A review of genetic counseling for Charcot Marie Tooth disease (CMT).

Charcot Marie Tooth disease (CMT) encompasses the inherited peripheral neuropathies. While four genes have been found to cause over 90 % of genetically identifiable causes of CMT (PMP22, GJB1, MPZ, MFN2), at least 51 genes and loci have been found to cause CMT when mutated, creating difficulties for clinicians to find a genetic subtype for families. Here, the classic features of CMT as well as characteristic features of the most common subtypes of CMT are described, as well as methods for narrowing down the possible subtypes. Psychosocial concerns particular to the CMT population are identified. This is the most inclusive publication for CMT-specific genetic counseling.

Novel deletion of lysine 7 expands the clinical, histopathological and genetic spectrum of TPM2-related myopathies.

The ß-tropomyosin gene encodes a component of the sarcomeric thin filament. Rod-shaped dimers of tropomyosin regulate actin-myosin interactions and ß-tropomyosin mutations have been associated with nemaline myopathy, cap myopathy, Escobar syndrome and distal arthrogryposis types 1A and 2B. In this study, we expand the allelic spectrum of ß-tropomyosin-related myopathies through the identification of a novel ß-tropomyosin mutation in two clinical contexts not previously associated with ß-tropomyosin. The first clinical phenotype is core-rod myopathy, with a ß-tropomyosin mutation uncovered by whole exome sequencing in a family with autosomal dominant distal myopathy and muscle biopsy features of both minicores and nemaline rods. The second phenotype, observed in four unrelated families, is autosomal dominant trismus-pseudocamptodactyly syndrome (distal arthrogryposis type 7; previously associated exclusively with myosin heavy chain 8 mutations). In all four families, the mutation identified was a novel 3-bp in-frame deletion (c.20_22del) that results in deletion of a conserved lysine at the seventh amino acid position (p.K7del). This is the first mutation identified in the extreme N-terminus of ß-tropomyosin. To understand the potential pathogenic mechanism(s) underlying this mutation, we performed both computational analysis and in vivo modelling. Our theoretical model predicts that the mutation disrupts the N-terminus of the α-helices of dimeric ß-tropomyosin, a change predicted to alter protein-protein binding between ß-tropomyosin and other molecules and to disturb head-to-tail polymerization of ß-tropomyosin dimers. To create an in vivo model, we expressed wild-type or p.K7del ß-tropomyosin in the developing zebrafish. p.K7del ß-tropomyosin fails to localize properly within the thin filament compartment and its expression alters sarcomere length, suggesting that the mutation interferes with head-to-tail ß-tropomyosin polymerization and with overall sarcomeric structure. We describe a novel ß-tropomyosin mutation, two clinical-histopathological phenotypes not previously associated with ß-tropomyosin and pathogenic data from the first animal model of ß-tropomyosin-related myopathies.

Neurogenetics: Five new things.

Clinical neurology has benefitted greatly from recent remarkable advances in molecular genetics. In 1991, we could approximate a patient's risk for Huntington disease (HD) based only on linkage analysis. Now, 20 years later, not only can we identify the HD mutation with certainty, we can do the same with several hundred diseases. Whole genome or exome sequencing will soon allow for one-step interrogation of multiple genes for an even larger range of diseases. The recognition of these genes and their associated proteins in combination with new technology has led to creative new approaches to treatment. The challenge for the practicing neurologist is to provide clinically relevant and accurate interpretation of the genetic test results, with successfully treating once "incurable" neurogenetic diseases our ultimate goal.

Impact of presymptomatic genetic testing for hereditary ataxia and neuromuscular disorders.

BACKGROUND: With the exception of Huntington disease, the psychological and psychosocial impact of DNA testing for neurogenetic disorders has not been well studied. OBJECTIVE: To evaluate the psychosocial impact of genetic testing for autosomal dominant forms of hereditary ataxia and neuromuscular disorders. Patients Fifty subjects at risk for autosomal dominant forms of spinocerebellar ataxia (n = 11), muscular dystrophy (n = 28), and hereditary neuropathy (n = 12). DESIGN AND SETTING: A prospective, descriptive, observational study in a university setting of individuals who underwent genetic counseling and DNA testing. Participants completed 3 questionnaires before testing and at regular intervals after testing. The questionnaire set included the Revised Impact of Event Scale, the Hospital Anxiety and Depression Scale, demographic information, and an assessment of attitudes and feelings about genetic testing. RESULTS: Thirty-nine subjects (78%) completed 6 months to 5 years of posttest follow-up. Common reasons for pursuing genetic testing were to provide an explanation for symptoms, emotional relief, and information for future planning. Thirty-four (68%) had positive and 16 (32%) had negative genetic results. In those with a positive result, 26 (76%) had nonspecific signs or symptoms of the relevant disorder. Forty-two participants (84%) felt genetic testing was beneficial. Groups with positive and negative test results coped well with results. However, 13 subjects (10 with positive and 3 with negative results) reported elevated anxiety levels, and 3 (1 with positive and 2 with negative results) expressed feelings of depression during the follow-up period. The test result was not predictive of anxiety or depression. CONCLUSIONS: Most individuals find neurogenetic testing to be beneficial, regardless of the result. Anxiety or depression may persist in some persons with positive or negative test results. Testing can have a demonstrable impact on family planning and interpersonal relationships. Further studies are needed to assess the long-term impact of such testing.