Hereditary Neuropathy Research Articles

Biallelic variants in WARS1 cause a highly variable neurodevelopmental syndrome and implicate a critical exon for normal auditory function.

Aminoacyl-tRNA synthetases (ARSs) are essential enzymes for faithful assignment of amino acids to their cognate tRNA. Variants in ARS genes are frequently associated with clinically heterogeneous phenotypes in humans and follow both autosomal dominant or recessive inheritance patterns in many instances. Variants in tryptophanyl-tRNA synthetase 1 (WARS1) cause autosomal dominantly inherited distal hereditary motor neuropathy and Charcot-Marie-Tooth disease. Presently, only one family with biallelic WARS1 variants has been described. We present three affected individuals from two families with biallelic variants (p.Met1? and p.(Asp419Asn)) in WARS1, showing varying severities of developmental delay and intellectual disability. Hearing impairment and microcephaly, as well as abnormalities of the brain, skeletal system, movement/gait, and behavior were variable features. Phenotyping of knocked down wars-1 in a Caenorhabditis elegans model showed depletion is associated with defects in germ cell development. A wars1 knockout vertebrate model recapitulates the human clinical phenotypes, confirms variant pathogenicity, and uncovers evidence implicating the p.Met1? variant as potentially impacting an exon critical for normal hearing. Together, our findings provide consolidating evidence for biallelic disruption of WARS1 as causal for an autosomal recessive neurodevelopmental syndrome and present a vertebrate model that recapitulates key phenotypes observed in patients.

WARS1 and SARS1: Two tRNA synthetases implicated in autosomal recessive microcephaly.

Aminoacylation of transfer RNA(tRNA) is a key step in protein biosynthesis, carried out by highly specific aminoacyl-tRNA synthetases (ARSs). ARSs have been implicated in autosomal dominant and autosomal recessive human disorders. Autosomal dominant variants in tryptophanyl-tRNA synthetase 1 (WARS1) are known to cause distal hereditary motor neuropathy and Charcot-Marie-Tooth disease, but a recessively inherited phenotype is yet to be clearly defined. Seryl-tRNA synthetase 1 (SARS1) has rarely been implicated in an autosomal recessive developmental disorder. Here, we report five individuals with biallelic missense variants in WARS1 or SARS1, who presented with an overlapping phenotype of microcephaly, developmental delay, intellectual disability, and brain anomalies. Structural mapping showed that the SARS1 variant is located directly within the enzyme's active site, most likely diminishing activity, while the WARS1 variant is located in the N-terminal domain. We further characterize the identified WARS1 variant by showing that it negatively impacts protein abundance and is unable to rescue the phenotype of a CRISPR/Cas9 wars1 knockout zebrafish model. In summary, we describe two overlapping autosomal recessive syndromes caused by variants in WARS1 and SARS1, present functional insights into the pathogenesis of the WARS1-related syndrome and define an emerging disease spectrum: ARS-related developmental disorders with or without microcephaly.

Peripheral Myelin Protein 22 Gene Mutations in Charcot-Marie-Tooth Disease Type 1E Patients.

Duplication and deletion of the peripheral myelin protein 22 (PMP22) gene cause Charcot-Marie-Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP), respectively, while point mutations or small insertions and deletions (indels) usually cause CMT type 1E (CMT1E) or HNPP. This study was performed to identify PMP22 mutations and to analyze the genotype–phenotype correlation in Korean CMT families. By the application of whole-exome sequencing (WES) and targeted gene panel sequencing (TS), we identified 14 pathogenic or likely pathogenic PMP22 mutations in 21 families out of 850 CMT families who were negative for 17p12 (PMP22) duplication. Most mutations were located in the well-conserved transmembrane domains. Of these, eight mutations were not reported in other populations. High frequencies of de novo mutations were observed, and the mutation sites of c.68C>G and c.215C>T were suggested as the mutational hotspots. Affected individuals showed an early onset-severe phenotype and late onset-mild phenotype, and more than 40% of the CMT1E patients showed hearing loss. Physical and electrophysiological symptoms of the CMT1E patients were more severely damaged than those of CMT1A while similar to CMT1B caused by MPZ mutations. Our results will be useful for the reference data of Korean CMT1E and the molecular diagnosis of CMT1 with or without hearing loss.

A Rare Phenotype of Uncommon Charcot-Marie-Tooth Genotypes Complicated With Inflammation Evaluated by Genetics and Magnetic Resonance Neurography.

The pathogenesis of Charcot–Marie–Tooth (CMT) disease, an inherited peripheral neuropathy, is associated with more than 60 nuclear genes. We reported a rare phenotype of the uncommon CMT genotype complicated with neuroinflammation, that is, an MPZ mutation, NC_000001.11 (NM_000530.6): c.308G > C detected by next-generation sequencing. Moreover, we present a case of the CMT type 1B, with atypical presentation as two patterns of hypertrophy in the brachial and lumbosacral plexus, as well as enhancement in the cauda equina and nerve roots on multimodal magnetic resonance neurography (MRN). MRN assessment facilitated the identification of coexisting neuroinflammation and provided more evidence, especially for patients with atypical symptoms in hereditary sensory and motor neuropathy, who could benefit from immunotherapy.

KCC3a, a Strong Candidate Pathway for K+ Loss in Alkalemia

Loss-of-function mutations in the human potassium chloride cotransporter-3 (KCC3) cause a hereditary motor sensory neuropathy associated with agenesis of the corpus callosum. While recapitulating the neuropathy, KCC3-knockout mice also exhibit high blood pressure. This phenotype is believed to have neurogenic and/or vascular origins. The role of KCC3 in the kidney is poorly understood. KCC3 is encoded by two major isoforms originating from alternative promoters: KCC3a and KCC3b, with KCC3b being the predominant transcript in the kidney. Although the transporter has previously been localized to the proximal tubule, we show here the unique expression of the KCC3a isoform in the connecting tubule. Using a KCC3a-specific polyclonal antibody validated for both immunofluorescence and immunoblotting, we showed an intense KCC3a signal restricted to cortical intercalated cells. No overlap is detected between KCC3a and sodium chloride cotransporter (NCC), a distal convoluted tubule (DCT) marker; or between KCC3a and ENaC or calbindin, which are both principal cell markers. KCC3a signal was observed in cells expressing the apical V-ATPase and pendrin, establishing a unique expression pattern characteristic of intercalated cells of type-B or type-nonA/nonB. We further show that treatment of wild-type mice with hydrochlorothiazide, amiloride, or fed a K+-deficient diet up-regulates KCC3a level, suggesting that volume depletion increases KCC3a abundance. This hypothesis was confirmed by showing a higher abundance of KCC3a protein after 23-h water restriction or after placing the mice on a low-salt diet. More importantly, abundance of the Cl−/HCO3 − exchanger, pendrin, which is known to secrete bicarbonate in alkalotic conditions, was significantly diminished in KCC3-knockout mice. In addition, KCC3a abundance increased significantly alongside pendrin abundance in bicarbonate-treated alkalotic mice, providing a credible mechanism for K+ loss in metabolic alkalosis.

Alpha-1 Antitrypsin Reduces Disease Progression in a Mouse Model of Charcot-Marie-Tooth Type 1A: A Role for Decreased Inflammation and ADAM-17 Inhibition

Charcot-Marie-Tooth disease type 1 (CMT1A) is a hereditary peripheral neuropathy for which there is no available therapy. Alpha-1 antitrypsin (AAT) is an abundant serine protease inhibitor with anti-inflammatory and immunomodulating properties. Here, we tested whether treatment with human AAT (hAAT) would have a therapeutic effect on CMT1A in a PMP22 transgenic mouse model. Our results show that hAAT significantly improved compound muscle action potential and histopathological features and decreased circulating IL-6 in CMT1A mice. We also investigated some of the possible underlying mechanisms in vitro. We confirmed that hAAT inhibits ADAM-17, a protease that has been implicated in blocking myelination. Furthermore, both hAAT and recombinant human AAT (rhAAT) were able to attenuate the activation of a macrophage/microglia cell line, markedly decreasing the activation of the MHC class II promoter and the expression of pro-inflammatory genes such as IL-1β and the endoplasmic reticulum (ER) stress marker ATF3. Taken together, our results demonstrate for the first time that hAAT is able to reduce the progression of CMT1A, possibly by dampening inflammation and by regulating ADAM-17. Given the already well-established safety profile of hAAT, specifically in AAT deficiency disease (AATD), we suggest that the findings of our study should be promptly investigated in CMT1A patients.

Keratoconus associated with hereditary sensory and autonomic neuropathy II.

Keratoconus associated with hereditary sensory and autonomic neuropathy II.

Novel heterozygous variants of SLC12A6 in Japanese families with Charcot-Marie-Tooth disease.

BackgroundRecessive mutations in SLC12A6 have been linked to hereditary motor sensory neuropathy with agenesis of the corpus callosum. Patients with early‐onset peripheral neuropathy associated with SLC12A6 heterozygous variants were reported in 2016. Only five families and three variants have been reported to date, and the spectrum is unclear. Here, we aim to describe the clinical and mutation spectra of SLC12A6‐related Charcot–Marie–Tooth (CMT) disease in Japanese patients.MethodsWe extracted SLC12A6 variants from our DNA microarray and targeted resequencing data obtained from 2598 patients with clinically suspected CMT who were referred to our genetic laboratory by neurological or neuropediatric departments across Japan. And we summarized the clinical and genetic features of these patients.ResultsIn seven unrelated families, we identified one previously reported and three novel likely pathogenic SLC12A6 heterozygous variants, as well as two variants of uncertain significance. The mean age of onset for these patients was 17.5 ± 16.1 years. Regarding electrophysiology, the median motor nerve conduction velocity was 39.6 ± 9.5 m/sec. For the first time, we observed intellectual disability in three patients. One patient developed epilepsy, and her brain MRI revealed frontal and temporal lobe atrophy without changes in white matter and corpus callosum.ConclusionsScreening for the SLC12A6 gene should be considered in patients with CMT, particularly those with central nervous system lesions, such as cognitive impairment and epilepsy, regardless of the CMT subtype.

Genetic pain loss disorders.

Genetic pain loss includes congenital insensitivity to pain (CIP), hereditary sensory neuropathies and, if autonomic nerves are involved, hereditary sensory and autonomic neuropathy (HSAN). This heterogeneous group of disorders highlights the essential role of nociception in protecting against tissue damage. Patients with genetic pain loss have recurrent injuries, burns and poorly healing wounds as disease hallmarks. CIP and HSAN are caused by pathogenic genetic variants in >20 genes that lead to developmental defects, neurodegeneration or altered neuronal excitability of peripheral damage-sensing neurons. These genetic variants lead to hyperactivity of sodium channels, disturbed haem metabolism, altered clathrin-mediated transport and impaired gene regulatory mechanisms affecting epigenetic marks, long non-coding RNAs and repetitive elements. Therapies for pain loss disorders are mainly symptomatic but the first targeted therapies are being tested. Conversely, chronic pain remains one of the greatest unresolved medical challenges, and the genes and mechanisms associated with pain loss offer new targets for analgesics. Given the progress that has been made, the coming years are promising both in terms of targeted treatments for pain loss disorders and the development of innovative pain medicines based on knowledge of these genetic diseases.

Analysis of a pedigree with distal hereditary motor neuropathy type 2A caused by mutation in HSPB8 gene

To explore phenotypic and mutational characteristics of a pedigree with distal hereditary motor neuropathy (dHMN). Clinical data of the proband and her family members was collected. Electrophysiology, muscle biopsy and whole exome sequencing were carried out for the proband. Patients of the family mainly presented with distal lower limb weakness. Electrophysiological test of the proband revealed distal motor neuropathy and sensory nerves were normal. Muscle biopsy suggested neurogenic atrophy of muscle fibers. Genetic analysis revealed a heterozygous c.421A>G (p.K141E) mutation in exon 2 of the HSPB8 gene, which was a hot spot mutation. This family was the first reported HSPB8 related dHMN2A in Chinese population, and p.K141E was the causative mutation, which enriched the mutational spectrum of dHMN in China.

Hereditary neuropathy with liability to pressure palsies (HNPP): Intrafamilial phenotypic variability and early childhood refusal to walk as the presenting symptom

BackgroundLimping and/or refusal to walk is a common complaint in the setting of the pediatric department, with a widely diverse differential diagnosis. An unusual etiology, is that of a hereditary neuropathy.Hereditary neuropathy with liability to pressure palsies (HNPP) is a recurrent, episodic demyelinating neuropathy, most commonly caused by a 17p11.2 chromosomal deletion encompassing the PMP22 gene.MethodsWe pursued chromosomal microarray analysis (CMA) in multiple affected individuals of a single extended family, manifesting a range of phenotypic features consistent with HNPP.ResultsA 4.5 years-old boy presented for in-patient evaluation due to refusal to walk. Initial investigations including spine MRI and bone scan failed to yield a conclusive diagnosis. Following family history, which implied an autosomal dominant mode of inheritance, CMA was pursued and confirmed a 17p11.2 deletion in the proband consistent with HNPP. Importantly, following this diagnosis, four additional affected family members were demonstrated to harbor the deletion. Their variable phenotypic features, ranging from a prenatal diagnosis of a 6 months-old sibling, to recurrent paresthesias manifesting in the fourth decade of life, are discussed.ConclusionsOur experience with the family reported herein demonstrates how a thorough anamnesis can lead to a rare genetic etiology with a favorable prognosis and prevent unnecessary investigations, and underscores HNPP as an uncommon diagnostic possibility in the limping child.

Candidate imaging biomarkers for PMP22-related inherited neuropathies.

ObjectiveCharcot–Marie–Tooth type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsy (HNPP) are caused by mutations to the peripheral myelin protein 22 (PMP22) gene. A need exists for sensitive and reliable biomarkers of progression and treatment response. Magnetic resonance imaging (MRI) metrics of nerve pathology and morphology were investigated for this purpose.MethodsMRI was performed at 3.0 T in the thigh of CMT1A (N = 11) and HNPP patients (N = 12) and controls (N = 23). Three potential imaging biomarkers of the sciatic nerve were investigated: 1) magnetization transfer ratio (MTR), which assays myelin content, and 2) cross‐sectional area (CSA) and 3) circularity, which assay morphological changes. Potential imaging biomarkers were compared across cohorts and assessed for relationships with disability in the legs (CMTESL), compound motor action potentials (CMAP), and motor conduction velocities (MCV). Inter‐rater reliability and test–retest repeatability were established for each imaging metric.ResultsSignificant differences in MTR, CSA, and circularity were observed in CMT1A relative to controls (p = 0.02, p < 0.001, and p = 0.003, respectively, via Wilcoxon rank‐sum tests). Differences were not observed in the HNPP cohort. Significant relationships were observed between MTR and clinical metrics (CMTESL: p = 0.003, CMAP: p = 0.03, MCV: p = 0.01); and between CSA and electrophysiology (CMAP: p = 0.002, MCV: p < 0.001). All metrics were reliable and repeatable with MTR the most reliable (intraclass correlation coefficient [ICC] >0.999, CV = 0.30%) and repeatable (ICC = 0.84, CV = 3.16%).InterpretationMTR, CSA, and circularity showed promise as reliable and sensitive biomarkers of CMT1A, but not HNPP. These warrant longitudinal investigation as response biomarkers in upcoming clinical trials of CMT1A, while other methods should be considered for HNPP.

Charcot-Marie-Tooth disease secondary to biallelic mutations in SORD

IntroductionSORD is a newly described autosomal recessive gene that is emerging as the commonest cause of autosomal recessive CMT (Charcot-Marie-Tooth disease) and hereditary motor neuropathy (HMN).MethodsWe present nine cases of SORD-related neuropathy.ResultsNine unrelated patients were found to have biallelic mutations in SORD. Eight were male (89%) and median age of assessment was 34 years (range 18–55 years). Median age of symptom onset was 15 years (range 12–18 years) and all patients initially presented with difficulty walking and/or problems involving distal lower limbs. Only one patient (11%) had sensory symptoms. 5/9 (56%) had distal upper limb weakness and all had distal lower limb weakness. Sensory examination was abnormal to at least one modality in 7/9 cases (78%). The median CMT Examination and CMT Neuropathy Scores were 6 (range 2–12) and 7.5 (range 3–14) respectively. Neurophysiology showed conduction velocities in the axonal or intermediate ranges in all cases. Clinical diagnosis was distal HMN in 5/9 (56%), CMT2 in 2/9 (22%) and CMT intermediate in 2/9 (22%).ConclusionsThe SORD phenotype is typically a slowly progressive, length-dependent motor neuropathy of onset during the second decade. Sensory symptoms are rare and sensory signs minimal.chris.record@ucl.ac.uk

100 All that glitters is not GARS

BackgroundA 22-year-old woman was initially assessed in the context of a family history of distal wasting and weakness, typically with upper limb onset, then lower limb involvement. When assessed as a child her phenotype was recognised to be atypical compared to her sister, but she was thought to be affected. Ultimately the family was diagnosed with distal hereditary motor neuropathy due to a GARS mutation. However, this patient did not carry the mutation, prompting further evaluation.CaseAt age 11 the left foot was smaller with some toe clawing and cavus deformity. Left sided wasting of tibialis anterior and the posterior compartment was seen, ankle dorsiflexors were grade 3.ResultsNerve conduction studies and EMG were normal in the right leg and arms. Chronic denervation was identified in L4, L5 and S1. MRI of lumbar spine was normal. However, 2 areas of marked thickening and enhancement were seen in the left sciatic nerve in the upper thigh and a further lesion in the mid- thigh. Fascicular preservation of the nerve was felt to be strongly suggestive of a perineurioma.DiscussionThis case highlights the importance of careful phenotyping when validating novel variants in potentially causative genes.c.doherty@ucl.ac.uk

Biallelic mutations in sord are a common cause of potentially treatable genetic neuropathy

IntroductionAs opposed to CMT1, for which over 90% of cases have mutations in known genes, only 20–30% of CMT2/dHMN patients receive a genetic diagnosis. Since up to 70% of CMT2 and dHMN cases are sporadic, identifying candidate pathogenic genes from single cases remains challenging also for next-generation sequencing techniques.MethodsWe took advantage of the largest collection of over 1,100 CMT patients in whom WES and/or WGS has been performed in the GENESIS analysis platform. We specifically looked for genes for which significant DNA variants are present in multiple families as well as for individual alleles overrepresented in CMT cases.ResultsWe identified 45 cases from 38 families across multiple ethnicities, carrying a particular nonsense mutation in SORD, c.753delG;p.Ala253GlnfsTer27, either in homozygous or compound heterozygous state with a second variant. With an allele frequency of 0.004 in healthy controls, the p.Ala253GlnfsTer27 variant represents one of the most common pathogenic alleles in humans. SORD is an enzyme that converts sorbitol into fructose, in the two-step polyol pathway that has been implicated in diabetic neuropathy. In patient-derived fibroblasts, we find a complete loss of SORD protein and increased intracellular sorbitol. Also, as a biomarker, serum fasting sorbitol level was over 100 times higher in patients compared to healthy individuals. In Drosophila, we show that loss of SORD orthologues causes synaptic degeneration and progressive motor impairment. Reducing the polyol influx by treatment with aldose reductase inhibi- tors normalized intracellular sorbitol levels in patient fibroblasts and in Drosophila, and also dramatically ameliorated motor and eye phenotypes.ConclusionsWe demonstrate biallelic mutations in sorbitol dehydrogenase (SORD) as the most frequent recessive form of hereditary neuropathies. These findings establish a potentially treatable cause in a sig- nificant fraction of patients with inherited neuropathies and may contribute to a better understanding of the pathophysiology of diabetic neuropathy.andrea.cortese@ucl.ac.uk

Blood biomarkers of peripheral neuropathy.

Traditionally, neurophysiology is the primary diagnostic and prognostic biomarker in peripheral neuropathy clinical practice; however, it may lack responsiveness in the context of slowly progressive neuropathies and where there is significant axonal damage. The development of ultrasensitive platforms for measuring serum proteins at the lower limit of detection of traditional ELISA techniques has transformed the field of blood biomarkers of peripheral neuropathy. A variety of blood biomarkers have been identified from inflammatory cytokines and apokines in diabetic neuropathy through to neuron-specific proteins such as neurofilament light chain, Schwann cell-specific proteins such as TMPRSS5 and microRNAs in other acquired and hereditary neuropathies. In this article, we review blood biomarkers of disease activity for the common subtypes of peripheral neuropathy including inflammatory demyelinating neuropathies, vasculitic neuropathy, diabetic neuropathy, chemotherapy-induced neuropathy and Charcot-Marie-Tooth disease and related disorders including TTR amyloidosis.

Neurological update: hereditary neuropathies

In this update, we review the recent discovery of autosomal recessive variants in sorbitol dehydrogenase as one of the commonest and potentially treatable causes of hereditary motor neuropathy and CMT2. We also report on recent therapeutic advances in hereditary neuropathy including the use of lipid nanoparticle sequestered antisense oligonucleotides in CMT1A and lipid nanoparticle delivered CRISPR-Cas9 gene editing in ATTR amyloidosis.

Distinct Phenotypic and microRNA Expression in X-Linked Charcot–Marie–Tooth Correlated with a Novel Mutation in the GJB1 Gene

We investigated genetic and clinical features in two siblings with an unreported frameshift mutation in the GJB1 gene, encoding connexin 32, to study CMTX-1 and its intrafamilial phenotypic variability. Connexin 32 is a gap junction protein that is located in paranodal regions and Schmidt–Lanterman incisures. Clinical features, family history, and genetic and microRNA information were collected. Genetic analysis determination was performed on genomic DNA from the two cases. Muscle-specific miR-206 was also investigated in serum. A muscle biopsy was conducted in one case, and EMG with conduction velocities was performed in both patients. In the first genetic analysis, no duplication of the PMP22 gene was found. A second genetic analysis of a panel of genes associated with inherited peripheral neuropathies was performed. We found a frameshift mutation in the connexin 32 (GJB1) gene, c.281_287del in hemizygosity, not previously reported, that segregated with the clinical phenotype. An X-linked hereditary sensory motor neuropathy was caused by the mutation in the connexin 32 gene. We found overexpression of miR-206 that was 4-fold up-regulated in the older brother and over 10-fold in the younger brother versus the controls; this might be correlated with a different muscle mass and regeneration. The two siblings presented differently evolving neuropathies due to environmental factors and lifestyles that caused nerve degeneration. We hypothesized that in this X-linked CMT, there is no expression of a truncated connexin 32 (Cx32) protein, with loss of function markedly reduced in the gap junction. In the peripheral nervous system (PNS), this might be mitigated by the presence of another connexin, Cx43. Such a reduction might affect not only gap junction formation but also myelination and muscle trophism, resulting in variable miR-206 expressivity.

Different electrophysiology patterns in GNE myopathy

BackgroundGNE myopathy is a rare distal myopathy caused by mutations of the GNE gene. A few cases of GNE myopathy accompanied by neurogenic features of electrophysiology mimicking hereditary motor neuropathy were reported recently. We confirmed this feature and described the clinical phenotype and mutations of GNE myopathy in these rare cases.ResultsThe absence of lower limb tendon reflexes, decreased compound muscle action potentials in lower leg motor nerves, and neurogenic pattern of electromyography suggested neuropathy in four patients. However, muscle pathology revealed a predominantly myogenic pattern. The follow-up electroneurography results implied that the compound motor action potential amplitudes deteriorated over time. Next-generation sequencing identified three novel variants of the GNE gene, c.2054T > C (p.Val685Ala), c.424G > A (p.Gly142Arg) and c.944T > C (p.Phe315Ser), as well as two hotspot mutations, c.115C > T(p.Arg39*) and c.620A > T(p.Asp207Val), in these patients. These novel mutations cosegregated with disease in the family.ConclusionsThese rare cases supported the existence of neurogenic features of electrophysiology different from the typical myopathic pattern of GNE myopathy.

Myasthenia gravis coexisting with HINT1-related motor axonal neuropathy without neuromyotonia: a case report

BackgroundHINT1 mutations cause an autosomal recessive axonal neuropathy with neuromyotonia. This is a first case report of coexistence of myasthenia gravis (MG) and HINT1-related motor axonal neuropathy without neuromyotonia.Case presentationA 32-year-old woman presented with recurrent ptosis for 8 years, diplopia for 2 years and limb weakness for 1 year and a half. Neostigmine test, elevated AChR antibody level and positive repetitive nerve stimulation supported the diagnosis of MG. Electroneurography (ENG) and electromyography (EMG) examinations revealed a motor axonal neuropathy without neuromyotonic or myokymic discharges. Next-generation sequencing and Sanger sequencing were performed to identify the gene responsible for suspected hereditary neuropathy. Genetic testing for a HINT1 mutation was performed and revealed a homozygous mutation at c.278G>T (p. G93V). The patient was treated with pyridostigmine, oral prednisolone and azathioprine. Her ptosis and diplopia have significantly improved at 6-month follow-up.ConclusionsConcurrence of MG and hereditary motor axonal neuropathy without neuromyotonia is quite rare. Detection of ptosis with or without ophthalmoplegia, distribution of limb weakness, and reflex can help in recognizing the combination of MG and peripheral neuropathy. Early diagnosis is important for initial treatment and prognosis. The novel homozygous variant c.278G>T(p.G93V) contributes to the pathogenic variants spectrum of the HINT1 gene.