Myotonic dystrophy type 2 (proximal myotonic myopathy, PROMM) is a progressive multisystem disorder with muscular symptoms (proximal weakness, pain, myotonia) and systemic manifestations such as diabetes mellitus, cataracts, and cardiac arrhythmias. A hallmark feature is the selective degeneration of type-II fibers, likely driven by chronic myotonia and sustained metabolic stress. In this study, proton magnetic resonance spectroscopy (1H-MRS) was applied to assess intramuscular carnosine as a potential noninvasive marker of type-II fiber integrity, alongside extramyocellular lipids (EMCL) and intracellular pH. We hypothesized that carnosine would be reduced in PROMM as a consequence of type-II fiber loss. Seventy participants (27 genetically confirmed PROMM patients, 43 healthy volunteers) underwent localized 1H-MRS of the quadriceps muscle at 3 T using a short-TE PRESS sequence. To ensure reliable carnosine quantification, spectra with voxel fat fraction ≥ 40% were excluded, yielding a final cohort of 19 patients and 19 matched healthy volunteers. Metabolites were quantified relative to total creatine, and exploratory correlations were assessed. PROMM patients showed significantly reduced carnosine compared with healthy volunteers (-50%, 0.05 ± 0.03 vs. 0.10 ± 0.05; p = 0.0022) and markedly elevated EMCL (threefold, 150.6 ± 80.5 vs. 48.6 ± 38.4; p = 0.0007). Intracellular pH did not differ between groups. Exploratory analysis revealed a negative correlation between carnosine and EMCL (r = -0.50, p = 0.03). This pilot study demonstrates that 1H-MRS can detect reduced intramuscular carnosine in PROMM, consistent with selective type-II-fiber loss. Carnosine thus emerges as a potential in vivo biomarker of fiber-type-specific degeneration. Validation in larger, longitudinal cohorts is warranted to establish its clinical and translational relevance. Myotonic dystrophy type 2 (DM2) is characterized by myotonia and muscle dysfunction (proximal and axial weakness, myalgia, and stiffness), and less commonly by posterior subcapsular cataracts, cardiac conduction defects, insulin-insensitive type 2 diabetes mellitus, and other endocrine abnormalities. While myotonia (involuntary muscle contraction with delayed relaxation) has been reported during the first decade, onset is typically in the third to fourth decade, most commonly with fluctuating or episodic muscle pain that can be debilitating and proximal and axial weakness of the neck flexors and the hip flexors. Subsequently, weakness occurs in the elbow extensors and finger flexors. Facial weakness and weakness of the ankle dorsiflexors are less common. Myotonia rarely causes severe symptoms. In a subset of individuals, calf hypertrophy in combination with brisk reflexes is notable. The diagnosis of DM2 is established in a proband by identification of a heterozygous pathogenic expansion of a CCTG repeat within the complex repeat motif of (TG)n(TCTG)n(CCTG)n(TCTG')n in CNBP. The number of CCTG repeats in a pathogenic expansion ranges from approximately 75 to more than 11,000, with a mean of approximately 5,000 repeats. The detection rate of a CNBP CCTG expansion is more than 99% with the combination of routine PCR, Southern blot analysis, and PCR repeat-primed assay. Treatment of manifestations: Ankle-foot orthoses, wheelchairs, or other assistive devices as needed for weakness; regular physical activity and exercise training appears to help maintain muscle strength and endurance and to control musculoskeletal pain; myotonia, especially of the legs, can require treatment and mexiletine or lamotrigine may be beneficial; medications used with some success in myalgia management include mexiletine, gabapentin, pregabalin, nonsteroidal anti-inflammatory drugs, cannabinoids, low-dose thyroid replacement, and tricyclic antidepressants; removal of cataracts or epiretinal membrane that impair vision; education regarding sleep hygiene; cognitive behavioral therapy and modafinil may be helpful for fatigue and daytime sleepiness; vitamin D supplementation for those with deficiency; treatment of diabetes and or dietary management per endocrinologist for insulin sensitivity and type 2 diabetes; lipid-lowering drugs for hyperlipidemia; hormone therapy for endocrine dysfunction; hearing aids for sensorineural hearing loss; treatment of arrhythmia and cardiomyopathy per cardiologist with defibrillator placement for those with arrhythmias; prokinetic agents may be helpful for gastrointestinal manifestations; vaccinations, respiratory training, and cough assist with noninvasive ventilation as needed; cognitive behavioral therapy and psychotropic medications as needed; standard treatment per oncologist for any cancers. Surveillance: Annual evaluation with neurologist, occupational therapist, and physical therapist; annual ophthalmology evaluation for posterior subcapsular cataracts and epiretinal membranes; assessment for sleep issues, polysomnography to identify sleep apnea, and serum vitamin D every six months; annual assessment of body mass index, clinical manifestations of diabetes mellitus, and thyroid disorders; measurement of fasting serum glucose, glycosylated hemoglobin level, thyroid hormone levels, and lipid panel annually; serum testosterone, inhibin B, luteinizing hormone, follicle-stimulating hormone, and dehydroeipandosterone sulfate annually in males; audiometry evaluation every six months; annual assessment for palpitations, syncope, dyspnea, orthopnea, and edema; annual EKG, 24-hour Holter monitoring, and echocardiogram to detect/monitor cardiac conduction defects and cardiomyopathy; cardiac MRI per cardiologist; assess for gastrointestinal manifestations and respiratory issues using the Respicheck assessment annually; pulmonary function test, cough peak flow, and nocturnal oximetry/capnometry annually; assessment of cardiac and respiratory function before and after surgery; assess for learning difficulties, memory deficits, executive dysfunction, and affective disorders as clinically indicated; neuropsychological testing and brain MRI as clinically indicated; annual assessment for clinical manifestations of associated tumors and follow standard population tumor screening guidelines. Agents/circumstances to avoid: Cholesterol-lowering medications when associated with increased weakness; medications that can exacerbate myotonia (depolarizing muscle relaxants). Monitor ventilation before, during, and after anesthesia. DM2 is inherited in an autosomal dominant manner. To date, all individuals whose biological parents have been evaluated with molecular genetic testing have had a parent with a pathogenic CNBP CCTG repeat expansion; de novo pathogenic CCTG repeat expansions have not been reported. Each child of an individual with a CCTG repeat expansion has a 50% chance of inheriting the expansion. The CCTG repeat expansion shows size differences between generations in the same family. In general, the repeat size appears to contract when passed on to the subsequent generation and then to increase in size as the affected individual ages. There is no confirmed maternal or paternal preference for contraction or expansion. Anticipation is not confirmed in DM2. To date, there is no significant correlation between CCTG repeat size and age of onset of weakness or other measures of disease severity. Once the pathogenic CNBP CCTG repeat expansion has been identified in an affected family member, predictive testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

We aimed at investigating the presence of patterns that account for the phenotypic variability in a myotonic dystrophy type 2 (DM2) retrospective cohort at the Mass General Brigham Neuromuscular Centers. We collected the presence or absence of 23 clinical variables at symptom onset and diagnosis (n = 67 patients) and follow-up (n = 37 patients). We first identified set/s of variables (factors or cluster/s) representative of the large research data pool at onset by performing factor analyses, then assigned each patient to the cluster for which they had the highest computed total factor score. Twelve variables grouped into two distinct clusters that, based on their variable content, we named as proximal myotonic myopathy (PROMM)-DM2 or non-PROMM-DM2. Patients assigned to non-PROMM-DM2 more frequently had clinical myotonia and positive family history, and less frequently multiorgan involvement. Most patients (67.2 %) remained assigned to same cluster during disease course and 11 non-PROMM eventually transitioned to PROMM-DM2. Dyslipidemia and early cataracts (both in PROMM-DM2 cluster) were the earliest extramuscular manifestations that occurred during disease course and they accounted for the conversion of up to 8 out of 11 non-PROMM to PROMM converters. Identification of phenotypically homogeneous patient subgroups may help investigating DM2 prognosis and disease biomarkers in future prospective studies.

Myotonic dystrophy type 2 (DM2) is an autosomal-dominant multisystemic disease with a core manifestation of proximal muscle weakness, muscle atrophy, myotonia, and myalgia. The disease-causing CCTG tetranucleotide expansion within the CNBP gene on chromosome 3 leads to an RNA-dominated spliceopathy, which is currently untreatable. Research exploring the pathophysiological mechanisms in myotonic dystrophy type 1 has resulted in new insights into disease mechanisms and identified mitochondrial dysfunction as a promising therapeutic target. It remains unclear whether similar mechanisms underlie DM2 and, if so, whether these might also serve as potential therapeutic targets. In this cross-sectional study, we studied DM2 skeletal muscle biopsy specimens on proteomic, molecular, and morphological, including ultrastructural levels in two separate patient cohorts consisting of 8 (explorative cohort) and 40 (confirmatory cohort) patients. Seven muscle biopsy specimens from four female and three male DM2 patients underwent proteomic analysis and respiratory chain enzymology. We performed bulk RNA sequencing, immunoblotting of respiratory chain complexes, mitochondrial DNA copy number determination, and long-range PCR (LR-PCR) to study mitochondrial DNA deletions on six biopsies. Proteomic and transcriptomic analyses revealed a downregulation of essential mitochondrial proteins and their respective RNA transcripts, namely of subunits of respiratory chain complexes I, III, and IV (e.g., mt-CO1, mt-ND1, mt-CYB, NDUFB6) and associated translation factors (TACO1). Light microscopy showed mitochondrial abnormalities (e.g., an age-inappropriate amount of COX-deficient fibers, subsarcolemmal accumulation) in most biopsy specimens. Electron microscopy revealed widespread ultrastructural mitochondrial abnormalities, including dysmorphic mitochondria with paracrystalline inclusions. Immunofluorescence studies with co-localization of autophagy (p62, LC-3) and mitochondrial marker proteins (TOM20, COX-IV), as well as immunohistochemistry for mitophagy marker BNIP3 indicated impaired mitophagic flux. Immunoblotting and LR-PCR did not reveal significant differences between patients and controls. In contrast, mtDNA copy number measurement showed a reduction of mtDNA copy numbers in the patient group compared to controls. This first multi-level study of DM2 unravels thus far undescribed functional and structural mitochondrial abnormalities. However, the molecular link between the tetranucleotide expansion and mitochondrial dysfunction needs to be further elucidated.

Proximal myotonic myopathy (PROMM) is normally associated with bilateral proximal weakness of lower limbs, slight elevation of liver enzymes, and cataracts. Myotonic dystrophy and PROMM are both autosomal dominant disorders, but gene study is completely normal in the case of PROMM. The most important differential diagnosis of PROMM is myotonic dystrophy. In our case, we reported late-onset PROMM in a patient 42 years old whose symptoms started at the age of 33 years; genetic evaluation of both myotonic dystrophy type 1 and myotonic dystrophy type 2 came out to be normal; therefore, the diagnosis of exclusion PROMM was made, which is a rare entity.

Myotonic Dystrophies (DM, Dystrophia Myotonia) are autosomal dominant inherited myopathies with a high prevalence across different ethnic regions. Despite some differences, mainly due to the pattern of muscle involvement and the age of onset, both forms, DM1 and DM2, share many clinical and genetic similarities. In this study, we retrospectively analyzed the medical record files of 561 Greek patients, 434 with DM1 and 127 with DM2 diagnosed in two large academic centers between 1994-2020. The mean age at onset of symptoms was 26.2 ± 15.3 years in DM1 versus 44.4 ± 17.0 years in DM2 patients, while the delay of diagnosis was 10 and 7 years for DM1 and DM2 patients, respectively. Muscle weakness was the first symptom in both types, while myotonia was more frequent in DM1 patients. Multisystemic involvement was detected in the great majority of patients, with cataracts being one of the most common extramuscular manifestations, even in the early stages of disease expression. In conclusion, the present work, despite some limitations arising from the retrospective collection of data, is the first record of a large number of Greek patients with myotonic dystrophy and emphasizes the need for specialized neuromuscular centers that can provide genetic counseling and a multidisciplinary approach.