Background and Objectives Oculopharyngeal muscular dystrophy (OPMD) is a late-onset, progressive muscle disease. Disease progression is known to be slow, but details on the natural history remain... Show moreBackground and Objectives Oculopharyngeal muscular dystrophy (OPMD) is a late-onset, progressive muscle disease. Disease progression is known to be slow, but details on the natural history remain unknown. We aimed to examine the natural history of OPMD in a large nationwide cohort to determine clinical outcome measures that capture disease progression and can be used in future clinical trials. Methods Patients invited by their treating physicians or identified from the national neuromuscular database and invited family members were examined twice 20 months apart with fixed dynamometry; Medical Research Council (MRC) grading; maximum bite force and isometric tongue strength; Motor Function Measure (MFM); 10-step stair test; maximum swallowing, chewing, and speech tasks; and quality of life assessments. Results Disease progression was captured by 8 of 18 measures over 20 months in 43 patients with genetically confirmed OPMD. The largest deterioration was seen in deltoid muscle strength (-27% [range -17% to -37%]), followed by the quadriceps (-14% [range -6 to -23%]), iliopsoas (-12.2%), tongue (-9.9%), and MRC sum score (-2.5%). The 10-step stair test (-12.5%), MFM part D1 (-7.1%), and maximum repetition rate of /pa/ (-5.3%) showed a significant decrease as well (all p < 0.05). The Physical Functioning domain of the Short Form-36 Health Survey significantly deteriorated (p = 0.044). No relationship was found between disease progression and genotype or disease duration (p > 0.05). Discussion Despite the slow disease progression of OPMD, this study showed that several outcome measures detected progression within 20 months. Deltoid muscle strength, measured by fixed dynamometry, showed the greatest decline. These longitudinal data provide clinical outcome measures that can be used as biomarkers in future clinical trials. Show less
Leeuw, R.H. de; Garnier, D.; Kroon, R.M.J.M.; Horlings, C.G.C.; Meijer, E. de; Buermans, H.; ... ; Raz, V. 2019
Short tandem repeats (STRs) are scattered throughout the human genome. Some STRs, like trinucleotide repeat expansion (TRE) variants, cause hereditable disorders. Unambiguous molecular diagnostics... Show moreShort tandem repeats (STRs) are scattered throughout the human genome. Some STRs, like trinucleotide repeat expansion (TRE) variants, cause hereditable disorders. Unambiguous molecular diagnostics of TRE disorders is hampered by current technical limitations imposed by traditional PCR and DNA sequencing methods. Here we report a novel pipeline for TRE variant diagnosis employing the massively parallel sequencing (MPS) combined with an opensource software package (FDSTools), which together are designed to distinguish true STR sequences from STR sequencing artifacts. We show that this approach can improve TRE diagnosis, such as Oculopharyngeal muscular dystrophy (OPMD). OPMD is caused by a trinucleotide expansion in the PABPN1 gene. A short GCN expansion, (GCN[10]), coding for a 10 alanine repeat is not pathogenic, but an alanine expansion is pathogenic. Applying this novel procedure in a Dutch OPMD patient cohort, we found expansion variants from GCN[11] to GCN[16], with the GCN[16] as the most abundant variant. The repeat expansion length did not correlate with clinical features. However, symptom severity was found to correlate with age and with the initial affected muscles, suggesting that aging and muscle-specific factors can play a role in modulating OPMD. Show less
