Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia
Authors: 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 , Darvish Hossein , Bakhtiari Somayeh , Kruer Michael C , Lim-Melia Elizabeth , Aydinli Nur , Alanay Yasemin , El-Rashidy Omnia , Nampoothiri Sheela , Patel Chirag , Beetz Christian , Bauer Peter , Yoon Grace , Guillot Mireille , Miller Steven P , Bourinaris Thomas , Houlden Henry , Robelin Laura , Anheim Mathieu , Alamri Abdullah S , Mahmoud Adel A H , Inaloo Soroor , Habibzadeh Parham , Faghihi Mohammad Ali , Jansen Anna C , Brock Stefanie , Roubertie Agathe , Darras Basil T , Agrawal Pankaj B , Santorelli Filippo M , Gleeson Joseph , Zaki Maha S , Sheikh Sarah I , Bennett James T , Sahin Mustafa 
Published: September 2019

Abstract
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.