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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.MethodsA cross-sectional retrospective study with molecular and clinical data collected in an anonymized database was performed.ResultsA 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).DiscussionThe 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. 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%, withmen 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 presentedmore 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 abnormalmotor 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.

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.

The molecular characterization of Hereditary Spastic Paraplegias (HSP) and inherited cerebellar ataxias (CA) is challenged by their clinical and molecular heterogeneity. The recent application of Next Generation Sequencing (NGS) technologies is increasing the diagnostic rate, which can be influenced by patients’ selection. To assess if a clinical diagnosis of CA/HSP received in a third-level reference center might impact the molecular diagnostic yield, we retrospectively evaluated the molecular diagnostic rate reached in our center on 192 unrelated families (90 HSP and 102 CA) (i) before NGS and (ii) with the use of NGS gene panels. Overall, 46.3% of families received a genetic diagnosis by first-tier individual gene screening: 43.3% HSP and 50% spinocerebellar ataxias (SCA). The diagnostic rate was 56.7% in AD-HSP, 55.5% in AR-HSP, and 21.2% in sporadic HSP. On the other hand, 75% AD-, 52% AR- and 33% sporadic CA were diagnosed. So far, 32 patients (24 CA and 8 HSP) were further assessed by NGS gene panels, and 34.4% were diagnosed, including 29.2% CA and 50% HSP patients. Eleven novel gene variants classified as (likely) pathogenic were identified. Our results support the role of experienced clinicians in the diagnostic assessment and the clinical research of CA and HSP even in the next generation era.

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.

Objective: Segmental demyelination is the pathological hallmark of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), but other elementary lesions are frequently observed, configuring a series of different pathological pictures. In this article, we review the pathological findings of a large series of sural nerve biopsies from our cohort of CIDP patients. Patients and Methods: Patients with CIDP who underwent nerve biopsy were retrospectively selected from those referred to the Institute of Neurology of the “Università Cattolica del Sacro Cuore” in Rome, Italy, from 1982 to February 2020. Sural nerve biopsy was performed according to standard protocols. Results: Sural nerve biopsy was performed in 43/130 CIDP patients. Demyelinating abnormalities and axonal loss were found in 67.4% and 83.7% of biopsies, respectively. Conversely, onion bulbs and inflammatory infiltrates were rare (18.6% and 4.7%, respectively). In three cases, we observed normal pathological findings. Conclusions: A pathognomonic pathological finding of CIDP cannot be established, but we confirm the utility of nerve biopsy in this setting to confirm the diagnosis (also in atypical phenotypes) and to elucidate pathogenic mechanisms.

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.268 DM1 subjects aged18 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.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.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.

Myotonic dystrophy type 2 (DM2) is an autosomal dominant muscular dystrophy caused by the expansion of an intronic tetranucleotide CCTG repeat in CNBP on chromosome 3. As DM1, DM2 is a multisystem disorder affecting, beside the skeletal muscle, various other tissues, including peripheral nerves. Indeed, a subclinical involvement of peripheral nervous system has been described in several cohorts of DM2 patients, whereas DM2 patients manifesting clinical signs and/or symptoms of neuropathy have been only rarely reported. Here, we describe 2 related DM2 patients both of whom displayed an atypical disease onset characterized by dysautonomic symptoms, possibly secondary to peripheral neuropathy.

The article by Hilbert et al.1 analyzed data from a large number of patients with myotonic dystrophy (DM) 1 and DM2 enrolled in a national disease registry and documented high frequency of gastrointestinal symptoms, particularly dysphagia, constipation, and gallbladder problems. The authors emphasized the need for reliable diagnostic tests to assess swallowing function that can influence disease prognosis of patients with DM,1 since self-reported data have limited sensitivity in their diagnostic management due to cognitive involvement.2,3