Background Charcot Marie Tooth disease (CMT) affects one in 2500 people and is caused by mutations in more than 30 genes. Identifying the genetic cause of CMT is often necessary for family planning, natural history studies and for entry into clinical trials. However genetic testing can be both expensive and confusing to patients and physicians. Methods We analyzed data from 1024 of our patients to determine the percentage and features of each CMT subtype within this clinic population. We identified distinguishing clinical and physiological features of the subtypes that could be used to direct genetic testing for patients with CMT. Findings Of 1024 patients evaluated, 787 received CMT diagnoses. Five hundred twenty-seven patients with CMT (67%) received a genetic subtype, while 260 did not have a mutation identified. The most common CMT subtypes were CMT1A, CMT1X, HNPP, CMT1B, and CMT2A. All other subtypes accounted for less than 1% each. Eleven patients had more than one genetically identified subtype of CMT. Patients with genetically identified CMT were separable into specific groups based on age of onset and the degree of slowing of motor nerve conduction velocities. Interpretation Combining features of the phenotypic and physiology groups allowed us to identify patients who were highly likely to have specific subtypes of CMT. Based on these results, we propose a strategy of focused genetic testing for CMT illustrated in a series of flow diagrams created as testing guides.

Objective: To identify the gene responsible for 14q32-linked dominant spinal muscular atrophy with lower extremity predominance (SMA-LED, OMIM 158600). Methods:Target exon capture and next generation sequencing was used to analyze the 73 genes in the 14q32 linkage interval in 3 SMA-LED family members. Candidate gene sequencing in additional dominant SMA families used PCR and pooled target capture methods. Patient fibroblasts were biochemically analyzed.Results: Regional exome sequencing of all candidate genes in the 14q32 interval in the original SMA-LED family identified only one missense mutation that segregated with disease state-a mutation in the tail domain of DYNC1H1 (I584L). Sequencing of DYNC1H1 in 32 additional probands with lower extremity predominant SMA found 2 additional heterozygous tail domain mutations (K671E and Y970C), confirming that multiple different mutations in the same domain can cause a similar phenotype. Biochemical analysis of dynein purified from patient-derived fibroblasts demonstrated that the I584L mutation dominantly disrupted dynein complex stability and function. Conclusions:We demonstrate that mutations in the tail domain of the heavy chain of cytoplasmic dynein (DYNC1H1) cause spinal muscular atrophy and provide experimental evidence that a human DYNC1H1 mutation disrupts dynein complex assembly and function. DYNC1H1 mutations were recently found in a family with Charcot-Marie-Tooth disease (type 2O) and in a child with mental retardation. Both of these phenotypes show partial overlap with the spinal muscular atrophy patients described here, indicating that dynein dysfunction is associated with a range of phenotypes in humans involving neuronal development and maintenance. Neurology ® 2012;78:1714-1720 GLOSSARY CMT ϭ Charcot-Marie-Tooth; gDNA ϭ genomic DNA; indels ϭ insertions/deletions; SDS-PAGE ϭ sodium dodecyl sulfate polyacrylamide gel electrophoresis; SMA ϭ spinal muscular atrophy; SMA-LED ϭ spinal muscular atrophy with lower extremity predominance; SNP ϭ single nucleotide polymorphism.Developmental and degenerative disorders affecting motor neurons or their axons produce a broad range of inherited human diseases, including spinal muscular atrophy (SMA), hereditary motor neuropathy, and amyotrophic lateral sclerosis. Many hypotheses regarding the pathophysiology of motor neuron loss (e.g., impaired axonal transport, aberrant protein aggregation, disrupted protein homeostasis, altered RNA metabolism 1,2 ) were first suggested by the identification of new genes producing hereditary motor neuron disease. To identify additional genes required for motor neuron survival, we studied a large pedigree with a rare form of dominantly inherited SMA with early childhood onset of weakness and disproportionate involvement of From the Department of Neurology

Data indicates that millions of motor vehicles accidents (MVA) occur each year and that MVAs are one of the leading causes of posttraumatic stress disorder (PTSD). Despite these findings, PTSD screening tools have not been identified for MVA populations. The current study examines two potential PTSD screening tools, the Impact of Event Scale (IES) and the PTSD Symptom Scale, SelfReport (PSS-SR), in a large sample of MVA survivors. For the IES using a cutoff score of 27, sensitivity was .91, specificity was .72 and overall correct classification was .80. For the PSS-SR using a cutoff score of 14, sensitivity was .91, specificity was .62 and overall correct classification was .74. These data support the use of the IES and the PSS-SR as PTSD screening tools in MVA samples. KeywordsPTSD; motor vehicle accident; screening; self-report measures; assessment Screening for PTSD in motor vehicle accident survivors: The use of the PSS-SR and IES-RAccording to the National Safety Council (1993), millions of motor vehicle accidents (MVAs) occur each year but only recently have the psychological consequences of MVAs been fully recognized. Norris (1992) has shed some light on the psychological sequela of MVAs by examining the frequency and impact of 10 potentially traumatic events in a large, multi-site epidemiological study. Among traumatized individuals in this study, MVAs were found to be a leading cause of posttraumatic stress disorder (PTSD), preceded only by sexual and physical assaults. Moreover, Norris states that "when both the frequency and severity data were considered together, [MVAs] emerged as perhaps the single most significant event among those studied" (pp. 416). Extrapolating from the rates of trauma and PTSD, Norris estimates that MVAs alone could account for 28 cases of PTSD for every 1000 adults in the United States.Other investigators have also examined the rates of PTSD and PTSD symptomatology in MVA populations. These investigations have produced a wide range of prevalence estimates depending on the methodology employed. For example, among consecutive admissions of MVA survivors at an emergency department, Mayou and colleagues found that 11% met criteria for PTSD in the following year (Mayou, Bryant & Duthie, 1993). In a similar study,

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Charcot-Marie-Tooth disease type 1A (CMT1A) is caused by a 1.4 Mb duplication on chromosome 17p11.2, which contains the peripheral myelin protein-22 (PMP22) gene. Increased levels of PMP22 in compact myelin of peripheral nerves have been demonstrated and presumed to cause the phenotype of CMT1A. The objective of the present study was to determine whether an extra copy of the PMP22 gene in CMT1A disrupts the normally coordinated expression of PMP22 protein in peripheral nerve myelin and to evaluate PMP22 over-expression in patients with CMT1A and determine whether levels of PMP22 are molecular markers of disease severity. PMP22 expression was measured by taking skin biopsies from patients with CMT1A (n = 20) and both healthy controls (n = 7) and patients with Hereditary Neuropathy with liability to Pressure Palsies (HNPP) (n = 6), in which patients have only a single copy of PMP22. Immunological electron microscopy was performed on the skin biopsies to quantify PMP22 expression in compact myelin. Similar biopsies were analysed by real time PCR to measure PMP22 mRNA levels. Results were also correlated with impairment in CMT1A, as measured by the validated CMT Neuropathy Score. Most, but not all patients with CMT1A, had elevated PMP22 levels in myelin compared with the controls. The levels of PMP22 in CMT1A were highly variable, but not in HNPP or the controls. However, there was no correlation between neurological disabilities and the level of over-expression of PMP22 protein or mRNA in patients with CMT1A. The extra copy of PMP22 in CMT1A results in disruption of the tightly regulated expression of PMP22. Thus, variability of PMP22 levels, rather than absolute level of PMP22, may play an important role in the pathogenesis of CMT1A.