Sindhu Ramchandren

CMT subtypes and disease burden in patients enrolled in the Inherited Neuropathies Consortium natural history study: a cross-sectional analysis.

Background The international Inherited Neuropathy Consortium (INC) was created with the goal of obtaining much needed natural history data for patients with Charcot-Marie-Tooth (CMT) disease. We analysed clinical and genetic data from patients in the INC to determine the distribution of CMT subtypes and the clinical impairment associated with them. Methods We analysed data from 1652 patients evaluated at 13 INC centres. The distribution of CMT subtypes and pathogenic genetic mutations were determined. The disease burden of all the mutations was assessed by the CMT Neuropathy Score (CMTNS) and CMT Examination Score (CMTES). Results 997 of the 1652 patients (60.4%) received a genetic diagnosis. The most common CMT subtypes were CMT1A/PMP22 duplication, CMT1X/GJB1 mutation, CMT2A/MFN2 mutation, CMT1B/MPZ mutation, and hereditary neuropathy with liability to pressure palsy/PMP22 deletion. These five subtypes of CMT accounted for 89.2% of all genetically confirmed mutations. Mean CMTNS for some but not all subtypes were similar to those previously reported. Conclusions Our findings confirm that large numbers of patients with a representative variety of CMT subtypes have been enrolled and that the frequency of achieving a molecular diagnosis and distribution of the CMT subtypes reflects those previously reported. Measures of severity are similar, though not identical, to results from smaller series. This study confirms that it is possible to assess patients in a uniform way between international centres, which is critical for the planned natural history study and future clinical trials. These data will provide a representative baseline for longitudinal studies of CMT. Clinical trial registration ID number NCT01193075.

Peripheral neuropathy in survivors of childhood acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is the most common form of cancer in children. Recent advances in treatment have led to dramatically improved survival rates. Standard ALL treatment includes multiple administrations of the chemotherapeutic drug vincristine, which is a known neurotoxic agent. Although peripheral neuropathy is a well‐known toxicity among children receiving vincristine acutely, the long‐term effects on the peripheral nervous system in these children are not clear. The objective of this study was to determine the prevalence of neuropathy and its impact on motor function and quality of life (QOL) among children who survived ALL. Thirty‐seven survivors of childhood ALL aged 8–18 underwent evaluation for neuropathy through self‐reported symptoms, standardized examinations, and nerve conduction studies (NCS). Functional impact of neuropathy was assessed using the Bruininks‐Oseretsky test of Motor Proficiency (BOT‐2). QOL was assessed using the PedsQL. Nerve conduction study abnormalities were seen in 29.7% of children who were longer than 2 years off therapy for ALL. Most children with an abnormal examination or NCS did not have subjective symptoms. Although overall motor function was below population norms on the BOT‐2, presence of neuropathy did not significantly correlate with motor functional status or QOL.

Biomarker evidence for mild central nervous system injury after surgically-induced circulation arrest

Previously, we identified 14-3-3 beta and zeta isoforms and proteolytic fragments of alpha-spectrin as proteins released from degenerating neurons that also rise markedly in cerebrospinal fluid (CSF) following experimental brain injury or ischemia in rodents, but these proteins have not been studied before as potential biomarkers for ischemic central nervous system injury in humans. Here we describe longitudinal analysis of these proteins along with the neuron-enriched hypophosphorylated neurofilament H (pNFH) and the deubiquitinating enzyme UCH-L1 in lumbar CSF samples from 19 surgical cases of aortic aneurysm repair, 7 involving cardiopulmonary bypass with deep hypothermic circulatory arrest (DHCA). CSF levels of the proteins were near the lower limit of detection by Western blot or enzyme-linked fluorescence immunoassay at the onset of surgical procedures, but increased substantially in a subset of cases, typically within 12-24 h. All cases involving DHCA were characterized by >3-fold elevations in CSF levels of the two 14-3-3 isoforms, UCH-L1, and pNFH. Six of 7 also exhibited marked increases in alpha-spectrin fragments generated by calpain, a protease known to trigger necrotic neurodegeneration. Among cases involving aortic cross-clamping but not DHCA, the proteins rose in CSF preferentially in the subset experiencing acute neurological complications. Our results suggest the neuron-enriched 14-3-3beta, 14-3-3zeta, pNFH, UCH-L1, and calpain-cleaved alpha-spectrin may serve as a panel of biomarkers with clinical potential for the detection and management of ischemic central nervous system injury, including for mild damage associated with surgically-induced circulation arrest.

Monoclonal gammopathy and neuropathy.

Purpose of reviewThe management of peripheral neuropathy associated with monoclonal gammopathies has been advanced by recent clinical studies. We review the causal association between monoclonal gammopathy and neuropathy, and critically review the recent evidence on treatment. Recent findingsIgM monoclonal gammopathy of undetermined significance (MGUS) is the most commonly found monoclonal gammopathy associated with neuropathy. Neuropathies associated with specific lymphoproliferative disorders may not respond to treatments aimed at that disorder. Standard immunomodulatory agents including steroids, intravenous immunoglobulin, and plasmapheresis have shown limited efficacy in IgM monoclonal gammopathy of undetermined significance. Newer studies have shown promising results with rituximab, a monoclonal antibody which targets the B cell surface antigen CD20 and results in a rapid and sustained depletion of B cells. SummaryThere is a clear association between peripheral neuropathy and IgM MGUS with characteristic clinical, electrophysiology and pathologic features that make the disorder distinct from chronic inflammatory demyelinating polyneuropathy. The IgG and IgA monoclonal gammopathies are rarely associated with specific neuropathies. Long-term studies looking at the association between specific immunologic markers and disease recurrence are needed to ultimately develop targeted therapies.

An Update on Monoclonal Gammopathy and Neuropathy

Peripheral neuropathy associated with monoclonal gammopathy is a rare but important cause of neuropathy that can herald serious underlying disease. IgM monoclonal gammopathy of undetermined significance (MGUS) is the most commonly found monoclonal gammopathy associated with neuropathy, with characteristic clinical, electrophysiologic, and pathologic features. The IgG and IgA monoclonal gammopathies are rarely associated with specific neuropathies. Standard immunomodulatory agents including steroids, intravenous immunoglobulin, and plasmapheresis have shown limited efficacy in IgM MGUS. Neuropathies associated with specific lymphoproliferative disorders may not respond to treatments aimed at that disorder. Case series had shown promising results with rituximab, a monoclonal antibody that targets the B cell surface antigen CD20 and results in a rapid and sustained depletion of B cells; however, two recent randomized controlled trials with rituximab failed to provide evidence of efficacy in primary outcome measures, despite reduction in antibody levels. Long-term studies looking at the association between specific immunologic markers and disease recurrence are needed to ultimately develop targeted therapies.

Determinants of reduced health-related quality of life in pediatric inherited neuropathies

Objective: We have shown that health-related quality of life (QOL) in children with inherited neuropathies (Charcot-Marie-Tooth disease [CMT]) is significantly reduced compared to population norms, thus establishing its utility as an outcome measure in therapeutic trials. However, the Australian ascorbic acid trial in children with CMT type 1A (CMT1A) identified no change in QOL scores despite a trend toward improvement in nerve conduction velocities in the treated group. The objective of this study was to identify clinical, electrophysiologic, and functional correlates of QOL in children with CMT1A, to guide future investigations of strategies to improve QOL and reduce disability in these patients. Methods: In this cross-sectional study, a series of multivariate regression models were developed to determine whether QOL scores could be explained by demographic and symptom data, standardized measures of gross motor function, foot/ankle and hand/finger involvement, electrophysiology, and gait characteristics in 70 children aged 5–16 years with CMT1A. Results: Independent determinants of reduced QOL in children with CMT1A, from strongest to weakest, were leg cramps, hand tremor, short step length, reduced long jump distance, ankle inflexibility, poor agility and endurance, advancing age, and foot drop. Many of the standardized clinical and electrophysiologic measures used as endpoints in clinical trials of CMT correlated poorly with QOL. Conclusion: QOL is negatively affected by CMT1A in children. Multivariate modeling suggests that interventions designed to improve leg cramps, tremor, agility, endurance, and ankle flexibility might have a substantial effect on QOL in children with CMT1A.

Phenotypic Variability of Childhood Charcot-Marie-Tooth Disease

IMPORTANCE Disease severity of childhood Charcot-Marie-Tooth disease (CMT) has not been extensively characterized, either within or between types of CMT to date. OBJECTIVE To assess the variability of disease severity in a large cohort of children and adolescents with CMT. DESIGN, SETTING, AND PARTICIPANTS A cross-sectional study was conducted among 520 children and adolescents aged 3 to 20 years at 8 universities and hospitals involved in the Inherited Neuropathies Consortium between August 6, 2009, and July 31, 2014, in Australia, Italy, the United Kingdom, and the United States. Data analysis was conducted from August 1, 2014, to December 1, 2015. MAIN OUTCOMES AND MEASURES Scores on the Charcot-Marie-Tooth Disease Pediatric Scale (CMTPedS), a well-validated unidimensional clinical outcome measure to assess disease severity. This instrument includes 11 items assessing fine and gross motor function, sensation, and balance to produce a total score ranging from 0 (unaffected) to 44 (severely affected). RESULTS Among the 520 participants (274 males) aged 3 to 20 years, CMT type 1A (CMT1A) was the most prevalent type (252 [48.5%]), followed by CMT2A (31 [6.0%]), CMT1B (15 [2.9%]), CMT4C (13 [2.5%]), and CMTX1 (10 [1.9%]). Disease severity ranged from 1 to 44 points on the CMTPedS (mean [SD], 21.5 [8.9]), with ankle dorsiflexion strength and functional hand dexterity test being most affected. Participants with CMT1B (mean [SD] CMTPedS score, 24.0 [7.4]), CMT2A (29.7 [7.1]), and CMT4C (29.8 [8.6]) were more severely affected than those with CMT1A (18.9 [7.7]) and CMTX1 (males: 15.3 [7.7]; females: 13.0 [3.6]) (P < .05). Scores on the CMTPedS tended to worsen principally during childhood (ages, 3-10 years) for participants with CMT4C and CMTX1 and predominantly during adolescence for those with CMT1B and CMT2A (ages, 11-20 years), while CMT1A worsened consistently throughout childhood and adolescence. For individual items, participants with CMT4C recorded more affected functional dexterity test scores than did those with all other types of CMT (P < .05). Participants with CMT1A and CMTX1 performed significantly better on the 9-hole peg test and balance test than did those with all other types of CMT (P < .05). Participants with CMT2A had the weakest grip strength (P < .05), while those with CMT2A and CMT4C exhibited the weakest ankle plantarflexion and dorsiflexion strength, as well as the lowest long jump and 6-minute walk test distances (P < .05). Multiple regression modeling identified increasing age (r = 0.356, β = 0.617, P < .001) height (r = 0.251, β = 0.309, P = .002), self-reported foot pain (r = 0.162, β = .114, P = .009), and self-reported hand weakness (r = 0.243, β = 0.203, P < .001) as independent predictors of disease severity. CONCLUSIONS AND RELEVANCE These results highlight the phenotypic variability within CMT genotypes and mutation-specific manifestations between types. This study has identified distinct functional limitations and self-reported impairments to target in future therapeutic trials.

Genotype–phenotype characteristics and baseline natural history of heritable neuropathies caused by mutations in the MPZ gene

We aimed to characterize genotype-phenotype correlations and establish baseline clinical data for peripheral neuropathies caused by mutations in the myelin protein zero (MPZ) gene. MPZ mutations are the second leading cause of Charcot-Marie-Tooth disease type 1. Recent research makes clinical trials for patients with MPZ mutations a realistic possibility. However, the clinical severity varies with different mutations and natural history data on progression is sparse. We present cross-sectional data to begin to define the phenotypic spectrum and clinical baseline of patients with these mutations. A cohort of patients with MPZ gene mutations was identified in 13 centres of the Inherited Neuropathies Consortium - Rare Disease Clinical Research Consortium (INC-RDCRC) between 2009 and 2012 and at Wayne State University between 1996 and 2009. Patient phenotypes were quantified by the Charcot-Marie-Tooth disease neuropathy score version 1 or 2 and the Charcot-Marie-Tooth disease paediatric scale outcome instruments. Genetic testing was performed in all patients and/or in first- or second-degree relatives to document mutation in MPZ gene indicating diagnosis of Charcot-Marie-Tooth disease type 1B. There were 103 patients from 71 families with 47 different MPZ mutations with a mean age of 40 years (range 3-84 years). Patients and mutations were separated into infantile, childhood and adult-onset groups. The infantile onset group had higher Charcot-Marie-Tooth disease neuropathy score version 1 or 2 and slower nerve conductions than the other groups, and severity increased with age. Twenty-three patients had no family history of Charcot-Marie-Tooth disease. Sixty-one patients wore foot/ankle orthoses, 19 required walking assistance or support, and 10 required wheelchairs. There was hearing loss in 21 and scoliosis in 17. Forty-two patients did not begin walking until after 15 months of age. Half of the infantile onset patients then required ambulation aids or wheelchairs for ambulation. Our results demonstrate that virtually all MPZ mutations are associated with specific phenotypes. Early onset (infantile and childhood) phenotypes likely represent developmentally impaired myelination, whereas the adult-onset phenotype reflects axonal degeneration without antecedent demyelination. Data from this cohort of patients will provide the baseline data necessary for clinical trials of patients with Charcot-Marie-Tooth disease caused by MPZ gene mutations.

Hypoglossal nerve conduction findings in obstructive sleep apnea

Denervation of oropharyngeal muscles in obstructive sleep apnea (OSA) has been suggested by needle electromyography (EMG) and muscle biopsy, but little is known about oropharyngeal nerve conduction abnormalities in OSA. We sought to compare hypoglossal nerve conduction studies in patients with and without OSA. Unilateral hypoglossal nerve conduction studies were performed on 20 subjects with OSA and 20 age‐matched controls using standard techniques. Median age was 48 years in OSA subjects and 47 years in controls. Hypoglossal compound muscle action potential (CMAP) amplitudes were significantly reduced (P = 0.01, Wilcoxon signed‐rank test), but prolongation of latencies in OSA subjects did not reach significance in comparison to those of controls. Among a subgroup of subjects without polyneuropathy (15 pairs), reduced amplitudes in OSA subjects retained borderline significance (P = 0.05). Hypoglossal nerve conduction abnormalities may distinguish patients with OSA from controls. These abnormalities could potentially contribute to, or arise from, OSA. Muscle Nerve, 2010

Heat shock proteins HSP70 and HSP27 in the cerebral spinal fluid of patients undergoing thoracic aneurysm repair correlate with the probability of postoperative paralysis

An understanding of the time course and correlation with injury of heat shock proteins (HSPs) released during brain and/or spinal cord cellular stress (ischemia) is critical in understanding the role of the HSPs in cellular survival, and may provide a clinically useful biomarker of severe cellular stress. We have analyzed the levels of HSPs in the cerebrospinal fluid (CSF) from patients who are undergoing thoracic aneurysm repair. Blood and CSF samples were collected at regular intervals, and CSF was analyzed by enzyme-linked immunosorbent assay for HSP70 and HSP27. These results were correlated with intraoperative somatosensory-evoked potentials measurements and postoperative paralysis. We find that the levels of these proteins in many patients are elevated and that the degree of elevation correlates with the risk of permanent paralysis. We hypothesize that sequential measurement intraoperatively of the levels of the heat shock proteins HSP70 and HSP27 in the CSF can predict those patients who are at greatest risk for paralysis during thoracic aneurysm surgery and will allow us to develop means of preventing or attenuating this severe and often fatal complication.