferase is frequent and requires no investigation unless progressively increasing or clinically concerning [2, 18].

The PNDS gives prominence to bladder, sphincter and anorectal disorders, which should be sought in all patients of any age [15]. Anal incontinence is more frequent than urinary incontinence, with prevalences above 30% in recent cohorts; it involves both the striated and smooth sphincters (reduced resting pressures and rectoanal inhibitory reflex, atrophy and myotonic contractions after rectal distension) and is aggravated by chronic constipation with episodes of overflow diarrhoea. Constipation is defined by the Rome IV criteria, stool consistency is assessed with the Bristol scale, and a plain abdominal radiograph or colonic transit time helps when the history is unreliable. Urinary manifestations include stress or urge incontinence, enuresis in children and, more rarely, bladder hypotonia with a risk of chronic retention and upper urinary tract damage; in children, constipation, encopresis and faecal leakage should be sought at every visit. Anal sphincter hypotonia in young children with DM1 has been mistaken for signs of sexual abuse in several published cases and should be recognised as a manifestation of the disease, to avoid investigations that are traumatic for the child and family [15]. Non-alcoholic fatty liver disease is associated with the metabolic syndrome and affects approximately 50% of patients, mainly men with high body mass index and HOMA-IR, with greater severity than in people without DM1 [15].

3.6. DM1: central nervous system, cognition and behaviour

In classic disease, intellectual deficits are generally mild, and reduced facial expression may lead to underestimation of intelligence; reduced working memory, executive function and processing speed, frontoparietal deficits and, in some adults, age-related cognitive decline occur [1]. Avoidant, obsessive–compulsive and passive–aggressive personality traits are described; among 62 assessed patients, 58% had pathological traits, particularly dependent and paranoid traits, and in a series of 200 patients, 27% had a high risk of psychiatric disorder [1]. Apathy, difficulty initiating actions and fatigue are often more disabling than weakness [2, 4]. Magnetic resonance imaging shows cortical atrophy and sometimes diffuse white matter abnormalities, with temporal pole FLAIR hyperintensities and enlarged perivascular spaces; spectroscopy suggests glutamatergic neuronal degeneration, and autopsy reveals tau-associated neurofibrillary tangles [1, 18]. Axonal neuropathy may contribute to weakness; it was demonstrated by conduction studies in one-third of 111 patients [1].

The PNDS describes, in the congenital form, an almost constant disorder of intellectual development with IQ between 40 and 60, generally without deterioration during development, and a pseudo-autistic picture; in the infantile form, mild intellectual disability or borderline intelligence with visuospatial, attentional, flexibility, working memory and social cognition deficits, and attention deficit hyperactivity disorder in 13–29% of children; in the juvenile form, executive and visuoconstructive dysfunction; in adults, predominantly executive dysfunction, impaired theory of mind and decision-making — which hampers adherence to care — and faster longitudinal worsening in late-onset forms (onset after 40 years) [15]. Neuropathology shows neuronal loss and neurofibrillary tangles with aggregates of the 0N3R tau isoform, whose splicing is altered, and brain MRI may reveal anterior temporal, insular and medial temporal hyperintensities, dilated Virchow–Robin spaces and masseter changes visible within the field of a brain MRI, which point to the diagnosis when the disease is unknown; systematic brain imaging is not indicated unless another diagnosis is suspected [15].

3.7. DM1: eyes, ears, endocrinology, skin and neoplasms

Posterior subcapsular cataracts, with multicoloured iridescent “Christmas tree” opacities on slit-lamp examination, develop in almost all patients and usually cause symptoms at 30–40 years; they may recur after surgery [1, 36]. One series found epiretinal membranes in 48% of patients, potentially amenable to surgery [2]. Orbicularis weakness causes incomplete eyelid closure and dry eyes; congenital and juvenile forms involve strabismus, hypermetropia, astigmatism and reduced acuity [1, 9, 18]. Endocrine manifestations include hyperinsulinism, insulin resistance and diabetes, thyroid dysfunction, calcium abnormalities with secondary hyperparathyroidism and low vitamin D (up to 18%), testicular atrophy (80% of men in Smith's book) with hypogonadism, infertility in both sexes and early menopause [1, 2, 36]. Skin manifestations include pilomatrixomas and epitheliomas, mainly on the scalp, sometimes mistaken for sebaceous cysts, and androgenetic alopecia, including in women [1, 2]. Neoplasm risk is increased: in a Swedish population-based study of 1968 patients with myotonic dystrophy, overall adult cancer risk was 2.26 times higher (95% CI 1.92–2.66), with increases for brain tumours (HR 10.44), thyroid cancer (3.92), non-thyroid endocrine tumours (7.49), endometrial (8.32), ovarian (4.00) and non-melanoma skin cancer (3.27), as well as increased paediatric brain tumour risk [45]. Choroidal melanoma, basal cell carcinoma and possibly colon, testicular and prostate cancers have also been described [1].

The PNDS adds ophthalmological and endocrine data from recent series [15]. In adult forms, cataract is diagnosed at around 47 ± 5 years in 30–56% of patients and precedes the diagnosis of DM1 by approximately 10 ± 2 years; DM1 accounts for less than 1% of cataracts, but a cataract before 50 years should raise suspicion of the diagnosis; in children the prevalence is low (7% in a series of 354). Ptosis affects about half of patients in ophthalmological series and is operated on in fewer than 10%. The risk of choroidal melanoma is estimated at 28 times that of the general population; Fuchs endothelial corneal dystrophy occurs in 36% (the CTG expansion in TCF4 that causes the isolated form shares the RNA toxicity mechanism and therefore also enters the differential diagnosis); and there are retinal dystrophies — reticular "butterfly-shaped" macular dystrophy (26.6%), pigment epithelium changes (24.5%) and polygonal peripheral retinal atrophy (43.9%) — with generally preserved acuity, as well as epiretinal membranes and lamellar macular holes [15]. Metabolically, the risk of diabetes is two to four times higher, insulin resistance ranges from 20% to 80% depending on the method, overweight affects approximately 50% and the metabolic syndrome 40% after systematic oral glucose tolerance testing, with hypertriglyceridaemia and low HDL cholesterol, elevated leptin and visceral obesity with reduced lean mass even with normal body mass index, and blood pressure generally normal. In the male gonadal axis, inhibin B and anti-Müllerian hormone are low and FSH is elevated owing to germ cell and Sertoli cell damage, with testosterone often normal; idiopathic non-obstructive azoospermia with neurological signs should prompt DM1 testing, and testosterone increases lean mass but not strength. In the thyroid, elevated TSH occurs in approximately 10% (6–13%) and anti-thyroid peroxidase antibodies in 45%, but the risk of a nodule or cyst is about ten times that of the general population (ultrasound nodules in 60%, goitre in 40%), with an excess of papillary carcinomas, mainly microcarcinomas with a good prognosis. There is also a tendency to hypernatraemia, possible hyperkalaemia due to hyporeninaemic hypoaldosteronism, and secondary hyperparathyroidism due to vitamin D deficiency and reduced intestinal calcium absorption, while densitometric osteoporosis is rare [15]. In the skin, the PNDS reports an excess of pilomatrixomas and basal cell carcinomas, without systematic dermatological surveillance, with advice on photoprotection and referral for any suspicious lesion [15].

3.8. Congenital and childhood-onset DM1

Congenital disease manifests before birth with polyhydramnios and reduced fetal movements. In an Oxford series of 17 affected pregnancies that continued, ultrasound showed polyhydramnios in 100%, clubfoot in 26.6% and borderline ventriculomegaly in 13.3%; unilateral or bilateral clubfoot was observed in 10 of 16 newborns (62.5%), there were eight perinatal deaths, mainly from respiratory failure, and the mother had grip myotonia in almost all cases [46]. At birth, the child is hypotonic, with facial diplegia, an inverted V-shaped upper lip (tented mouth), respiratory failure with diaphragmatic hypoplasia, sucking and swallowing difficulties, clubfoot or multiple contractures, enlarged cerebral ventricles, oedema and cutaneous haematomas; myotonia, atrophy and cataracts are initially absent [1, 2, 36]. Neonatal mortality is 20% in the Oxford Desk Reference and approximately 25% in Smith's book; in children ventilated for more than three months, first-year mortality is 30% [2, 9, 36]. Survivors progressively improve during the first decade — most walk by three years — but strength begins declining in the second decade, and adult-form manifestations become superimposed from adolescence [1, 36]. In a series of 55 children with a mean of 1263 repeats, mean intelligence quotient (IQ) was 64.1, with 65.6% in the extremely low range, and adaptive functioning was significantly low in 57.1% [47]. Autism spectrum disorders, attention deficits, anxiety, visuospatial abnormalities and sleepiness are frequent; the Welsh survey reports few deaths between 1 and 20 years, but only half survived to their mid-30s [1, 2, 9].

The PNDS reports neonatal mortality above 15% in the congenital form, below the 20–25% estimates of the cited textbooks, and a classification proposed by some teams into type Ia (with respiratory failure requiring ventilation) and type Ib (without respiratory distress, but with hypotonia, sucking–swallowing disorder, bilateral clubfoot and adducted thumbs in a context of polyhydramnios) [2, 15, 36]. Myotonia is absent at birth and becomes clinically apparent only at around 3–5 years. Foot deformities affect 47–95% of children with paediatric onset (talipes equinovarus in 14–17% of congenital forms, equinovarus or equinus without clubfoot in 23–29%, pes planovalgus in 19%, pes cavus in 14%), scoliosis 30–43% (38% in the congenital form, 23% in the infantile form and 31% in the juvenile form in a North American series; 43% in a German series) and hyperkyphosis 29%; in the French cohort, 6% of children wore a brace [15]. The duration of neonatal ventilatory dependence predicts severe respiratory failure and later decompensations, and the probability that a tracheostomised child becomes independent of the tracheostomy is low. Children with the congenital form take on average one third of the recommended daily steps (approximately 3900). In a Canadian study of 64 patients with paediatric-onset disease, 54% lived with their parents or in foster families, most needed help with activities of daily living and 21% were under guardianship or curatorship [15].

3.9. DM2: clinical spectrum

DM2 is a multisystem disease characterised by muscle hyperexcitability and progressive proximal and axial weakness. The table summarises frequencies from the 2025 GeneReviews [3].

Onset is usually in the third or fourth decade; fatigue, myalgia and stiffness often precede weakness, which begins in the neck flexors, hip flexors and elbow extensors, while distal weakness is mild except in the thumb extensor [3]. Calf hypertrophy with brisk reflexes, sometimes with restless legs syndrome, is characteristic of a subgroup [3]. Fluctuating myalgia exacerbated by exertion may be the predominant, disabling complaint, explaining misdiagnosis as fibromyalgia [3, 6]. In the TREAT-NMD registry (1720 patients across 10 registries), median age at entry was 51 years, 14% had symptom onset before 20 years, 20% used walking aids, 4% were non-ambulatory, 4% had a pacemaker or implantable cardioverter-defibrillator (ICD), and 7% used non-invasive ventilation [48]. Among 234 patients characterised by Day and colleagues, 90% had electrical myotonia, 82% weakness, 61% cataracts, 23% diabetes and 19% cardiac involvement [38]. Conduction abnormalities and arrhythmias affect 10% to 20% and may be early and severe; sudden death, a Brugada-like syndrome and cardiomyopathy have been described [3]. Respiratory failure is less frequent than in DM1: non-invasive ventilation is required in 6% to 15%, compared with 20% to 40% in DM1 [3]. More than 60% of patients in a small study had high-frequency sensorineural hearing loss exceeding that expected for age [3]. Approximately 28% to 29% had autoimmune disease (Hashimoto's thyroiditis, rheumatoid arthritis, Sjögren syndrome) in one registry, and hypogammaglobulinaemia (low IgG or IgM) is a suggestive laboratory finding [3]. Among 68 patients, 35.3% had cognitive impairment defined by two domains below two standard deviations, without intellectual disability; magnetic resonance imaging shows white matter abnormalities stable over five years, and positron emission tomography reveals prefrontal, temporal and pericentral hypometabolism [3]. Women have an increased gallstone risk, and pregnancy may exacerbate stiffness and myotonia [3]. Survival is reduced (section 11), and thyroid, colon, pancreatic, prostate and endometrial tumours have been described [3, 12].

4. Clinical Recognition and Warning Signs

Recognition requires bringing together signs presenting to different specialties. The Oxford Desk Reference structures adult history around a three-generation pedigree with targeted questions about cataracts, diabetes, myotonia, weakness and anaesthetic deaths, and questions about hands that “lock” (using a can opener, turning a key, holding a steering wheel, peeling potatoes), falls, respiratory infections, snoring and morning headaches, palpitations and syncope, bowel symptoms, dysphagia for solids, daytime sleepiness, apathy and fatigue [2]. Examination seeks ptosis, an elongated face with inability to wrinkle the forehead, bury the eyelashes on tight eye closure or contract the masseters firmly, frontal baldness in both sexes, sternocleidomastoid weakness and atrophy tested against a hand on the chin, distal weakness, thenar percussion and grip myotonia, reduced reflexes, pilomatrixomas and lens opacities visible by ophthalmoscopy [2].

Infants with congenital DM1 combine central and peripheral hypotonia, and diagnosis generally becomes evident when the mother is examined [49]. The Oxford Desk Reference's approaches to arthrogryposis, fetal akinesia and clubfoot explicitly include maternal examination and maternal DM1 testing when clinically suspected [49]. DM1 should be considered in any child with family history or ptosis, oromotor weakness, distal weakness without contractures or neck flexor weakness, myotonia, autistic traits, attention deficits, intellectual disability, specific learning disorders, daytime sleepiness, bowel symptoms, scoliosis, arrhythmia or anaesthetic complications [9]. DM1 has occasionally been mistaken for motor neurone disease, cerebral palsy, non-specific intellectual disability or parkinsonism, and DM2 for fibromyalgia or motor neurone disease [1, 3].

The French PNDS adds circumstances of discovery. In anaesthesia, DM1 should enter the differential diagnosis in the event of rapid loss of consciousness or apnoea after a usual dose of a hypnotic or benzodiazepine, unexplained postoperative confusion, marked respiratory depression after a usual dose of intravenous or neuraxial opioid, prolonged neuromuscular blockade after a usual dose of a non-depolarising neuromuscular blocker, generalised or localised muscle contracture, difficulty weaning from ventilation in intensive care, and unexplained dilated cardiomyopathy or arrhythmia [15]. In respiratory medicine and intensive care, the disease is often revealed by respiratory decompensation after bronchitis, pneumonia (including aspiration pneumonia) or anaesthesia, with myotonia inapparent because of atrophy or sedation. Other entry points are the incidental finding of myotonic discharges on electromyography requested for another reason, anterior temporal hyperintensities or masseter changes on brain MRI, muscle changes on fat-suppressed T2 sequences in musculoskeletal MRI, infertility (low ovarian reserve, oligozoospermia or azoospermia), dysarthria with a nasal voice, recurrent aspiration pneumonia and daytime sleepiness without a respiratory cause [15]. In neonatal hypotonia with "apparently" de novo disease, moderate cognitive difficulties, facial dysmorphism and, above all, grip myotonia in the mother are the most useful clues; when the disease is already known in the family, delivery should be planned in a level 3 maternity unit. In childhood, the juvenile form is distinguished from the other paediatric forms by early cardiac involvement, and feeding difficulties, constipation or neurodevelopmental disorders may be the first sign [15].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Suggestive findings

There are no validated formal clinical criteria; diagnosis is molecular, and suspicion rests on combinations of signs. In adult DM1, GeneReviews highlights distal leg, hand, neck and facial weakness, grip or percussion myotonia, and posterior subcapsular cataracts with red and green iridescent opacities on slit-lamp examination; in newborns, the combination of hypotonia, facial and generalised weakness, positional malformations such as clubfoot, and respiratory failure [1]. In DM2, suspicion rests on initial neck and finger flexor weakness followed by pelvic girdle weakness (iliopsoas), grip, percussion or lower limb myotonia, cataracts, electrical myotonia (which may require examination of multiple muscle groups, including proximal and paraspinal muscles), conduction defects, dilated cardiomyopathy, insulin insensitivity, hypogammaglobulinaemia and autosomal dominant family history; absence of family history does not exclude diagnosis [3].

5.2. Molecular tests and their limitations

According to European best practices, the first laboratory step is to establish whether the individual has two distinct normal-sized alleles by conventional PCR and fragment analysis; if only one size is detected, the sample may represent a normal homozygote or a heterozygote with an expansion that does not amplify, requiring complementary methods [4]. In DM2, a single allele is observed in 15% of unaffected individuals (homozygotes) and in all affected individuals [3].

GeneReviews states that targeted analysis identifies expansion in 100% of DM1 patients and more than 99% of DM2 patients when PCR, Southern blot and bidirectional RP-PCR are combined; European best practices assign clinical sensitivity and specificity above 99% to both tests [1, 3, 4]. The proportion of variants detectable by a method is not equivalent to a particular test's clinical sensitivity: it depends on the laboratory's combination of techniques, DNA quality and molecular weight — requiring careful isolation in DM2 because expansions may exceed 40 kb — and the presence of interruptions [3, 4].

The 2024 French PNDS describes the same pathway with the techniques of the French laboratory network: first-line PCR-based methods at the DM1 locus — fluorescent PCR, TP-PCR from the 3' and/or 5' ends of the repeat and QMPSF (Quantitative Multiplex PCR of Short Fluorescent Fragments); a positive diagnosis with ≥51 CTG; exclusion when two normal-sized alleles are detected; and Southern blot of long-PCR products or genomic DNA to quantify expansions above approximately 200 repeats [15]. Because non-CTG interruptions may produce false negatives, the PNDS recommends using two independent techniques to search for the expansion, and considers long-read sequencing useful for characterising interruptions and the methylation profile of the region; it also attributes part of the clinical variability to interruptions and to methylation of the adjacent CpG islands [15]. In France, testing requires prior information and written consent, and the result of a presymptomatic diagnosis must be confirmed on a second independent sample (section 8.3) [15]. A neuromuscular disease panel is appropriate only if it includes non-sequencing-based repeat tests; for hypotonic infants, GeneReviews recommends panels also including SMN1 copy number, methylation testing for Prader–Willi syndrome and chromosome 14 uniparental disomy [1].

5.3. Interpretation and reporting

Reports should identify the gene, versioned transcript, HGVS repeat notation, method and measurement uncertainty, allele class and limitations. European best practices consider a repeat range sufficient (for example, “expansion >150”) and require any exact value to include the laboratory's measurement uncertainty; in DM2, analytical variation may be two units for PCR-measured alleles [4].

Source: EMQN/EuroGentest best practices, which provide the complete reporting table as supplementary material [4].

Blood repeat size does not predict an individual's onset age, severity or progression rate because of phenotypic overlap and somatic mosaicism; the paediatric consensus advises against using CTG numbers for prognosis or counselling without a genetics professional [1, 9]. In DM2, neither predominant size nor the number of detectable expansions in a sample predicts phenotype [3]. Testing an asymptomatic individual with non-specific or questionable symptoms is predictive rather than diagnostic and follows the rules in section 8 [1].

5.4. Non-molecular investigations

These investigations now have a supportive or investigative role when molecular testing is negative. Electromyography shows myotonic discharges and myopathic motor units, predominantly distally in DM1; typical myotonic discharges are absent in infants, but rapid bursts of single-fibre discharges are suggestive [1]. Creatine kinase (CK) is normal or slightly elevated, and a normal value does not exclude diagnosis [1, 3, 32]. On biopsy, preferential type 1 fibre atrophy characterises DM1 and type 2 fibre atrophy DM2, although many findings (internal nuclei, atrophic fibres with pyknotic nuclei) are shared [2, 3]. The Brazilian chapter states that electroneuromyography and biopsy are no longer used diagnostically; GeneReviews retains them for differential diagnosis when expansion testing is negative [1, 3, 32]. At initial assessment, electrocardiography (PR, QRS, left axis deviation, bundle branch block), blood glucose, ophthalmological assessment and respiratory function establish the extent of involvement [1, 2].

5.5. Algorithm

The source-derived algorithm is sequential. With clinical suspicion of myotonic dystrophy, first investigate the DMPK CTG expansion by fragment PCR supplemented with TP-PCR or Southern blot if only one allele is visible. If the DMPK repeat is normal, investigate CNBP CCTG expansion using a combination including bidirectional RP-PCR; the Oxford Desk Reference explicitly recommends this second investigation when the first is negative. If both are negative, electromyography, CK and possibly biopsy guide investigation of other myopathies and channelopathies (section 6); GeneReviews suggests considering DNA banking when molecular diagnosis is not established [1–4]. In hypotonic infants, maternal examination and testing are frequently the quickest route [1, 49]. In prenatal diagnosis, maternal DNA analysis is required to exclude contamination of the fetal sample [4].

5.6. Population screening

There is no routine newborn screening programme for DM1. A research study of 50,382 consecutive dried blood spots from the New York State screening programme (2013–2014), using TP-PCR, melting curves and fragment analysis confirmation, identified 24 newborns with ≥50 CTG (4.76 per 10,000; 95% CI 2.86–6.67; approximately 1 in 2100) and 96 with 35–49 repeats (1 in 525) [14]. More than half of expansions were between 50 and 150 repeats, a range in which many carriers will have few or no symptoms but retain cardiac and transmission risks [1]. This measures genetic prevalence rather than clinically diagnosed disease [6, 14].

6. Differential Diagnosis

6.1. DM1 versus DM2

Sources: DM1 and DM2 GeneReviews, Oxford Desk Reference, cardiogenetics book and DM2 consensus [1–3, 19, 33].

6.2. Other entities

For DM2, GeneReviews also compares, in a separate table, desminopathy (DES; onset 20–60 years; CK 2–10×; cardiomyopathy and conduction defects), zaspopathy (LDB3) and myotilinopathy (MYOT), both beginning after 40 years, GNE myopathy (onset 20–40 years, loss of ambulation after 12–15 years), and limb-girdle dystrophies involving more than 30 genes [3]. Proximal myotonia, cataracts and multisystem involvement together strongly suggest DM2 [3].

The PNDS estimates the combined prevalence of non-dystrophic myotonias (CLCN1, SCN4A) at approximately 1:50,000, identifies muscle hypertrophy, cold sensitivity, the warm-up phenomenon and response to mexiletine, carbamazepine or lacosamide as distinguishing features, and lists, for adult autosomal dominant distal weakness of all four limbs, the myofibrillar and distal myopathies (ACTN2, CAV3, CRYAB, DES, DNAJB6, DNM2, FLNC, GIPC1, HNRNPA1, HSPB8, KLHL9, LDB3, LRP12, MATR3, MB, MYH7, MYOT, NEB, NOTCH2NLC, PLIN4, RYR1, TIA1, TTN, VCP), as well as, in the presence of bilateral ptosis and bulbar involvement, oculopharyngodistal myopathy [15]. In practice, the combination of autosomal dominant inheritance, a suggestive facies and marked myotonic discharges on electromyography makes suspicion of DM1 straightforward for an experienced neurologist. Anal sphincter hypotonia in children with DM1 must be distinguished from signs of sexual abuse (section 3.5), and isolated Fuchs endothelial corneal dystrophy, due to a CTG expansion in TCF4, enters the ophthalmological differential [15].

7. Treatments and Risk Management Strategies

7.1. Principles

No disease-modifying therapy is authorised for DM1 or DM2; management is symptomatic, preventive and multidisciplinary [1, 3, 6]. MDF recommendations were developed by consensus (single-text procedure and nominal group technique, involving 66 clinicians for adult DM1, 11 for paediatric disease and 15 for DM2), and the authors emphasise the absence of evidence-based guidelines [9, 18, 19]. Most monitoring intervals and thresholds presented here therefore derive from expert opinion, and different sources propose different intervals.

7.2. System-specific management

Differences in intervals do not alter the shared principle: baseline ECG and regular surveillance are mandatory in both types, with increased frequency when symptoms or abnormalities occur [1, 3, 18, 19].

The 2024 French PNDS details respiratory and sleep management [15]. In the absence of associated pulmonary or vascular disease, there is no indication for oxygen alone, daytime or nocturnal, and persistent hypoxaemia under ventilation is corrected by adjusting the settings. Continuous positive airway pressure (CPAP) is indicated for moderate to severe obstructive apnoea, avoiding auto-adjusting modes and monitoring by oxycapnography. Bilevel non-invasive ventilation is started when there are one or more daytime or nocturnal symptoms and at least one of the following criteria: FVC <50% predicted (best of three measurements) or MIP and SNIP <60 cmH2O; daytime PaCO2 ≥45 mmHg (6.0 kPa); or suspected nocturnal hypoventilation, defined by a rise in PaCO2 ≥8 mmHg (1 kPa) between the evening and morning blood gases, PtcCO2 >50 mmHg (6.7 kPa) for more than 50% of sleep time or, where CO2 is not measured, SpO2 ≤88% for 5 consecutive minutes or <90% for more than 10% of sleep time. With PaCO2 >50 mmHg, ventilation should begin within one month; between 45 and 50 mmHg, the patient is referred to respiratory medicine and the decision depends on symptoms; a suspicion based on capnography alone warrants a consultation within three months. The initial interface is nasal or nasal pillows (oronasal mask or chin strap if there are leaks), adherence is considered adequate with at least 4 h per 24 h, and follow-up is at least annual, ideally with capnography under ventilation; sleepiness that persists despite CPAP or ventilation requires a search for associated hypersomnia (section 7.6). In children, it is first established whether an ear, nose and throat intervention resolves obstructive apnoea, with follow-up polysomnography at 3 months, and ventilation is monitored by oxycapnography every 6 to 12 months; the increased metabolic demand in ambulant adolescents justifies repeating nocturnal studies even when functional tests are stable. Instrumental cough techniques (mechanical insufflation–exsufflation, hyperinflation with manual compression, intrapulmonary percussive ventilation) begin when peak cough flow is below 270 L/min and should be adjusted outside periods of airway congestion, with caregiver training. The PNDS recommends pneumococcal vaccination (every five years), COVID-19 and annual influenza vaccination, and respiratory syncytial virus vaccination in children and those over 65 years, according to the current schedule [15]. The ventilation thresholds coincide with those of the MDF adult consensus (FVC <50%, MIP <60 cmH2O, peak cough flow <270 L/min), to which the PNDS adds explicit blood gas and oximetry criteria and time frames for initiation [15, 18].

In endocrinology, the PNDS finds no specific recommendations for diabetes in DM1 and applies those of the Société Francophone du Diabète for type 2 diabetes: a diet low in rapidly absorbed sugars and alcohol, adapted physical activity, smoking cessation and, first line, metformin, which may also improve the 6-minute walk; followed by GLP-1 receptor agonists, SGLT2 inhibitors and possibly DPP-4 inhibitors, reserving sulfonylureas, repaglinide and insulin for treatment failure or insulinopenia [15]. For male hypogonadism, the PNDS proposes testosterone enantate (heptylate) 250 mg intramuscularly once a month, in the absence of a history of thromboembolism and with monitoring of PSA and full blood count (polycythaemia), noting that no muscular benefit has been demonstrated [15]; the US label for injectable testosterone enanthate indicates, in male hypogonadism, 50–400 mg every 2 to 4 weeks and generally considers total doses above 400 mg per month unnecessary, so the PNDS schedule lies at the most widely spaced end of the label [50]. The cardiovascular risk of phosphodiesterase 5 inhibitors for erectile dysfunction is poorly known in this population. For calcium–phosphate metabolism, the PNDS recommends monthly oral supplementation with 50,000 IU of vitamin D and annual measurement of calcium and vitamin D; for the thyroid, annual neck palpation and TSH, free T4 and ultrasound at baseline, repeated every five years if normal; it does not recommend adrenal screening in the absence of symptoms [15].

For the lower digestive tract, the PNDS prioritises treatment of the chronic bowel transit disorder: dietary fibre (at least 8 g/day) and at least 1.5 L of water per day, then bulk-forming and osmotic laxatives (the latter may worsen bloating and pain), transanal irrigation at regular times (for example, Peristeen®) and pelvic floor re-education with biofeedback; it notes that an antimyotonic agent such as procainamide has been proposed in published cases of anal incontinence, only after cardiological advice, and refers refractory cases for anorectal manometry and endoscopic ultrasound [15]. The preference for bulk-forming and osmotic laxatives differs from the first-line list of the MDF adult consensus, which includes polyethylene glycol, senna, docusate and linaclotide [15, 18]. For the urinary tract, in the absence of intervention studies in DM1, a bladder diary, the ICIQ-UI SF questionnaire, renal and bladder ultrasound and 24-hour urinary creatinine clearance (or cystatin C, because serum creatinine underestimates renal dysfunction when muscle mass is low) are proposed, together with pelvic floor re-education and posterior tibial nerve stimulation, the latter contraindicated in pacemaker carriers, with referral to urology or neuro-urology for urodynamics [15].

For dysphagia, the PNDS recommends systematic screening, even without complaints, with a water swallow test and speech and language therapy assessment, texture modification according to the IDDSI framework (from level 6, with pieces up to 1.5 cm × 1.5 cm, to level 4), safe swallowing postures and, second line, nasendoscopy, videofluoroscopy and pharyngo-oesophageal manometry; oesophageal balloon dilatation or cricopharyngeal myotomy may be considered case by case in severe dysphagia with isolated cricopharyngeal hypertrophy, with no demonstrated long-term efficacy, and enteral nutrition is discussed in severe dysphagia or malnutrition (in the congenital form, gastrostomy is often necessary, sometimes temporarily) [15]. In children, lip-strengthening training for 15 minutes a day, 5 days a week for 16 weeks, improves lip tone and endurance, without systematic improvement in speech or feeding, and speech and language therapy takes place one to four times a week, with augmentative communication (gestures, codes, computer-based aids) when needed. In adults, vocal warm-up reduces phonatory problems over the course of a conversation; surgery for velopharyngeal insufficiency (pharyngeal flap) has not been evaluated in DM1 and the benefit must be weighed against the anaesthetic risk. Obstructive apnoea with an obvious obstruction (tonsils, adenoids) may justify ear, nose and throat surgery, and mandibular advancement splints are an option in retrognathia. Dentomaxillofacial deformities (class III, anterior open bite, posterior crossbite, high-arched palate) justify orthopaedic and orthodontic treatment and, when the anaesthetic risk allows, bimaxillary osteotomy (Le Fort I advancement, bilateral sagittal split osteotomy of the mandibular rami and genioplasty), with a high risk of occlusal relapse due to persistent hypotonia and an informed collegial decision [15].

In cataract surgery, the PNDS notes more frequent posterior capsule opacification that recurs after YAG capsulotomy, anterior capsular phimosis and cases with up to eight capsulotomies, attributed to DMPK expression in the lens epithelium; it recommends a wide capsulorhexis, careful capsular polishing, a hydrophobic acrylic intraocular lens and avoidance of multifocal lenses, in addition to anaesthetic precautions [15]. In moderate ptosis, the rule is to refrain from intervention; eyelid crutches attached to spectacles (Mercier type) or adhesive tape are alternatives, and surgery (frontalis suspension or levator resection) is discussed only in severe ptosis occluding the pupillary axis, after assessing ocular motility and Bell's phenomenon, because of the risk of lagophthalmos and keratitis; ectropion and entropion with ocular surface damage are operated on, and the ocular surface is treated with eyelid hygiene, artificial tears and vitamin A ointment at bedtime [15].

7.3. Myotonia, pain and mexiletine

DM1 myotonia is generally mild to moderate and rarely requires pharmacological treatment; in DM2, particularly in the lower limbs, it may warrant therapy [1, 3]. Mexiletine, a class IB antiarrhythmic, has the strongest evidence in DM1. In two randomised, placebo-controlled crossover trials with 20 patients each, mexiletine 150 mg and 200 mg three times daily for seven weeks reduced grip relaxation time without serious adverse events or PR, QRS or QTc prolongation [51]. In a six-month randomised trial involving 42 ambulatory adults (40 completed), 150 mg three times daily did not alter six-minute walk distance (primary endpoint), improved objectively measured grip myotonia but not patient-perceived myotonia, and did not change electrocardiographic intervals [52]. These doses are those used in the cited trials; mexiletine has no myotonic dystrophy indication in the US or EU, so its use is off-label [6, 53, 54]. The closest reference label is that of Namuscla® for the analogous condition (non-dystrophic myotonia), whose dose is expressed as mexiletine base (166.62 mg of base corresponds to 200 mg of hydrochloride): in adults, 167 mg/day, increased to 333 mg/day and then to 500 mg/day after at least 1 week at each level, maintenance of 167–500 mg/day and a maximum of 500 mg/day; from 6 to 17 years, an indication already included in the SmPC and on the EPAR page updated on 3 June 2026, the dose depends on weight, with daily maxima of approximately 187 mg (20–30 kg), 250 mg (30–40 kg), 375 mg (40–60 kg) and 500 mg (≥60 kg); in mild to moderate hepatic impairment, increases are made only after 2 weeks [55]. The doses of the DM1 trials (150–200 mg of hydrochloride three times daily, approximately 375–500 mg/day of base) fall within this range; their application to DM is an extrapolation, outside the terms of the label.

Cardiac safety is central. The adult DM1 consensus considers mexiletine contraindicated with cardiac involvement and refers to dedicated MDF guidance; the paediatric consensus requires ECG before initiation, at three months and periodically thereafter, and advises administration with food to reduce dyspepsia and dizziness; recommendations for cardiologists require prior assessment of structural or functional abnormalities and monitoring at initiation; the French expert group recommends more intensive cardiac assessment than in non-dystrophic myotonias [9, 18, 29, 56]. The HRS consensus recommends (class 1, level C-LD) close monitoring for arrhythmic complications when mexiletine or another sodium channel blocker is used in patients with conduction disease; without formal evaluation of this strategy, it suggests inpatient telemetry or serial outpatient ECGs over several days with comparison to baseline QRS morphology and duration, preferring admission for prolonged PR or bundle branch block, and notes that intravenous flecainide or ajmaline may trigger severe ventricular tachyarrhythmias or reveal a type 1 Brugada pattern in DM1 [44]. The most frequent adverse effects in the US label are upper gastrointestinal discomfort (41%), tremor (12.6%), dizziness (10.5%) and coordination abnormalities (10.2%), generally reversible with dose reduction or administration with food; the label also reports postmarketing acute liver injury [53]. Carbamazepine has been used anecdotally in DM1, and DM2 GeneReviews mentions lamotrigine as an alternative [1, 3].

The 2024 French PNDS is the only one of the guidelines consulted that sets a mexiletine dosage for DM1 and, under the rule followed in this article, becomes the dose reference, with the trials and the Namuscla® SmPC serving as comparison [15]. Mexiletine is an option for symptomatic myotonia (grip, dysarthria, swallowing, chewing or digestive symptoms), in the absence of cardiac contraindication, after validation by the cardiologist and on prescription by an expert from a neuromuscular reference or competence centre, taken with meals to avoid dyspepsia and transient fatigue. In adolescents, titration is progressive and the same as in adults, with 167 mg capsules (dose as mexiletine base, the Namuscla® presentation) up to three a day, that is, up to 500 mg/day, within a French framework of temporary use outside the terms of the marketing authorisation; in younger children, progressive doses of 5 to 15 mg/kg/day are used as a compounded preparation, and the PNDS refers to an ongoing study in children aged 6 to 18 years [15]; this open-label pharmacokinetic, safety and efficacy study, sponsored by Lupin and conducted only in France (NCT04624750), enrolled 12 patients and ended in August 2024, with no results posted on the registry at the time of consultation [60]. The PNDS considers mexiletine contraindicated with a history of arrhythmia, left ventricular systolic dysfunction or myocardial infarction; with moderate conduction disease (PR 200–240 ms, QRS 100–120 ms), the decision is made case by case, with ECG and Holter at least every six months and echocardiography every one or two years, possibly with an implantable loop recorder; a conduction defect treated with a pacemaker is not, as a rule, a contraindication; and it requires an ECG before initiation, at each dose change and then annually. If mexiletine fails or is contraindicated, other sodium channel blockers used in epilepsy — carbamazepine, lamotrigine, lacosamide — may be discussed, also off-label, on specialist prescription and with the usual laboratory monitoring for each drug [15]. Compared with the label, the PNDS adult and adolescent maximum (500 mg/day of base) coincides with that of the Namuscla® SmPC in non-dystrophic myotonia and with the upper limit of the DM1 trials, whereas the upper end of the PNDS paediatric range (15 mg/kg/day) exceeds the SmPC daily maxima by weight band — for example, 375 mg/day for a 25 kg child, against approximately 187 mg/day in the SmPC — and the PNDS does not specify whether the paediatric dose is expressed as salt or base [15, 55]. Positions on conduction disease also differ: the MDF adult consensus considers mexiletine contraindicated when there is cardiac involvement, whereas the PNDS, supported by the opinion of French experts, allows case-by-case use with moderately abnormal conduction or with a pacemaker, subject to enhanced monitoring [15, 18, 56].

Muscle pain has no consistently effective treatment. Mexiletine, gabapentin, pregabalin (in DM2), non-steroidal anti-inflammatory drugs, low-dose thyroid hormone or corticosteroids, tricyclic antidepressants and cannabinoids have been used; opioids should be avoided or used at low doses with monitoring because they depress respiration and induce tolerance [1, 3, 19]. The neuropathic component documented by quantitative sensory testing should inform analgesic planning [3]. For pain, the PNDS proposes massage, heat and hydrotherapy (water at 35 °C), transcutaneous electrical nerve stimulation, positioning in bed and chair without pressure points, technical aids that reduce joint loading, step 1 to 2 analgesics according to assessment, and treatment of the myotonic component; spa treatments, without a specific indication, make sense only when integrated into a rehabilitation programme [15].

7.4. Prevention of sudden death and cardiac management

Sources agree that the 12-lead ECG is the fundamental tool. The adult consensus considers sinus rate <50/min, PR >200 ms, QRS >100 ms, anterior or posterior fascicular block, abnormal Q waves, tachycardia, atrial flutter or fibrillation, and ventricular arrhythmias indicative of cardiac involvement, and the Oxford Desk Reference recommends cardiology referral for PR >200 ms, QRS >120 ms, atrial fibrillation or flutter, new bundle branch block or symptoms [2, 18]. Recommendations for cardiologists propose baseline and annual ECG, baseline cardiac imaging (echocardiography with strain or magnetic resonance imaging), then every one to five years if normal, with annual surveillance after 40 years or with an abnormal ECG, and ambulatory monitoring when ECG is abnormal or symptoms occur [29].

The French PNDS sets out the cardiac surveillance schedule [15]. At diagnosis, even without symptoms, an ECG, 24-hour Holter and transthoracic echocardiogram are performed; thereafter, an annual ECG, which need not be performed by a cardiologist when it is the only test indicated; Holter repeated in the presence of palpitations, presyncope or conduction abnormalities, and annually in higher-risk patients (significant conduction abnormalities, arrhythmia or myocardial abnormalities); and echocardiography every 2 to 5 years with preserved LVEF, more often with symptoms, conduction abnormalities or arrhythmias, and at least annually with LVEF <50%. In paediatric forms and in the children of patients, the initial assessment may be made from 10 years of age — the earliest age at which serious rhythm and conduction events have been described — with ECG, Holter and echocardiography if the ECG is abnormal, and with exercise testing if the child practises school or extracurricular sport and mandatorily in the presence of exertional palpitations or presyncope; in congenital and infantile forms, surveillance is annual with ECG, Holter and echocardiography [15]. Elsewhere, the PNDS states that cardiac involvement should be sought from 6 years of age even without symptoms, because of the risk of sudden death, leaving an internal inconsistency between 6 and 10 years; the MDF paediatric consensus calls for an ECG at diagnosis and annually thereafter, with no minimum age [9, 15]. With first-degree AVB (PR >200 ms) and/or QRS >100 ms, at diagnosis or during follow-up, the PNDS recommends an electrophysiological study with measurement of the HV interval, which should be systematic when the diagnosis is made in adulthood and repeated only if conduction worsens on the surface ECG; an HV >70 ms justifies a prophylactic pacemaker, and programmed ventricular stimulation is not systematic, being discussed case by case in the presence of unexplained syncope or palpitations. Cardiac MRI is discussed only with poor echogenicity or systolic dysfunction, and long-term Holter or an implantable loop recorder (mean duration 3 years) serve for unexplained symptoms, bearing in mind that the symptomatic hypotension characteristic of the disease complicates the interpretation of presyncope [15].

Invasive electrophysiological study measures the HV interval and inducibility of ventricular tachycardia, including bundle branch re-entry. In the French DM1 Heart Registry, among 486 patients with PR >200 ms and/or QRS >100 ms, an invasive strategy (electrophysiological study with prophylactic pacemaker, 341 patients) was associated with greater nine-year survival than a non-invasive strategy (145 patients) after propensity score adjustment (adjusted HRs 0.47–0.61), mainly through fewer sudden deaths (HR 0.24–0.28); unadjusted analysis was not significant (HR 0.74; 95% CI 0.47–1.16), and the design was retrospective [61]. The cardiogenetics book considers prophylactic pacing first-line for prevention of conduction-related sudden death and ICDs for patients with non-sustained ventricular tachycardia or severe ventricular dysfunction, noting that guidance accepting pacing for any AVB degree, including first-degree, or bifascicular block rests on limited data and lacks consensus [33, 42]. Recommendations for cardiologists classify pacing with PR >240 ms and QRS >120 ms as IIb, recommend ICDs with ejection fraction <35%, prefer dual-chamber systems, advise against subcutaneous ICDs with conduction disease, and consider resynchronisation for heart failure with left bundle branch block [29]. The 2023 Brazilian Guideline on Implantable Electronic Cardiac Devices assigns class I (level B) to pacing for second-degree type II or advanced AVB and third-degree AVB, with or without symptoms, and class IIb (level C) to pacing in asymptomatic myotonic dystrophy patients with PR >240 ms or QRS >120 ms, citing a series of 49 patients with HV ≥70 ms in whom 47% recorded high-grade AVB after implantation [62]. More recent cardiology references for device decisions are the Heart Rhythm Society (HRS) 2022 consensus on arrhythmic risk in neuromuscular disorders and European Society of Cardiology (ESC) 2021 pacing and resynchronisation guidelines and 2022 ventricular arrhythmia and sudden death prevention guidelines, which provide dedicated myotonic dystrophy recommendations and, for HRS and ESC 2022, a specific algorithm [44, 63, 64]. Grading systems differ: HRS uses ACC/AHA classes (1, 2a, 2b, 3) with evidence levels B-R, B-NR, C-LD and C-EO, while ESC uses classes I, IIa, IIb and III with levels A–C. All HRS device recommendations depend on consistency with patients' care goals and clinical status; HRS applies the same recommendations to children and adults, although PR and QRS thresholds were studied only in adults and may be overly aggressive in children, and extrapolates the DM1 approach to DM2 because dedicated studies are lacking [44]. ESC 2021 formulates pacing recommendations for “neuromuscular diseases such as DM1”, and ESC 2022 for “myotonic dystrophy” without distinguishing types [63, 64].

Differences mainly concern recommendation strength rather than direction. For PR ≥240 ms or QRS ≥120 ms, HRS considers prophylactic pacing reasonable (2a), whereas ESC 2021 assigns IIb — as do the cardiologists' recommendations and Brazilian guideline — and ESC 2022 favours electrophysiological study in this setting (IIa), retaining the device as IIb in the algorithm [29, 44, 62–64]. For HV ≥70 ms, ESC 2021 gives class I (level C) and HRS class 2a (level B-NR) [44, 63]. For induced ventricular arrhythmia, HRS recommends an ICD for any clinically relevant arrhythmia (1), while ESC 2022 distinguishes bundle branch re-entry VT, treated by ablation followed by pacemaker or ICD, from other VT mechanisms, for which an ICD should be considered (IIa) with palpitations or, in the algorithm, syncope [44, 64]. ESC 2022 lists age, CTG expansion size, personal or family sudden death history, conduction abnormalities and ECG PR prolongation, left bundle branch block, atrial arrhythmias, non-sustained VT, left ventricular dysfunction and magnetic resonance structural abnormalities as factors favouring ICD over pacemaker [64]. HRS considers non-invasive (12-lead and ambulatory ECG) and invasive (ECG and electrophysiological study) strategies equivalent in the absence of direct comparisons of predictive utility and cost-effectiveness, and prefers a transvenous or pacing-capable system when implanting an ICD because subcutaneous ICDs provide no rate support [44].

The French PNDS aligns with these recommendations and cites the HRS classes (pacemaker class 1, level B, for symptomatic bradycardia with any degree of AVB or sinoatrial block and for asymptomatic second-degree Mobitz II or third-degree AVB; 2a, B with PR >240 ms or QRS >120 ms and with HV >70 ms) and those of the ESC 2021 (I, C with HV ≥70 ms; IIb, C with PR >240 ms or QRS >120 ms) [15]. In practice, the PNDS implants a pacemaker mostly prophylactically in asymptomatic patients with an abnormal ECG and HV >70 ms, sometimes with PR >240 ms or QRS >120 ms even without an electrophysiological study, after presyncope or syncope with documented conduction abnormalities, or with sinus node dysfunction or Mobitz II or complete AVB recorded on continuous monitoring; resynchronisation is indicated with LVEF ≤35%, sinus rhythm, left bundle branch block and QRS >150 ms in NYHA class II–IV, or in cardiomyopathy induced by right ventricular pacing; the ICD is reserved, in the absence of serious comorbidity (particularly respiratory) compromising the prognosis within the following year, for primary prevention with LVEF ≤35% despite optimised therapy and for secondary prevention after resuscitated sudden death or ventricular arrhythmia induced on programmed stimulation [15]. The PNDS preference for the invasive strategy, supported by the French registry, contrasts with the HRS position, which considers invasive and non-invasive strategies equivalent in the absence of a direct comparison [15, 44, 61].

Quantitative data supporting these recommendations come from adult cohorts cited by HRS itself. Annual sudden death incidence in DM1 and DM2 ranges from 0.53% to 1.16% [44]. Criteria of PR ≥240 ms, QRS ≥120 ms, non-sinus rhythm or second- or third-degree AVB had sensitivity of 74.1%, specificity of 61.7%, positive predictive value of 12.1% and negative predictive value of 97.1% for sudden death prediction, showing that most patients with these findings will not die suddenly but their absence is reassuring [44]. In a prospective study of 49 DM1 patients with HV ≥70 ms (mean 79 ± 11 ms), advanced AVB or sinus node dysfunction incidence was 51.0% over a mean follow-up of 4.4 years, and in a retrospective study HV increased by a mean of 1.2 ms annually between successive studies [44]. In a large unselected DM1 and DM2 cohort followed for 12 years, sustained VT incidence was 2.3%, and non-sustained VT was the only independent predictor [44]. Sudden death in pacemaker and even ICD recipients suggests other contributing mechanisms, such as bundle branch re-entry VT or pulmonary embolism [44]. HRS also notes that third-degree AVB has not been described in DM1 patients younger than 18 years and that, in one paediatric series, atrial arrhythmias and, less often, sustained VT developed after 10 years, mainly triggered by exercise [44].

HRS illustrates shared decision-making with DM1 clinical scenarios: in a 63-year-old man with syncope causing facial trauma, PR 180 ms and right bundle branch block, electrophysiological study was undertaken with a pacemaker planned and a possible ICD if ventricular arrhythmia was induced; in a 72-year-old woman with marked weakness, dizziness and falls, PR 260 ms and left bundle branch block, prioritisation of quality of life led to empirical pacemaker implantation; and in a bedbound 68-year-old woman with asymptomatic atrial fibrillation, CHA2DS2-VASc 3 and HAS-BLED 2, oral anticoagulation was recommended and accepted [44]. For all neuromuscular diseases, HRS recommends (class 1, level C-EO) periodically discussing device function and deactivation, aligning pacemaker or ICD implantation with care goals, discussing deferral of ICD replacement and shock deactivation in advance care planning, and considers it reasonable (2a, C-EO) to honour a request to deactivate pacing at the end of life after explaining the consequences [44].

In DM2, stratification and prevention should follow the same approach, although complete AVB occurs mainly in the seventh decade and sudden death risk appears lower; left ventricular dysfunction and atrial fibrillation-related thromboembolic complications are proportionally more frequent [33]. DM2 GeneReviews considers defibrillators beneficial in patients with arrhythmias and their role unknown in asymptomatic patients [3].

In atrial fibrillation, general anticoagulation criteria apply, considering falls and intracranial haemorrhage risk, difficulties monitoring vitamin K antagonists, frequent hypotension and overestimation of renal function from low creatinine (cystatin C is an alternative); ablation may be effective, and antiarrhythmics may worsen bradycardia or ventricular tachyarrhythmias [29, 33]. Heart failure is treated according to general guidelines, with doses limited by hypotension; beta-blockers and renin–angiotensin system inhibitors may be considered with mild dysfunction (ejection fraction 40–50%) [29]. The PNDS treats left ventricular dysfunction as heart failure with reduced ejection fraction, with a beta-blocker and an angiotensin-converting enzyme inhibitor first line, monitoring hypotension and hyperkalaemia; for arrhythmias, it uses beta-blockers in the absence of significant conduction disease and contraindicates flecainide and the other class I antiarrhythmics, which may worsen conduction and ventricular arrhythmias. Anticoagulation for atrial fibrillation or flutter follows general population rules, discussed case by case when the risk of falls is high; because thromboembolic events have been described with a CHA2DS2-VASc score of 0 or 1, the PNDS recommends anticoagulation at least during periods of sustained supraventricular arrhythmia and for the month following cardioversion, a more interventionist position than the score-based application of general guidelines recommended by the HRS [15, 44].

7.5. Anaesthesia, sedation and drugs to avoid

Anaesthesia is a period of particularly high risk, including in mildly affected or presymptomatic patients [2, 18]. In a series of 219 DM patients undergoing their first operation under general anaesthesia in Chicoutimi (Quebec), 8.2% had complications, 16 of 18 being pulmonary; risk was greater after upper abdominal surgery (OR 24.4) and with proximal weakness (OR 14.1), without association with a specific drug; the authors consider early postoperative surveillance, airway protection, respiratory physiotherapy and incentive spirometry mandatory in symptomatic patients [65]. In DM2, among 340 general anaesthetics in 121 patients, serious complications occurred in 0.6%, attributed to less respiratory involvement [66]. Practical recommendations include pre-anaesthetic ECG and echocardiography, regional techniques when possible, procedures in hospitals with intermediate or intensive care, prolonged postoperative monitoring and combining procedures under one sedation in children [2, 9, 18]. DM1 GeneReviews advises avoiding suxamethonium (suxamethonium), notes that propofol-induced pain may trigger myotonia, that sevoflurane has been used uneventfully, that malignant hyperthermia has been described but is very rare, and that doxorubicin chemotherapy caused atrial fibrillation in one patient; opioids and sedatives require reduced doses because of increased sensitivity [1, 2]. Statins may cause pain and weakness but are not absolutely contraindicated in DM2 and may be used with monitoring [1, 3, 29]. Hypothyroidism worsens weakness and myotonia and should be corrected [1, 3]. MDF publishes detailed anaesthetic guidance that consensus documents require consultation of before any procedure [18, 19].

The French PNDS, based on the Orphananesthesia recommendations and recent series, is more detailed [15]. Preoperative assessment is multidisciplinary and recent: ECG, Holter and echocardiography (and pacemaker or ICD check), respiratory function tests, cough effectiveness, swallowing and sleep apnoea, degree of weakness by MIRS (risk, mainly respiratory, increases with motor deficit), blood glucose, thyroid function, gastric emptying and baseline CK; drugs that may trigger myotonia, such as propranolol, potassium, neostigmine and anticholinergics, should be anticipated. DM1 is not considered a myopathy with increased risk of malignant hyperthermia (two documented cases; contracture tests difficult to interpret). It is recommended to reduce preoperative anxiety, waiting and fasting, to avoid tourniquets and nerve stimulation, to monitor temperature mandatorily and to warm the patient actively from the outset (room, blanket, fluids), avoiding contact with cold surfaces; during cardiopulmonary bypass, a body temperature above 31 °C did not provoke myotonia. Halogenated agents are not contraindicated but require caution because of shivering on emergence and myocardial depression; all hypnotics and benzodiazepines may be used at reduced, titrated doses, propofol being the hypnotic of choice (EEG-guided total intravenous anaesthesia), remimazolam an option because of its very short duration and etomidate indicated in heart failure; intravenous opioids are used cautiously and should be short- or intermediate-acting (remifentanil, sufentanil), dexmedetomidine at a reduced dose (particularly the loading dose) and magnesium sulfate with caution. Suxamethonium is contraindicated because of the risk of generalised contracture; if neuromuscular blockade is needed, rocuronium is recommended, reversed with sugammadex to avoid neostigmine, with quantitative EMG-based neuromuscular monitoring rather than acceleromyography. Dysphagia, pharyngeal stasis and delayed gastric emptying make systematic tracheal intubation advisable (laryngeal mask discouraged), with classic or modified rapid sequence induction and possibly gastric ultrasound; extubation is performed with the patient fully awake and warm. Regional anaesthesia, neuraxial or peripheral, is recommended whenever possible, ultrasound-guided rather than nerve stimulator-guided, with cautious sedation, neuraxial opioids under continuous respiratory monitoring and slow infiltration with a fine needle (for example, lidocaine buffered with bicarbonate). After surgery, a myotonic crisis remains possible, the respiratory risk is high and prolonged ileus may occur; day-case surgery is not recommended, except under regional anaesthesia without sedation (or, according to the PNDS annex, with moderate muscle involvement and superficial surgery), and monitoring takes place in high-dependency or intensive care, with motor and respiratory physiotherapy. In children, a newborn or infant with suspected DM1 is managed as a very hypotonic child, and in adolescents the choices are those for adults [15]. For delivery, the PNDS recommends regional anaesthesia (epidural, spinal or combined) for analgesia and for caesarean section, anticipates a risk of postpartum haemorrhage due to uterine atony and requires the presence of a paediatrician (section 7.7) [15].

7.6. Sleepiness, fatigue, cognition and non-pharmacological interventions

Consensus recommendations consider modafinil when a central cause of sleepiness is suspected; the systematic review cited by GeneReviews found no evidence supporting routine psychostimulants, although some studies report benefit [1, 18]. No label includes DM, and the available dosages are those of the analogous condition, excessive sleepiness in narcolepsy (off-label use in DM): modafinil 200 mg/day, as a single morning dose or in two doses (morning and midday), up to 400 mg/day if the response is insufficient, 100 mg/day initially above 65 years, half the dose in severe hepatic impairment and not to be used below 18 years (Portuguese SmPC); the FDA label (Provigil®) recommends 200 mg once daily, with no consistent benefit from 400 mg [67, 68]. For immediate-release methylphenidate (Ritalin®), whose FDA label includes narcolepsy, the average adult dose is 20–30 mg/day in two or three doses, with a maximum of 60 mg/day, and the label requires prior cardiac evaluation [69]. Since psychostimulants may be proarrhythmic, decisions are shared and arrhythmia surveillance may be intensified [9, 29]. Cognitive behavioural therapy has trial evidence: in OPTIMISTIC, 255 adults with DM1 and severe fatigue across four European centres were randomised to cognitive behavioural therapy (10–14 sessions over 10 months, with optional graded exercise) or usual care; DM1-Activ-c improved by 3.27 points in favour of intervention (95% CI 0.93–5.62; p=0.007), with similar adverse events, mainly falls [70]. Moderate-intensity strength training causes no harm, and a controlled exercise programme showed neither benefit nor harm [1, 71]. Obesity, smoking, inactivity and alcohol or drug use are associated with more severe phenotypes and should be addressed [1].

The French PNDS adds practical guidance [15]. For hypersomnia of central origin, after correcting sleep-disordered breathing and reviewing sleep hygiene (fixed schedules, avoiding light at night, stimulants and antidepressants in the evening, sleep diary, actigraphy in adolescents), it cites the American Academy of Sleep Medicine consensus (2007 and 2021), which considers methylphenidate, modafinil and selegiline reasonable options, but advises against selegiline as first choice in DM1 because of its cardiac effects (bradycardia, supraventricular tachycardia, orthostatic hypotension) and its contraindication with antidepressants; it prefers pitolisant and modafinil to methylphenidate because they have no cardiovascular effects, mentions solriamfetol, and indicates for pitolisant, authorised in paediatric narcolepsy, a starting dose of 4.5 mg with progressive increase up to 36 mg [15]. The European SmPC of Wakix® authorises pitolisant in narcolepsy from 6 years of age (the PNDS states 7 years), starting at 4.5 mg/day in children with weekly increases to 9 and 18 mg/day, a maximum of 18 mg/day below 40 kg and of 36 mg/day from 40 kg; in adults it is started at 9 mg/day and the maximum is 36 mg/day; use in DM1 is an extrapolation from narcolepsy [72]. For attention deficit hyperactivity disorder, the PNDS uses methylphenidate at a starting dose of 0.5–1 mg/kg/day, after systematic cardiological advice and exclusion of contraindications, with variable results depending on the cognitive profile; the FDA label (Ritalin®) indicates, from 6 years of age, 5 mg twice daily with weekly increases of 5–10 mg and does not recommend more than 60 mg/day, so the PNDS weight-based starting dose lies above the label starting dose of 10 mg/day (for example, 15–30 mg/day in a 30 kg child) [15, 69].

For adult rehabilitation, the PNDS distinguishes patients with MIRS 1–4, candidates for complex re-education interventions, from those with MIRS 4–5, for whom readaptation and compensation predominate [15]. Strength training is not contraindicated, applies only to muscle groups with strength >3/5 on the MRC scale, may be high-intensity dynamic training while remaining below 40% of maximal voluntary strength, with a rest day between sessions, and the programmes studied lasted 8–12 weeks (20–36 sessions, 3–4 per week); strength gains are small and without functional translation, but they reduce isolation and the risk of falling. Aerobic training, after cardiac risk stratification, is performed on a treadmill or cycle ergometer, for at least 30 minutes 2–3 times a week with a rest day, at 60–70% of maximal heart rate, aiming at 150 minutes per week (approximately 7000 steps a day); it did not consistently improve the 6-minute walk, but caused no adverse effects and improved generic quality of life. Physiotherapy, on medical prescription, takes place 2–3 times a week, and adapted physical activity is structured over at least 6 weeks with 2–3 sessions a week. Fall prevention reduces the risk by only about 30% when it combines therapeutic education, personalised exercise, assessment of bone fragility, footwear and home adaptation; the PNDS calls for banning slippers and socks (11 times more falls than with closed shoes), favouring custom-made orthopaedic footwear with Velcro fastening, and notes that anti-equinus orthoses have not been shown to reduce falls or improve balance or walking speed. Occupational therapy offers technical aids (built-up handles, button hooks, adapted cutlery, reachers, long-handled brushes), home and vehicle adaptation and assessment for a powered wheelchair or scooter, taking into account joystick handling, cognition and vision [15]. In children, rehabilitation begins immediately after diagnosis (in the congenital form, from the neonatal unit) and includes adapted physical activity (adapted tricycle), hydrotherapy, paediatric exoskeletons from a height of 1 metre, a 12-week programme with therapy putty for wrist strength, a seating brace, a standing frame and orthoses, and classic clubfoot treatment, which may require surgery in up to 70% of cases; in infantile and juvenile forms with proximal involvement (9% and 4%), the quadriceps and hip extensors and flexors are strengthened [15]. Therapeutic patient education is considered particularly relevant, although limited by cognitive deficits, personality traits and socio-economic circumstances, and may take place outside structured programmes [15].

The PNDS recommends informing the patient that DM1 is also a brain disease and offering neuropsychological assessment even without complaints: in children before schooling or at diagnosis and then two to three times until adulthood; in adults at diagnosis and again years later or if there is deterioration, after excluding a cataract that reduces acuity [15]. Difficulties with flexibility, planning and initiative, apathy and irritability justify appointment reminders, booking subsequent appointments in the patient's presence and involving the family; cognitive behavioural therapy, cognitive remediation (including of social cognition, with tools developed for schizophrenia) and psychological support at key moments are proposed, with direct questions about mood, because patients tend to mask distress. Sex education and the notion of consent should be addressed with adolescents and young adults. Fitness to drive should be discussed when the results of the neuropsychological assessment are given, assessing the visual field (ptosis), acuity (cataract, macular dystrophy), sleepiness and executive and attentional functions; in France, the person must declare the disease to the prefecture's medical committee for driving licences, and the PNDS lists useful cognitive tests (TAP subtests, Trail Making Test, Stroop, Rey figure, Wisconsin) and vehicle adaptations [15].

7.7. Pregnancy and childbirth

DM1 pregnancy is associated with miscarriage, preterm delivery, polyhydramnios, prolonged or failed labour, placenta praevia, retained placenta, postpartum haemorrhage and respiratory failure, particularly in the third trimester [1, 18]. The Oxford Desk Reference reports polyhydramnios in 15%, prematurity below 38 weeks in 13%, retained placenta in 10% and postpartum haemorrhage in 5% [2]. In a German survey of 178 women with neuromuscular diseases, preterm delivery occurred in 30.7% of DM1 and 12.6% of DM2 pregnancies, caesarean section in 36.7% in DM1, and abnormal presentation in 34.6% in DM1 [73]. The adult consensus recommends high-risk obstetric follow-up, induction only by obstetric decision with all teams informed, caution with analgesics and anaesthetics, and a neonatologist at delivery even if the fetus is known to be unaffected [18]. In DM2, pregnancy may worsen myotonia, and smooth and striated muscle involvement may complicate labour [3, 19]. Information on medicines during pregnancy should be checked through specialist services, such as MotherToBaby, referenced by GeneReviews [1].

The French PNDS recommends a preconception consultation with an obstetrician, geneticist and/or neurologist to review transmission, the risk of the congenital form and the options for preimplantation or prenatal diagnosis, and referral to a type 2 or level 3 maternity unit, the latter when the fetus may be affected, when the disease is known in the family or when there is severe left ventricular dysfunction [15]. The figures it cites come from small series: only 25% of pregnancies reach term without complications; in a series of 31 women, 39% were diagnosed only after their child's diagnosis; there is polyhydramnios in 17% when the fetus is affected, peripartum haemorrhage in 14% (uterine atony or abnormal placental implantation) and caesarean section in 36% in one series; labour may be prolonged or shortened, and progestogenic impregnation often worsens weakness. Cardiac assessment (symptoms, ECG, echocardiography ± Holter) and respiratory assessment (symptoms, functional tests, blood gases on waking and nocturnal oximetry) should be preconceptional or early, with capnography or oximetry throughout the trimesters; NYHA III–IV dyspnoea, LVEF <45% and a history of arrhythmia or stroke require monthly or quarterly echocardiography, ECG and Holter. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are contraindicated, metoprolol and digoxin are permitted, continuous epidural analgesia limits pain-induced tachycardia and oxytocin boluses may cause tachycardia [15]. Vaginal delivery under regional anaesthesia is possible, with instrumental delivery if necessary; caesarean section may become necessary because of abnormal blood gases, vital capacity ≤1–1.5 L, pulmonary hypertension, right heart failure, marked diaphragmatic–abdominal weakness or pelvic abnormalities. Postpartum, the newborn is assessed by a paediatrician with access to neonatal intensive care and respiratory and nutritional support, and the mother is monitored for the risk of respiratory failure linked to the distended diaphragm after uterine involution, with attention to vitamin D, iron, thyroid function and contraception [15].

7.8. Transition and palliative care

The paediatric consensus recommends introducing palliative care from congenital disease diagnosis, establishing an emergency plan and advance directives, recognising caregiver burden — caregivers may also have DM1 — and ensuring coordination between healthcare, school and social support [9]. In adults, ventilation, gastrostomy, cardiac devices and ICD deactivation should be discussed within care goals [9, 29]. Transition should maintain adult screening from adolescence [9]. The French PNDS applies to DM1 the general principles of transition in rare diseases — planning from adolescence, a multidisciplinary approach, active patient participation, age-appropriate education, transfer of the medical record and psychosocial support — and recommends discussing advance directives early, particularly regarding intubations that may end in permanent tracheostomy, as soon as dysphagia or respiratory failure appears, bearing in mind that cognitive deficits make them harder to draw up; in France, decisions to limit or withdraw treatment follow the 2016 Claeys–Leonetti law [15]. In the congenital form, tracheostomy should be discussed in multidisciplinary ethical deliberation, because the probability of future weaning is low, and the respiratory course may justify a palliative approach [15].

7.9. Clinical trials and therapies in development

The predominant strategy is to reduce toxic muscle DMPK RNA using oligonucleotides (siRNA, antisense oligonucleotides or peptide conjugates) coupled to delivery vehicles that cross the membrane through transferrin receptor 1. The table distinguishes each programme's evidence level.

Interpretation requires distinguishing evidence levels. Peer-reviewed MARINA demonstrated muscle delivery and partial splicing correction, but its primary endpoint was safety and it was not designed to demonstrate clinical benefit [30]. At the time of this article, HARBOR is known only through a press release: the primary endpoint, a new myotonia measure, was not met, and reported activity in secondary endpoints cannot be assessed without numbers, confidence intervals and multiple-comparison correction [31]. DYNE-101 data compare treated patients with a natural history cohort and a small placebo group, are not phase 3 results and come from a press release; selection of the same endpoint (vHOT) that failed in HARBOR for the registrational cohort and a different functional endpoint (5×STS) in HARMONIA reflects uncertainty about which measure best captures benefit [58, 78]. Programmes cannot legitimately be ranked through indirect comparisons of trials with different populations, durations and endpoints. Tideglusib did not demonstrate primary endpoint benefit, and pitolisant results come from a small study without registry statistical inference [87, 88]. None of these programmes has US or EU authorisation; no INFARMED or ANVISA decisions specific to myotonic dystrophy were identified in the consulted sources.

7.10. Emergency situations and emergency card

The French PNDS organises the emergency pathway around information being available at the right time [15]. The neuromuscular filière and the general practitioner help the family put together an emergency liaison file (DLU) kept at home, with the "Steinert disease" care and emergency card issued by the French Ministry of Health (credit-card format, issued by the referring physician or the attending physician and carried at all times), identity, trusted person, contact details of the attending physician and the reference centre, conditions, risks, latest tests, treatments and contraindicated drugs, advance directives, ventilation settings and pacemaker model; with the patient's consent, the patient may be flagged to the SAMU (emergency medical service) as a "notable patient", and teams can consult the Orphanet emergency guidelines [15]. Serious situations result mainly from cardiac complications (conduction or rhythm disorders, embolism from atrial fibrillation, sudden death) and acute respiratory failure (infection, aspiration, pulmonary embolism), but there are also digestive emergencies (bowel obstruction, cholecystitis, appendicitis), trauma (fractures and dislocations due to falls) and psychiatric emergencies, and patients and families underestimate the severity; isolated cardiac forms without muscle involvement exist, so presyncope, syncope and palpitations should not be dismissed. In the prehospital setting, it is recommended to retrieve the DLU, always perform an ECG, use opioids and sedatives with caution, remember the contraindicated drugs (depolarising neuromuscular blockers, anticholinergics, mucolytics), not to introduce beta-blockers without prior echocardiography, to prefer non-invasive ventilation to intubation (which causes weaning problems), to keep the patient semi-seated and at rest, to be cautious with high-flow oxygen and, in a tracheostomised patient in difficulty, to change the inner cannula and perform suction [15]. In acute respiratory failure, often due to hypoventilation or aspiration pneumonia in a patient who appears calm, arterial or capillary blood gases show hypoxaemia, hypercapnia and acidosis; non-invasive ventilation should start early, with manual airway clearance and insufflation–exsufflation, reserving endotracheal suction for second line. In cardiac decompensation, treatment is conventional, limiting beta-blockers until echocardiographic assessment is available (in rapid atrial fibrillation, only after assessing LVEF, output and volaemia), avoiding class I antiarrhythmics and considering amiodarone case by case, particularly in recurrent VT; pulmonary embolism should always be considered. Discharge involves local care services and caregivers, because these patients are admitted repeatedly [15].

7.11. Differences between the French PNDS and the other recommendations

Most of the differences reflect differences in method: the PNDS was prepared by a group of French experts according to the HAS method for rare diseases, relies heavily on the French DM-Scope registry and French cardiac cohorts, and favours more invasive strategies and closer surveillance, whereas the MDF and HRS recommendations result from international consensus with explicit grading of evidence [15, 18, 44].

8. Reproductive Options and Family Counselling

8.1. Transmission risks

Both forms are autosomal dominant, and each child of a carrier has a 50% probability of inheriting the expanded allele [1, 3]. In DM1, virtually all probands inherited expansion from a parent who also has an abnormal allele, although the parent may appear unaffected because of unrecognised mild disease or a small expansion; new expansions from normal alleles are rare. If neither parent has expansion in leucocyte DNA, non-medical explanations such as alternative paternity or maternity or undisclosed adoption should be considered [1]. The Brazilian chapter emphasises that late onset and frequently mild disease in older relatives cause pedigrees to underestimate affected individuals [32]. In DM2, de novo expansions have not been described; an apparently isolated proband usually reflects unrecognised parental disease or early parental death, and age-dependent penetrance approaches 100% [3].

8.2. Congenital disease risk and empirical counselling

These data have wide confidence intervals and do not permit precise individual estimates; a frequent scenario is an asymptomatic mother with fewer than 100 repeats having a child with congenital disease and thousands of repeats, with maternal diagnosis made only then [1]. In DM2, no parental sex effect is confirmed and repeats tend to contract during transmission, but the association between maternal inheritance and earlier onset described in small series should be communicated as uncertain [3, 39].

8.3. Predictive testing and testing in minors

A sibling or child aged 21–40 years with a normal clinical examination has an approximately 10% probability of carrying expansion, and only half of these individuals will have significant neuromuscular involvement [2]. Testing asymptomatic adult relatives is appropriate for early diagnosis of cardiac manifestations, diabetes and cataracts, should occur within formal genetic counselling, and does not predict onset age, severity or progression [1]. Decisions should consider implications for children, insurance and financial circumstances [2]. DM1 GeneReviews discourages predictive testing in asymptomatic minors for adult-onset disorders without benefit from early intervention, whereas DM2 GeneReviews recommends discussing the issue in formal counselling while prioritising autonomy; in both, symptomatic minors from families with an established diagnosis may be tested [1, 3]. Cascade family testing is recommended, alerting all carriers, including asymptomatic carriers, to anaesthetic risk [2]. Individuals with premutations (35–49 or 37–49 repeats, depending on source) should receive transmission-risk counselling [1, 4, 9].

The French PNDS sets out its own rules [15]. The genetics clinic informs patients of the legal duty to pass the information on to relatives (bioethics law and Decree No. 2013-527 of 20 June 2013); if the patient does not wish to do so, they may ask the prescribing physician in writing to inform relatives (Article L.1131-1-2 of the French Public Health Code). Presymptomatic diagnosis takes place in a multidisciplinary consultation declared to the Agence de la Biomédecine, with a period of reflection and psychological support, and the result must be confirmed on a second independent sample. The PNDS considers presymptomatic screening strongly recommended in at-risk adults, because of the risk of arrhythmia and sudden death, and allows it in minors from 10 years of age, because of the direct individual benefit of cardiac surveillance; this position differs from that of GeneReviews DM1, which discourages testing in asymptomatic minors [1, 15]. A negative result reassures the patient about themselves and their offspring, and psychological support is offered whatever the result [15].

8.4. Prenatal diagnosis and preimplantation genetic testing

Prenatal diagnosis by chorionic villus sampling or amniocentesis is possible when familial expansion is known and usually distinguishes expansion compatible with minimal or adult disease from expansion posing congenital disease risk; PCR is rapid, but Southern blot expansion sizing may take two to three weeks [2]. Most infants with congenital disease have more than 1000 repeats, but some children with this size have childhood onset, and somatic mosaicism limits prediction [1, 2]. The paediatric consensus recommends describing fetal tissue with long repeats as “fetal DM1”, reserving “congenital” for newborns [9]. In pregnancies with low prior risk, fetal expansion testing may be considered for third-trimester polyhydramnios and/or reduced fetal movements [1].

Preimplantation genetic testing (PGT-M) has been performed for many years. In a Belgian series of 78 couples (54 affected women and 24 affected men, 50–1330 repeats, mean 410), repeat size did not influence reproductive outcome, and the cumulative delivery rate was 46% in 205 cycles; in a Spanish series of 59 cycles in 35 couples, live birth rate per cycle was 18.6%, with less favourable outcomes when the woman was affected because of fewer mature oocytes and lower fertilisation [1, 89, 90]. In DM2, prenatal diagnosis and PGT-M are possible, but repeat size does not predict onset age or manifestations [3].

According to the French PNDS, chorionic villus sampling is performed between 11 and 13 weeks of gestation and amniocentesis from 15 weeks, with a risk of fetal loss estimated at 0.5%; a fetal expansion above 150 repeats may be associated with the congenital form, but does not predict age at onset or severity [15]. A request for termination of pregnancy for medical reasons is assessed by a multidisciplinary prenatal diagnosis centre (CPDPN); if the pregnancy continues with an identified expansion, specialised ultrasound surveillance for signs of fetal hypomobility and delivery in a level 3 maternity unit are offered. Preimplantation diagnosis depends on assessment by reproductive medicine and on the informativeness of the markers for indirect diagnosis, and is performed in one of the authorised French centres [15].

8.5. Reproduction and fertility

Fertility is reduced in men and women; male hypogonadism with low testosterone is treated with replacement when symptomatic [1–3]. Reproductive counselling should precede pregnancy and be offered to affected or at-risk young adults, including family planning options [1, 9, 18]. Professionals and families may differ in their views on prenatal and preimplantation diagnosis, and decisions are personal [3]. The PNDS reports lower ovarian reserve, an altered response to ovarian stimulation and poorer-quality embryos in vitro in women, and quantitative and qualitative sperm abnormalities, up to azoospermia, in men [15].

9. Special Considerations: Population Diversity and Epidemiology

9.1. DM1 frequency

Estimates vary with ascertainment. GeneReviews reports prevalence from 1:100,000 in some Japanese regions to 1:10,000 in Iceland, with a worldwide estimate of 1:20,000 [1]. The meta-analysis by Liao and colleagues (17 studies) obtained pooled DM1 prevalence of 9.27 per 100,000 (95% CI 4.73–15.21), ranging from 0.37 to 36.29 per 100,000 with high heterogeneity [13]. The Oxford Desk Reference gives 1:8000 in Western Europe, the cardiogenetics book an incidence of 1:8000 births and prevalence of approximately 5 per 100,000 in most American and European populations, and the MDF consensus a range of 1:3000 to 1:8000 [2, 18, 33]. Orphanet, cited by GeneGuidance, provides a validated European point prevalence of 5.0 per 100,000, with national values from 0.46 (Taiwan) to 18.1 (Croatia) per 100,000 and much higher values in founder populations [6]. These figures describe clinically diagnosed disease; the New York study measuring carriers of ≥50 CTG expansions at birth obtained 1:2100, up to five times above clinical estimates, indicating underdiagnosis of mild forms and not to be interpreted as symptomatic disease prevalence [1, 14]. The French PNDS estimates approximately 1 in 8000 people affected in France [15]. The French DM-Scope registry, created in 2008 with support from AFM-Téléthon and fed by 55 reference or competence centres, comprised, in its 2019 description, approximately 3000 patients — 2828 with DM1 and 142 with DM2, including 322 children — making it the largest registry dedicated to DM1; it is a cohort of patients followed in centres, not a prevalence estimate [15].

9.2. Founder effects

Saguenay–Lac-Saint-Jean in northeastern Quebec (Canada) has the highest reported DM1 prevalence because of a founder effect; carrier frequency reaches 1:550, compared with 1:5000 to 1:50,000 in other regions cited by the authors [37, 91]. Haplotype study of 50 DM1 chromosomes identified haplotype A, currently with a carrier frequency of 1:730, as the “driver” of the founder effect, with an estimated age of nine generations — compatible with settlement of Charlevoix in the 17th century — while minority haplotypes contribute frequencies comparable to other populations [91]. The region has operated family screening and predictive testing since 1988, and the 219-patient Chicoutimi anaesthetic complication series comes from the same population [37, 65]. A large Canadian family study cited by the Oxford Desk Reference documented that 20% of affected men and 50% of affected women had never worked [2].

9.3. DM2 frequency and distribution

DM2 predominates in Central Europe. Accumulated German evidence estimates prevalence at approximately 9 per 100,000, similar to DM1; in Finland, genotyping of 5496 samples (blood donors and neuromuscular patients) identified three expansions, a frequency of 1:1830, exceeding DM1 in the same sample and suggesting many carriers, particularly older individuals, remain undiagnosed [3, 16, 17]. Expansion linkage to specific haplotypes indicates a common ancestral founder [3]. In TREAT-NMD, the largest groups come from Czechia (445), Germany (430) and the US (339), with registration rates of 4.2 and 2.0 per 100,000 in Czechia and Serbia and high DM2:DM1 ratios in Central Europe [48]. The Oxford Desk Reference describes DM2 as almost as frequent as DM1 in Germany, Eastern Europe and Finland and progressively less common westwards [2]. The meta-analysis pooled 2.29 per 100,000 (95% CI 0.17–6.53) [13]. Orphanet's ORPHA:606 prevalence category of 1–9 per 1,000,000 with reference to the United Kingdom illustrates geographic variation and should not be extrapolated to Central Europe [6]. Since genotyping-based carrier frequency greatly exceeds clinical prevalence, carrier frequency and disease prevalence are not interchangeable [6, 17].

9.4. Brazilian and Portuguese data

For DM1, the Brazilian genetic syndromes chapter reports prevalence of 1:20,000 in the general population and 1:8000 in populations of European ancestry, cites the Brazilian Muscular Dystrophy Association (ABDIM) for an incidence of approximately 1 case per 10,000–20,000 births (the printed text gives only denominator ranges), and states that DM2 accounts for 1% to 5% of myotonic dystrophy cases in most countries; it also reports male predominance not described in other consulted sources [32]. The 2023 Brazilian Guideline on Implantable Electronic Cardiac Devices includes specific myotonic dystrophy recommendations (section 7.4) [62]. No Portuguese epidemiological data were found in the consulted sources; this absence does not establish that no published studies exist.

9.5. Special populations

Premutation and small-expansion carriers (50–150 repeats) form a frequently undiagnosed group retaining cardiac, anaesthetic and reproductive risks [1, 14]. Women with mild or asymptomatic DM1 may have offspring with congenital disease, making obstetrics and neonatology frequent entry points for diagnosis [1, 46]. Patients with congenital or childhood DM1 require ongoing educational and social support, and an affected parent may need additional help [9]. Older DM2 patients may be classified as having fibromyalgia, non-specific myopathy or age-related changes, particularly outside Central Europe [3, 17].

9.6. Reference networks and patient organisations

In the European Union, care is provided through the European Reference Network for rare neuromuscular diseases (ERN EURO-NMD) [20]. GeneReviews and the Oxford Desk Reference identify resources including the Myotonic Dystrophy Foundation (US), which publishes consensus recommendations and anaesthetic guidance, the European Dystrophia Myotonica Association (Euro-DyMA), Myotonic Dystrophy Support Group (United Kingdom), Muscular Dystrophy UK, Muscular Dystrophy Association (US), TREAT-NMD network, Myotonic Dystrophy Family Registry and National Registry for Myotonic Dystrophy and Facioscapulohumeral Dystrophy (University of Rochester) [1–3]. In Brazil, the genetic syndromes chapter mentions ABDIM [32].

In France, the 2024 PNDS organises care within the FILNEMUS health filière, with neuromuscular reference centres (CRMR) and competence centres (CCMR) grouped into regional networks — for example, Nord/Est/Île-de-France (coordinated in Garches, AP-HP), PACA-Réunion-Rhône-Alpes (coordinated in Marseille) and Atlantique-Occitanie-Caraïbe (coordinated in Bordeaux) — in which the referring neurologist or paediatric neurologist coordinates with the attending physician a first circle of regular follow-up (neurology, cardiology, respiratory medicine, physical and rehabilitation medicine, ophthalmology) and a second, occasional circle (genetics, obstetrics, sleep medicine, ear, nose and throat, gastroenterology, urology, endocrinology, nephrology, psychiatry, occupational medicine) [15]. DM1 may be recognised as a long-term condition (ALD 8, severe forms of neurological and muscular disorders). Medico-social support includes the Maison départementale des personnes handicapées (MDPH), recognition as a disabled worker (RQTH), the AAH, AEEH and PCH allowances, adapted schooling (PAP, PPS, PAI, ULIS, SEGPA, support from an AESH), facilities such as CAMSP, SESSAD, IME, IEM and ITEP, sheltered employment (ESAT) and adult support services (SAVS, SAMSAH) [15]. AFM-Téléthon supports patients through departmental delegations, regional services with a healthcare pathway coordinator assigned to each patient and the Groupe d'intérêt Steinert, and represents them in the European federation Euro-DyMA, which brought together associations from 12 countries in 2024 [15].

10. Illustrative Clinical Case

10.1. Congenital myotonic dystrophy type 1 with multiple ultrasound findings and diagnosis across three generations

In 2024, Strelcovienė and colleagues from the Lithuanian University of Health Sciences published the case of a 38-year-old White woman, second delivery (G3P2), with a 13-year-old daughter and a pregnancy achieved through in vitro fertilisation [92]. First-trimester biochemical screening indicated increased trisomy 21 risk (1:75), but non-invasive prenatal testing was low-risk, and first- and second-trimester anomaly scans were normal. At 30 weeks, during admission for suspected intrahepatic cholestasis, ultrasonography showed polyhydramnios and a possible right diaphragmatic hernia. Two weeks later, she reported reduced fetal movements compared with her previous pregnancy; specialist ultrasonography at 32 weeks showed severe polyhydramnios (deepest vertical pocket 142 mm), bilateral clubfoot, lower limb akinesia with arthrogryposis, macrocephaly (head circumference +3 standard deviations) with mild bilateral ventriculomegaly (lateral ventricles 13 mm), right pleural effusion and right diaphragmatic eventration or hernia; amnioreduction was required. She reported longstanding hand weakness and lower limb fatigue. Neurological examination showed grip myotonia and mild myopathic facial features with hollow cheeks and ptosis. Testing of amniotic fluid and maternal blood identified expansion exceeding 150 repeats in one DMPK allele in both; the laboratory could report only “more than 150”, without sizing the expansion [92].

The male newborn was delivered at 36 weeks by elective caesarean section (breech presentation), weighing 3590 g, with no respiratory effort, cyanosis, atonia, bradycardia of 60/min and Apgar score 1 at 1, 5 and 10 minutes; he was intubated at five minutes, and effective ventilation was achieved only at ten minutes. He had bilateral clubfoot, extreme hip flexion with knee extension, a tented mouth and head circumference of 40 cm. Tracheostomy and gastrostomy were required; congenital hydrocephalus and bilateral hydronephrosis needed no treatment, radiography did not confirm diaphragmatic pathology, and pleural effusion resolved spontaneously. He spent 56 days in neonatal intensive care before transfer to paediatric intensive care with a palliative approach; bilateral sensorineural deafness was diagnosed at six months, and he became more responsive to his environment after hearing aid fitting [92]. Testing first-degree relatives confirmed DM1 across three generations: the patient's father, with mild ptosis and frontal baldness, had 70 repeats (mild DM1); her brother, with grip myotonia and weakness, had more than 150 (classic disease); and her 13-year-old daughter, with mild learning difficulties, weakness and grip myotonia, also had classic DM1 [92]. The article's figures — diaphragmatic eventration at 30 weeks, polyhydramnios at 32 weeks, macrocephaly and ventriculomegaly, akinesia with extended lower limbs at 35 weeks and pleural effusion — are accessible in the open-access article (Figure 2, polyhydramnios; Figure 4, fetal akinesia).

10.2. Commentary

The case illustrates several diagnostic and counselling issues. First, congenital ultrasound findings emerge late and are not pathognomonic; polyhydramnios and clubfoot, described in 100% and 26.6% of affected Oxford-series pregnancies, should prompt maternal neurological examination [46, 49]. Second, the mother had symptoms for years without diagnosis, a frequent pattern with mild maternal disease [1]. Third, the family illustrates anticipation: the grandfather with 70 repeats and mild disease, the next generation with classic disease, and the grandson with maternally transmitted congenital disease [1, 2]. Fourth, a laboratory report stating only “>150 repeats” accords with best practice for reporting ranges but cannot distinguish the congenital range in a fetus; even exact sizing would not reliably predict individual prognosis [1, 4]. Macrocephaly, pleural effusion and transient diaphragmatic pathology are described by the authors as additional findings to consider based on reports and small series; they do not replace classic signs. The palliative care decision was individual rather than a general recommendation: the paediatric consensus states that invasive and non-invasive ventilation and gastrostomy are acceptable components of congenital disease treatment, and many survivors improve during the first decade [9]. Finally, counselling of the 13-year-old daughter and other relatives of reproductive age, and cardiac and anaesthetic assessment of all identified carriers, follow directly from this diagnosis [1, 18].

11. Prognosis and Long-Term Follow-Up

11.1. Survival and causes of death in DM1

In a southern Limburg (Netherlands) registry followed for 47 years (1950–1997), 180 adult-onset DM1 patients had median survival of 60 years in men and 59 in women; observed survival from age 15 to 25, 45 and 65 years was 99%, 88% and 18%, versus expected population values of 99%, 95% and 78%, and pneumonia and arrhythmias each accounted for approximately 30% of deaths as primary causes [2, 11]. In the US series of 406 adults, sudden deaths (27) and deaths from neuromuscular respiratory failure (32) predominated; larger repeats are associated with earlier onset and lower survival [1, 10]. In Belgrade, cumulative 15-year survival probability was 50%, and survival correlates with age, diabetes, need for walking support, arrhythmias, blood pressure and vital capacity [1]. The most frequent causes of death in series assembled by GeneReviews are pneumonia/respiratory failure, cardiovascular disease, sudden death/arrhythmia and neoplasms [1]. In mild disease, life expectancy is normal or slightly reduced; in classic disease, mean age at death is 48–55 years; in congenital disease, approximately 45 years excluding neonatal deaths [1]. In congenital disease, the Welsh survey recorded few deaths between 1 and 20 years, but only half survived to their mid-30s and none beyond 40 (few studied at that age); most require specialist educational support and continued adult support, and few live independently [2]. The Brazilian chapter emphasises that patients die mainly from untreated and surgical complications, reinforcing surveillance's value [32].

11.2. Survival and causes of death in DM2

In the Dutch cohort of 125 patients, 26 died between 2000 and 2023 at a median age of 70.9 years, below sex- and age-adjusted cohort (78.1 years) and period (82.1 years) life expectancy; leading causes were heart disease (31%) and pneumonia (27%), and 27% had active neoplasia at death [12]. The authors suggest integrating advance care planning into follow-up [3, 12].

11.3. Consolidated follow-up plan

Research outcome measures — vHOT, 5×STS, 10-metre walk, quantitative muscle testing, DM1-Activ and Myotonic Dystrophy Health Index (MDHI) — also help document progression in specialist clinics, particularly in trial-eligible patients [31, 58, 70]. Patients are advised to carry diagnostic information (medical alert card or bracelet), particularly for unexpected anaesthetic situations [2]. In France, the national "Steinert disease" emergency card and the emergency liaison file fulfil this function (section 7.10) [15].

12. Summary and Final Considerations

Myotonic dystrophy types 1 and 2 are autosomal dominant multisystem disorders caused by non-coding expansions — CTG in the DMPK 3' untranslated region and CCTG in CNBP intron 1 — whose RNA sequesters splicing regulators and restores an embryonic isoform programme in adult tissues. DM1 ranges from isolated cataracts to congenital disease, with anticipation and maternal transmission of the most severe cases; DM2 is adult-onset, proximal and painful, without confirmed anticipation or an established congenital form. Diagnosis requires repeat-targeted testing because conventional exome and sequencing panels do not detect these expansions; reports should specify transcript, notation, method, repeat range and limitations, and premutation and disease thresholds differ slightly between GeneReviews, IDMC and European best practices.

Survival is determined mainly by respiratory complications, cardiac conduction disease with sudden death risk, anaesthetic complications and neoplasms. Annual electrocardiographic surveillance, early cardiology referral, electrophysiological study and pacing strategies in selected patients, serial respiratory assessment, anaesthetic preparation and high-risk obstetric follow-up are the most consequential available interventions, supported mainly by consensus and observational studies. Mexiletine improves grip myotonia in trials but is off-label and requires cardiac assessment; cognitive behavioural therapy improved participation in adults with severe fatigue. The 2024 French PNDS adds time frames for ventilation, a mexiletine dosage for adolescents and children, an emergency pathway with a national card, explicit criteria for endocrine, urological and anorectal surveillance and the possibility of presymptomatic testing from 10 years of age, points on which it partly diverges from the North American recommendations.

In 2026, MARINA publication demonstrated that DMPK RNA can be reduced in human muscle, but phase 3 HARBOR did not meet its primary endpoint according to the sponsor's press release, and other programmes remain in phases 1–3 without authorisation in any jurisdiction. Geneticists' central tasks remain diagnosing the entire family from the proband, counselling about congenital disease risk, discussing prenatal and preimplantation diagnostic options, and coordinating multidisciplinary care, including links to reference networks and registries providing trial access.

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