Myotonic dystrophy type 1 (DM1) and type 2 (DM2) represent the most frequent multisystemic muscular dystrophies in adulthood. They are progressive, autosomal dominant diseases caused by an abnormal expansion of an unstable nucleotide repeat located in the non-coding region of their respective genes DMPK for DM1 and CNBP in DM2. Clinically, these multisystemic disorders are characterized by a high variability of muscular and extramuscular symptoms, often causing a delay in diagnosis. For both subtypes, many symptoms overlap, but some differences allow their clinical distinction. This article highlights the clinical core features of myotonic dystrophies, thus facilitating their early recognition and diagnosis. Particular attention will be given to signs and symptoms of muscular involvement, to issues related to respiratory impairment, and to the multiorgan involvement. This article is part of a Special Issue entitled “Beyond Borders: Myotonic Dystrophies—A European Perception.”

Pompe disease is a rare metabolic disorder, due to mutations in the gene encoding acid alpha-glucosidase (GAA), of which infantile and late-onset forms may occur. Aim of the work was to analyze clinical and laboratory data of a cohort of late-onset Pompe disease (LOPD) patients, collected during the last 15 years and to point out unusual phenotypic/genotypic features as well as enzyme replacement therapy (ERT) responses. We diagnosed 30 LOPD patients; at follow-up, they underwent motor, respiratory, cardiac and muscle MRI evaluations. Motor performances were tested by Walton Gardner-Medwin, GSGC and 6MWT tests. Respiratory function was assessed as FVC% in upright/supine position. LOPD presentations were represented by presymptomatic hyperCKemia (37%), proximal/axial muscle weakness (53%) and respiratory impairment (10%). Median diagnostic delay was 8.6 years (± 8.8). Atypical features were observed in 4 patients: marked distal muscle weakness and severe hearing loss at onset, as well as leukoencephalopathy and mesial temporal sclerosis during the disease course. By GAA sequence analysis, two causing mutations were detected in 22/30 patients, only one in the remaining 8 subjects. Overall, 29/30 patients harbored the common c.-32-13T>G mutation (2 were homozygous). Two new DNA variations were discovered (c.2395C>G, c.1771C>T). 14 patients received ERT for up to 60 months. Our study confirms LOPD clinical and genetic heterogeneity: atypical features may contribute to expand the clinical phenotype highlighting its multi-systemic nature. A timely diagnosis could allow early ERT start. An accurate follow-up is recommended to evaluate treatment responses.

Quantitative imaging techniques are emerging in the field of magnetic resonance imaging of neuromuscular diseases (NMD). T 2 of water (T 2w ) is considered an important imaging marker to assess acute and chronic alterations of the muscle fibers, being generally interpreted as an indicator for "disease activity" in the muscle tissue.To validate the accuracy and robustness of quantitative imaging methods, 1 H magnetic resonance spectroscopy (MRS) can be used as a gold standard.The purpose of the present work was to investigate T 2w of remaining muscle tissue in regions of higher proton density fat fraction (PDFF) in 40 patients with defined NMD using multi-TE single-voxel 1 H MRS. Patients underwent MR measurements on a 3 T system to perform a multi-TE single-voxel stimulated echo acquisition method (STEAM) MRS (TE = 11/15/20/25(/35) ms) in regions of healthy, edematous and fatty thigh muscle tissue. Muscle regions for MRS were selected based on T 2weighted water and fat images of a two-echo 2D Dixon TSE.MRS results were confined to regions with qualitatively defined remaining muscle tissue without edema and high fat content, based on visual grading of the imaging data.The results showed decreased T 2w values with increasing PDFF with R 2 = 0.45 (p < 10 −3 ) (linear fit) and with R 2 = 0.51 (exponential fit).The observed dependence of T 2w on PDFF should be considered when using T 2w as a marker in NMD imaging and when performing single-voxel MRS for T 2w in regions enclosing edematous, nonedematous and fatty infiltrated muscle tissue. KEYWORDS fatty infiltration, imaging marker, MRS, NMD, PDFF, quantitative imaging techniques, skeletal muscle, T 2 of water Abbreviations used: ALS, amyotrophic lateral sclerosis; CNM, centronuclear myopathy; DM2, myotonic dystrophy type 2; EPG, extended phase graph; FSHD, facioscapulohumeral muscular dystrophy; GRASE, gradient and spin echo; IBM, inclusion body myositis; LGMD2A, limb girdle muscular dystrophy type 2A; LGMD2I, limb girdle muscular dystrophy type 2I; LGMD2L, limb girdle muscular dystrophy type 2L; MESE, multi-echo spin-echo; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy; NMD, neuromuscular diseases; PDFF, proton density fat fraction; STEAM, stimulated echo acquisition method; T2f, T2 of fat; T2w, T2 of water; TSE, turbo spin-echo; VOI, volume of interest

Inherited ataxias are a group of heterogeneous disorders in children or adults but their genetic definition remains still undetermined in almost half of the patients. However, CoQ10 deficiency is a rare cause of cerebellar ataxia and ADCK3 is the most frequent gene associated with this defect. We herein report a 48 year old man, who presented with dysarthria and walking difficulties. Brain magnetic resonance imaging showed a marked cerebellar atrophy. Serum lactate was elevated. Tissues obtained by muscle and skin biopsies were studied for biochemical and genetic characterization. Skeletal muscle biochemistry revealed decreased activities of complexes I+III and II+III and a severe reduction of CoQ10, while skin fibroblasts showed normal CoQ10 levels. A mild loss of maximal respiration capacity was also found by high-resolution respirometry. Molecular studies identified a novel homozygous deletion (c.504del_CT) in ADCK3, causing a premature stop codon. Western blot analysis revealed marked reduction of ADCK3 protein levels. Treatment with CoQ10 was started and, after 1 year follow-up, patient neurological condition slightly improved. This report suggests the importance of investigating mitochondrial function and, in particular, muscle CoQ10 levels, in patients with adult-onset cerebellar ataxia. Moreover, clinical stabilization by CoQ10 supplementation emphasizes the importance of an early diagnosis.

This study aims to provide a detailed clinical characterization of a large cohort of myotonic dystrophy type 2 (DM2) patients investigating the influence of age and gender as modifying factors of DM2 phenotype. A retrospective study was conducted on 307 patients with genetically confirmed DM2. The following data were analyzed: (1) demographics, (2) clinical features (first symptom, muscular complaints, and multisystemic involvement), (3) diagnostics (serological tests, electromyography, and muscle biopsy). In this cohort (186 females, 121 males), a proximal weakness was the leading symptom at onset (55.4%), followed by myalgia (35.5%) and myotonia (25.4%). Proximal weakness was more common in women than men (64.9 vs. 43.8%, p = 0.0006), whereas being male was associated with higher odds for developing myalgia [OR 2.94 (95% CI 1.53-5.67)]. Patients with muscle weakness at onset were older than those with myalgia and myotonia (p < 0.0001), while each additional disease year was associated with 10% decrease in the odds of developing myotonia [OR 0.9 (95% CI 0.87-0.93)] and 6% decrease of myalgia [OR 0.94 (95% CI 0.91-0.97)]. Cataract and thyroid diseases occurred more frequently in women (p = 0.002 and p = 0.002, respectively). Early onset of DM2 is an independent risk factor for the occurrence of multisystemic involvement [OR 0.94 (95% CI 0.90-0.98)]. In this updated clinical description of DM2 emerges a profound gender and age influence on the phenotype, emphasizing that female gender and ageing may be associated with a higher disease burden. These age- and gender-specific differences should be considered in diagnostics, management, and future clinical studies of DM2.