Physical activity practiced at a young age is associated with a less severe subsequent clinical presentation in facioscapulohumeral muscular dystrophy.

BACKGROUND: In facioscapulohumeral muscular dystrophy (FSHD), it is not known whether physical activity (PA) practiced at young age is associated with the clinical presentation of disease. To assess this issue, we performed a retrospective cohort study concerning the previous practice of sports and, among them, those with medium-high cardiovascular commitment in clinically categorized carriers of a D4Z4 reduced allele (DRA). METHODS: People aged between 18 and 60 were recruited as being DRA carriers. Subcategory (classical phenotype, A; incomplete phenotype, B; asymptomatic carriers, C; complex phenotype, D) and FSHD score, which measures muscle functional impairment, were assessed for all participants. Information on PAs was retrieved by using an online survey dealing with the practice of sports at a young age. RESULTS: 368 participants were included in the study, average age 36.6 years (SD = 9.4), 47.6% male. The FSHD subcategory A was observed in 157 (42.7%) participants with average (± SD) FSHD score of 5.8 ± 3.0; the incomplete phenotype (category B) in 46 (12.5%) participants (average score 2.2 ± 1.7) and the D phenotype in 61 (16.6%, average score 6.5 ± 3.8). Asymptomatic carriers were 104 (subcategory C, 28.3%, score 0.0 ± 0.2). Time from symptoms onset was higher for patients with A (15.8 ± 11.1 years) and D phenotype (13.3 ± 11.9) than for patients with B phenotype (7.3 ± 9.0). The practice of sports was associated with lower FSHD score (-17%) in participants with A phenotype (MR = 0.83, 95% CI = 0.73-0.95, p = 0.007) and by 33% in participants with D phenotype (MR = 0.67, 95% CI = 0.51-0.89, p = 0.006). Conversely, no improvement was observed in participants with incomplete phenotype with mild severity (B). CONCLUSIONS: PAs at a young age are associated with a lower clinical score in the adult A and D FSHD subcategories. These results corroborate the need to consider PAs at the young age as a fundamental indicator for the correct clinical stratification of the disease and its possible evolution.

Comparison of quantitative muscle ultrasound and whole-body muscle MRI in facioscapulohumeral muscular dystrophy type 1 patients.

INTRODUCTION: Muscle ultrasound is a fast, non-invasive and cost-effective examination that can identify structural muscular changes by assessing muscle thickness and echointensity (EI) with a quantitative analysis (QMUS). To assess applicability and repeatability of QMUS, we evaluated patients with genetically confirmed facioscapulohumeral muscular dystrophy type 1 (FSHD1), comparing their muscle ultrasound characteristics with healthy controls and with those detected by MRI. We also evaluated relationships between QMUS and demographic and clinical characteristics. MATERIALS AND METHODS: Thirteen patients were included in the study. Clinical assessment included MRC sum score, FSHD score and The Comprehensive Clinical Evaluation Form (CCEF). QMUS was performed with a linear transducer scanning bilaterally pectoralis major, deltoid, rectus femoris, tibialis anterior and semimembranosus muscles in patients and healthy subjects. For each muscle, we acquired three images, which were analysed calculating muscle EI by computer-assisted grey-scale analysis. QMUS analysis was compared with semiquantitative 1.5 T muscle MRI scale. RESULTS: All muscles in FSHD patients showed a significant increased echogenicity compared to the homologous muscles in healthy subjects. Older subjects and patients with higher FSHD score presented increased muscle EI. Tibialis anterior MRC showed a significant inverse correlation with EI. Higher median EI was found in muscles with more severe MRI fat replacement. CONCLUSIONS: QMUS allows quantitative evaluation of muscle echogenicity, displaying a tight correlation with muscular alterations, clinical and MRI data. Although a confirmation on larger sample is needed, our research suggests a possible future application of QMUS in diagnosis and management of muscular disorders.

Distal upper limb involvement in myasthenia-myositis association.

INTRODUCTION: Myasthenia gravis-inflammatory myopathy (MG-IM) association has been rarely reported as specific clinical entity characterized by variable myositis manifestations, ranging from subclinical to diffuse muscle involvement with characteristic distal upper limb weakness. Although, in view of this, it has been hypothesized that distal muscle weakness in MG-IM could be due to the muscle inflammation instead of a pure neuromuscular transmission impairment, a biopsy-proven myositis process of distal muscles of upper limbs has not yet been provided. METHODS: We report on clinical, immunological, and myopathological characterization of a novel case affected by MG-IM association showing the typical distal upper limb weakness, including muscle biopsy of a weak forearm muscle. RESULTS: Histological and immunohistochemical studies showed a marked inflammatory process on muscle biopsy of extensor digitorum communis. The patient, a 47-year-old man with 10-year history of anti-acetylcholine receptor (AChR) and anti-titin antibody-positive MG with thymoma, developed a progressive, diffuse, and non-fatigable weakness predominant in distal upper limb muscles, unresponsive to acetylcholinesterase inhibitors associated to myalgia and creatine kinase (CK) elevation. DISCUSSION: We provide the histopathological evidence of a prominent inflammatory process responsible of distal upper limb weakness in MG-IM association. Muscle biopsy does not reveal any typical histopathological feature of other nosologically definite inflammatory myopathy, leading MG-IM association to come close to the group of overlap-myositis (OM) with the myopathological features of non-specific myositis (NSM).

Muscle magnetic resonance imaging in myotonic dystrophy type 1 (DM1): Refining muscle involvement and implications for clinical trials.

BACKGROUND: Only a few studies have reported muscle imaging data on small cohorts of patients with myotonic dystrophy type 1 (DM1). We aimed to investigate the muscle involvement in a large cohort of patients in order to refine the pattern of muscle involvement, to better understand the pathophysiological mechanisms of muscle weakness, and to identify potential imaging biomarkers for disease activity and severity. METHODS: One hundred and thirty-four DM1 patients underwent a cross-sectional muscle magnetic resonance imaging (MRI) study. Short tau inversion recovery (STIR) and T1 sequences in the lower and upper body were analyzed. Fat replacement, muscle atrophy and STIR positivity were evaluated using three different scales. Correlations between MRI scores, clinical features and genetic background were investigated. RESULTS: The most frequent pattern of muscle involvement in T1 consisted of fat replacement of the tongue, sternocleidomastoideus, paraspinalis, gluteus minimus, distal quadriceps and gastrocnemius medialis. Degree of fat replacement at MRI correlated with clinical severity and disease duration, but not with CTG expansion. Fat replacement was also detected in milder/asymptomatic patients. More than 80% of patients had STIR-positive signals in muscles. Most DM1 patients also showed a variable degree of muscle atrophy regardless of MRI signs of fat replacement. A subset of patients (20%) showed a 'marbled' muscle appearance. CONCLUSIONS: Muscle MRI is a sensitive biomarker of disease severity alsofor the milder spectrum of disease. STIR hyperintensity seems to precede fat replacement in T1. Beyond fat replacement, STIR positivity, muscle atrophy and a 'marbled' appearance suggest further mechanisms of muscle wasting and weakness in DM1, representing additional outcome measures and therapeutic targets for forthcoming clinical trials.

Changes of clinical, neurophysiological and nerve ultrasound characteristics in CIDP over time: a 3-year follow-up.

OBJECTIVES: To evaluate, in a prospective study, high-resolution ultrasound (HRUS) changes of nerve segments in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and their relationships with clinical and electrodiagnostic (EDX) characteristics. METHODS: Twenty-three consecutive patients with CIDP were included in a 3-year follow-up (FU) study. Each patient underwent neurologic examination, EDX and HRUS study. HRUS was performed on median, ulnar and peroneal nerves, yielding a total of 319 scanned nerve segments. INCAT and MRC-sum scores, motor nerve conduction velocity (NCV), compound muscle action potential (cMAP) amplitude, and nerve cross-sectional area (NCSA) were collected at baseline and at FU end, and were used for statistical analysis. Twenty-two healthy individuals, matched to patients for age and BMI, served as controls. RESULTS: NCSA was higher in patients than in controls (p < 0.0001) and showed significant direct correlation with disease severity, and inverse correlation with NCV and cMAP amplitude, both at baseline and at FU end. Disease duration, clinical scores and EDX were predictors of NCSA enlargement at both time points. During FU, NCSA increased in 51% of nerve segments (p = 0.006), in correlation with INCAT increase and with NCV and cMAP reduction. Considering EDX changes in subgroups that reflect the different types of nerve damage, NCSA significantly increased in those nerve segments that from normal EDX switched to prevalent myelinopathic EDX characteristics. CONCLUSIONS: Peripheral nerve size tends to increase over time in patients with CIDP, in correlation with clinical and EDX changes, in particular in those nerve segments that undergo a predominantly demyelinating damage.

Novel ACTA1 mutation causes late-presenting nemaline myopathy with unusual dark cores.

ACTA1 gene encodes the skeletal muscle alpha-actin, the core of thin filaments of the sarcomere. ACTA1 mutations are responsible of several muscle disorders including nemaline, cores, actin aggregate myopathies and fiber-type disproportion. We report clinical, muscle imaging, histopatological and genetic data of an Italian family carrying a novel ACTA1 mutation. All affected members showed a late-presenting, diffuse muscle weakness with sternocleidomastoideus and temporalis atrophy. Mild dysmorphic features were also detected. The most affected muscles by muscle MRI were rectus abdominis, gluteus minimus, vastus intermedius and both gastrocnemii. Muscle biopsy showed the presence of nemaline bodies with several unusual dark areas at Gomori Trichrome, corresponding to unstructured cores with abundant electrodense material by electron microscopy. The molecular analysis revealed missense variant c.148G>A; p.(Gly50Ser) in the exon 3 of ACTA1, segregating with affected members in the family. We performed a functional essay of fibre contractility showing a higher pCa50 (a measure of the calcium sensitivity of force) of type 1 fibers compared to control subjects' type 1 muscle fibers. Our findings expand the clinico-pathological spectrum of ACTA1-related congenital myopathies and the genetic spectrum of core-rod myopathies.

A 5-year clinical follow-up study from the Italian National Registry for FSHD.

BACKGROUND: The natural history of facioscapulohumeral muscular dystrophy (FSHD) is undefined. METHODS: An observational cohort study was conducted in 246 FSHD1 patients. We split the analysis between index cases and carrier relatives and we classified all patients using the Comprehensive Clinical Evaluation Form (CCEF). The disease progression was measured as a variation of the FSHD score performed at baseline and at the end of 5-year follow-up (ΔFSHD score). FINDINGS: Disease worsened in 79.4% (112/141) of index cases versus 38.1% (40/105) of carrier relatives and advanced more rapidly in index cases (ΔFSHD score 2.3 versus 1.2). The 79.1% (38/48) of asymptomatic carriers remained asymptomatic. The highest ΔFSHD score (1.7) was found in subject with facial and scapular weakness at baseline (category A), whereas in subjects with incomplete phenotype (facial or scapular weakness, category B) had lower ΔFSHD score (0.6) p < 0.0001. CONCLUSIONS: The progression of disease is different between index cases and carrier relatives and the assessment of the CCEF categories has strong prognostic effect in FSHD1 patients.

Gender effect on cardiac involvement in myotonic dystrophy type 1.

BACKGROUND AND PURPOSE: Cardiac involvement is observed in about 80% of subjects with myotonic dystrophy type 1 (DM1) and is mainly characterized by cardiac conduction and/or rhythm abnormalities (CCRAs), possibly leading to sudden cardiac death (SCD). Our objective was to investigate whether the gender difference may influence the cardiac involvement and SCD in DM1. METHODS: We analyzed prevalence and incidence of cardiological abnormalities in males versus females in 151 consecutive DM1 patients over a 35-year follow-up period. RESULTS: Fifty-five patients, 35 males (62.5%) and 20 females (42.5%), developed some type of CCRA during the follow-up period (mean 7.82 ± 6.21 years). CCRA overall, and specifically cardiac conduction abnormalities (CCAs), were significantly more frequent in males than in females (p = 0.043 and p = 0.031, respectively). CCRAs progressed in 16 males (45.7%) and six females (30%). Twenty-four patients, 14 males (25.0%) and 10 females (21.3%), died during the follow-up. Nine of them, six males (10.7%) and three females (6.4%), had SCD. After correction for Muscular Impairment Rating Scale progression, cytosine thymine-guanine expansion, and follow-up duration, a higher prevalence of CCAs was independently associated with male gender (p = 0.039), but independent association with gender was not detected for CCRAs overall, cardiac rhythm abnormalities, and SCD prevalence, even if prevalence was higher in males than females. CONCLUSIONS: The overall risk of occurrence of CCAs in DM1 is significantly higher in males than females regardless of genetic background and disease severity and progression. Moreover, the data also suggest a similar impact for male gender for CCRAs overall, CCAs, and SCD even if not statistically significant.

Large genotype-phenotype study in carriers of D4Z4 borderline alleles provides guidance for facioscapulohumeral muscular dystrophy diagnosis.

Facioscapulohumeral muscular dystrophy (FSHD) is a myopathy with prevalence of 1 in 20,000. Almost all patients affected by FSHD carry deletions of an integral number of tandem 3.3 kilobase repeats, termed D4Z4, located on chromosome 4q35. Assessment of size of D4Z4 alleles is commonly used for FSHD diagnosis. However, the extended molecular testing has expanded the spectrum of clinical phenotypes. In particular, D4Z4 alleles with 9-10 repeat have been found in healthy individuals, in subjects with FSHD or affected by other myopathies. These findings weakened the strict relationship between observed phenotypes and their underlying genotypes, complicating the interpretation of molecular findings for diagnosis and genetic counseling. In light of the wide clinical variability detected in carriers of D4Z4 alleles with 9-10 repeats, we applied a standardized methodology, the Comprehensive Clinical Evaluation Form (CCEF), to describe and characterize the phenotype of 244 individuals carrying D4Z4 alleles with 9-10 repeats (134 index cases and 110 relatives). The study shows that 54.5% of index cases display a classical FSHD phenotype with typical facial and scapular muscle weakness, whereas 20.1% present incomplete phenotype with facial weakness or scapular girdle weakness, 6.7% display minor signs such as winged scapula or hyperCKemia, without functional motor impairment, and 18.7% of index cases show more complex phenotypes with atypical clinical features. Family studies revealed that 70.9% of relatives carrying 9-10 D4Z4 reduced alleles has no motor impairment, whereas a few relatives (10.0%) display a classical FSHD phenotype. Importantly all relatives of index cases with no FSHD phenotype were healthy carriers. These data establish the low penetrance of D4Z4 alleles with 9-10 repeats. We recommend the use of CCEF for the standardized clinical assessment integrated by family studies and further molecular investigation for appropriate diagnosis and genetic counseling. Especially in presence of atypical phenotypes and/or sporadic cases with all healthy relatives is not possible to perform conclusive diagnosis of FSHD, but all these cases need further studies for a proper diagnosis, to search novel causative genetic defects or investigate environmental factors or co-morbidities that may trigger the pathogenic process. These evidences are also fundamental for the stratification of patients eligible for clinical trials. Our work reinforces the value of large genotype-phenotype studies to define criteria for clinical practice and genetic counseling in rare diseases.

Phenotypic Variability Among Patients With D4Z4 Reduced Allele Facioscapulohumeral Muscular Dystrophy.

Importance: Facioscapulohumeral muscular dystrophy (FSHD) is considered an autosomal dominant disorder, associated with the deletion of tandemly arrayed D4Z4 repetitive elements. The extensive use of molecular analysis of the D4Z4 locus for FSHD diagnosis has revealed wide clinical variability, suggesting that subgroups of patients exist among carriers of the D4Z4 reduced allele (DRA). Objective: To investigate the clinical expression of FSHD in the genetic subgroup of carriers of a DRA with 7 to 8 repeat units (RUs). Design, Setting, and Participants: This multicenter cross-sectional study included 422 carriers of DRA with 7 to 8 RUs (187 unrelated probands and 235 relatives) from a consecutive sample of 280 probands and 306 relatives from the Italian National Registry for FSHD collected between 2008 and 2016. Participants were evaluated by the Italian Clinical Network for FSHD, and all clinical and molecular data were collected in the Italian National Registry for FSHD database. Data analysis was conducted from January 2017 to June 2018. Main Outcomes and Measures: The phenotypic classification of probands and relatives was obtained by applying the Comprehensive Clinical Evaluation Form which classifies patients in the 4 following categories: (1) participants presenting facial and scapular girdle muscle weakness typical of FSHD (category A, subcategories A1-A3), (2) participants with muscle weakness limited to scapular girdle or facial muscles (category B, subcategories B1 and B2), (3) asymptomatic or healthy participants (category C, subcategories C1 and C2), and (4) participants with myopathic phenotypes presenting clinical features not consistent with FSHD canonical phenotype (category D, subcategories D1 and D2). Results: A total of 187 probands (mean [SD] age at last neurological examination, 53.5 [15.2] years; 103 [55.1%] men) and 235 relatives (mean [SD] age at last neurologic examination, 45.1 [17.0] years; 104 [44.7%] men) with a DRA with 7 to 8 RUs and a molecular diagnosis of FSHD were evaluated. Of 187 probands, 99 (52.9%; 95% CI, 45.7%-60.1%) displayed the classic FSHD phenotype, whereas 86 (47.1%; 95% CI, 39.8%-54.3%) presented incomplete or atypical phenotypes. Of 235 carrier relatives from 106 unrelated families, 124 (52.8%; 95% CI, 46.4%-59.7%) had no motor impairment, whereas a small number (38 [16.2%; 95% CI, 9.8%-23.1%]) displayed the classic FSHD phenotype, and 73 (31.0%; 95% CI, 24.7%-38.0%) presented with incomplete or atypical phenotypes. In 37 of 106 families (34.9%; 95% CI, 25.9%-44.8%), the proband was the only participant presenting with a myopathic phenotype, while only 20 families (18.9%; 95% CI, 11.9%-27.6%) had a member with autosomal dominant FSHD. Conclusions and Relevance: This study found large phenotypic variability associated with individuals carrying a DRA with 7 to 8 RUs, in contrast to the indication that a positive molecular test is the only determining aspect for FSHD diagnosis. These findings suggest that carriers of a DRA with 7 to 8 RUs constitute a genetic subgroup different from classic FSHD. Based on these results, it is recommended that clinicians use the Comprehensive Clinical Evaluation Form for clinical classification and, whenever possible, study the extended family to provide the most adequate clinical management and genetic counseling.

Muscle involvement in myasthenia gravis: Expanding the clinical spectrum of Myasthenia-Myositis association from a large cohort of patients.

Myastenia-Inflammatory Myopathy (MG-IM) association has been described in less than 50 cases, as isolated reports or in few case series. In most cases, MG and IM onset occur simultaneously even if the overlapping clinical manifestations could lead to delay the diagnosis in the early stage of disease. In these cases, thymic pathology is present in more than 50% of cases. Pathological findings can be consistent of polymyositis (63%), dermatomyositis (25%) or granulomatosis (12%). Accurate clinical manifestations and severity of IM in MG, including muscle specific antibodies (MSA) and muscle MRI, have not been systematically investigated and focal or mild subclinical myositis have not been reported. We observed that focal myositis or asymptomatic CK elevation can also occur in MG. In this review we have also retrospectively re-analyzed the clinical, serological, pathological and muscle imaging data from 13 patients with MG- IM from our cohort of 441 MG patients (2,9%). Clinical onset occurred simultaneously in 10/13 patients, whereas in 2 patients the IM appeared later in MG disease course (range 10-14 years) and conversely in 1 patient MG symptoms occurred later in IM disease course (4 years). Median age at disease onset was 51 year (range 24-73 years) regardless of clinical onset (MG or IM). Median clinical follow-up was 88 months (range 31-237 months). IM was suspected by CK elevation in all patients (ranging 800-3000 UI/L at first detection) and non-fatigable muscle weakness unresponsive to acetylcholinesterase inhibitors. All the patients presented mild to moderate MG symptoms. Three main categories of muscle involvement, sometimes overlapping, were recognizable: distal, proximal and subclinical myositits, leading to three main clinical groups (A,B,C) and two overlapping subgroups (A/B and B/C). Thymus pathology was present in 10/13 patients. Anti-AChR was detected in al all patients associated with anti-Titin and -RyR1 in those patients with thymoma. No MSA, nor MAA antibodies were detected. Muscle biopsy confirmed IM in all patients. In conclusion we redefined the clinical spectrum of muscle involvement in MG-IM association, which represent a continuum among 3 main clinical groups: distal, proximal and subclinical muscle involvement. Minimal muscle involvement and focal myositis could be underestimated among myasthenic patients and early aggressive immunotherapy could be required in focal group.

Prevalence and predictor factors of respiratory impairment in a large cohort of patients with Myotonic Dystrophy type 1 (DM1): A retrospective, cross sectional study.

INTRODUCTION: Respiratory complications are relevant in DM1, leading to a significantly increased morbidity and mortality risk in these patients; however, so far only few studies concerning respiratory function have been conducted in DM1 patients. We report a retrospective, multicenter, cross sectional study on a large cohort of DM1 patients widely characterized in the phenotype, to assess prevalence and identify predictors of restrictive respiratory syndrome. METHODS: 268 DM1 subjects aged >18 years, who had recently performed spirometric tests were included; restrictive syndrome was diagnosed if forced vital capacity (FVC) <80% of predicted. This cut-off was used for statistical univariate and multivariate analysis. RESULTS: 51.9% patients showed a restrictive syndrome, and half of them had indication to non-invasive ventilation (NIV), yet only 50% resulted compliant to NIV. CTG expansion size in leukocytes, clinical muscle severity, most functional parameters of respiratory muscle involvement, presence of cardiac conduction disturbances, pacemaker (PMK), exertion dyspnea, obstructive sleep apnea, and indication and compliance to NIV were all significantly associated with restrictive syndrome at the univariate analysis; in the multivariate model only the first two factors resulted independent predictors. DISCUSSION: A high prevalence of restrictive syndrome in our DM1 cohort, mainly due to respiratory muscles weakness, was observed and documented; the severity of muscle impairment and the CTG expansion size confirmed to be independent predictors of respiratory restriction. Our data suggest that optimization of respiratory therapeutic management, particularly regarding launching of NIV, might help to reduce the rate of deaths due to respiratory complications in DM1.

A 34-year longitudinal study on long-term cardiac outcomes in DM1 patients with normal ECG at baseline at an Italian clinical centre.

Cardiac conduction and/or rhythm abnormalities (CCRA) are the most frequent and life-threatening complications in DM1. In order to determine prevalence, incidence, characteristics, age of onset and predictors of CCRA, CCRA progression and sudden cardiac death (SCD) in DM1, we collected ECG/24hECG-Holter data from a yearly updated 34-year database of a cohort of 103 DM1 patients without cardiac abnormalities at baseline, followed for at least 1 year. Fifty-five patients developed CCRA [39 developed conduction abnormalities (CCA) and 16 rhythm abnormalities (CRA)], which progressed in 22. Nine had SCD. Risk and incidence of CCRA amounted to 53.4 and 6.83% person-years (CCA: 37.9 and 4.8%; CRA 15.5 and 2%), respectively; risk and incidence of SCD amounted to 8.74 and 0.67% person-years, respectively. CTG expansion represented a predictor of CCRA incidence (HR 1.10, p = 0.04), CCRA progression (HR 1.28, p = 0.001) and SCD (HR 1.39, p = 0.002). MIRS progression during follow-up was associated with CCRA prevalence (OR 5.82, p = 0.004); older age and larger CTG expansion to SCD prevalence (OR 2.67, p = 0.012; OR 1.54, p = 0.005). Age of CCRA onset and CCRA progression was significantly lower in patients with larger CTG expansion and in those with MIRS progression. Age when SCD occurred was significantly lower in patients with larger CTG expansion. Amongst recorded cardiac abnormalities, both atrial flutter (OR 8.70; p = 0.031) and paroxysmal supraventricular tachycardia (OR 8.67; p = 0.040) were associated with SCD. Although all DM1patients may develop cardiac abnormalities at any time in their life, patients older than 30 years with larger CTG expansion and MIRS progression in particular should be carefully monitored via periodical ECG.

"I Know that You Know that I Know": Neural Substrates Associated with Social Cognition Deficits in DM1 Patients.

Myotonic dystrophy type-1 (DM1) is a genetic multi-systemic disorder involving several organs including the brain. Despite the heterogeneity of this condition, some patients with non-congenital DM1 can present with minimal cognitive impairment on formal testing but with severe difficulties in daily-living activities including social interactions. One explanation for this paradoxical mismatch can be found in patients' dysfunctional social cognition, which can be assessed in the framework of the Theory of Mind (ToM). We hypothesize here that specific disease driven abnormalities in DM1 brains may result in ToM impairments. We recruited 20 DM1 patients who underwent the "Reading the Mind in the Eyes" and the ToM-story tests. These patients, together with 18 healthy controls, also underwent resting-state functional MRI. A composite Theory of Mind score was computed for all recruited patients and correlated with their brain functional connectivity. This analysis provided the patients' "Theory of Mind-network", which was compared, for its topological properties, with that of healthy controls. We found that DM1 patients showed deficits in both tests assessing ToM. These deficits were associated with specific patterns of abnormal connectivity between the left inferior temporal and fronto-cerebellar nodes in DM1 brains. The results confirm the previous suggestions of ToM dysfunctions in patients with DM1 and support the hypothesis that difficulties in social interactions and personal relationships are a direct consequence of brain abnormalities, and not a reaction symptom. This is relevant not only for a better pathophysiological comprehension of DM1, but also for non-pharmacological interventions to improve clinical aspects and impact on patients' success in life.

A novel clinical tool to classify facioscapulohumeral muscular dystrophy phenotypes.

Based on the 7-year experience of the Italian Clinical Network for FSHD, we revised the FSHD clinical form to describe, in a harmonized manner, the phenotypic spectrum observed in FSHD. The new Comprehensive Clinical Evaluation Form (CCEF) defines various clinical categories by the combination of different features. The inter-rater reproducibility of the CCEF was assessed between two examiners using kappa statistics by evaluating 56 subjects carrying the molecular marker used for FSHD diagnosis. The CCEF classifies: (1) subjects presenting facial and scapular girdle muscle weakness typical of FSHD (category A, subcategories A1-A3), (2) subjects with muscle weakness limited to scapular girdle or facial muscles (category B subcategories B1, B2), (3) asymptomatic/healthy subjects (category C, subcategories C1, C2), (4) subjects with myopathic phenotype presenting clinical features not consistent with FSHD canonical phenotype (D, subcategories D1, D2). The inter-rater reliability study showed an excellent concordance of the final four CCEF categories with a κ equal to 0.90; 95 % CI (0.71; 0.97). Absolute agreement was observed for categories C and D, an excellent agreement for categories A [κ = 0.88; 95 % CI (0.75; 1.00)], and a good agreement for categories B [κ = 0.79; 95 % CI (0.57; 1.00)]. The CCEF supports the harmonized phenotypic classification of patients and families. The categories outlined by the CCEF may assist diagnosis, genetic counseling and natural history studies. Furthermore, the CCEF categories could support selection of patients in randomized clinical trials. This precise categorization might also promote the search of genetic factor(s) contributing to the phenotypic spectrum of disease.

An Age-Standardized Prevalence Estimate and a Sex and Age Distribution of Myotonic Dystrophy Types 1 and 2 in the Rome Province, Italy.

BACKGROUND: Prevalence estimates for the 2 forms of myotonic dystrophy types 1 and 2 (DM1 and DM2) are not exhaustive or non-available. Our aim was to estimate the minimum prevalence of DM1 and DM2 in Italy in the Rome province, applying standards of descriptive epidemiology. METHODS: All patients with a molecular diagnosis of DM1/DM2 and residents in the Rome province in 2013 have been enrolled, and the age-standardized prevalence has been calculated, assuming a Poisson distribution and adjusting for age. RESULTS: We identified 395 DM1 patients: the age-standardized prevalence for total, females and males was 9.65, 8.35 and 11.07/100,000, respectively. The mean age of subjects differed considerably according to CTG repeat length (p = 0.001). Forty DM2 patients were identified. The age-standardized prevalence for total, females and males was 0.99, 1.07 and 0.90/100,000, respectively. The mean age was 57.05. CONCLUSIONS: We estimated for the first time the age-standardized prevalence and the sex and age distribution of DM1 and DM2 in a general population. A higher prevalence of males in DM1 and females in DM2 and a higher mean age of DM2 patients (+8 years) were ascertained. Prevalence of DM2 was 10% that of DM1. These prevalence values are probably lower than mutational rates due to the incomplete penetrance of DM1 mutations and to the clinical elusiveness of DM2. Our findings will be useful in designing cohort studies and for developing a disease registry.

Clinical expression of facioscapulohumeral muscular dystrophy in carriers of 1-3 D4Z4 reduced alleles: experience of the FSHD Italian National Registry.

OBJECTIVES: Facioscapulohumeral muscular dystrophy type 1 (FSHD1) has been genetically linked to reduced numbers (≤ 8) of D4Z4 repeats at 4q35. Particularly severe FSHD cases, characterised by an infantile onset and presence of additional extra-muscular features, have been associated with the shortest D4Z4 reduced alleles with 1-3 repeats (1-3 DRA). We searched for signs of perinatal onset and evaluated disease outcome through the systematic collection of clinical and anamnestic records of de novo and familial index cases and their relatives, carrying 1-3 DRA. SETTING: Italy. PARTICIPANTS: 66 index cases and 33 relatives carrying 1-3 DRA. OUTCOMES: The clinical examination was performed using the standardised FSHD evaluation form with validated inter-rater reliability. To investigate the earliest signs of disease, we designed the Infantile Anamnestic Questionnaire (IAQ). Comparison of age at onset was performed using the non-parametric Wilcoxon rank-sum or Kruskal-Wallis test. Comparison of the FSHD score was performed using a general linear model and Wald test. Kaplan-Meier survival analysis was used to estimate the age-specific cumulative motor impairment risk. RESULTS: No patients had perinatal onset. Among index cases, 36 (54.5%) showed the first signs by 10 years of age. The large majority of patients with early disease onset (26 out of 36, 72.2%) were de novo; whereas the majority of patients with disease onset after 10 years of age were familial (16, 53.3%). Comparison of the disease severity outcome between index cases with age at onset before and over 10 years of age, failed to detect statistical significance (Wald test p value=0.064). Of 61 index cases, only 17 (27.9%) presented extra-muscular conditions. Relatives carrying 1-3 DRA showed a large clinical variability ranging from healthy subjects, to patients with severe motor impairment. CONCLUSIONS: The size of the D4Z4 allele is not always predictive of severe clinical outcome. The high degree of clinical variability suggests that additional factors contribute to the phenotype complexity.

Increased risk of tumor in DM1 is not related to exposure to common lifestyle risk factors.

Recent studies documented an increased risk of neoplasm in patients with myotonic dystrophies (DM). Yet, none of these studies evaluated the contribution of common cancer risk factors in such observation. In this study, we included a cohort of patients (n = 255) with an established molecular diagnosis of DM type 1 (DM1), and who receives their treatment in one of the four centers with recognized expertise in neuromuscular disorders in Rome. We estimated the prevalence of benign and malignant tumors, and assessed if lifestyle factors and/or specific disease features would be associated to their occurrence. Overall, 59 benign tumors in 54 patients and 19 malignant tumors in 17 patients were diagnosed. The most common malignant neoplasms were cancers of the skin (31.6%), thyroid (21.0%), ovary (10.5%), and breast (10.5%). Uterine fibroid was the most common benign tumor (37.6%) in women, while pilomatricoma was the most common in men (28.6%). Age at enrollment (OR = 1.02, 95% CI 1.00-1.05), and female gender (OR = 5.71, 95% CI 2.90-11.22) were associated with tumor development in DM1 patients, while thyroid disorders was associated with malignant tumors only in women (OR = 5.12, 95% CI 1.35-19.37). There was no association between tumor development and evaluated lifestyle factors. In conclusion, the lack of association between common cancer risk factors and tumor development in DM1 support a pathogenic link between tumors and DM1 itself, emphasizing the need for a systematic surveillance. Our observation of an association between thyroid diseases in women and cancer development needs confirmation.