[en] Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to prototypical yet poorly understood forms of childhood-onset and complex hereditary spastic paraplegia: SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). Here, we report a detailed cross-sectional analysis of clinical, imaging and molecular data of 156 patients from 101 families. Enrolled patients were of diverse ethnic backgrounds and covered a wide age range (1.0-49.3 years). While the mean age at symptom onset was 0.8 ± 0.6 years [standard deviation (SD), range 0.2-5.0], the mean age at diagnosis was 10.2 ± 8.5 years (SD, range 0.1-46.3). We define a set of core features: early-onset developmental delay with delayed motor milestones and significant speech delay (50% non-verbal); intellectual disability in the moderate to severe range; mild hypotonia in infancy followed by spastic diplegia (mean age: 8.4 ± 5.1 years, SD) and later tetraplegia (mean age: 16.1 ± 9.8 years, SD); postnatal microcephaly (83%); foot deformities (69%); and epilepsy (66%) that is intractable in a subset. At last follow-up, 36% ambulated with assistance (mean age: 8.9 ± 6.4 years, SD) and 54% were wheelchair-dependent (mean age: 13.4 ± 9.8 years, SD). Episodes of stereotypic laughing, possibly consistent with a pseudobulbar affect, were found in 56% of patients. Key features on neuroimaging include a thin corpus callosum (90%), ventriculomegaly (65%) often with colpocephaly, and periventricular white-matter signal abnormalities (68%). Iron deposition and polymicrogyria were found in a subset of patients. AP4B1-associated SPG47 and AP4M1-associated SPG50 accounted for the majority of cases. About two-thirds of patients were born to consanguineous parents, and 82% carried homozygous variants. Over 70 unique variants were present, the majority of which are frameshift or nonsense mutations. To track disease progression across the age spectrum, we defined the relationship between disease severity as measured by several rating scales and disease duration. We found that the presence of epilepsy, which manifested before the age of 3 years in the majority of patients, was associated with worse motor outcomes. Exploring genotype-phenotype correlations, we found that disease severity and major phenotypes were equally distributed among the four subtypes, establishing that SPG47, SPG50, SPG51 and SPG52 share a common phenotype, an 'AP-4 deficiency syndrome'. By delineating the core clinical, imaging, and molecular features of AP-4-associated hereditary spastic paraplegia across the age spectrum our results will facilitate early diagnosis, enable counselling and anticipatory guidance of affected families and help define endpoints for future interventional trials.
Disciplines :
Genetics & genetic processes
Author, co-author :
Ebrahimi-Fakhari, Darius
Teinert, Julian
Behne, Robert
Wimmer, Miriam
D'Amore, Angelica
Eberhardt, Kathrin
Brechmann, Barbara
Ziegler, Marvin
Jensen, Dana M.
Nagabhyrava, Premsai
Geisel, Gregory
Carmody, Erin
Shamshad, Uzma
Dies, Kira A.
Yuskaitis, Christopher J.
Salussolia, Catherine L.
Ebrahimi-Fakhari, Daniel
Pearson, Toni S.
Saffari, Afshin
Ziegler, Andreas
Kölker, Stefan
Volkmann, Jens
Wiesener, Antje
Bearden, David R.
Lakhani, Shenela
Segal, Devorah
Udwadia-Hegde, Anaita
Martinuzzi, Andrea
Hirst, Jennifer
Perlman, Seth
Takiyama, Yoshihisa
Xiromerisiou, Georgia
Vill, Katharina
Walker, William O.
Shukla, Anju
Dubey Gupta, Rachana
Dahl, Niklas
Aksoy, Ayse
Verhelst, Helene
Delgado, Mauricio R.
Kremlikova Pourova, Radka
Sadek, Abdelrahim A.
Elkhateeb, Nour M.
Blumkin, Lubov
Brea-Fernández, Alejandro J.
Dacruz-Álvarez, David
Smol, Thomas
Ghoumid, Jamal
Miguel, Diego
Heine, Constanze
Schlump, Jan-Ulrich
Langen, Hendrik
Baets, Jonathan
BULK, Saskia ; Centre Hospitalier Universitaire de Liège - CHU > Unilab > Clinique de génétique
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