Distal hereditary motor neuropathy (dHMN) is a progressive neurological disease characterized by distal limb muscle weakness and amyotrophy. Sigma 1 receptor (σ1R), a gene product of SIGMAR1, mutations have been reported to induce dHMN, but its mechanism remains unknown. This study aims to explore the effect of C238T and 31_50del mutations in σ1R on neuronal SH-SY5Y cell functions. The SH-SY5Y cells that overexpressed σ1R, C238T mutant σ1R (σ1RC238T) or 31_50del mutant σ1R (σ1R31_50del) were constructed by pEGFPN1 vectors. We used Western blot (WB) and immunofluorescence (IF) staining to detect the expression of σ1R and green fluorescent proteins (GFP). Then, we evaluated the impact of σ1R mutation on apoptosis, autophagy, endoplasmic reticulum stress, and the involvement of the unfolded protein response (UPR) pathway in SH-SY5Y cells. We found that σ1RC238T and σ1R31_50del downregulated σ1R and promoted the apoptosis of SH-SY5Y cells. σ1RC238T and σ1R31_50del increased p-PERK, p-eIF2α, p-JNK, BIP, ATF4, CHOP, ATF6, XBP1, Caspase3, Caspase12 expressions and Ca2+ concentration, whereas decreased ATP content in SH-SY5Y cells. Besides, the expressions of LC3B, Lamp1, ATG7, Beclin-1 and phosphorylation of AMPK and ULK1 were increased, while the p62 level decreased after C238T or 31_50del mutation of σ1R. Additionally, AMPK knockdown abolished the apoptosis mediated by σ1RC238T or σ1R31_50del in SH-SY5Y cells. Our results indicated that C238T or 31_50del mutation in σ1R promoted motor neuron apoptosis through the AMPK/ULK1 pathway in dHMN. This study shed light on a better understanding of the neurons pathological mechanisms mediated by σ1R C238T and σ1R 31-50del in dHMN.

The heat-shock protein beta-1 (HSPB1) is one of small heat-shock proteins that play an important role in cell functioning by promoting correct folding of other proteins. The HSPB1 mutations are known to cause distal Hereditary Motor Neuropathy type 2B (dHMN2B) and Charcot-Marie-Tooth disease type 2F (CMT2F). More than 30 different mutations in the HSPB1 have been found in patients with CMT2F and dHMN2B. There are cases of the Thr151Ile HSPB1 mutation described in 4 countries: Croatia, Japan, France and Poland. In this paper we present a Polish family with p.Thr151Ile mutation causing distal hereditary motor neuropathy. A 48-year-old male patient presented progressive bilateral lower limb weakness and gait difficulty of typical onset. The presentation of the disease in his daughter, who carries the same mutation is yet uncertain. She has currently no clinical symptoms of the disease but registered mild muscle damage in EMG with correct conduction parameter in ENG.

Heterozygous RTN2 variants have been previously identified in a limited cohort of families affected by autosomal dominant spastic paraplegia (SPG12-OMIM:604805) with a variable age of onset. Nevertheless, the definitive validity of SPG12 remains to be confidently confirmed due to the scarcity of supporting evidence. In this study, we identified and validated seven novel or ultra-rare homozygous loss-of-function RTN2 variants in 14 individuals from seven consanguineous families with distal hereditary motor neuropathy (dHMN) using exome, genome and Sanger sequencing coupled with deep-phenotyping. All affected individuals (seven males and seven females, aged 9-50 years) exhibited weakness in the distal upper and lower limbs, lower limb spasticity and hyperreflexia, with onset in the first decade of life. Nerve conduction studies revealed axonal motor neuropathy with neurogenic changes in the electromyography. Despite a slowly progressive disease course, all patients remained ambulatory over a mean disease duration of 19.71 ± 13.70 years. Characterization of Caenorhabditis elegans RTN2 homologous loss-of-function variants demonstrated morphological and behavioural differences compared with the parental strain. Treatment of the mutant with an endoplasmic/sarcoplasmic reticulum Ca2+ reuptake inhibitor (2,5-di-tert-butylhydroquinone) rescued key phenotypic differences, suggesting a potential therapeutic benefit for RTN2-disorder. Despite RTN2 being an endoplasmic reticulum (ER)-resident membrane shaping protein, our analysis of patient fibroblast cells did not find significant alterations in ER structure or the response to ER stress. Our findings delineate a distinct form of autosomal recessive dHMN with pyramidal features associated with RTN2 deficiency. This phenotype shares similarities with SIGMAR1-related dHMN and Silver-like syndromes, providing valuable insights into the clinical spectrum and potential therapeutic strategies for RTN2-related dHMN.

Biallelic mutations in the sorbitol dehydrogenase (SORD) gene have been identified as a genetic cause of autosomal recessive axonal Charcot-Marie-Tooth disease 2 (CMT2) and distal hereditary motor neuropathy (dHMN). We herein review the main phenotypes associated with SORD mutations and report the case of a 16-year-old man who was referred to our outpatient clinic for a slowly worsening gait disorder with wasting and weakness of distal lower limbs musculature. Since creatine phosphokinase (CPK) values were persistently raised (1.5fold increased) and a Next-Generation Sequencing CMT-associated panel failed in identifying pathogenic variants, a muscle biopsy was performed with evidence of alterations suggestive of a protein surplus distal myopathy. Finally, Whole-Exome Sequencing (WES) identified two pathogenic SORD variants in the heterozygous state: c.458C > A (p.Ala153Asp) and c.757delG (p.Ala253Glnfs*27). This is an isolated report of compound heterozygosity for two SORD mutations associated with clinical and histological signs of skeletal muscle involvement, expanding the phenotypic expression of SORD mutations.

Hereditary motor neuropathies (HMN) were first defined as a group of neuromuscular disorders characterized by lower motor neuron dysfunction, slowly progressive length-dependent distal muscle weakness and atrophy, without sensory involvement. Their cumulative estimated prevalence is 2.14/100 000 and, to date, around 30 causative genes have been identified with autosomal dominant, recessive,and X-linked inheritance. Despite the advances of next generation sequencing, more than 60% of patients with HMN remain genetically uncharacterized. Of note, we are increasingly aware of the broad range of phenotypes caused by pathogenic variants in the same gene and of the considerable clinical and genetic overlap between HMN and other conditions, such as Charcot-Marie-Tooth type 2 (axonal), spinal muscular atrophy with lower extremities predominance, neurogenic arthrogryposis multiplex congenita and juvenile amyotrophic lateral sclerosis. Considering that most HMN present during childhood, in this review we primarily aim to summarize key clinical features of paediatric forms, including recent data on novel phenotypes, to help guide differential diagnosis and genetic testing. Second, we describe newly identified causative genes and molecular mechanisms, and discuss how the discovery of these is changing the paradigm through which we approach this group of conditions.

Mutations in HSPB1 are known to cause Charcot-Marie-Tooth disease type 2F (CMT2F) and distal hereditary motor neuropathy (dHMN). In this study, we presented three patients with mutation in HSPB1 who were diagnosed with dHMN. Proband 1 was a 14-year-old male with progressive bilateral lower limb weakness and walking difficulty for four years. Proband 2 was a 65-year-old male with chronic lower limb weakness and restless legs syndrome from the age of 51. Proband 3 was a 50-year-old female with progressive weakness, lower limbs atrophy from the age of 44. The nerve conduction studies (NCS) suggested axonal degeneration of the peripheral motor nerves and needle electromyography (EMG) revealed chronic neurogenic changes in probands. Open sural nerve biopsy for proband 2 and the mother of proband 1 showed mild to moderate loss of myelinated nerve fibers with some nerve fiber regeneration. A novel p.V97L in HSPB1 was identified in proband 3, the other two variants (p.P182A and p.R127W) in HSPB1 have been reported previously. The functional studies showed that expressing mutant p.V97L HSPB1 in SH-SY5Y cells displayed a decreased cell activity and increased apoptosis under stress condition. Our study expands the clinical phenotypic spectrum and etiological spectrum of HSPB1 mutation.

The distal hereditary motor neuropathies (dHMN) encompass a group of peripheral nervous system disorders characterized by progressive distal predominant weakness and wasting, usually in a length-dependent pattern. The classical neurophysiological pattern is a motor axonal neuropathy with chronic distal denervation/reinnervation on needle examination. Conduction block (CB) and temporal dispersion (TD) are electrophysiological features classically associated with acquired demyelinating neuropathies. Although they have rarely been reported in hereditary neuropathies, to date they have not been described in dHMN. We report a sporadic case of a patient with neurophysiological criteria consistent with multifocal motor neuropathy with CB (MMN) refractory to immunomodulation. WES revealed a homozygous nonsense pathogenic variant in sigma nonopioid intracellular receptor-1 gene (SIGMAR1). SIGMAR1-related disorders have been reported with distinctive features suggesting it is not a typical length-dependent neuropathy. Nevertheless, CB and TD are unexpected and as far as we have known not been described previously in such patients. This case expands the neurophysiological spectrum of this disease and alerts clinicians to this acquired demyelinating motor neuropathy mimic.

Autosomal recessive axonal neuropathy with neuromyotonia (ARAN-NM) is a rare hereditary neuropathy within the Charcot-Marie-Tooth disease (CMT) spectrum, linked to mutations in the histidine triad nucleotide-binding protein 1 (HINT1) gene. HINT1-related neuropathy is particularly common in selected populations from Central and Eastern Europe but rare in Western European cohorts. It has not been investigated to date in the Greek population. We presently investigated the frequency of HINT1-neuropathy in a selected cohort of 42 Greek index patients with autosomal recessive or sporadic axonal hereditary neuropathy according to standard molecular genetics procedures. We identified 4 patients with biallelic mutations in HINT1, comprising 9.5% of all cases and 44.4% of cases also displaying neuromyotonia. The c.110G> C (p.Arg37Pro) HINT1 mutation was present in all cases (2 homozygous) and the c.250T> C (p.Cys84Arg) in 2 cases (compound heterozygous). HINT1-related neuropathy patients were characterized by early onset and neuromyotonia. Two patients had noteworthy clinical features, one case developing myoclonic epilepsy and the other displaying \"adducted thumbs.\" We conclude that HINT1-related neuropathy is common in selected Greek patients with hereditary neuropathy within the CMT spectrum, in accordance with some, but not all, European populations.

Mutations in the DCTN1 gene have been found in patients with various neurodegenerative diseases, and the spectrum is still expanding. Here, we report a mutation in DCTN1 (c.175G > C, p.G59R) identified in two patients, who manifested dHMN and ALS, respectively, in an affected family. The clinical manifestations and eightyear follow-up suggested that this mutation is pathogenic. The phenomena observed in this family with the same DCTN1 mutation illustrate the clinical heterogeneity of DCTN1 gene mutations and expand our understanding of their genotype-phenotype relationships. Further research and functional experiments, especially mutation at amino acid position 59 of DCTN1, are required.

Introduction: Charcot-Marie-Tooth disease (CMT) and related neuropathies represent the most prevalent inherited neuromuscular disorders. Nonetheless, there is still no pharmacological treatment available for any CMT type. However, the landscape is rapidly evolving and several novel approaches are providing encouraging results in preclinical studies and leading to clinical trials.Areas covered: The authors review the most promising therapies under study and the ongoing/planned clinical trials. Several approaches to address PMP22 overexpression underlying CMT1A, the most frequent subtype, are being tested. Gene silencing, targeting PMP22, and gene therapy, to introduce specific genes or to substitute or modulate defective ones, are being experimented in animal models. Compounds acting on ER stress, unfolded protein response, neuregulin pathways, phosphoinositides metabolism, axonal transport and degeneration, inflammation, polyol pathway, deoxysphingolipid metabolism, purine nucleotide pool are potential therapeutic candidates for different forms of CMT and related neuropathies.Expert opinion: We are getting closer to find effective therapies for CMT, but are far behind the exciting examples of other genetic neuromuscular disorders. The authors analyze the possible reasons for this gap and the way to fill it. Preclinical and clinical research is ongoing with coordinated efforts and they are confident that in the next few years we will see the first effective treatments.