Disease Progression in Charcot-Marie-Tooth Disease Related to MPZ Mutations: A Longitudinal Study.

OBJECTIVE: The paucity of longitudinal natural history studies in MPZ neuropathy remains a barrier to clinical trials. We have completed a longitudinal natural history study in patients with MPZ neuropathies across 13 sites of the Inherited Neuropathies Consortium. METHODS: Change in Charcot-Marie-Tooth Examination Score (CMTES) and Rasch modified CMTES (CMTES-R) were evaluated using longitudinal regression over a 5-year period in subjects with MPZ neuropathy. Data from 139 patients with MPZ neuropathy were examined. RESULTS: The average baseline CMTES and CMTES-R were 10.84 (standard deviation [SD] = 6.0, range = 0-28) and 14.60 (SD = 7.56, range = 0-32), respectively. A mixed regression model showed significant change in CMTES at years 2-5 (mean change from baseline of 0.87 points at 2 years, p = 0.008). Subgroup analysis revealed greater change in CMTES at 2 years in subjects with axonal as compared to demyelinating neuropathy (mean change of 1.30 points [p = 0.016] vs 0.06 points [p = 0.889]). Patients with a moderate baseline neuropathy severity also showed more notable change, by estimate, than those with mild or severe neuropathy (mean 2-year change of 1.14 for baseline CMTES 8-14 [p = 0.025] vs -0.03 for baseline CMTES 0-7 [p = 0.958] and 0.25 for baseline CMTES ≥ 15 [p = 0.6897]). The progression in patients harboring specific MPZ mutations was highly variable. INTERPRETATION: CMTES is sensitive to change over time in adult patients with axonal but not demyelinating forms of MPZ neuropathy. Change in CMTES was greatest in patients with moderate baseline disease severity. These findings will inform future clinical trials of MPZ neuropathies. ANN NEUROL 2023;93:563-576.

A study concept of expeditious clinical enrollment for genetic modifier studies in Charcot-Marie-Tooth neuropathy 1A.

BACKGROUND: Caused by duplications of the gene encoding peripheral myelin protein 22 (PMP22), Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common hereditary neuropathy. Despite this shared genetic origin, there is considerable variability in clinical severity. It is hypothesized that genetic modifiers contribute to this heterogeneity, the identification of which may reveal novel therapeutic targets. In this study, we present a comprehensive analysis of clinical examination results from 1564 CMT1A patients sourced from a prospective natural history study conducted by the RDCRN-INC (Inherited Neuropathy Consortium). Our primary objective is to delineate extreme phenotype profiles (mild and severe) within this patient cohort, thereby enhancing our ability to detect genetic modifiers with large effects. METHODS: We have conducted large-scale statistical analyses of the RDCRN-INC database to characterize CMT1A severity across multiple metrics. RESULTS: We defined patients below the 10th (mild) and above the 90th (severe) percentiles of age-normalized disease severity based on the CMT Examination Score V2 and foot dorsiflexion strength (MRC scale). Based on extreme phenotype categories, we defined a statistically justified recruitment strategy, which we propose to use in future modifier studies. INTERPRETATION: Leveraging whole genome sequencing with base pair resolution, a future genetic modifier evaluation will include single nucleotide association, gene burden tests, and structural variant analysis. The present work not only provides insight into the severity and course of CMT1A, but also elucidates the statistical foundation and practical considerations for a cost-efficient and straightforward patient enrollment strategy that we intend to conduct on additional patients recruited globally.

Genetic analysis and natural history of Charcot-Marie-Tooth disease CMTX1 due to GJB1 variants.

Charcot-Marie-Tooth disease (CMT) due to GJB1 variants (CMTX1) is the second most common form of CMT. It is an X-linked disorder characterized by progressive sensory and motor neuropathy with males affected more severely than females. Many reported GJB1 variants remain classified as variants of uncertain significance (VUS). In this large, international, multicentre study we prospectively collected demographic, clinical and genetic data on patients with CMT associated with GJB1 variants. Pathogenicity for each variant was defined using adapted American College of Medical Genetics criteria. Baseline and longitudinal analyses were conducted to study genotype-phenotype correlations, to calculate longitudinal change using the CMT Examination Score (CMTES), to compare males versus females, and pathogenic/likely pathogenic (P/LP) variants versus VUS. We present 387 patients from 295 families harbouring 154 variants in GJB1. Of these, 319 patients (82.4%) were deemed to have P/LP variants, 65 had VUS (16.8%) and three benign variants (0.8%; excluded from analysis); an increased proportion of patients with P/LP variants compared with using ClinVar's classification (74.6%). Male patients (166/319, 52.0%, P/LP only) were more severely affected at baseline. Baseline measures in patients with P/LP variants and VUS showed no significant differences, and regression analysis suggested the disease groups were near identical at baseline. Genotype-phenotype analysis suggested c.-17G>A produces the most severe phenotype of the five most common variants, and missense variants in the intracellular domain are less severe than other domains. Progression of disease was seen with increasing CMTES over time up to 8 years follow-up. Standard response mean (SRM), a measure of outcome responsiveness, peaked at 3 years with moderate responsiveness [change in CMTES (ΔCMTES) = 1.3 ± 2.6, P = 0.00016, SRM = 0.50]. Males and females progressed similarly up to 8 years, but baseline regression analysis suggested that over a longer period, females progress more slowly. Progression was most pronounced for mild phenotypes (CMTES = 0-7; 3-year ΔCMTES = 2.3 ± 2.5, P = 0.001, SRM = 0.90). Enhanced variant interpretation has yielded an increased proportion of GJB1 variants classified as P/LP and will aid future variant interpretation in this gene. Baseline and longitudinal analysis of this large cohort of CMTX1 patients describes the natural history of the disease including the rate of progression; CMTES showed moderate responsiveness for the whole group at 3 years and higher responsiveness for the mild group at 3, 4 and 5 years. These results have implications for patient selection for upcoming clinical trials.

Plasma neurofilament light chain concentrations are elevated in youth-onset type 2 diabetes and associated with neuropathy.

BACKGROUND AND AIMS: The lack of easily measurable biomarkers remains a challenge in executing clinical trials for diabetic neuropathy (DN). Plasma Neurofilament light chain (NFL) concentration is a promising biomarker in immune-mediated neuropathies. Longitudinal studies evaluating NFL in DN have not been performed. METHODS: A nested case-control study was performed on participants with youth-onset type 2 diabetes enrolled in the prospective Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. Plasma NFL concentrations were measured at 4-year intervals from 2008 to 2020 in 50 participants who developed DN and 50 participants with type 2 diabetes who did not develop DN. RESULTS: NFL concentrations were similar in the DN and no DN groups at the first assessment. Concentrations were higher in DN participants at all subsequent assessment periods (all p < .01). NFL concentrations increased over time in both groups, with higher degrees of change in DN participants (interaction p = .045). A doubling of the NFL value at Assessment 2 in those without DN increased the odds of ultimate DN outcome by an estimated ratio of 2.86 (95% CI: [1.30, 6.33], p = .0046). At the final study visit, positive Spearman correlations (controlled for age, sex, diabetes duration, and BMI) were observed between NFL and HbA1c (0.48, p < .0001), total cholesterol (0.25, p = .018), and low-density lipoprotein (LDL (0.30, p = .0037)). Negative correlations were observed with measures of heart rate variability (-0.42 to -0.46, p = <.0001). INTERPRETATION: The findings that NFL concentrations are elevated in individuals with youth-onset type 2 diabetes, and increase more rapidly in those who develop DN, suggest that NFL could be a valuable biomarker for DN.

Adult-onset Krabbe disease presenting as isolated sensorimotor demyelinating polyneuropathy: A case report.

Krabbe disease is a rare autosomal recessive neurodegenerative disease, caused by mutations in the GALC gene, which encodes for the lysosomal enzyme galactocerebrosidase. Typical clinical manifestations of Krabbe include psychomotor deterioration, visual loss, seizures, and spasticity, that result from central nervous system demyelination. We report a case of a 35-year-old male with Krabbe who presented in adulthood with isolated severe, upper extremity predominant demyelinating sensorimotor polyneuropathy and did not develop other distinguishing clinical or radiological features of Krabbe until the later stages of the disease. The patient's diagnostic odyssey lasted 13 years from presentation to diagnosis, which was ultimately determined with the use of whole exome sequencing (WES) at the age of 48 years. The expanding phenotypic spectrum of adult-onset Krabbe Disease (AOKD) presents a diagnostic challenge that can lead to diagnostic delays and potentially affect treatment options. Our patient's case underscores the importance of pursuing WES in those with undiagnosed progressive neuromuscular disorders.

Diabetic neuropathy: what does the future hold?

Frustratingly, disease-modifying treatments for diabetic neuropathy remain elusive. Glycaemic control has a robust effect on preventing neuropathy in individuals with type 1 but not in those with type 2 diabetes, which constitute the vast majority of patients. Encouragingly, recent evidence points to new metabolic risk factors and mechanisms, and thus also at novel disease-modifying strategies, which are desperately needed. Obesity has emerged as the second most important metabolic risk factor for neuropathy (diabetes being the first) from consensus findings of seven observational studies in populations across the world. Moreover, dyslipidaemia and altered sphingolipid metabolism are emergent novel mechanisms of nerve injury that may lead to new targeted therapies. Clinical history and examination remain critical components of an accurate diagnosis of neuropathy. However, skin biopsies and corneal confocal microscopy are promising newer tests that have been used as outcome measures in research studies but have not yet demonstrated clear clinical utility. Given the emergence of obesity as a neuropathy risk factor, exercise and weight loss are potential interventions to treat and/or prevent neuropathy, although evidence supporting exercise currently outweighs data supporting weight loss. Furthermore, a consensus has emerged advocating tricyclic antidepressants, serotonin-noradrenaline (norepinephrine) reuptake inhibitors and gabapentinoids for treating neuropathic pain. Out-of-pocket costs should be considered when prescribing these medications since their efficacy and tolerability are similar. Finally, the downsides of opioid treatment for chronic, non-cancer pain are becoming increasingly evident. Despite these data, current clinical practice frequently initiates and continues opioid prescriptions for patients with neuropathic pain before prescribing guideline-recommended treatments.

Natural history and biomarkers in hereditary sensory neuropathy type 1.

INTRODUCTION: Hereditary sensory and autonomic neuropathy type 1 (HSAN1) is most commonly caused by missense mutations in SPTLC1. In this study we mapped symptom progression and compared the utility of outcomes. METHODS: We administered retrospective surveys of symptoms and analyzed results of nerve conduction, autonomic function testing (AFT), and PGP9.5-immunolabeled skin biopsies. RESULTS: The first symptoms were universally sensory and occurred at a median age of 20 years (range 14-54 years). The onset of weakness, ulcers, pain, and balance problems followed sequentially. Skin biopsies revealed universally absent epidermal innervation at the distal leg with relative preservation in the thigh. Neurite density was highly correlated with total Charcot-Marie-Tooth Examination Score (CMTES; r2 = -0.8) and median motor amplitude (r2 = -0.75). CONCLUSIONS: These results confirm sensory loss as the initial symptom of HSAN1 and suggest that skin biopsy may be the most promising biomarker for future clinical trials.

Inherited Neuropathies.

Hereditary neuropathies (HNs) are among the most common inherited neurologic disorders and are diverse both clinically and genetically. Recent genetic advances have contributed to a rapid expansion of identifiable causes of HN and have broadened the phenotypic spectrum associated with many of the causative mutations. The underlying molecular pathways of disease have also been better delineated, leading to the promise for potential treatments. This chapter reviews the clinical and biological aspects of the common causes of HN and addresses the challenges of approaching the diagnostic workup of these conditions in a rapidly evolving genetic landscape.

Long-term effects of l-serine supplementation upon a mouse model of diabetic neuropathy.

Deoxysphingolipids (1-deoxySLs) are neurotoxic sphingolipids associated with obesity and diabetic neuropathy (DN) and have been linked to severity of functional peripheral neuropathies. While l-serine supplementation can reduce 1-deoxySL accumulation and improve insulin sensitivity and sensory nerve velocity, long-term outcomes have not yet been examined. To assess this, we treated 2 month old db/db mice, a model of DN, with 5-20 % oral l-serine for 6 months and longitudinally quantified the extent of functional neuropathy progression. We examined putative biomarkers of neuropathy in blood and tissue and quantified levels of small fiber neuropathy, looking for associations between lowered 1-deoxySL and phenotypes. Toxic 1-deoxySLs were suppressed long-term in plasma and various tissue including the sciatic nerve, which is particularly targeted in DN. Functional neuropathy and sensory modalities were significantly improved in the treatment group well into advanced stages of disease. However, structural assessments revealed prominent axonal degeneration, apoptosis and Schwann cell pathology, suggesting that neuropathy was ongoing. Hyperglycemia and dyslipidemia persisted during our study, and high levels of glutathione were seen in the spinal cord. Our results demonstrate that despite significant functional improvements, l-serine does not prevent chronic degenerative changes specifically at the structural level, pointing to other processes such as oxidative damage and hyperglycemia, that persist despite 1-deoxySL reduction.

Graduating US neurology residents' experience with tissue-type plasminogen activator for acute stroke: a 10-year comparison.

BACKGROUND AND PURPOSE: A survey of graduating neurology residents conducted in 2000 showed that many residents had limited experience and comfort treating with tissue-type plasminogen activator (tPA). We examined changes in residents' experience during the past decade. METHODS: A 12-item survey was sent to US neurology residents in their final year of training. Items examined residents' experience and confidence with assessment of the acute stroke patient and use of tPA for treatment. Questions were worded identically in the 2000 and 2010 surveys, and responses were compared between the two. RESULTS: Of 491 residents, 286 (58%) responded. There was a significant increase from 2000 to 2010 in the percentage of residents who felt comfortable independently treating with tPA (73% versus 94%, P<0.001), who had observed administration of tPA (88% versus 99%, P<0.001), who had personally treated with tPA (80% versus 95%, P<0.001), and who had been involved in post-tPA care (89% versus 98%, P<0.001). There was a substantial increase in residents with formal training in using the National Institutes of Health Stroke Scale (65% versus 92%, P<0.001) and who had dedicated stroke teams at their institution (84% versus 93%, P=0.001). CONCLUSIONS: Neurology residents' experience and comfort treating acute ischemic stroke with tPA increased significantly between 2000 and 2010, as did resident exposure to stroke teams and formal training in the National Institutes of Health Stroke Scale.

Mechanisms and Treatments in Demyelinating CMT.

Demyelinating forms of Charcot-Marie-Tooth disease (CMT) are genetically and phenotypically heterogeneous and result from highly diverse biological mechanisms including gain of function (including dominant negative effects) and loss of function. While no definitive treatment is currently available, rapid advances in defining the pathomechanisms of demyelinating CMT have led to promising pre-clinical studies, as well as emerging clinical trials. Especially promising are the recently completed pre-clinical genetic therapy studies in PMP-22, GJB1, and SH3TC2-associated neuropathies, particularly given the success of similar approaches in humans with spinal muscular atrophy and transthyretin familial polyneuropathy. This article focuses on neuropathies related to mutations in PMP-22, MPZ, and GJB1, which together comprise the most common forms of demyelinating CMT, as well as on select rarer forms for which promising treatment targets have been identified. Clinical characteristics and pathomechanisms are reviewed in detail, with emphasis on therapeutically targetable biological pathways. Also discussed are the challenges facing the CMT research community in its efforts to advance the rapidly evolving biological insights to effective clinical trials. These considerations include the limitations of currently available animal models, the need for personalized medicine approaches/allele-specific interventions for select forms of demyelinating CMT, and the increasing demand for optimal clinical outcome assessments and objective biomarkers.

Prevalence and significance of cranial nerve imaging abnormalities in patients with hereditary neuropathies: Clinical implications at the skull base.

OBJECTIVE: To estimate the prevalence and significance of cranial nerve (CN) imaging abnormalities in patients with hereditary neuropathy and discuss clinical implications. METHODS: We retrospectively analyzed data from patients at four tertiary academic medical centers with hereditary neuropathy diagnoses who had undergone gadolinium-enhanced magnetic resonance imaging (MRI) of the brain or skull base between 2004 and 2018. MRI scans, as well as computed tomography imaging when available, were reviewed and bivariable analysis was performed to identify predictors of CN abnormalities on imaging. RESULTS: Among 39 patients meeting study criteria, 11 had clinical CN deficits (28%) and 8 had CN abnormalities on imaging (21%). Of the patients with CN abnormalities on imaging, half had CN deficits (4/8) and only a quarter had imaging abnormalities of the CNs with the deficits (2/8). Imaging abnormalities were found in varied CNs, including CNs III, V, VII, and the VII/VIII complex in the internal auditory canal. MRI obtained for the purpose of evaluating CN deficits had a statistically significant increased likelihood of containing CN imaging abnormalities. However, CN deficits themselves were not predictive of imaging abnormalities. CONCLUSION: Thickening and enhancement of CNs on MRI may be found in approximately 1/5 of patients with hereditary neuropathies and are inconsistently associated with clinical deficits. These imaging findings should not be mistaken for neoplastic and infectious processes as they may be manifestations of the patients' underlying genetic neuropathy. LEVEL OF EVIDENCE: 4.

A longitudinal study of CMT1A using Rasch analysis based CMT neuropathy and examination scores.

OBJECTIVE: To evaluate the sensitivity of Rasch analysis-based, weighted Charcot-Marie-Tooth Neuropathy and Examination Scores (CMTNS-R and CMTES-R) to clinical progression in patients with Charcot-Marie-Tooth disease type 1A (CMT1A). METHODS: Patients with CMT1A from 18 sites of the Inherited Neuropathies Consortium were evaluated between 2009 and 2018. Weighted CMTNS and CMTES modified category responses were developed with Rasch analysis of the standard scores. Change from baseline for CMTNS-R and CMTES-R was estimated with longitudinal regression models. RESULTS: Baseline CMTNS-R and CMTES-R scores were available for 517 and 1,177 participants, respectively. Mean ± SD age of participants with available CMTES-R scores was 41 ± 18 (range 4-87) years, and 56% were female. Follow-up CMTES-R assessments at 1, 2, and 3 years were available for 377, 321, and 244 patients. A mixed regression model showed significant change in CMTES-R score at years 2 through 6 compared to baseline (mean change from baseline 0.59 points at 2 years, p = 0.0004, n = 321). Compared to the original CMTES, the CMTES-R revealed a 55% improvement in the standardized response mean (mean change/SD change) at 2 years (0.17 vs 0.11). Change in CMTES-R at 2 years was greatest in mildly to moderately affected patients (1.48-point mean change, 95% confidence interval 0.99-1.97, p < 0.0001, for baseline CMTES-R score 0-9). CONCLUSION: The CMTES-R demonstrates change over time in patients with CMT1A and is more sensitive than the original CMTES. The CMTES-R was most sensitive to change in patients with mild to moderate baseline disease severity and failed to capture progression in patients with severe CMT1A. CLINICALTRIALSGOV IDENTIFIER: NCT01193075.

Randomized trial of l-serine in patients with hereditary sensory and autonomic neuropathy type 1.

OBJECTIVE: To evaluate the safety and efficacy of l-serine in humans with hereditary sensory autonomic neuropathy type I (HSAN1). METHODS: In this randomized, placebo-controlled, parallel-group trial with open-label extension, patients aged 18-70 years with symptomatic HSAN1 were randomized to l-serine (400 mg/kg/day) or placebo for 1 year. All participants received l-serine during the second year. The primary outcome measure was the Charcot-Marie-Tooth Neuropathy Score version 2 (CMTNS). Secondary outcomes included plasma sphingolipid levels, epidermal nerve fiber density, electrophysiologic measurements, patient-reported measures, and adverse events. RESULTS: Between August 2013 and April 2014, we enrolled and randomized 18 participants, 16 of whom completed the study. After 1 year, the l-serine group experienced improvement in CMTNS relative to the placebo group (-1.5 units, 95% CI -2.8 to -0.1, p = 0.03), with evidence of continued improvement in the second year of treatment (-0.77, 95% CI -1.67 to 0.13, p = 0.09). Concomitantly, deoxysphinganine levels dropped in l-serine-treated but not placebo-treated participants (59% decrease vs 11% increase; p < 0.001). There were no serious adverse effects related to l-serine. CONCLUSION: High-dose oral l-serine supplementation appears safe in patients with HSAN1 and is potentially effective at slowing disease progression. CLINICALTRIALSGOV IDENTIFIER: NCT01733407. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that high-dose oral l-serine supplementation significantly slows disease progression in patients with HSAN1.

Electrodiagnostic evaluation of lower extremity mononeuropathies.

This article discusses the anatomy of lower limb mononeuropathies and reviews the general approach to evaluating patients in the electrodiagnostic laboratory with suspected mononeuropathies of the lower limb. Through illustrative cases of patients presenting with a floppy foot, buckling knee, or painful foot, the approaches using nerve conduction studies and needle electromyography are reviewed, and the pattern of findings of peroneal, tibial, sciatic, femoral, and obturator neuropathies is shown.