Background and Objectives: The prevalence and progression of respiratory muscle dysfunction in patients with limb girdle muscular dystrophies (LGMDs) has been only partially described to date. Most reports include cross-sectional data on a limited number of patients making it difficult to gain a wider perspective on respiratory involvement throughout the course of the disease and to compare the most prevalent LGMD subtypes. Methods: We reviewed the results of spirometry studies collected longitudinally in our cohort of patients in routine clinical visits from 2002 to 2020 along with additional clinical and genetic data. A linear mixed model was used to investigate the factors associated with the progression of respiratory dysfunction. Results: We followed up 156 patients with 5 different forms of LGMDs for a median of 8 years (range 1-25 years). Of them, 53 patients had pathogenic variants in the Capn3 gene, 47 patients in the Dysf gene, 24 patients in the Fkrp gene, 19 in the Ano5 gene, and 13 in one of the sarcoglycan genes (SCG). At baseline, 58 patients (37.1%) had a forced vital capacity percentage predicted (FVCpp) below 80%, while 14 patients (8.9%) had peak cough flow (PCF) values below 270 L/min. As a subgroup, FKRP was the group with a higher number of patients having FVC <80% and/or PCF <270 L/min at initial assessment (66%). We observed a progressive decline in FVCpp and PCF measurements over time, being age, use of wheelchair, and LGMD subtype independent factors associated with this decline. Fkrp and sarcoglycan patients had a quicker decline in their FVC (Kaplan-Meier curve, F test, p < 0.001 and p = 0.02, respectively). Only 7 of the 58 patients with low FVCpp values reported symptoms of respiratory dysfunction, which are commonly reported by patients with FVCpp below 50%-60%. The number of patients ventilated increased from 2 to 8 during follow-up. Discussion: Respiratory dysfunction is a frequent complication of patients with LGMDs that needs to be carefully studied and has direct implications in the care offered in daily clinics. Respiratory dysfunction is associated with disease progression because it is especially seen in patients who are full-time wheelchair users, being more frequent in patients with mutations in the Fkrp and sarcoglycan genes.
Background and Objectives: Sporadic Creutzfeldt-Jakob disease (sCJD) has established genetic risk factors, but, in contrast to genetic and acquired CJD, the initial trigger for misfolded prion aggregation and spread is not known. In this study, we tested the hypotheses that pathologic somatic variants in the prion gene PRNP are increased in sCJD, potentially leading to the seeding of misfolded prion protein. Methods: High-depth amplicon-based short read sequencing of the PRNP coding region was performed on postmortem brain tissue from patients with a clinical and neuropathologic diagnosis of sCJD (n = 142), Alzheimer disease (AD) (n = 51) and controls with no clinical or neuropathologic diagnosis of a neurodegenerative disease (n = 71). Each DNA sample was sequenced twice, including independent PCR amplification, library preparation, and sequencing. We used RePlow to call somatic variants with high sensitivity and specificity and optimal sequence kernel association test to compare variant burden between groups. Results: Two sCJD cases had somatic (variant allele frequency 0.5-1%) PRNP variants not previously identified, but with high in silico predicated pathogenicity. However, the pathogenicity of these variants is uncertain, as both located in the octapeptide repeat region where no point variations have previously been associated with sCJD. There was no overall difference in burden somatic PRNP in sCJD compared with controls and a lower burden compared with Alzheimer disease. Discussion: Somatic variants in PRNP are unlikely to play a major role in sCJD but may contribute to the disease mechanism in a minority of cases.
