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.

Clinical and genetic characterization of an Italian family with slow-channel syndrome.

INTRODUCTION: The slow-channel congenital myasthenic syndrome (SCCMS) is a postsynaptic form of congenital myasthenic syndromes (CMSs), a clinically heterogeneous group of disorders caused by genetic defects leading to an abnormal signal transmission at the endplate. METHODS: We report clinical and molecular data of a multigenerational family in which the presentation of a progressive proximal-distal weakness with ocular involvement led to a number of different clinical diagnoses. RESULTS: A comprehensive genetic study which included whole-genome linkage analysis and whole-exome sequencing identified a heterozygous missense substitution (c.721C>T, p.L241F) in the ε subunit of the acetylcholine receptor (CHRNE) that was consistent with clinical weakness in all patients. DISCUSSION: SCCMS is characterized by a broad and heterogeneous clinical phenotype in which disease onset, symptoms, severity, and progression can be highly variable even between family members. The identification of a CHRNE mutation allowed to make the definitive diagnosis of CMS in this family and contributed to define the clinical spectrum of this disease.

Loss-of-function mutations in the SIGMAR1 gene cause distal hereditary motor neuropathy by impairing ER-mitochondria tethering and Ca2+ signalling.

Distal hereditary motor neuropathies (dHMNs) are clinically and genetically heterogeneous neurological conditions characterized by degeneration of the lower motor neurons. So far, 18 dHMN genes have been identified, however, about 80% of dHMN cases remain without a molecular diagnosis. By a combination of autozygosity mapping, identity-by-descent segment detection and whole-exome sequencing approaches, we identified two novel homozygous mutations in the SIGMAR1 gene (p.E138Q and p.E150K) in two distinct Italian families affected by an autosomal recessive form of HMN. Functional analyses in several neuronal cell lines strongly support the pathogenicity of the mutations and provide insights into the underlying pathomechanisms involving the regulation of ER-mitochondria tethering, Ca2+ homeostasis and autophagy. Indeed, in vitro, both mutations reduce cell viability, the formation of abnormal protein aggregates preventing the correct targeting of sigma-1R protein to the mitochondria-associated ER membrane (MAM) and thus impinging on the global Ca2+ signalling. Our data definitively demonstrate the involvement of SIGMAR1 in motor neuron maintenance and survival by correlating, for the first time in the Caucasian population, mutations in this gene to distal motor dysfunction and highlight the chaperone activity of sigma-1R at the MAM as a critical aspect in dHMN pathology.

Myoimaging in the NGS era: the discovery of a novel mutation in MYH7 in a family with distal myopathy and core-like features--a case report.

BACKGROUND: Myosin heavy chain 7 related myopathies are rare disorders characterized by a wide phenotypic spectrum and heterogeneous pathological features. In the present study, we performed clinical, morphological, genetic and imaging investigations in three relatives affected by autosomal dominant distal myopathy. Whilst earlier traditional Sanger investigations had pointed to the wrong gene as disease causative, next-generation sequencing allowed us to obtain the definitive molecular genetic diagnosis in the family. CASE PRESENTATION: The proposita, being found to harbor a novel heterozygous mutation in the RYR1 gene (p.Glu294Lys), was initially diagnosed with core myopathy. Subsequently, consideration of muscle magnetic resonance imaging (MRI) features and extension of family study led this diagnosis to be questioned. Use of next-generation sequencing analysis identified a novel mutation in the MYH7gene (p.Ser1435Pro) that segregated in the affected family members. CONCLUSIONS: This study identified a novel mutation in MYH7 in a family where the conclusive molecular diagnosis was reached through a complicated path. This case report might raise awareness, among clinicians, of the need to interpret NGS data in combination with muscle MRI patterns so as to facilitate the pinpointing of the main molecular etiology in inherited muscle disorders.

Idiopathic pes cavus in adults is not associated with neurophysiological impairment in the lower limbs.

The nerve conduction characteristics of adults with idiopathic pes cavus/hammer toes have not been studied extensively. Among 2048 out-patients (59.5 ± 13.9 years) referring to a laboratory of Neurophysiology in Rome, we recruited 18 patients with idiopathic pes cavus (61.3 ± 12.5 years). Fifty-four age/sex-matched controls were also studied. No nerve conduction differences were observed between patients with and without cavus foot (p > 0.05). The absence of deep tendon reflexes and slight muscle weakness and hypotrophy in the lower limbs were more common in subjects with cavus foot deformity than in controls (p < 0.001). Adult patients with idiopathic pes cavus/hammer toes do not differ from healthy controls from a neurophysiological standpoint, but they could show minor signs of clinical impairment, such as lower limb weakness, hypotrophy and areflexia.

Electrophysiological abnormalities in iatrogenic botulism: Two case reports and review of the literature.

Therapeutic use of botulinum neurotoxin type A (BoNT/A) is effective, and generally safe. Nevertheless, iatrogenic botulism (IB) is rarely reported as a result of systemic spread of the BoNT/A, causing general weakness, bulbar symptoms and dysautonomia. Suggestive clinical feature are decisive to raise the diagnostic suspicion, which however needs a confirmation in the electrodiagnostic (EDX) study, above all to exclude other treatable diseases. In this study, we report 2 patients who developed IB after receiving therapeutic doses of BoNT/A, assessing the EDX changes, and reviewing the literature on EDX in IB. Although there is not enough data to draw solid conclusions we propose that, in a subject with suggestive clinical features and recent exposure to BoNT/A, the absence of a decremental or incremental response to repetitive nerve stimulation in muscles showing acute denervation changes, is a suggestive finding for the diagnosis of IB.

Impact of Mézières Rehabilitative Method in Patients with Parkinson's Disease: A Randomized Controlled Trial.

The aim of this study was to assess the efficacy of Mézières method in improving trunk flexibility of the back muscles and balance in patients with Parkinson's disease (PD). Materials and Methods. Thirty-six patients were randomized into 2 groups: the Mézières treatment group and the control group (home exercise group). The primary outcome was the improvement in balance per the Berg Balance Scale (BBS) and the trunk flexibility of the back for the anterior flexion trunk test. Also, we evaluated pain, gait balance for the Functional Gait Assessment (FGA), disease-related disability for the Modified Parkinson's Activity Scale and the Unified Parkinson's Disease Rating Scale (UPDRS), the quality of life, and the functional exercise capacity. All the measures were evaluated at baseline (T0), at the end of the rehabilitative program (T1), and at the 12-week follow-up (T2). Results. In the Mézières group, the BBS (p < .001) and trunk flexion test (p < .001) improved significantly at T1 and remained the same at T2. Between groups, significant changes were reported in FGA (p = .027) and UPDRS Total (p = .007) at T1 and in FGA (p = .03) at T2. Conclusion. The Mézières approach is efficacious in improving the flexibility of the trunk and balance in PD patients.

Neuromuscular transmission abnormalities in myotonic dystrophy type 1: A neurophysiological study.

OBJECTIVES: Weakness and fatigue are frequent symptoms in myotonic dystrophy type 1 (DM1), mainly as a result of muscle impairment. However, neuromuscular junction (NMJ) abnormalities could play an additional role in determining these manifestations. We aimed to document the possible NMJ involvement in DM1. PATIENTS AND METHODS: In order to substantiate this hypothesis we performed low rate repetitive nerve stimulation (RNS) and single fiber electromyography (SFEMG), in 14 DM1 subjects. RESULTS: RNS resulted abnormal in four patients while SFEMG revealed a pathological jitter in ten. A significative correlation was found between jitter values and decrementing response (p<0.000311; r=0.822). CONCLUSION: These results suggest a possible involvement of NMJ in DM1.

How genetics affects the brain to produce higher-level dysfunctions in myotonic dystrophy type 1.

Myotonic dystrophy type 1 (DM1) is a multisystemic disorder dominated by muscular impairment and brain dysfunctions. Although brain damage has previously been demonstrated in DM1, its associations with the genetics and clinical/neuropsychological features of the disease are controversial. This study assessed the differential role of gray matter (GM) and white matter (WM) damage in determining higher-level dysfunctions in DM1. Ten patients with genetically confirmed DM1 and 16 healthy How genetics affects the brain to produce higher-level dysfunctions in myotonic dystrophy type 1 matched controls entered the study. The patients underwent a neuropsychological assessment and quantification of CTG triplet expansion. All the subjects underwent MR scanning at 3T, with studies including T1-weighted volumes and diffusion-weighted images. Voxel-based morphometry and tractbased spatial statistics were used for unbiased quantification of regional GM atrophy and WM integrity. The DM1 patients showed widespread involvement of both tissues. The extent of the damage correlated with CTG triplet expansion and cognition. This study supports the idea that genetic abnormalities in DM1mainly target the WM, but GM involvement is also crucial in determining the clinical characteristics of DM1.