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Möller, B, Becker, L-L, Saffari, A, Afenjar, A, Coci, E G, Williamson, R, Ward-Melver, C, Gibaud, M, Sedlácková, L, Laššuthová, P, Libá, Z, Vlcková, M, William, N, Klee, E W, Gavrilova, R H, Lévy, J, Capri, Y, Scavina, M, Körner, R W, Valuvullah, Z, Weiß, C, Möller, G M, Thiel, M, Sinnema, M, Kamsteeg, E-J, Donkervoort, S, Duboc, V, Zaafrane-Khachnaoui, K, Elkhateeb, N, Selim, L, Margot, H, Marin, V, Beneteau, C, Isidor, B, Cogne, B, Keren, B, Küsters, B, Beggs, A H, Genetti, C A, Nicolai, J, Dötsch, J, Koy, A, Bönnemann, C G, von der Hagen, M, von .... |
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Intracellular trafficking involves an intricate machinery of motor complexes, including the dynein complex, to shuttle cargo for autophagolysosomal degradation. Deficiency in dynein axonemal chains, as well as cytoplasmic light and intermediate chains, have been linked with ciliary dyskinesia and skeletal dysplasia. The cytoplasmic dynein 1 heavy chain protein (DYNC1H1) serves as a core complex for retrograde trafficking in neuronal axons. Dominant pathogenic variants in DYNC1H1 have been previously implicated in peripheral neuromuscular disorders (NMD) and neurodevelopmental disorders (NDD). As heavy-chain dynein is ubiquitously expressed, the apparent selectivity of heavy chain dyneinopathy for motor neuronal phenotypes remains currently unaccounted for. Here, we aimed to evaluate the full DYNC1H1-related clinical, molecular and imaging spectrum, including multisystem features and novel phenotypes presenting throughout life. We identified 47 cases from 43 families with pathogenic heterozygous variants in DYNC1H1 (aged 0–59 years) and collected phenotypic data via a comprehensive standardized survey and clinical follow-up appointments. Most patients presented with divergent and previously unrecognized neurological and multisystem features, leading to significant delays in genetic testing and establishing the correct diagnosis. Neurological phenotypes include novel autonomic features, previously rarely described behavioral disorders, movement disorders and periventricular lesions. Sensory neuropathy was identified in nine patients (median age of onset 10.6 years), of which five were only diagnosed after the second decade of life, and three had a progressive age-dependent sensory neuropathy. Novel multisystem features included primary immunodeficiency, bilateral sensorineural hearing loss, organ anomalies and skeletal manifestations, resembling the phenotypic spectrum of other dyneinopathies. We also identified an age-dependent biphasic disease course with developmental regression in the first decade and, ... |