Chronic inflammatory demyelinating polyneuropathy and HEV antibody status: A case-control study from Lazio, Italy.

INTRODUCTION: Few studies have pointed to the possible role of infectious diseases in triggering Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP). Given the association of Hepatitis E Virus (HEV) with Guillain Barrè syndrome, we conducted a case-control study to determine the possible association of HEV infection with CIDP, analyzing possible risk factors for acquiring HEV infection in both CIDP patients and controls. MATERIALS AND METHODS: 82 CIDP and 260 from the general population have provided some personal information (demographics, anamnestic data and recognized risk factors for HEV infection) and underwent venipuncture blood sampling for virological assays testing for anti-HEV IgG and IgM with ELISA and RNA-HEV performing RT-PCR. RESULTS: Anti-HEV IgG seropositivity resulted in 32 CIDP patients (39.0%) and in 45 controls (17.3%), indicating a significant association between anti-HEV IgG positivity and CIDP (OR 3.04; 95% CI 1.70-5.43, p-value <0.001), but in multivariate logistic regression the only significant associations with anti-HEV positivity were eating pork liver sausages (OR 10.443, 95% CI 2.268-60.12, p-value 0.004) and IVIg/SCIg administration (OR 31.32, 95% CI 7.914-171.7, p-value <0.001). DISCUSSION: The higher prevalence of anti-HEV IgG in CIDP patients than in controls could be justified by chronically administering IVIg/SCIg with a passive acquisition of anti-HEV antibodies. Furthermore, all the 20 CIDP patients who underwent IVIg/SCIg administration reported HEV risk factors, so that they could have acquired the infection. CONCLUSIONS: Further studies in a larger CIDP patient sample in treatment with therapy other than IVIg/SCIg are necessary to rule out the possible confounding effect of IVIg/SCIg.

Familial childhood onset, slowly progressive myopathy plus cardiomyopathy expands the phenotype related to variants in the TTN gene.

This report describes a novel TTN -related phenotype in two brothers, both affected by a childhood onset, very slowly progressive myopathy with cores, associated with dilated cardiomyopathy only in their late disease stages. Clinical exome sequencing documented in both siblings the heterozygous c.2089A>T and c.19426+2T>A variants in TTN. The c.2089A>T, classified in ClinVar as possibly pathogenic, introduces a premature stop codon in exon 14, whereas the c.19426+2T>A affects TTN alternative splicing. The unfeasibility of segregation studies prevented us from establishing the inheritance mode of the muscle disease in this family, although the lack of any reported muscle or heart symptoms in both parents might support an autosomal recessive transmission. In this view, the occurrence of cardiomyopathy in both probands might be related to the c.2089A>T truncating variant in exon 14, and the childhood onset, slowly progressive myopathy to the c.19426+2T>A splicing variant, possibly allowing translation of an almost full length TTN protein.

Hereditary spastic paraparesis type 18 (SPG18): new ERLIN2 variants in a series of Italian patients, shedding light upon genetic and phenotypic variability.

INTRODUCTION: Hereditary spastic paraparesis (HSP) is a group of central nervous system diseases primarily affecting the spinal upper motor neurons, with different inheritance patterns and phenotypes. SPG18 is a rare, early-onset, complicated HSP, first reported as linked to biallelic ERLIN2 mutations. Recent cases of late-onset, pure HSP with monoallelic ERLIN2 variants prompt inquiries into the zygosity of such genetic conditions. The observed relationship between phenotype and mode of inheritance suggests a potential dominant negative effect of mutated ERLIN2 protein, potentially resulting in a milder phenotype. This speculation suggests that a wider range of HSP genes could be linked to various inheritance patterns. PURPOSE AND BACKGROUND: With documented cases of HSP loci exhibiting both dominant and recessive patterns, this study emphasizes that the concept of zygosity is no longer a limiting factor in the establishment of molecular diagnoses for HSP. Recent cases have demonstrated phenoconversion in SPG18, from HSP to an amyotrophic lateral sclerosis (ALS)-like syndrome. METHODS AND RESULTS: This report highlights two cases out of five exhibiting HSP-ALS phenoconversion, discussing an observed prevalence in autosomal dominant SPG18. Additionally, the study emphasizes the relatively high incidence of the c.502G>A variant in monoallelic SPG18 cases. This mutation appears to be particularly common in cases of HSPALS phenoconversion, indicating its potential role as a hotspot for a distinctive SPG18 phenotype with an ALS-like syndrome. CONCLUSIONS: Clinicians need to be aware that patients with HSP may show ALS signs and symptoms. On the other hand, HSP panels must be included in genetic testing methods for instances of familial ALS.

Retrospective observational study on the use of acetyl-L-carnitine in ALS.

ALCAR (Acetyl-L-carnitine) is a donor of acetyl groups and increases the intracellular levels of carnitine, the primary transporter of fatty acids across the mitochondrial membranes. In vivo studies showed that ALCAR decrease oxidative stress markers and pro-inflammatory cytokines. In a previous double-blind placebo-controlled phase II trial showed positive effects on self-sufficiency (defined as a score of 3+ on the ALSFRS-R items for swallowing, cutting food and handling utensils, and walking) ALSFRS-R total score and FVC. We conducted an observational, retrospective, multicentre, case-control study to provide additional data on the effects of ALCAR in subjects with ALS in Italy. Subjects treated with ALCAR 1.5 g/day or 3 g/day were included and matched with not treated subjects by sex, age at diagnosis, site of onset, and time from diagnosis to baseline, (45 subjects per group). ALCAR 3 g/day vs not treated: 22 not treated subjects (48.9%) were still alive at 24 months after baseline, compared to 23 (51.1%) treated subjects (adj. OR 1.18, 95% CI 0.46-3.02). No statistically significant differences were detected in ALSFRS nor FVC nor self-sufficiency. ALCAR 1.5 g/day vs not treated: 22 not treated subjects (48.9%) were still alive at 24 months after baseline, compared to 32 (71.1%) treated subjects (adj. OR 0.27, 95% CI 0.10-0.71). For ALSFRS-R, a mean slope of - 1.0 was observed in treated subjects compared to - 1.4 in those not treated (p = 0.0575). No statistically significant difference was detected in the FVC nor self-sufficiency. Additional evidence should be provided to confirm the efficacy of the drug and provide a rationale for the dosage.

NEFL-Related Charcot-Marie Tooth Disease due to P440L Mutation in Two Italian Families: Expanding the Phenotype and Defining Modulating Factors.

INTRODUCTION: Mutations in the neurofilament polypeptide light chain (NEFL) gene account for <1% of all forms of Charcot-Marie-Tooth (CMT) diseases and present with different phenotypes, including demyelinating, axonal and intermediate neuropathies, and with diverse pattern of transmission, with dominant and recessive inheritance being described. METHODS: Here, we present clinical and molecular data in two new unrelated Italian families, affected with CMT. RESULTS: We studied fifteen subjects (11 women, 4 men), age range 23-62 year. Onset of symptoms was mainly in childhood, with running/walking difficulties; some patients were pauci-asymptomatic; almost all shared variably distributed features of absent/reduced deep tendon reflexes, impaired gait, reduced sensation, and distal weakness in the legs. Skeletal deformities were seldom documented and were of mild degree. Additional features included sensorineural hearing loss in 3 patients, underactive bladder in 2 patients, and cardiac conduction abnormalities, requiring pacemaker implantation, in one child. Central nervous system (CNS) impairment was not documented in any subject. Neurophysiological investigation disclosed feature suggestive of demyelinating sensory-motor polyneuropathy in one family and resembling an intermediate form in the other. Multigene panel analysis of all known CMT genes revealed two heterozygous variants in NEFL: p.E488K and p.P440L. While the latter change segregated with the phenotype, the p.E488K variant appeared to act as a modifier factor being associated with axonal nerve damage. CONCLUSIONS: CMT related to P440L mutation in NEFL is associated with a mild, childhood-onset phenotype, showing prevalently sensory distal limbs involving and with motor impairment predominantly involving anterolateral leg muscles, in the absence of CNS involvement. Additional findings, never reported so far in patients with NEFL mutation, are cardiological and urinary dysfunctions. Our study expands the array of clinical features associated with NEFL-related CMT.

A Clinical and Epidemiological Prevalence Study on Friedreich's Ataxia in Latium, Italy.

OBJECTIVE: The aim of this study was to estimate the Friedreich's ataxia (FRDA) prevalence in a highly populated region of Italy (previous studies in small geographic areas gave a largely variable prevalence) and to define the patients' molecular and clinical characteristics. METHODS: For the point-prevalence study, we considered patients belonging to families with a molecular diagnosis of FRDA and resident in Latium on 1 January 2019. The crude prevalence of FRDA, specific for age and sex, was calculated and standardized for age using the Italian population. Moreover, we investigated possible correlations among patients' genetic profile, symptoms, and age of onset. RESULTS: We identified 63 FRDA patients; the crude prevalence for total, males, and females were 1.07 (95% CI: 0.81-1.37), 0.81 (95% CI: 0.54-1.22), and 1.32 (95% CI: 0.97-1.79), per 100,000 inhabitants. We divided FRDA patients by three age-at-onset groups (early-EOFA 73%; late-LOFA 11.1%; very late-VLOFA 15.9%) and found significant differences in the scale for the assessment and rating of ataxia (SARA; p = 0.001), a biased distribution of the shorter allele (p = 0.001), an excess of scoliosis and cardiomyopathy (p = 0.001) in EOFA. To determine the contribution of patients' molecular and clinical characteristics to the annual rate of progression, we performed a multivariate regression analysis that gave an R2 value of 45.3%. CONCLUSIONS: We estimated the crude and standardized prevalence of FRDA in Latium. A clinical classification (EOFA, LOFA, VLOFA) gave significant correlations. This epidemiological estimate allows monitoring disease prevalence over time in cohort studies and/or for developing disease registry.

Clinical-Genetic Features Influencing Disability in Spastic Paraplegia Type 4: A Cross-sectional Study by the Italian DAISY Network.

Background and Objectives: Hereditary spastic paraplegias (HSPs) are a group of inherited rare neurologic disorders characterized by length-dependent degeneration of the corticospinal tracts and dorsal columns, whose prominent clinical feature is represented by spastic gait. Spastic paraplegia type 4 (SPG4, SPAST-HSP) is the most common form. We present both clinical and molecular findings of a large cohort of patients, with the aim of (1) defining the clinical spectrum of SPAST-HSP in Italy; (2) describing their molecular features; and (3) assessing genotype-phenotype correlations to identify features associated with worse disability. Methods: A cross-sectional retrospective study with molecular and clinical data collected in an anonymized database was performed. Results: A total of 723 Italian patients with SPAST-HSP (58% men) from 316 families, with a median age at onset of 35 years, were included. Penetrance was 97.8%, with men showing higher Spastic Paraplegia Rating Scale (SPRS) scores (19.67 ± 12.58 vs 16.15 ± 12.61, p = 0.009). In 26.6% of patients with SPAST-HSP, we observed a complicated phenotype, mainly including intellectual disability (8%), polyneuropathy (6.7%), and cognitive decline (6.5%). Late-onset cases seemed to progress more rapidly, and patients with a longer disease course displayed a more severe neurologic disability, with higher SPATAX (3.61 ± 1.46 vs 2.71 ± 1.20, p < 0.001) and SPRS scores (22.63 ± 11.81 vs 12.40 ± 8.83, p < 0.001). Overall, 186 different variants in the SPAST gene were recorded, of which 48 were novel. Patients with SPAST-HSP harboring missense variants displayed intellectual disability (14.5% vs 4.4%, p < 0.001) more frequently, whereas patients with truncating variants presented more commonly cognitive decline (9.7% vs 2.6%, p = 0.001), cerebral atrophy (11.2% vs 3.4%, p = 0.003), lower limb spasticity (61.5% vs 44.5%), urinary symptoms (50.0% vs 31.3%, p < 0.001), and sensorimotor polyneuropathy (11.1% vs 1.1%, p < 0.001). Increasing disease duration (DD) and abnormal motor evoked potentials (MEPs) were also associated with increased likelihood of worse disability (SPATAX score>3). Discussion: The SPAST-HSP phenotypic spectrum in Italian patients confirms a predominantly pure form of HSP with mild-to-moderate disability in 75% of cases, and slight prevalence of men, who appeared more severely affected. Early-onset cases with intellectual disability were more frequent among patients carrying missense SPAST variants, whereas patients with truncating variants showed a more complicated disease. Both longer DD and altered MEPs are associated with worse disability.

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.

Validation of the DYALS (dysphagia in amyotrophic lateral sclerosis) questionnaire for the evaluation of dysphagia in ALS patients.

BACKGROUND: Dysphagia is a common symptom during the trajectory of ALS, and it can significantly impact on the quality of life and prognosis of patients. Nowadays, no specific tool for the screening of dysphagia in ALS is validated, and the approach is heterogeneous across the Italian centres. OBJECTIVE: To validate the DYALS (dysphagia in amyotrophic lateral sclerosis) questionnaire, adapting the DYMUS (dysphagia in multiple sclerosis) questionnaire, for the assessment of dysphagia in ALS patients, in order to uniform the evaluations across the Italian ALS network. METHODS: We included 197 patients diagnosed with ALS following the El Escorial criteria, in sixteen Italian ALS centres between 1st December 2019 and 1st July 2020. For each patient, we collected clinical and demographic data and obtained ALSFRS-r score, ALSAQ-5 score, DYMUS score, and EAT-10 score. RESULTS: Across the 197 patients, the ratio M/F was 113/84, and the median age was 64 years (IQR 56-72.5). Bulbar patients were 20%, and spinal patients 80%. The median ALSFRSr total score of patients was 35 (IQR 28-39). DYALS score was statistically higher in bulbar ALS than in spinal ALS (median = 6, IQR 4.5-9 vs median = 1, IQR 0-5, z = 6.253, p < 0.0001). DYALS questionnaire showed a high internal consistency (Cronbach's alpha = 0.88). There was a statistically significant correlation between DYALS and EAT-10 (rho = 0.90, p < 0.0001). CONCLUSIONS: DYALS scale is reliable, manageable, and easily usable for the screening of dysphagia in ALS. It can be shared with all the Italian ALS centres in order to collect uniform data for therapeutic strategies and clinical trials.

Prevalence of amyotrophic lateral sclerosis in Latium region, Italy.

OBJECTIVE: Prevalence estimate of amyotrophic lateral sclerosis (ALS) ranged between 1.1/100,000 and 11.2/100,000 inhabitants with different design of the study (prospective or retrospective) and sample size. The aim of this study is to conduct for the first time an estimate of the ALS prevalence in the Latium region. MATERIALS AND METHODS: The study was performed in Latium, a region located in the center of Italy, with a population, as of January 1, 2016, of 5888.472 inhabitants. In this region, a network of 15 clinical centers (of which 4 referral ALS centers are located in Rome) and 10 local health authorities involved in the diagnosis and treatment of ALS patients has been identified. Each patient was classified according to the El Escorial revised criteria. RESULTS: The prevalence study in 2016 identified 353 ALS cases (200 males). By considering population aged >=20 years, the total crude prevalence rate resulted 7.33 (CI95% 6.59-8.14) × 100,000 and 8.75 and 6.05 in males and females, respectively. Age-specific prevalence rates did not differ among males and females in the population aged less than 49 years. The difference emerged in population aged > 50 years. This type of diagnosis was recorded for 343 patients (11 missing). 68% of these patients have a definite diagnosis, 14% likely, 11% possible, and 12% defined as suspect. CONCLUSIONS: The estimate of prevalence rates observed in this study is probably in line with the values reported in the literature for prospective prevalence studies.

NGS in Hereditary Ataxia: When Rare Becomes Frequent.

The term hereditary ataxia (HA) refers to a heterogeneous group of neurological disorders with multiple genetic etiologies and a wide spectrum of ataxia-dominated phenotypes. Massive gene analysis in next-generation sequencing has entered the HA scenario, broadening our genetic and clinical knowledge of these conditions. In this study, we employed a targeted resequencing panel (TRP) in a large and highly heterogeneous cohort of 377 patients with a clinical diagnosis of HA, but no molecular diagnosis on routine genetic tests. We obtained a positive result (genetic diagnosis) in 33.2% of the patients, a rate significantly higher than those reported in similar studies employing TRP (average 19.4%), and in line with those performed using exome sequencing (ES, average 34.6%). Moreover, 15.6% of the patients had an uncertain molecular diagnosis. STUB1, PRKCG, and SPG7 were the most common causative genes. A comparison with published literature data showed that our panel would have identified 97% of the positive cases reported in previous TRP-based studies and 92% of those diagnosed by ES. Proper use of multigene panels, when combined with detailed phenotypic data, seems to be even more efficient than ES in clinical practice.

A 14-Year Italian Experience in DM2 Genetic Testing: Frequency and Distribution of Normal and Premutated CNBP Alleles.

Myotonic dystrophy type 2 (DM2) is a multisystemic disorder caused by a (CCTG) n in intron 1 of the CNBP gene. The CCTG repeat tract is part of a complex (TG) v (TCTG) w (CCTG) x (NCTG) y (CCTG) z motif generally interrupted in CNBP healthy range alleles. Here we report our 14-year experience of DM2 postnatal genetic testing in a total of 570 individuals. The DM2 locus has been analyzed by a combination of SR-PCR, TP-PCR, LR-PCR, and Sanger sequencing of CNBP alleles. DM2 molecular diagnosis has been confirmed in 187/570 samples analyzed (32.8%) and is mainly associated with the presence of myotonia in patients. This set of CNBP alleles showed unimodal distribution with 25 different alleles ranging from 108 to 168 bp, in accordance with previous studies on European populations. The most frequent CNBP alleles consisted of 138, 134, 140, and 136 bps with an overall locus heterozygosity of 90%. Sequencing of 103 unexpanded CNBP alleles in DM2-positive patients revealed that (CCTG)5(NCTG)3(CCTG)7 and (CCTG)6(NCTG)3(CCTG)7 are the most common interruption motifs. We also characterized five CNBP premutated alleles with (CCTG) n repetitions from n = 36 to n = 53. However, the molecular and clinical consequences in our cohort of samples are not unequivocal. Data that emerged from this study are representative of the Italian population and are useful tools for National and European centers offering DM2 genetic testing and counseling.

ATTRv in Lazio-Italy: A High-Prevalence Region in a Non-Endemic Country.

Hereditary transthyretin amyloidosis (ATTRv, v for variant) prevalence in Italy, a non-endemic region, has been established by ATTRv amyloidosis Italian Registry. However, values of prevalence were extremely heterogeneous, considering different regions. To properly establish the prevalence of the disease in the Lazio region, a survey was sent to university regional hospitals and to main regional hospitals, in order to collect all affected patients regularly followed. We identified 100 ATTRv patients and, considering a Lazio population of 5.8/million, we estimated a ATTRv prevalence of 17.2/million. The ATTRv amyloidosis Italian Registry reported a prevalence of 8.0/million in Lazio, while our survey showed a value of double this. Our survey documented a high-prevalence for a non-endemic country. The increased awareness of the disease among general practitioners and medical specialists is a fundamental step to reduce the diagnostic delay and start an effective treatment of this disease.

Novel TNNT1 mutation and mild nemaline myopathy phenotype in an Italian patient.

Mutations in the TNNT1 gene cause an infantile, lethal form of myopathy named "Amish" Nemaline Myopathy. Adult patients are very rarely described. We report a 49-year-old patient who presented a slowly progressive phenotype characterized by myalgia, exercise intolerance and dyspnea since infancy. In adult life she lapsed into a coma as a result of acute respiratory failure, with the need of tracheostomy, subsequently removed once her respiratory condition improved. Afterwards, non-invasive ventilation was started. Short stature, contractures, a small size posterior cranial fossa and osteonecrosis were additional clinical findings. Muscle MRI showed minor hypotrophy and degenerative changes of the muscles of the posterior thigh compartment and involvement of the paraspinal, medial gastrocnemius and soleus muscles with sparing of the gracilis muscle. Muscle biopsy revealed multiminicores and nemaline rods. Genetic analysis identified a new pathogenetic biallelic deletion c.786delG p.(Lys263Serfs*36) in exon 13 of TNNT1 gene. This case confirms that recessive mutations in TNNT1 gene can manifest mainly with respiratory failure in adult life.

A longitudinal study defined circulating microRNAs as reliable biomarkers for disease prognosis and progression in ALS human patients.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease associated with motor neuron degeneration, muscle atrophy and paralysis. To date, multiple panels of biomarkers have been described in ALS patients and murine models. Nevertheless, none of them has sufficient specificity and thus the molecular signature for ALS prognosis and progression remains to be elucidated. Here we overcome this limitation through a longitudinal study, analyzing serum levels of circulating miRNAs, stable molecules that are recently used as promising biomarkers for many types of human disorders, in ALS patients during the progression of the pathology. We performed next-generation sequencing (NGS) analysis and absolute RT quantification of serum samples of ALS patients and healthy controls. The expression levels of five selected miRNAs were quantitatively analyzed during disease progression in each patient and we demonstrated that high levels of miR-206, miR-133a and miR-151a-5p can predict a slower clinical decline of patient functionality. In particular, we found that miR-206 and miR-151a-5p serum levels were significantly up-regulated at the mild stage of ALS pathology, to decrease in the following moderate and severe stages, whereas the expression levels of miR-133a and miR-199a-5p remained low throughout the course of the disease, showing a diagnostic significance in moderate and severe stages for miR-133a and in mild and terminal ones for miR-199a-5p. Moreover, we found that miR-423-3p and 151a-5p were significantly downregulated respectively in mild and terminal stages of the disease. These data suggest that these miRNAs represent potential prognostic markers for ALS disease.

Lesion distribution and substrate of white matter damage in myotonic dystrophy type 1: Comparison with multiple sclerosis.

Myotonic Dystrophy type 1 (DM1) is an autosomal dominant condition caused by expansion of the CTG triplet repeats within the myotonic dystrophy protein of the kinase (DMPK) gene. The central nervous system is involved in the disease, with multiple symptoms including cognitive impairment. A typical feature of DM1 is the presence of widespread white matter (WM) lesions, whose total volume is associated with CTG triplet expansion. The aim of this study was to characterize the distribution and pathological substrate of these lesions as well as the normal appearing WM (NAWM) using quantitative magnetization transfer (qMT) MRI, and comparing data from DM1 patients with those from patients with multiple sclerosis (MS). Twenty-eight patients with DM1, 29 patients with relapsing-remitting MS, and 15 healthy controls had an MRI scan, including conventional and qMT imaging. The average pool size ratio (F), a proxy of myelination, was computed within lesions and NAWM for every participant. The lesion masks were warped into MNI space and lesion probability maps were obtained for each patient group. The lesion distribution, total lesion load and the tissue-specific mean F were compared between groups. The supratentorial distribution of lesions was similar in the 2 patient groups, although mean lesion volume was higher in MS than DM1. DM1 presented higher prevalence of anterior temporal lobe lesions, but none in the cerebellum and brainstem. Significantly reduced F values were found within DM1 lesions, suggesting a loss of myelin density. While F was reduced in the NAWM of MS patients, it did not differ between DM1 and controls. Our results provide further evidence for a need to compare histology and imaging using new MRI techniques in DM1 patients, in order to further our understanding of the underlying disease process contributing to WM disease.

Cochlear Dysfunction Is a Frequent Feature of Facioscapulohumeral Muscular Dystrophy Type 1 (FSHD1).

INTRODUCTION: Facioscapulohumeral muscular dystrophy type 1 (FSHD) represents one of the most common forms of muscular hereditary diseases and it is characterized by a great clinical variability with the typical muscular symptoms and other clinical features, including hearing impairment. However, etiopathogenetic mechanisms of auditory dysfunction are still not completely understood and it has been suggested that it could be assigned to a cochlear alteration that is present even in those subjects with a normal pure tonal audiometry (PTA) examination. METHODS: We found out the cochlear function in 26 patients with molecular diagnosis of FSHD1 and in healthy controls. All patients underwent complete neurological and audiological examinations, including FSHD clinical score, pure-tone audiometry (PTA), and otoacoustic emissions (OAEs), in particular transient evoked otoacoustic emissions (TEOAEs) and distortion product evoked otoacoustic emissions (DPOAEs). RESULTS: All FSHD1 patients showed significantly reduced DPOAEs and TEOAEs, bilaterally and at all frequencies, even when considering only subjects with a normal PTA or a mild muscular involvement (FSHD score ≤ 2). No correlation between OAEs and FSHD clinical score was found. DISCUSSION: Cochlear echoes represent a sensitive tool in detecting subclinical cochlear dysfunction in FSHD1 even in subjects with normal hearing and/or subtle muscle involvement. Our study is focused on the importance of evaluating the cochlear alteration through OAEs and, in particular, by performing TEOAEs and DPOAEs sequentially, to evaluate more frequent specificities of cochlear dysfunction with a wider spectrum of analysis.

High Prevalence and Gender-Related Differences of Gastrointestinal Manifestations in a Cohort of DM1 Patients: A Perspective, Cross-Sectional Study.

Myotonic dystrophy type 1 (DM1, MIM #160900), the most common muscular dystrophy among adults, is a multisystem disorder, which affects, besides the skeletal muscle, several other tissues and/or organs, including the gastrointestinal apparatus, with manifestations that frequently affect the quality of life of DM1 patients. So far, only few, mainly retrospective studies evaluated this specific topic in DM1, so we performed a perspective study, enrolling 61 DM1 patients who underwent an extensive diagnostic protocol, including administration of the Gastrointestinal Symptom Rating Scale (GSRS), a validated patient-reported questionnaire about GI symptoms, laboratory tests, liver US scan, and an intestinal permeability assay, in order to characterize frequency and assess correlations regarding specific gastrointestinal manifestations with demographic or other DM1-related features. Our results in our DM1 cohort confirm the high frequency of various gastrointestinal manifestations, with the most frequent being constipation (45.9%). γGT levels were pathologically increased in 65% of DM1 patients and GPT in 29.82%; liver ultrasound studies showed steatosis in 34.4% of patients. Significantly, 91.22% of DM1 patients showed signs of altered intestinal permeability at the specific assay. We documented a gender-related prevalence and severity of gastrointestinal manifestations in DM1 females compared to DM1 males, while males showed higher serum GPT and γGT levels than females. Correlation studies documented a direct correlation between severity of muscle weakness estimated by MIRS score and γGT and alkaline phosphatase levels, suggesting their potential use as biomarkers of muscle disease severity in DM1.

Creatine Kinase and Progression Rate in Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with no recognized clinical prognostic factor. Creatinine kinase (CK) increase in these patients is already described with conflicting results on prognosis and survival. In 126 ALS patients who were fast or slow disease progressors, CK levels were assayed for 16 months every 4 months in an observational case-control cohort study with prospective data collection conducted in Italy. CK was also measured at baseline in 88 CIDP patients with secondary axonal damage and in two mouse strains (129SvHSD and C57-BL) carrying the same SOD1G93A transgene expression but showing a fast (129Sv-SOD1G93A) and slow (C57-SOD1G93A) ALS progression rate. Higher CK was found in ALS slow progressors compared to fast progressors in T1, T2, T3, and T4, with a correlation with Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) scores. Higher CK was found in spinal compared to bulbar-onset patients. Transgenic and non-transgenic C57BL mice showed higher CK levels compared to 129SvHSD strain. At baseline mean CK was higher in ALS compared to CIDP. CK can predict the disease progression, with slow progressors associated with higher levels and fast progressors to lower levels, in both ALS patients and mice. CK is higher in ALS patients compared to patients with CIDP with secondary axonal damage; the higher levels of CK in slow progressors patients, but also in C57BL transgenic and non-transgenic mice designs CK as a predisposing factor for disease rate progression.