Homozygosity of a Founder Variant c.1508dupC in DOK7 Causes Congenital Myasthenia With Variable Severity.

Background and Objectives: Description of 15 patients with the same variant in DOK7 causing congenital myasthenic syndrome (CMS). Methods: Nine adult and 6 pediatric patients were studied with molecular genetic and clinical investigations. Results: All patients were identified with the c.1508dupC variant in DOK7, of whom 13 were homozygous and 2 patients compound heterozygous. Only 2 patients had limb girdle phenotype, while all adult patients also had ptosis, ophthalmoplegia, facial weakness, as well as inspiratory stridor. Pediatric patients had severe respiratory insufficiency and feeding difficulties at birth. Discussion: The disease severity in our patients varied extensively from ventilator or wheelchair dependence to mild facial weakness, ptosis, and ophthalmoparesis. Most of the patients had normal transmission in conventional 3 Hz stimulation electrophysiologic studies, making the diagnosis of CMS challenging. Our cohort of adult and pediatric patients expands the phenotype of DOK7 CMS and shows the importance of correct and early diagnosis.

Unusual clinical presentation and neuropathology in two subjects with fused-in sarcoma (FUS) positive inclusions.

We report two unusual autopsy cases with frontotemporal lobar degeneration (FTLD) that were hyperphosphorylated-tau- and TAR DNA binding protein 43 (TDP-43)- negative. The behavioral symptoms in both cases were compatible with frontotemporal dementia, but they exhibited more prominent speech and language related symptoms than previously reported. Moreover, they displayed a short duration of the disease; the male case had a disease onset age of 45 years, and duration of 5 years, and the female case suffered even shorter disease duration and a later onset of the symptoms, at the age of 67 years. Moreover, the motor functions had deteriorated in different ways in these cases. The male patient showed progressive motor symptoms, weakness of extremities and bulbar muscles suggesting motor neuron disease with a muscle biopsy supporting neurogenic deficits, whereas the female patient exhibited dyskinesias and tremor with progressive swallowing disorders. The father of the male case displayed dementia of similar type at the age of 68 years. In both cases, neuropathological examination showed fused-in sarcoma (FUS)-positive pathology. The male patient had intensely FUS-positive cytoplasmic and intranuclear inclusions that resembled the characteristics previously reported in FTLD FUS, whereas the female patient did not exhibit any cytoplasmic inclusions but had roundish, dense FUS-positive intranuclear inclusions. She also displayed a plethora of other pathologies including α-synuclein, hyperphosphorylated-tau, ß-amyloid aggregation and some neuronal polyglutamine aggregation (1C2) but no well-demarcated inclusions were observed. We conclude that clinical phenotypes of FUS pathologies also include elderly patients and are more variable with motor and speech disorders than previously reported.