A novel Lys141Thr mutation in small heat shock protein 22 (HSPB8) gene in Charcot–Marie–Tooth disease type 2L

Charcot–Marie–Tooth disease (CMT) is a group of clinically and genetically heterogeneous peripheral neuropathies. HSPB8 gene encodes heat shock protein 22 (HSP22) which belongs to the superfamily of small stress induced proteins. Mutations in HSPB8 are implicated to CMT2L and distal hereditary motor neuropathy 2A (dHMN2A). All three reported HSPB8 mutations are interestingly located in the Lys141 residue. In the present study, we examined a Korean axonal CMT patient who presented distal limb atrophy, sensory loss, areflexia, and axonal loss of large myelinated fibers. Whole exome sequencing identified a novel missense mutation c.422A>C (p.Lys141Thr) in HSPB8 as the underlying cause of the CMT2 patient. The mutation was regarded as a de novo case because both unaffected parents have no such mutation. The patient with HSPB8 mutation is the first case in Koreans. Clinical heterogeneities have been revealed in patients with Lys141 mutation; the present patient revealed similar phenotype of CMT2L. In addition, the lower limb MRI revealed a similarity between our HSPB8 and HSPB1 patients. It seems that the Lys141 site in the alpha-crystallin domain of HSPB8 is regarded as a mutational hot spot for peripheral neuropathy development, and mutations even in the same codon can exhibit different CMT phenotypes.     

The first Japanese case of Charcot–Marie–Tooth disease type 4H with a novel FGD4 c.837-1G>A mutation

Charcot–Marie–Tooth disease type 4H (CMT4H) is an autosomal recessive demyelinating neuropathy. It presents as infancy or early childhood-onset neuropathy associated with FGD4 mutations. Clinically it causes predominantly distal muscle weakness. On nerve biopsy examination, myelin outfoldings are seen. The previous case reports have been from regions bordering the Mediterranean, as well as a family from Northern Ireland. This paper presents the detailed clinical course of the first reported case of CMT4H in a Japanese woman. The patient showed mild weakness without scoliosis and a severe sensory disturbance; her functional impairment was less severe than the previously published cases. In addition, a novel homozygous FGD4 c.837-1G>A mutation was identified in this patient.     

Clinical features of a family with late-onset distal hereditary motor neuropathy harboring p.Pro39Leu variant of HSPB1

Background and Aims

Pathogenic variants of HSPB1, the gene encoding the small heat shock protein 27, have been reported to cause autosomal dominant distal hereditary motor neuropathy (dHMN) type II and autosomal dominant Charcot–Marie-Tooth (CMT) disease with minimal sensory involvement (CMT2F). This study aimed to describe the clinical features of patients in a family with late-onset dHMN carrying the Pro39Leu variant of HSPB1.

Methods

Whole-exome sequence analysis identified a heterozygous pathogenic variant (Pro39Leu) of HSPB1 in the proband. The presence of the HSPB1 Pro39Leu variant in two affected individuals was confirmed using direct nucleotide sequence analysis.

Results

Both patients exhibited distal muscle weakness with lower extremity predominance and no obvious sensory deficits, leading to a clinical diagnosis of late-onset dHMN. Nerve conduction studies (NCSs) revealed a subclinical complication of sensory disturbance in one of the patients. The clinical and electrophysiological findings of patients with the HSPB1 Pro39Leu variant in this study and previous reports are summarized.

Interpretation

This study suggests that the clinical spectrum of patients carrying HSPB1 Pro39Leu variants, especially the disease onset, might be broader than expected, and HSPB1 variants should be considered in patients diagnosed with late-onset dHMN. Furthermore, patients with dHMN may have concomitant sensory deficits that should be evaluated using NCSs.     

Late onset dHMN II caused by c.404C>G mutation in HSPB1 gene

Distal hereditary motor neuropathy (dHMN) type II is genetically heterogeneous. We report three siblings of a German family with late onset distal motor neuropathy due to the c.404C>G mutation in heat‐shock 27‐kDa protein 1 gene (HSPB1/HSP27). A 36‐year‐old mutation carrier, daughter of one sibling, did not present any clinical or electrophysiological abnormalities. The index patient (oldest brother) developed weakness of the distal lower limbs and nocturnal muscle cramps at the age of 54. After 5 years this patient developed an l ‐DOPA‐responsive hypokinetic rigid syndrome, establishing a diagnosis of Parkinson's disease. Although none of the three other mutation carriers displayed Parkinsonian signs, a pathogenic relationship with Parkinson's disease remains a possibility, based on the known molecular pathology of HSPB1. The rare pathogenic HSPB1 c.404C>G mutation may predispose for late‐onset of dHMN type II.     

Toxic medications in Charcot–Marie–Tooth patients: A systematic review

Background and Aims

Several widely used medications, with a relevant efficacy profile, are toxic to the peripheral nervous system and an even larger number of agents are suspected to be neurotoxic. There are concerns about the use of these drugs in patients with Charcot–Marie–Tooth disease (CMT), a hereditary motor and sensory neuropathy. This review provides evidence-based updated recommendations on this clinically relevant topic.

Methods

A systematic review of the available studies/reports written in English was performed from July to September 2022 including in the search string all reported putative neurotoxic drugs.

Results

The results of our systematic review provide evidence-based support for the statement that use of vincristine, and possibly paclitaxel, can occasionally induce an atypical, and more severe, course of drug-related peripheral neurotoxicity in CMT patients. It is therefore reasonable to recommend caution in the use of these compounds in CMT patients. However, no convincing evidence for a similar recommendation could be found for all other drugs.

Interpretation

It is important that patients with CMT are not denied effective treatments that may prolong life expectancy for cancer or improve their health status if affected by non-oncological diseases. Accurate monitoring of peripheral nerve function in CMT patients treated with any neurotoxic agent remains mandatory to detect the earliest signs of neuropathy worsening and atypical clinical courses. Neurologists monitoring CMT patients as part of their normal care package or for natural history studies should keep detailed records of exposures to neurotoxic medications and support reporting of accelerated neuropathy progression if observed.     

A novel heterozygous mutation in the C-terminal region of HSPB8 leads to limb-girdle rimmed vacuolar myopathy

Mutations in heat shock protein B8 were initially identified in inherited neuropathies and were more recently found to cause a predominantly distal myopathy with myofibrillar pathology and rimmed vacuoles. Rare patients also had proximal weakness. Only very few pathogenic variants have been identified in HSPB8. Disruption of the chaperone activity of heat shock protein B8 impairs chaperone-assisted selective autophagy and results in protein aggregation. We report a 23-year-old patient who presented with a 4-year history of predominantly proximal lower limb weakness due to a novel variant in HSPB8. The creatine kinase level was mildly elevated. Electrodiagnostic studies demonstrated a proximal-predominant myopathy without evidence of neuropathy, and muscle histopathology revealed rimmed vacuoles and myofibrillar protein aggregates. Whole exome sequencing identified a de novo frameshift variant in the C-terminal region of HSPB8 (c.577_580dupGTCA, p.Thr194Serfs*23). This case demonstrates that HSPB8-related disorders can present with early onset limb-girdle myopathy without associated neuropathy.     

Clinical and genetic features of Charcot‐Marie‐Tooth disease 2F and hereditary motor neuropathy 2B in Japan

Mutations in small heat shock protein beta‐1 (HspB1) have been linked to Charcot‐Marie‐Tooth (CMT) disease type 2F and distal hereditary motor neuropathy type 2B. Only four cases with HSPB1 mutations have been reported to date in Japan. In this study between April 2007 and October 2014, we conducted gene panel sequencing in a case series of 1,030 patients with inherited peripheral neuropathies (IPNs) using DNA microarray, targeted resequencing, and whole‐exome sequencing. We identified HSPB1 variants in 1.3% (13 of 1,030) of the patients with IPNs, who exhibited a male predominance. Based on neurological and electrophysiological findings, seven patients were diagnosed with CMT disease type 2F, whereas the remaining six patients were diagnosed with distal hereditary motor neuropathy type 2B. P39L, R127W, S135C, R140G, K141Q, T151I, and P182A mutations identified in 12 patients were described previously, whereas a novel K123* variant with unknown significance was found in 1 patient. Diabetes and impaired glucose tolerance were detected in 6 of the 13 patients. Our findings suggest that HSPB1 mutations result in two phenotypes of inherited neuropathies and extend the phenotypic spectrum of HSPB1‐related disorders.     

MRI as outcome measure in facioscapulohumeral muscular dystrophy: 1-year follow-up of 45 patients

There is no effective treatment available for facioscapulohumeral muscular dystrophy type 1 (FSHD1), but emerging therapies are under way that call for a better understanding of natural history in this condition. In this prospective, longitudinal study, we used quantitative MRI to assess yearly disease progression in patients with FSHD1. Ambulatory patients with confirmed diagnosis of FSHD1 (25/20 men/women, age 20–75 years, FSHD score: 0–12) were tested with 359–560-day interval between tests. Using the MRI Dixon technique, muscle fat replacement was evaluated in paraspinal, thigh, and calf muscles. Changes were compared with those in FSHD score, muscle strength (hand-held dynamometry), 6-minute-walk-distance, 14-step-stair-test, and 5-time-sit-to-stand-test. Composite absolute fat fraction of all assessed muscles increased by 0.036 (CI 0.026–0.046, P < 0.001), with increases in all measured muscle groups. The clinical severity FSHD score worsened (10%, P < 0.05), muscle strength decreased over the hip (8%), neck (8%), and back (17%) (P < 0.05), but other strength measures, 6-minute-walk-distance, 5-times-sit-to-stand-test, and 14-step-stair-test were unchanged. Changes in muscle strength, FSHD score, and fat fraction did not correlate. This first study to systemically monitor quantitative fat replacement longitudinally in FSHD1 shows that MRI provides an objective measure of disease progression, often before changes can be appreciated in strength and functional tests. The study indicates that quantitative MRI can be a helpful end-point in follow-up and therapeutic trials of patients with FSHD1.     

Magnetic resonance imaging of the anterior compartment of the lower leg is a biomarker for weakness,disability, and impaired gait in childhood Charcot–Marie–Tooth disease

Introduction: Biomarkers of disease severity in Charcot–Marie–Tooth disease (CMT) are required to evaluate early responses to treatment. In this study we used magnetic resonance imaging (MRI) to evaluate the relationship between muscle volume and intramuscular fat accumulation with weakness, disability, and impaired gait in affected children and adolescents. Methods: Fifty-five participants underwent MRI of the anterior compartment of the lower leg. Muscle and fat volumes were calculated. Strength was measured using hand-held dynamometry, disability using the CMT Pediatric Scale, and 3-dimensional gait analysis using an 8-camera Vicon Nexus motion capture system. Results: Lower muscle volume was significantly associated with reduced dorsiflexion strength, increased disability, impaired gait profile score, and foot drop. Intramuscular fat accumulation was associated with reduced dorsiflexion strength and impaired gait profile score. Discussion: The MRI protocol described was feasible, reliable, and sensitive to the magnitude of weakness, disability, and walking difficulties in children with CMT. Muscle Nerve 59 :213–217, 2019     

A novel p.Glu175X premature stop mutation in the C-terminal end of HSP27 is a cause of CMT2

Mutations in the gene HSPB1, encoding the small heat shock protein 27 (HSP27), are a cause of distal hereditary motor neuropathy (dHMN) and axonal Charcot-Marie-Tooth disease (CMT2). dHMN and CMT2 are differentiated by the presence of a sensory neuropathy in the latter although in the case of HSPB1 this division is artificial as CMT2 secondary to HSPB1 mutations is predominantly a motor neuropathy with only minimal sensory involvement. A recent study in mice has suggested that mutations in the C-terminus result in a motor only phenotype resembling dHMN, whereas mutations at the N-terminus result in a CMT2-like phenotype. However, we present a family with a novel mutation in the C-terminus of HSP27 (p.Glu175X) with a motor predominant distal neuropathy but with definite sensory involvement compatible with CMT2. This case highlights the artificial distinction between patients with motor predominant forms of CMT2 and dHMN and argues against the hypothesis that mutations in the C-terminus have no sensory involvement.     

X-linked Charcot–Marie–Tooth disease type 5 with recurrent weakness after febrile illness

X-linked Charcot–Marie–Tooth disease type 5 (CMTX5) is an X-linked disorder characterized by early-onset sensorineural hearing impairment, peripheral neuropathy, and progressive optic atrophy. It is caused by a loss-of-function mutation in the phosphoribosyl pyrophosphate synthetase 1 gene (PRPS1), which encodes isoform I of phosphoribosyl pyrophosphate synthetase (PRS-I). A decreased activity leads to nonsyndromic sensorineural deafness (DFN2), CMTX5, and Arts syndrome depending upon residual PRS-I activity. Clinical and neurophysiological features of pediatric CMTX5 are poorly defined. We report two male siblings with peripheral neuropathy and prelingual sensorineural hearing loss who carried a novel c.319A>G (p.Ile107Val) PRPS1 missense mutation. They exhibited recurrent episodes of transient proximal muscle weakness, showing Gowers’ sign and waddling gait after suffering from febrile illness. This transient weakness has not been previously reported in CMTX5. A patient with Arts syndrome was reported to have transient proximal weakness after febrile illness. The transient weakness presenting in both CMTX5 and Arts syndrome suggests an overlap of signs and a continuous spectrum of PRS-I hypoactivity disease. Children presenting with transient neurological signs should be evaluated for peripheral neuropathy and consider genetic analysis for PRPS1.     

The utility of the Total Neuropathy Score as an instrument to assess neuropathy severity in chronic kidney disease: A validation study

Objective

To demonstrate construct validity of the Total Neuropathy Score (TNS) in assessing peripheral neuropathy in subjects with chronic kidney disease (CKD).

Small heat shock protein B3 (HSPB3) mutation in an axonal Charcot‐Marie‐Tooth disease family

Heat shock protein B3 (HSPB3) gene encodes a small heat‐shock protein 27‐like protein which has a high sequence homology with HSPB1. A mutation in the HSPB3 was reported as the putative underlying cause of distal hereditary motor neuropathy 2C (dHMN2C) in 2010. We identified a heterozygous mutation (c.352T>C, p.Tyr118His) in the HSPB3 from a Charcot‐Marie‐Tooth disease type 2 (CMT2) family by the method of targeted next generation sequencing. The mutation was located in the well conserved alpha‐crystalline domain, and several in silico predictions indicated a pathogenic effect of the mutation. Clinical and electrophysiological features of the patients indicated the axonal type of CMT. Clinical symptoms without sensory involvements were similar between the present family and the previous family. Mutations in the HSPB1 and HSPB8 genes have been reported to be relevant with both types of CMT2 and dHMN. Our findings will help in the molecular diagnosis of CMT2 by expanding the phenotypic range due to the HSPB3 mutations.     

Long-term clinical and MRI follow-up in two POMT2-related limb girdle muscular dystrophy (LGMDR14) patients

IntroductionPOMT2-related limb girdle muscular dystrophy (LGMDR14) is a rare muscular dystrophy caused by mutations in the POMT2 gene. Thus far only 26 LGMDR14 subjects have been reported and no longitudinal natural history data are available.Case reportWe describe two LGMDR14 patients followed for 20 years since infancy. Both patients presented a childhood-onset, slowly progressive pelvic girdle muscular weakness leading to loss of ambulation in the second decade in one patient, and cognitive impairment without detectable brain structural abnormalities. Glutei, paraspinal, and adductor muscles were the primarily involved muscles at MRI.DiscussionThis report provides natural history data on LGMDR14 subjects, with a focus on longitudinal muscle MRI. We also reviewed the LGMDR14 literature data, providing information on the LGMDR14 disease progression. Considering the high prevalence of cognitive impairment in LGMDR14 patients, a reliable application of functional outcome measures can be challenging, therefore a muscle MRI follow-up to assess disease evolution is recommended.     

The absence of curly hair is associated with a milder phenotype in Giant Axonal Neuropathy

Giant Axonal Neuropathy is a pediatric neurodegenerative disorder caused by autosomal recessive mutations in the GAN gene on chromosome 16q24.1. Mutations in the GAN gene lead to functional impairment of the cytoskeletal protein gigaxonin and a generalized disorder of intermediate filaments, including neurofilaments in axons. Tightly curled hair is a common but not universal feature of Giant Axonal Neuropathy. The pathogenesis of curly hair is unknown, although disruption of keratin architecture is thought to play a role. As part of a broader natural history study of Giant Axonal Neuropathy, we found that the absence of curly hair is correlated with superior motor function (p = 0.013) when controlling for age, as measured by the Gross Motor Function Measure. Theoretically, higher levels of functional gigaxonin protein or compensatory mechanisms could produce fewer abnormalities of neurofilaments and keratin, accounting for this phenotype. We suggest that straight-haired patients with Giant Axonal Neuropathy are potentially underdiagnosed due to their divergence from the classic phenotype of the disease. Due to their non-specific features of an axonal neuropathy, these patients may be misdiagnosed with Charcot–Marie–Tooth Disease type 2. Genetic testing for Giant Axonal Neuropathy should be considered in relevant cases of Charcot–Marie–Tooth Disease type 2.     

Ultrasound imaging for diagnosis and follow‐up of persistent median artery thrombosis

Introduction: Adult‐onset Krabbe disease is clinically rare and usually affects the pyramidal tracts in the central nervous system. Patients develop a spastic gait, and peripheral neuropathy sometimes occurs simultaneously. Methods: A 55‐year‐old woman with consanguineous parents developed slowly progressive, asymmetric muscle weakness and atrophy in her forearms, while her ability to walk remained unaffected without pyramidal tract signs after onset at age 51 years. Results: Nerve conduction studies demonstrated an asymmetric demyelinating‐type peripheral neuropathy, and sural nerve biopsy documented reduced myelinated nerve fiber density with uniformly thin myelin sheaths, suggesting hypomyelination. Brain MRI demonstrated minor white‐matter injury along the optic radiations, which was associated with asymptomatic, mild, prolonged latency on visual evoked potentials. Laboratory analysis documented low enzyme activity of galactocerebrosidase (GALC) and a known mutation of the GALC gene. Conclusion: Isolated peripheral neuropathy occurs very rarely in adult‐onset Krabbe disease. Muscle Nerve 54 : 152–157, 2016     

Exercise induced muscle blood flow is decreased in Charcot–Marie–Tooth disease type 1 polyneuropathy: a power Doppler analysis

Background and purpose

Intramuscular blood flow increases during physical activity and may be quantified immediately following exercise using power Doppler sonography. Post-exercise intramuscular blood flow is reduced in patients with muscular dystrophy, associated with disease severity and degenerative changes. It is not known if intramuscular blood flow is reduced in patients with neuropathy, nor if it correlates with muscle strength and structural changes. The aim was to determine whether blood flow is reduced in patients with polyneuropathy due to Charcot–Marie–Tooth disease type 1 (CMT1) and to compare more affected distal to less affected proximal muscles.

Methods

This was a cross-sectional study including 21 healthy volunteers and 17 CMT patients. Power Doppler ultrasound was used to quantify post-exercise intramuscular blood flow in distal (gastrocnemius) and proximal (elbow flexor) muscles. Intramuscular blood flow was compared to muscle echo intensity, muscle strength, disease severity score, patient age and electromyography.

Results

Polyneuropathy patients showed reduced post-exercise blood flow in both gastrocnemius and elbow flexors compared to controls. A more prominent reduction was seen in the gastrocnemius (2.51% vs. 10.34%, p < 0.0001) than in elbow flexors (4.48% vs. 7.03%, p < 0.0001). Gastrocnemius intramuscular blood flow correlated with muscle strength, disease severity and age. Receiver operating characteristic analysis showed that quantification of intramuscular blood flow was superior to echo intensity for detecting impairment in the gastrocnemius (area under the curve 0.962 vs. 0.738, p = 0.0126).

Conclusion

Post-exercise intramuscular blood flow is reduced in CMT1 polyneuropathy. This reduction is present in both impaired distal and minimally affected proximal muscles, indicating it as an early marker of muscle impairment due to neuropathy.     

Clinical and Electrodiagnostic Features Of Nontraumatic Sciatic Neuropathy

Introduction: In this study we sought to characterize etiologies and features of sciatic neuropathy unrelated to penetrating nerve trauma. Methods: This investigation was a retrospective review of 109 patients with electrodiagnostically confirmed sciatic neuropathies. Results: Hip replacement surgery represented the most common (34.9%) etiology, whereas inflammatory sciatic neuropathy was seen in 7.3%. Electrodiagnostic testing revealed an axonal neuropathy in 95.4% and a demyelinating neuropathy in 4.6%. Predominant involvement of the peroneal division was seen in 39.4% and was tibial in 5.5%. Nine of 31 (29.0%) patients who had MRI or neuromuscular ultrasound study showed abnormalities within the sciatic nerve. At the final visit, 46.4% of patients required assistance for ambulation. Young age, lack of severe initial weakness, and presence of tibial compound muscle action potential or sural sensory nerve action potential were predictors of favorable outcome. Discussion: Sciatic neuropathies are usually axonal on electrodiagnostic testing, affect preferentially the peroneal division, and are commonly associated with incomplete recovery. Muscle Nerve 59 :309–314, 2019     

A novel HSPB1 mutation associated with a late onset CMT2 phenotype: Case presentation and systematic review of the literature

Mutations in the HSPB1 gene are associated with Charcot‐Marie‐Tooth (CMT) disease type 2F (CMT2F) and distal hereditary motor neuropathy type 2 (dHMN2). More than 18 pathogenic mutations spanning across the whole HSPB1 gene have been reported. Three family members with a novel p.P57S (c.169C>T) HSPB1 mutation resulting in a late onset axonal neuropathy with heterogeneous clinical and electrophysiological features are detailed. We systematically reviewed published case reports and case series on HSPB1 mutations. While a genotype‐phenotype correlation was not obvious, we identified a common phenotype, which included adult onset, male predominance, motor more frequently than sensory involvement, distal and symmetric distribution with preferential involvement of plantar flexors, and a motor and axonal electrophysiological picture.