Large normal ('intermediate') alleles may produce de novo expansions in Huntington disease; nevertheless, there is very little evidence about their population prevalence and impact in daily practice, and there are conflicting reports about the extent of their instability. We estimated the frequency of large normal alleles (27-35 CAGs) and of reduced penetrance alleles (36-39 CAGs), as well as the frequency of genotypes carrying them, in (i) a diagnostic laboratory, (ii) a genetic counselling clinic and (iii) the general population. Large normal alleles were present in 6% of a large control sample, 7% of consultands who took pre-symptomatic testing and 7% of samples in the laboratory. Reduced penetrance alleles were found in 1 of 1772 control chromosomes (0.1% of individuals), 5% of 146 pre-symptomatic testees and over 2% of 1214 diagnostic samples (350 families). All 16 alleles sized 27-32 CAGs seemed to be transmitted stably; alleles ≥ 36 repeats were unstable in five families. Seven small full penetrance alleles contracted into the reduced penetrance range, but none into the large normal range. Evidence showed that large normal alleles are relatively frequent and that those with reduced penetrance are not a rare event, either at the laboratory or the clinic. This reinforces the need to understand the genomic context of repeat instability in each family and population.
Huntington disease (HD) is an autosomal dominant neurodegenerative disorder characterised by chorea, cognitive impairment, dementia and personality changes, caused by the expansion of a CAG repeat in the HD gene. Often, patients with a similar clinical presentation do not carry expansions of the CAG repeat in this gene [Huntington disease-like (HDL) patients]. We report the genetic analysis of 107 Portuguese patients with an HDL phenotype. The HDL genes PRNP and JPH3, encoding the prion protein and junctophilin-3, respectively, were screened for repeat expansions in these patients. Given the partial clinical overlap of SCA17, DRPLA and neuroferritinopathy with HD, their causative genes (TBP, ATN1, and FTL, respectively) were also analysed. Finally, repeat expansions in two candidate genes, CREBBP and POU3F2, which encode the nuclear transcriptional coactivator CREB-binding protein and the CNS-specific transcription factor NOct-3, respectively, were also studied. Expansions of the repetitive tracts of the PRNP, JPH3, TBP, ATN1, CREBBP and POU3F2 genes were excluded in all patients, as were sequence alterations in the FTL gene. Since none of the genes already included in the differential diagnosis of HD was responsible for the disease in our sample, the genetic heterogeneity of the HDL phenotype is still open for investigation.
BackgroundIt is essential to understand, characterize, and measure the embouchure mechanism of a wind instrumentalists, where the applied forces on the perioral tissues can usually promote discomfort or pain.MethodsThe sample consisted of five clarinet players and five saxophone players. The embouchure force measurements at the lower lip area were assessed using a piezoresistive sensor (FlexiForceTM, Tekscan, Boston, USA, 0.07 kgf/cm2) placed on the lower part of the mouthpiece of the single reed instrument. Furthermore, each participant performed three times three different notes at different pitches: high, medium, and low. An intraoral device was manufactured in order to dissipate the existing pressures.ResultsThe piezoresistive sensors applied to the mouthpiece of the five clarinetists presented values between 16 and 226 g of force. In the case of the five saxophonists, the values registered were between 5 and 320 g of force.ConclusionsPiezoresistive sensors are a valid option to characterize that single reed instrumentalists apply substantial forces at the lower lip that can be equivalent to medium orthodontic forces. The implementation of the Lip Pressure Appliance can be a valid solution on the prevention of eventual lesions resulting from the embouchure forces.
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