article published yes Rauan Kaiyrzhanov author Aboulfazl Rad author Sheng-Jia Lin author Aida Bertoli-Avella author Wouter W Kallemeijn author Annie Godwin author Maha S Zaki author Kevin Huang author 3b3d2888-1ff6-11ee-9fa6-8f209ca91fe30000-0002-2512-7812 Tracy Lau author Cassidy Petree author Stephanie Efthymiou author Ehsan Ghayoor Karimiani author Maja Hempel author Elizabeth A Normand author Sabine Rudnik-Schöneborn author Ulrich A Schatz author Marc P Baggelaar author Muhammad Ilyas author Tipu Sultan author Javeria Raza Alvi author Manizha Ganieva author Ben Fowler author Ruxandra Aanicai author Gulsen Akay Tayfun author Abdulaziz Al Saman author Abdulrahman Alswaid author Nafise Amiri author Nilufar Asilova author Vorasuk Shotelersuk author Patra Yeetong author Matloob Azam author Meisam Babaei author Gholamreza Bahrami Monajemi author Pouria Mohammadi author Saeed Samie author Selina Husna Banu author Jorge Pinto Basto author Fanny Kortüm author Mislen Bauer author Peter Bauer author Christian Beetz author Masoud Garshasbi author Awatif Hameed Issa author Wafaa Eyaid author Hind Ahmed author Narges Hashemi author Kazem Hassanpour author Isabella Herman author Sherozjon Ibrohimov author Ban A Abdul-Majeed author Maria Imdad author Maksudjon Isrofilov author Qassem Kaiyal author Suliman Khan author Brian Kirmse author Janet Koster author Charles Marques Lourenço author Tadahiro Mitani author Oana Moldovan author David Murphy author Maryam Najafi author Davut Pehlivan author Maria Eugenia Rocha author Vincenzo Salpietro author Miriam Schmidts author Adel Shalata author Mohammad Mahroum author Jawabreh Kassem Talbeya author Robert W Taylor author Dayana Vazquez author Annalisa Vetro author Hans R Waterham author Mashaya Zaman author Tina A Schrader author Wendy K Chung author Renzo Guerrini author James R Lupski author Joseph Gleeson author Mohnish Suri author Yalda Jamshidi author Kailash P Bhatia author Barbara Vona author Michael Schrader author Mariasavina Severino author Matthew Guille author Edward W Tate author Gaurav K Varshney author Henry Houlden author Reza Maroofian author GradSch department The acyl-CoA-binding domain-containing protein 6 (ACBD6) is ubiquitously expressed, plays a role in the acylation of lipids and proteins, and regulates the N-myristoylation of proteins via N-myristoyltransferase enzymes (NMTs). However, its precise function in cells is still unclear, as is the consequence of ACBD6 defects on human pathophysiology. Utilizing exome sequencing and extensive international data sharing efforts, we identified 45 affected individuals from 28 unrelated families (consanguinity 93%) with bi-allelic pathogenic, predominantly loss-of-function (18/20) variants in ACBD6. We generated zebrafish and Xenopus tropicalis acbd6 knockouts by CRISPR/Cas9 and characterized the role of ACBD6 on protein N-myristoylation with YnMyr chemical proteomics in the model organisms and human cells, with the latter also being subjected further to ACBD6 peroxisomal localization studies. The affected individuals (23 males and 22 females), with ages ranging from 1 to 50 years old, typically present with a complex and progressive disease involving moderate-to-severe global developmental delay/intellectual disability (100%) with significant expressive language impairment (98%), movement disorders (97%), facial dysmorphism (95%), and mild cerebellar ataxia (85%) associated with gait impairment (94%), limb spasticity/hypertonia (76%), oculomotor (71%) and behavioural abnormalities (65%), overweight (59%), microcephaly (39%) and epilepsy (33%). The most conspicuous and common movement disorder was dystonia (94%), frequently leading to early-onset progressive postural deformities (97%), limb dystonia (55%), and cervical dystonia (31%). A jerky tremor in the upper limbs (63%), a mild head tremor (59%), parkinsonism/hypokinesia developing with advancing age (32%), and simple motor and vocal tics were among other frequent movement disorders. Midline brain malformations including corpus callosum abnormalities (70%), hypoplasia/agenesis of the anterior commissure (66%), short midbrain and small inferior cerebellar vermis (38% each), as well as hypertrophy of the clava (24%) were common neuroimaging findings. acbd6-deficient zebrafish and Xenopus models effectively recapitulated many clinical phenotypes reported in patients including movement disorders, progressive neuromotor impairment, seizures, microcephaly, craniofacial dysmorphism, and midbrain defects accompanied by developmental delay with increased mortality over time. Unlike ACBD5, ACBD6 did not show a peroxisomal localisation and ACBD6-deficiency was not associated with altered peroxisomal parameters in patient fibroblasts. Significant differences in YnMyr-labelling were observed for 68 co- and 18 post-translationally N-myristoylated proteins in patient-derived fibroblasts. N-Myristoylation was similarly affected in acbd6-deficient zebrafish and Xenopus tropicalis models, including Fus, Marcks, and Chchd-related proteins implicated in neurological diseases. The present study provides evidence that bi-allelic pathogenic variants in ACBD6 lead to a distinct neurodevelopmental syndrome accompanied by complex and progressive cognitive and movement disorders. https://research-explorer.ista.ac.at/download/14543/17254/2024_Brain_Kaiyrzhanov.pdf application/pdfno https://creativecommons.org/licenses/by/4.0/ Oxford University Press2024 eng Neurology (clinical) 0006-8950 1460-2156 3795159710.1093/brain/awad380 14741436-1456 yes Kaiyrzhanov R, Rad A, Lin S-J, Bertoli-Avella A, Kallemeijn WW, Godwin A, Zaki MS, Huang K, Lau T, Petree C, Efthymiou S, Ghayoor Karimiani E, Hempel M, Normand EA, Rudnik-Schöneborn S, Schatz UA, Baggelaar MP, Ilyas M, Sultan T, Alvi JR, Ganieva M, Fowler B, Aanicai R, Akay Tayfun G, Al Saman A, Alswaid A, Amiri N, Asilova N, Shotelersuk V, Yeetong P, Azam M, Babaei M, Bahrami Monajemi G, Mohammadi P, Samie S, Banu SH, Basto JP, Kortüm F, Bauer M, Bauer P, Beetz C, Garshasbi M, Hameed Issa A, Eyaid W, Ahmed H, Hashemi N, Hassanpour K, Herman I, Ibrohimov S, Abdul-Majeed BA, Imdad M, Isrofilov M, Kaiyal Q, Khan S, Kirmse B, Koster J, Lourenço CM, Mitani T, Moldovan O, Murphy D, Najafi M, Pehlivan D, Rocha ME, Salpietro V, Schmidts M, Shalata A, Mahroum M, Talbeya JK, Taylor RW, Vazquez D, Vetro A, Waterham HR, Zaman M, Schrader TA, Chung WK, Guerrini R, Lupski JR, Gleeson J, Suri M, Jamshidi Y, Bhatia KP, Vona B, Schrader M, Severino M, Guille M, Tate EW, Varshney GK, Houlden H, Maroofian R. 2024. Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders. Brain. 147(4), 1436–1456. Kaiyrzhanov, Rauan, et al. “Bi-Allelic ACBD6 Variants Lead to a Neurodevelopmental Syndrome with Progressive and Complex Movement Disorders.” <i>Brain</i>, vol. 147, no. 4, Oxford University Press, 2024, pp. 1436–56, doi:<a href="https://doi.org/10.1093/brain/awad380">10.1093/brain/awad380</a>. Kaiyrzhanov, Rauan, Aboulfazl Rad, Sheng-Jia Lin, Aida Bertoli-Avella, Wouter W Kallemeijn, Annie Godwin, Maha S Zaki, et al. “Bi-Allelic ACBD6 Variants Lead to a Neurodevelopmental Syndrome with Progressive and Complex Movement Disorders.” <i>Brain</i>. Oxford University Press, 2024. <a href="https://doi.org/10.1093/brain/awad380">https://doi.org/10.1093/brain/awad380</a>. R. Kaiyrzhanov, A. Rad, S.-J. Lin, A. Bertoli-Avella, W.W. Kallemeijn, A. Godwin, M.S. Zaki, K. Huang, T. Lau, C. Petree, S. Efthymiou, E. Ghayoor Karimiani, M. Hempel, E.A. Normand, S. Rudnik-Schöneborn, U.A. Schatz, M.P. Baggelaar, M. Ilyas, T. Sultan, J.R. Alvi, M. Ganieva, B. Fowler, R. Aanicai, G. Akay Tayfun, A. Al Saman, A. Alswaid, N. Amiri, N. Asilova, V. Shotelersuk, P. Yeetong, M. Azam, M. Babaei, G. Bahrami Monajemi, P. Mohammadi, S. Samie, S.H. Banu, J.P. Basto, F. Kortüm, M. Bauer, P. Bauer, C. Beetz, M. Garshasbi, A. Hameed Issa, W. Eyaid, H. Ahmed, N. Hashemi, K. Hassanpour, I. Herman, S. Ibrohimov, B.A. Abdul-Majeed, M. Imdad, M. Isrofilov, Q. Kaiyal, S. Khan, B. Kirmse, J. Koster, C.M. Lourenço, T. Mitani, O. Moldovan, D. Murphy, M. Najafi, D. Pehlivan, M.E. Rocha, V. Salpietro, M. Schmidts, A. Shalata, M. Mahroum, J.K. Talbeya, R.W. Taylor, D. Vazquez, A. Vetro, H.R. Waterham, M. Zaman, T.A. Schrader, W.K. Chung, R. Guerrini, J.R. Lupski, J. Gleeson, M. Suri, Y. Jamshidi, K.P. Bhatia, B. Vona, M. Schrader, M. Severino, M. Guille, E.W. Tate, G.K. Varshney, H. Houlden, R. Maroofian, Brain 147 (2024) 1436–1456. Kaiyrzhanov R, Rad A, Lin S-J, et al. Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders. <i>Brain</i>. 2024;147(4):1436-1456. doi:<a href="https://doi.org/10.1093/brain/awad380">10.1093/brain/awad380</a> R. Kaiyrzhanov <i>et al.</i>, “Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders,” <i>Brain</i>, vol. 147, no. 4. Oxford University Press, pp. 1436–1456, 2024. Kaiyrzhanov, R., Rad, A., Lin, S.-J., Bertoli-Avella, A., Kallemeijn, W. W., Godwin, A., … Maroofian, R. (2024). Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders. <i>Brain</i>. Oxford University Press. <a href="https://doi.org/10.1093/brain/awad380">https://doi.org/10.1093/brain/awad380</a> 145432023-11-16T12:36:51Z2024-07-16T08:23:24Z