Inherited peripheral neuropathies, like many other degenerative disorders, have been challenging to treat. At this point, there is little specific therapy for the inherited neuropathies other than genetic counseling as well as symptomatic treatment and rehabilitation. In the past, ascorbic acid, progesterone antagonists, and subcutaneous neurotrophin-3 (NT3) injections have demonstrated improvement in animal models of CMT 1A, the most common inherited neuropathy, but have failed to translate any effect in humans. Given the difficulty in treatment, it is important to understand the molecular pathogenesis of hereditary neuropathies in order to strategize potential future therapies. The hereditary neuropathies are in an era of molecular insight and over the past 20 years, more than 78 subtypes of Charcot Marie Tooth disease (CMT) have been identified and extensively studied to understand the biological pathways in greater detail. Next generation molecular sequencing has also improved the diagnosis as well as the understanding of CMT. A greater understanding of the molecular pathways will help pave the way to future therapeutics of CMT. This article is part of a Special Issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis.

Objectives To analyse and describe the clinical and genetic spectrum of Charcot-Marie-Tooth disease (CMT) caused by mutations in the neurofilament light polypeptide gene (NEFL). Methods Combined analysis of new patients with NEFL-related CMT, identified from those attending clinics at the participating institutions, and all previously reported cases from the literature. Results Five new unrelated patients with CMT carrying heterozygous NEFL mutations (N98S, P8R and L311P) were identified. Combined data from these cases and 62 kindreds from the literature revealed four common mutations (P8R, P22S, N98S and E396K) and three mutational hotspots accounting for 55% and 75% of kindreds, respectively. De novo mutations were identified in eight patients. Loss of large-myelinated fibres was a uniform feature in 21 sural nerve biopsies, and ‘onion bulb’ formations and/or thin myelin sheaths were observed in 67%. The neurophysiological phenotype was broad but most patients carrying the mutations E90K and N98S had all reported upper limb motor conduction velocities <38 m/s. Age of symptoms onset was ≤ 3 years in 25 cases. Pyramidal tract signs were described in 13 patients and seven patients were initially diagnosed with or tested for inherited ataxia. Patients with E90K and N98S frequently presented before age 3 years and developed hearing loss or other neurological features including ataxia or cerebellar atrophy on brain MRI. Conclusions NEFL-related CMT is clinically and genetically heterogeneous. Based on this study, however, we propose mutational hotspots and relevant clinical-genetic associations that may be helpful in the evaluation of NEFL sequence variants and the differential diagnosis with other forms of CMT.

Background We aimed to test the hypothesis that 3-D volume-based scoring of computed tomographic (CT) images of the paranasal sinuses was superior to Lund-Mackay CT scoring of disease severity in chronic rhinosinusitis (CRS). We determined correlation between changes in CT scores (using each scoring system) with changes in other measures of disease severity (symptoms, endoscopic scoring, and quality of life) in patients with CRS treated with triamcinolone. Methods The study group comprised 48 adult subjects with CRS. Baseline symptoms and quality of life were assessed. Endoscopy and CT scans were performed. Patients received a single systemic dose of intramuscular triamcinolone and were reevaluated 1 month later. Strengths of the correlations between changes in CT scores and changes in CRS signs and symptoms and quality of life were determined. Results We observed some variability in degree of improvement for the different symptom, endoscopic, and quality-of-life parameters after treatment. Improvement of parameters was significantly correlated with improvement in CT disease score using both CT scoring methods. However, volumetric CT scoring had greater correlation with these parameters than Lund-Mackay scoring. Conclusion Volumetric scoring exhibited higher degree of correlation than Lund-Mackay scoring when comparing improvement in CT score with improvement in score for symptoms, endoscopic exam, and quality of life in this group of patients who received beneficial medical treatment for CRS.

Background and Purpose There are few population-based data regarding gender differences in signs and symptoms of acute ischemic stroke. Previously reported data have been inconsistent and conflicting. This study addresses these gender differences in a population-based study. Methods All patients with first ischemic stroke occurring in Rochester, MN residents during 1985-1989 were identified. Signs and symptoms were collected via review of the comprehensive medical records. Differences were identified by Pearson’s Chi-square test. Results Symptoms at ischemic stroke presentation differed between men and women as follows: Women more commonly presented with generalized weakness (p=0.005) and mental status change (p=0.0001). Men more commonly presented with paresthesia (p=0.003), ataxia (p=0.006), and double vision (p =0.005). Signs at ischemic presentation of stroke differed between men and women as follows: Men more commonly presented with nystagmus (p=0.002) on exam. Significant trends were that women more commonly presented with fatigue (p=0.02), disorientation (p=0.04), and fever (p=0.02), and men more commonly presented with sensory abnormalities (p=0.02). Conclusions There are differences by gender in signs and symptoms at presentation of ischemic stroke. In addition to selected focal symptoms, women more commonly present with diffuse symptoms of generalized weakness, fatigue, disorientation, and mental status change.

Leukemia may initially present as a peripheral neuropathy, leading to a delay in diagnosis. Leukemic infiltration of peripheral nerves, or neuroleukemiosis (NL), is exceedingly rare, with no established diagnostic or therapeutic guidelines. Five cases are presented. All patients were men with a median age of 68 years (range 46-72). Three patients had acute myeloid leukemia (AML) and two had chronic lymphocytic leukemia (CLL). In two patients, leukemia presented with peripheral nerve involvement and both were found to have positive cerebrospinal fluid (CSF) cytology, making the diagnosis AML, despite negative bone marrow and peripheral smear. All patients had painful, progressive, motor and sensory deficits. Clinical patterns were mononeuropathy (n =1), multiple mononeuropathies (n =1) and plexopathy (n =3). Magnetic resonance imaging (MRI) detected mass lesions in 4/5 cases, with avid fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET) useful in all of these for following clinical disease progression. Three cases of nerve biopsy were performed, two of which were diagnostic of leukemic infiltration. Radiation treatment rapidly relieved pain in patients with mass lesions, in combination with chemotherapy. Four patients had disease relapse, four systemic and one also in peripheral nerves. These cases are discussed in the context of the broader literature.