Charcot-Marie-Tooth Research Articles

Diagnosis of Charcot–Marie–Tooth Disease in a Patient With Decreased Vision From Optic Atrophy and No Other Neurological Symptoms

Diagnosis of Charcot–Marie–Tooth Disease in a Patient With Decreased Vision From Optic Atrophy and No Other Neurological Symptoms

DNAJB2-related Charcot-Marie-Tooth disease type 2: Pathomechanism insights and phenotypic spectrum widening.

Background and purposeMutations in DNAJB2 are associated with autosomal recessive hereditary motor neuropathies/ Charcot‐Marie‐Tooth disease type 2 (CMT2). We describe an Italian family with CMT2 due to a homozygous DNAJB2 mutation and provide insight into the pathomechanisms.MethodsPatients with DNAJB2 mutations were characterized clinically, electrophysiologically and by means of skin biopsy. mRNA and protein levels were studied in lymphoblastoid cells (LCLs) from patients and controls.ResultsThree affected siblings were found to carry a homozygous DNAJB2 null mutation segregating with the disease. The disease manifested in the second to third decade of life. Clinical examination showed severe weakness of the thigh muscles and complete loss of movement in the foot and leg muscles. Sensation was reduced in the lower limbs. All patients had severe hearing loss and the proband also had Parkinson’s disease (PD). Nerve conduction studies showed an axonal motor and sensory length‐dependent polyneuropathy. DNAJB2 expression studies revealed reduced mRNA levels and the absence of the protein in the homozygous subject in both LCLs and skin biopsy. Interestingly, we detected phospho‐alpha‐synuclein deposits in the proband, as already seen in PD patients, and demonstrated TDP‐43 accumulation in patients’ skin.ConclusionsOur results broaden the clinical spectrum of DNAJB2‐related neuropathies and provide evidence that DNAJB2 mutations should be taken into account as another causative gene of CMT2 with hearing loss and parkinsonism. The mutation likely acts through a loss‐of‐function mechanism, leading to toxic protein aggregation such as TDP‐43. The associated parkinsonism resembles the classic PD form with the addition of abnormal accumulation of phospho‐alpha‐synuclein.

Combined neurodegenerative disease associated with mutations in SLC5A7 and TGM6 genes

Introduction. Hereditary neurodegenerative diseases are a large genetic deterministic group of nosologies, which is based on the clinic of steadily progressing processes of destruction of neuronal systems. Damage to the nervous system can have various combinations, but the most common are atrophy of the cerebellum, brain stem, spinal cord columns, and also possible damage to the peripheral nervous system. Despite the classical descriptions of the clinical picture of various forms of neurodegenerative pathology and the corresponding genetic markers of the disease, in the practice of a neurologist, there are cases that are difficult to determine the nosological form of the disease.Materials and methods. The article describes a case of combined hereditary pathology associated with laboratory-confirmed mutations in the SLC5A7 genes (associated with the development of type 7A hereditary motor sensory neuropathy) and TGM6 (affecting the development of type 35 spinocerebellar ataxia) and the clinical picture of lower spastic paraplegia.Results. The clinical case presents a combined form of hereditary spastic paraplegia with pseudobulbar syndrome, mild motor-sensory neuropathy of the lower extremities, signs of cerebellar hypotrophy on MRI and moderate impairment of walking and speech function against the background of two mutations previously identified in type 35 spinocerebellar ataxia and hereditary motor-sensory ataxia of type 35 type 7A neuropathy.Discussion. Diagnosis of nosological forms of hereditary pathology, manifested by a combination of lesions of the peripheral and central nervous systems, requires a detailed analysis of the hereditary history, neurological status and genetic examination results from a neurologist.Conclusion. The clinical case demonstrates polymorphism of clinical manifestations of hereditary forms of neurodegenerative pathology and a possible combination of various phenotypic and genotypic variants.

Mitochondrial Phenotypes in Genetically Diverse Neurodegenerative Diseases and Their Response to Mitofusin Activation.

Mitochondrial fusion is essential to mitochondrial fitness and cellular health. Neurons of patients with genetic neurodegenerative diseases often exhibit mitochondrial fragmentation, reflecting an imbalance in mitochondrial fusion and fission (mitochondrial dysdynamism). Charcot–Marie–Tooth (CMT) disease type 2A is the prototypical disorder of impaired mitochondrial fusion caused by mutations in the fusion protein mitofusin (MFN)2. Yet, cultured CMT2A patient fibroblast mitochondria are often reported as morphologically normal. Metabolic stress might evoke pathological mitochondrial phenotypes in cultured patient fibroblasts, providing a platform for the pre-clinical individualized evaluation of investigational therapeutics. Here, substitution of galactose for glucose in culture media was used to redirect CMT2A patient fibroblasts (MFN2 T105M, R274W, H361Y, R364W) from glycolytic metabolism to mitochondrial oxidative phosphorylation, which provoked characteristic mitochondrial fragmentation and depolarization and induced a distinct transcriptional signature. Pharmacological MFN activation of metabolically reprogrammed fibroblasts partially reversed the mitochondrial abnormalities in CMT2A and CMT1 and a subset of Parkinson’s and Alzheimer’s disease patients, implicating addressable mitochondrial dysdynamism in these illnesses.

Predicting Mitochondrial Dynamic Behavior in Genetically Defined Neurodegenerative Diseases.

Mitochondrial dynamics encompass mitochondrial fusion, fission, and movement. Mitochondrial fission and fusion are seemingly ubiquitous, whereas mitochondrial movement is especially important for organelle transport through neuronal axons. Here, we review the roles of different mitochondrial dynamic processes in mitochondrial quantity and quality control, emphasizing their impact on the neurological system in Charcot–Marie–Tooth disease type 2A, amyotrophic lateral sclerosis, Friedrich’s ataxia, dominant optic atrophy, and Alzheimer’s, Huntington’s, and Parkinson’s diseases. In addition to mechanisms and concepts, we explore in detail different technical approaches for measuring mitochondrial dynamic dysfunction in vitro, describe how results from tissue culture studies may be applied to a better understanding of mitochondrial dysdynamism in human neurodegenerative diseases, and suggest how this experimental platform can be used to evaluate candidate therapeutics in different diseases or in individual patients sharing the same clinical diagnosis.

Clinical genetics of Charcot-Marie-Tooth disease.

Recent research in the field of inherited peripheral neuropathies (IPNs) such as Charcot-Marie-Tooth (CMT) disease has helped identify the causative genes provided better understanding of the pathogenesis, and unraveled potential novel therapeutic targets. Several reports have described the epidemiology, clinical characteristics, molecular pathogenesis, and novel causative genes for CMT/IPNs in Japan. Based on the functions of the causative genes identified so far, the following molecular and cellular mechanisms are believed to be involved in the causation of CMTs/IPNs: myelin assembly, cytoskeletal structure, myelin-specific transcription factor, nuclear related, endosomal sorting and cell signaling, proteasome and protein aggregation, mitochondria-related, motor proteins and axonal transport, tRNA synthetases and RNA metabolism, and ion channel-related mechanisms. In this article, we review the epidemiology, genetic diagnosis, and clinicogenetic characteristics of CMT in Japan. In addition, we discuss the newly identified novel causative genes for CMT/IPNs in Japan, namely MME and COA7. Identification of the new causes of CMT will facilitate in-depth characterization of the underlying molecular mechanisms of CMT, leading to the establishment of therapeutic approaches such as drug development and gene therapy.

Pathology of the peripheral neuropathy Charcot-Marie-Tooth disease type 4H in Holstein Friesian cattle with a splice site mutation in FGD4.

Charcot-Marie-Tooth disease (CMT) is a hereditary sensory and motor peripheral neuropathy that is one of the most common inherited neurological diseases of humans and may be caused by mutations in a number of different genes. The subtype Charcot-Marie-Tooth disease type 4H (CMT4H) is caused by homozygous mutations in the FGD4 (FYVE, RhoGEF, and PH domain-containing 4) gene. A previous genome-wide association study involving 130,783 dairy cows found 6 novel variants, one of which was a homozygous splice site mutation in the FGD4 gene. Descendants of carriers were genotyped to identify 9 homozygous Holstein Friesian calves that were raised to maturity, of which 5 were euthanized and sampled for histopathology and electron microscopy at 2 and 2.5 years of age. Three control Holstein Friesian animals were raised with the calves and euthanized at the same time points. No macroscopic lesions consistent with CMT4H were seen at necropsy. Microscopically, peripheral nerves were hypercellular due to hyperplasia of S100-positive Schwann cells, and there was onion bulb formation, axonal degeneration with demyelination, and increased thickness of the endoneurium. On electron microscopy, decreased axonal density, onion bulb formations, myelin outfoldings, and increased numbers of mitochondria were present. These changes are consistent with those described in mouse models and humans with CMT4H, making these cattle a potential large animal model for CMT.

Unexpected Intermediate Nerve Conduction Velocity Findings in Charcot-Marie-Tooth Syndromes Classified as Demyelinated or Axonal in a Pediatric Population.

Among the hereditary motor and sensory neuropathies (HMSN), demyelinating forms are the best characterized, with a clear predominance of CMT1A. The axonal and intermediate forms are less described. The aim of this study is to report the genetic diagnosis of Charcot-Marie-Tooth (CMT) according to the nerve conduction velocity (NCV) findings in a pediatric population. We retrospectively described a population of HMSN children with a confirmed genetic diagnosis of demyelinated, intermediate, or axonal forms. We compared the results of the genetic analyses with those of motor NCV in median nerve according to whether they were below 25 m/s (demyelinating group); between 25 and 45 m/s (intermediate group), or above 45 m/s (axonal group). Among the 143 children with an HMSN, 107 had a genetic diagnosis of which 61 had an electromyogram. On NCV findings: seven (11%) pertain to the axonal group, 20 (32%) to the intermediate group, and 34 (55%) to the demyelinating group. When NCV was above 45 m/s, CMT2A was the predominant genetic diagnosis (70%) when NCV were below 25 m/s, CMT1A was the predominant genetic diagnosis (71%). Intermediate NCV findings group was the more heterogeneous with seven genetic CMT subgroups (60% CMT1A, CMT1B, CMT1X, CMT2A, CMT2N, CMT4G). Taking NCV values between 25 and 45 m/s to define an intermediate group of CMT in children leads to the inclusion of non-typically "intermediate", especially CMT1A. We emphasize the broad spectrum of NCV in CMT1A that justified the systematic search of PMP22 duplication/deletion screening before next generation sequencing panel.

Genetic Workup for Charcot-Marie-Tooth Neuropathy: A Retrospective Single-Site Experience Covering 15 Years.

Charcot–Marie–Tooth (CMT) disease is the most commonly inherited neurological disorder. This study includes patients affected by CMT during regular follow-ups at the CMT clinic in Genova, a neuromuscular university center in the northwest of Italy, with the aim of describing the genetic distribution of CMT subtypes in our cohort and reporting a peculiar phenotype. Since 2004, 585 patients (447 index cases) have been evaluated at our center, 64.9% of whom have a demyelinating neuropathy and 35.1% of whom have an axonal neuropathy. A genetic diagnosis was achieved in 66% of all patients, with the following distribution: CMT1A (48%), HNPP (14%), CMT1X (13%), CMT2A (5%), and P0-related neuropathies (7%), accounting all together for 87% of all the molecularly defined neuropathies. Interestingly, we observe a peculiar phenotype with initial exclusive lower limb involvement as well as lower limb involvement that is maintained over time, which we have defined as a “strictly length-dependent” phenotype. Most patients with this clinical presentation shared variants in either HSPB1 or MPZ genes. The identification of distinctive phenotypes such as this one may help to address genetic diagnosis. In conclusion, we describe our diagnostic experiences as a multidisciplinary outpatient clinic, combining a gene-by-gene approach or targeted gene panels based on clinical presentation.

Subtalar realignment arthrodesis in the mid-stage neurogenic cavovarus foot

Charcot Marie Tooth (CMT) disease is a progressive neuromuscular disorder that is often the underlying condition involved in the development of a symptomatic cavovarus foot. End-stage foot deformities frequently result in triple arthrodesis procedures performed later in the disease process. The main surgical goal is to achieve a stable, plantigrade foot. Ideally, treatment would avoid triple arthrodesis as this procedure increases adjacent joint demands and expedites development of resultant arthrosis. Some authors have stated that earlier intervention by tendon balancing techniques may alleviate the need for joint fusions in the future. Therefore, the timing of surgical intervention is paramount in the medical decision making process. Our case series reviews mid-stage cavovarus progression in patients with pedal instability and gait disturbances. Realignment subtalar arthrodesis is utilized to improve Kite’s angle, reduce heel varus and re-establish subtalar joint (STJ) stability. Tendon balancing procedures should be performed in conjunction with STJ arthrodesis in order to achieve long standing correction and hopefully prevent the future need for conversion to triple arthrodesis.

The impact of pain and nocturnal cramps on sleep quality in Charcot Marie Tooth disease: a case-control study.

IntroductionCharcot-Marie-Tooth disease is an inherited neuropathy that presents two main forms - type 1 and type 2 -, differentiated by the speed of the nervous conduction. Our goal was to assess sleep in Charcot-Marie-Tooth disease and its relationship with pain perception and nocturnal cramps.Material and MethodsThis was a case-control study. The case group was composed of 10 volunteers diagnosed with the type 1 and 23 with the type 2. The control group was composed of 22 individuals from the same family matched by age and gender. Volunteers underwent clinical screening to assess the presence of nocturnal cramps and filled the brief pain inventory, the Chalder fatigue scale, the Epworth sleepiness scale, and the Pittsburgh sleep quality index. Sleep was evaluated by actigraphy.ResultsType 2 patients presented a more severe perception of pain and fatigue, more time spend awake after sleep onset, and had lower sleep efficiency. The individuals who reported nocturnal cramps also had worse perception of pain, reduced sleep latency, and increased sleep fragmentation.ConclusionThe Charcot-Marie-Tooth type 2 was related with worse sleep quality, perception of pain, and fatigue and these parameters were negatively related.

Five Cases of Charcot-Marie-Tooth Disease With Positive COVID-19 Infection Reported Using Cerner Real-World Data™.

Digala, Lakshmi P. MBBS*; Prasanna, Shivika MS†; Rao, Praveen PhD†; Qureshi, Adnan I. MD*; Govindarajan, Raghav MD* Author Information

Brain MR imaging findings in children with congenital muscular dystrophies

Congenital muscular dystrophies (CMDs) are a heterogeneous group of disorders presenting early in life during infancy or soon after birth with muscle weakness and hypotonia, sometime associated to severe brain involvement and histologically presenting with dystrophic lesions. They are classified on the basis of the clinical features, pathologic findings and pattern of inheritance. In fact most of these disorders are inherited and linked to specific genes. Several CDMs classifications have been proposed [1-3]. The main CMD subtypes, classified by pathogenic gene, are laminin alpha‐2 (merosin) deficiency (MDC1A), collagen VI-related CMD (COL6-RD), the dystroglycanopathies -such as Walker‐Warburg syndrome (WWS), Fukuyama CMD (FCMD), and muscle-eye-brain disease (MEB)-, SELENON (SEPN1)‐related CMD, and LMNA‐related CMD (L‐CMD) [4]. The incidence and prevalence of CMDs in various populations is not sufficiently known and may have been underestimated in early published CMD surveys owing to more limited diagnostic means available. Point prevalence in various studies ranges from 0.56 to 2.5 per 100,000 [5-10]. The relative frequency of CMD subtypes also varies in different populations. The most common CMD subtypes are laminin-α2 related CMD and dystroglycanopathies, followed by collagen VI-related CMD. The forms of congenital muscular dystrophy related to mutations in SEPN1 and LMNA are less frequent [9,11]. CMDs are often autosomal recessive, but some cases have been found to follow autosomal dominant patterns, by direct inheritance, spontaneous mutations, or mosaicism. Clinical genetic testing is available for virtually all genes known to be associated with CMDs. However, many affected individuals remain without a genetic diagnosis, an indicator that novel disease genes have yet to be identified [3]. Differential diagnosis of patients presenting with weakness in early infancy includes: Congenital myopathies like central core, nemaline road, and centronuclear myopathy and those secondary to metabolic disorders; Disorders of the myoneural junction including congenital myasthenia gravis and infant botulism and Neuropathies like spinal muscular atrophy (SMA) and hereditary motor sensory neuropathy (HMSN) [12]. Nowadays the diagnosis is based on clinical presentation, laboratory tests and genetic investigations. Muscular biopsy can be an important diagnostic tool if genetic tests are not available. Brain MRI and muscular MRI are performed if available. We discuss brain MR imaging findings in our patients with CMDs trying to outline common features and differences in order to aid in the diagnosis of these rare disorders before performing genetic tests.

Early targeting of endoneurial macrophages alleviates the neuropathy and affects abnormal Schwann cell differentiation in a mouse model of Charcot‐Marie‐Tooth 1A

AbstractWe have previously shown that targeting endoneurial macrophages with the orally applied CSF‐1 receptor specific kinase (c‐FMS) inhibitor PLX5622 from the age of 3 months onwards led to a substantial alleviation of the neuropathy in mouse models of Charcot‐Marie‐Tooth (CMT) 1X and 1B disease, which are genetically‐mediated nerve disorders not treatable in humans. The same approach failed in a model of CMT1A (PMP22‐overexpressing mice, line C61), representing the most frequent form of CMT. This was unexpected since previous studies identified macrophages contributing to disease severity in the same CMT1A model. Here we re‐approached the possibility of alleviating the neuropathy in a model of CMT1A by targeting macrophages at earlier time points. As a proof‐of‐principle experiment, we genetically inactivated colony‐stimulating factor‐1 (CSF‐1) in CMT1A mice, which resulted in lower endoneurial macrophage numbers and alleviated the neuropathy. Based on these observations, we pharmacologically ablated macrophages in newborn CMT1A mice by feeding their lactating mothers with chow containing PLX5622, followed by treatment of the respective progenies after weaning until the age of 6 months. We found that peripheral neuropathy was substantially alleviated after early postnatal treatment, leading to preserved motor function in CMT1A mice. Moreover, macrophage depletion affected the altered Schwann cell differentiation phenotype. These findings underscore the targetable role of macrophage‐mediated inflammation in peripheral nerves of inherited neuropathies, but also emphasize the need for an early treatment start confined to a narrow therapeutic time window in CMT1A models and potentially in respective patients.

MPZ gene variant site in Chinese patients with Charcot-Marie-Tooth disease.

BackgroundCharcot–Marie–Tooth disease (CMT) is a hereditary monogenic peripheral nerve disease. Variants in the gene encoding myelin protein zero (MPZ) lead to CMT, and different variants have different clinical phenotypes. A variant site, namely, c.389A > G (p.Lys130Arg), in the MPZ gene has been found in Chinese people. The pathogenicity of this variant has been clarified through pedigrees, and peripheral blood‐related functional studies have been conducted.MethodWhole‐exome sequencing and Sanger sequencing were used to detect the c.389A > G (p.Lys130Arg) variant in the MPZ gene in family members of the proband. Physical examination was performed in the case group to assess the clinical characteristics of MPZ site variants. The expression of MPZ and phosphorylated MPZ in the blood of 12 cases and 12 randomly selected controls was compared by RT–qPCR, Western blotting, and ELISA.ResultsThe proband and 12 of her family members presented the AG genotype with different clinical manifestations. The expression of MPZ mRNA in the case group was increased compared with that in the control group, and the levels of MPZ and phosphorylated MPZ in peripheral blood were higher than those in normal controls.ConclusionThe heterozygous genotype of the c.389A > G (p.Lys130Arg) variant in the MPZ gene mediated the increase in MPZ and phosphorylated MPZ levels in peripheral blood and was found to be involved with CMT.

Neuropathic pain in Charcot-Marie-Tooth disease: A clinical and laser-evoked potential study.

Pain, either nociceptive or neuropathic (NP), is a common symptom in Charcot-Marie-Tooth (CMT) disease. We investigated small fibers involvement and its correlation with pain in different CMT subtypes through a systematic clinical and neurophysiological study. We enrolled 50 patients: 19 with duplication of PMP22 (CMT1A), 11 with mutation of MPZ (CMT1B, CMT2I/J, or CMTDID), 12 with mutation of GJB1 (CMTX1), and 8 with mutation of MFN2 (CMT2A and CMT2A2B). Pain was rated with the 11-point Numerical Rating Scale and characterized through Neuropathic Pain Symptoms Inventory. Laser-evoked potentials (LEPs) were recorded after right foot and hand stimulation and N2-P2 complex amplitude and latency were compared with those of 41 controls. Overall pain prevalence was 36%. NP was present in 14.6% of patients, with a length-dependent distribution in 85.7% of cases, and it was significantly more frequent in CMT1A (p<0.001). Aδ fibers involvement greatly varies between CMT subtypes, reflecting differences in molecular pathology and pathophysiologic mechanisms. Prolonged N2 latency from foot stimulation was noted in 11 CMT1A patients, 5 of which report NP. MPZ-CMTs displayed different neurophysiological phenotypes and a very low prevalence of NP. LEPs were normal in all but one CMTX1 patients, although lower limbs N2-P2 amplitude was significantly reduced in males (p=0.043). MFN2-CMTs were NP free and LEPs recordings were all normal. NP strictly correlated with LEPs alterations (p=0.017). NP prevalence varies among CMTs subtypes and is mainly related to Aδ fibers impairment. Neuropathic pain is a frequent finding in Charcot-Marie Tooth disease and is related to Aδ fibers impairment. Patients at higher risk are those belonging to certain genetic subtypes (i.e. CMT1A and CMT2J) or with laser-evoked potentials abnormalities. While managing this disease, clinicians should be aware of this symptom in order to offer best treatment options to their patients.

Neurofilament Light Regulates Axon Caliber, Synaptic Activity, and Organelle Trafficking in Cultured Human Motor Neurons.

Neurofilament light (NFL) is one of the proteins forming multimeric neuron-specific intermediate filaments, neurofilaments, which fill the axonal cytoplasm, establish caliber growth, and provide structural support. Dominant missense mutations and recessive nonsense mutations in the neurofilament light gene (NEFL) are among the causes of Charcot–Marie–Tooth (CMT) neuropathy, which affects the peripheral nerves with the longest axons. We previously demonstrated that a neuropathy-causing homozygous nonsense mutation in NEFL led to the absence of NFL in patient-specific neurons. To understand the disease-causing mechanisms, we investigate here the functional effects of NFL loss in human motor neurons differentiated from induced pluripotent stem cells (iPSC). We used genome editing to generate NEFL knockouts and compared them to patient-specific nonsense mutants and isogenic controls. iPSC lacking NFL differentiated efficiently into motor neurons with normal axon growth and regrowth after mechanical axotomy and contained neurofilaments. Electrophysiological analysis revealed that motor neurons without NFL fired spontaneous and evoked action potentials with similar characteristics as controls. However, we found that, in the absence of NFL, human motor neurons 1) had reduced axonal caliber, 2) the amplitude of miniature excitatory postsynaptic currents (mEPSC) was decreased, 3) neurofilament heavy (NFH) levels were reduced and no compensatory increases in other filament subunits were observed, and 4) the movement of mitochondria and to a lesser extent lysosomes was increased. Our findings elaborate the functional roles of NFL in human motor neurons. NFL is not only a structural protein forming neurofilaments and filling the axonal cytoplasm, but our study supports the role of NFL in the regulation of synaptic transmission and organelle trafficking. To rescue the NFL deficiency in the patient-specific nonsense mutant motor neurons, we used three drugs, amlexanox, ataluren (PTC-124), and gentamicin to induce translational read-through or inhibit nonsense-mediated decay. However, the drugs failed to increase the amount of NFL protein to detectable levels and were toxic to iPSC-derived motor neurons.

HP39: PMP22 neuropathies: Charcot-Marie-Tooth disease type 1A in a boy and changes in electroneuromyography

Charcot-Marie-Tooth (CMT) disease is the most frequent inherited neuropathy, affecting 1/1500 to 1/10000 (60%-70% of all CMT and is caused by a duplication on chromosome 17p11.2 leading to an overexpression of the Peripheral Myelin Protein 22 (PMP22)). CMT1A characterized by distal muscle weakness and atrophy, sensory loss, and slow nerve conduction velocity. Early diagnosis is necessary for further prognosis and management of the patient. At the boy from 9 years parents noticed gait disturbances: it was difficult to step on a heel. Within a few years, the symptoms progressed and there was a sensitivity disorder. According to the neurological status, the knee reflexes were reduced and there were no Achilles. We performed electroneuromyography and recorded a significant decrease in motor and sensory responses (less than 1 μV). Needle myography showed secondary denervation changes in the muscles. We sent the patient's blood for genetic analysis (Comprehensive Neuropathies Panel). We received a Pathogenic variant, Gain (Entire coding sequence), was identified in PMP22. This variant is a gross duplication of the genomic region encompassing exons 2-5 of the PMP22 gene. Therefore, it is assumed that the entire gene is duplicated. Duplications of the region on chromosome 17p11.2 which contain the PMP22 gene cause Charcot-Marie-Tooth type 1A (CMT1A). The patient was also found to have mutations of uncertain significance: in SCN11A (associated with autosomal dominant hereditary sensory and autonomic neuropathy type 7) and SCN9A. After the diagnosis, we also provided him with recommendations for multidisciplinary management together with rehabilitation specialists and orthopedists.

SARM1 knockout does not rescue neuromuscular phenotypes in a Charcot-Marie-Tooth disease Type 1A mouse model.

Charcot-Marie-Tooth disease Type 1A (CMT1A) is caused by duplication of the PMP22 gene and is the most common inherited peripheral neuropathy. Although CMT1A is a dysmyelinating peripheral neuropathy, secondary axon degeneration has been suggested to drive functional deficits in patients. Given that SARM1 knockout is a potent inhibitor of the programmed axon degeneration pathway, we asked whether SARM1 knockout rescues neuromuscular phenotypes in CMT1A model (C3-PMP) mice. CMT1A mice were bred with SARM1 knockout mice to generate CMT1A/SARM1-/- mice. A series of behavioral assays were employed to evaluate motor and sensorimotor function. Electrophysiological and histological studies of the tibial branch of the sciatic nerve were performed. Additionally, gastrocnemius and soleus muscle morphology were evaluated histologically. Although clear behavioral and electrophysiological deficits were observed in CMT1A model mice, genetic deletion of SARM1 conferred no significant improvement. Nerve morphometry revealed predominantly myelin deficits in CMT1A model mice and SARM1 knockout yielded no improvement in all nerve morphometry measures. Similarly, muscle morphometry deficits in CMT1A model mice were not improved by SARM1 knockout. Our findings demonstrate that programmed axon degeneration pathway inhibition does not provide therapeutic benefit in C3-PMP CMT1A model mice. Our results indicate that the clinical phenotypes observed in CMT1A mice are likely caused primarily by prolonged dysmyelination, motivate further investigation into mechanisms of dysmyelination in these mice and necessitate the development of improved CMT1A rodent models that recapitulate the secondary axon degeneration observed in patients.

Counter-movement jump characteristics in children with Charcot–Marie–Tooth type 1a disease

BackgroundPoor performance in sports, especially activities that require explosive movements, is a common reason for initial presentation of children with Charcot–Marie–Tooth type 1a (CMT1a) to the paediatric neuromuscular specialist. Research questionThe aim of this descriptive, retrospective study was to analyse counter-movement jump characteristics in children with CMT1a in comparison to those in typically developing children (TDC). MethodsThis retrospective study included seven patients with CMT1a and 44 TDC from our data pool. All the participants performed counter-movement jumps, and jump height, peak force, time to peak force, average and peak rate of force development and net vertical impulse were then calculated. For statistical comparison by means of an independent Student’s t-test, children with CMT1a were compared to seven sex- and age-matched TDC. Correlation coefficients were calculated to determine the relationship between the force-time variables and jump height. ResultsPeak force, net vertical impulse and jump height values in the CMT1a group were significantly lower than those in the TDC group. There were no between-group differences in the time to peak force or average and peak rate of force development. In terms of task symmetry, the correlation between the time-force curve of the left and right leg in the CMT1a group was reduced as compared with that in the TDC group. In both groups, among the parameters measured, there was a significant correlation between jump height and net vertical impulse. SignificanceThis study showed that reduced jump performance in children with CMT1a, as demonstrated by decreased counter-movement jump height, was due to a reduced net impulse during this explosive movement task. This finding is critical for children with CMT1a and has to be considered in clinical management and activities of daily living (e.g. sports lessons in school).