{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:14:25Z","timestamp":1760058865890,"version":"build-2065373602"},"reference-count":21,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,4,30]],"date-time":"2025-04-30T00:00:00Z","timestamp":1745971200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Union (EU)\/University of Rwanda Enabel-Kwigira Project","award":["RWA210001-10016"],"award-info":[{"award-number":["RWA210001-10016"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: Hereditary spastic paraplegia type 52 (SPG52) is a rare, inherited neurodevelopmental condition passed down in an autosomal recessive pattern. In this report, we describe two siblings from Rwanda who exhibited classic signs of the disorder, including progressive lower-limb spasticity, significant delays in motor development, and exaggerated deep tendon reflexes. Methods: Genetic testing through Whole-Exome Sequencing (WES) reveals a rare homozygous splice-site variant (NM_001128126.3:c.295-3C&gt;A) in the AP4S1 gene. Results: Despite the severity of symptoms, both children responded positively to treatment with muscle relaxants and regular physiotherapy. Notably, MRI scans of the brain and spine showed no structural abnormalities. Conclusions: By documenting this case, we add to the growing understanding of SPG52, particularly within under-represented Sub-Saharan African populations, and underscore the critical role of early genetic testing in guiding timely diagnosis and intervention.<\/jats:p>","DOI":"10.3390\/genes16050542","type":"journal-article","created":{"date-parts":[[2025,5,1]],"date-time":"2025-05-01T03:50:43Z","timestamp":1746071443000},"page":"542","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A Rare Homozygous AP4S1 Variant in Rwandan Siblings with Autosomal Recessive Hereditary Spastic Paraplegia Type 52 (SPG52)"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-4787-7728","authenticated-orcid":false,"given":"Sylvine","family":"Niyoyita","sequence":"first","affiliation":[{"name":"Centre for Human Genetics, School of Medicine and Pharmacy, College of Medicine and Health Sciences, University of Rwanda, Kigali 4285, Rwanda"},{"name":"Department of Paediatrics and Clinical Genetics, Rwanda Military Referral and Teaching Hospital, Kigali 3377, Rwanda"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2046-9495","authenticated-orcid":false,"given":"Esther","family":"Uwibambe","sequence":"additional","affiliation":[{"name":"Centre for Human Genetics, School of Medicine and Pharmacy, College of Medicine and Health Sciences, University of Rwanda, Kigali 4285, Rwanda"},{"name":"Department of Paediatrics and Clinical Genetics, Rwanda Military Referral and Teaching Hospital, Kigali 3377, Rwanda"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5103-8881","authenticated-orcid":false,"given":"Janvier","family":"Ndinkabandi","sequence":"additional","affiliation":[{"name":"Centre for Human Genetics, School of Medicine and Pharmacy, College of Medicine and Health Sciences, University of Rwanda, Kigali 4285, Rwanda"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Placide","family":"Sesonga","sequence":"additional","affiliation":[{"name":"Centre for Human Genetics, School of Medicine and Pharmacy, College of Medicine and Health Sciences, University of Rwanda, Kigali 4285, Rwanda"},{"name":"Department of Paediatrics and Clinical Genetics, Rwanda Military Referral and Teaching Hospital, Kigali 3377, Rwanda"},{"name":"Clinical Division, University of Global Health Equity, Kigali 6955, Rwanda"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2776-0627","authenticated-orcid":false,"given":"Josse Belladone","family":"Niyongere","sequence":"additional","affiliation":[{"name":"Centre for Human Genetics, School of Medicine and Pharmacy, College of Medicine and Health Sciences, University of Rwanda, Kigali 4285, Rwanda"},{"name":"Department of Paediatrics and Clinical Genetics, Rwanda Military Referral and Teaching Hospital, Kigali 3377, Rwanda"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7319-3024","authenticated-orcid":false,"given":"Benjamin","family":"Tuyishimire","sequence":"additional","affiliation":[{"name":"Centre for Human Genetics, School of Medicine and Pharmacy, College of Medicine and Health Sciences, University of Rwanda, Kigali 4285, Rwanda"},{"name":"Department of Paediatrics and Clinical Genetics, Rwanda Military Referral and Teaching Hospital, Kigali 3377, Rwanda"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7502-1075","authenticated-orcid":false,"given":"Adelaide","family":"Urugwiro","sequence":"additional","affiliation":[{"name":"Centre for Human Genetics, School of Medicine and Pharmacy, College of Medicine and Health Sciences, University of Rwanda, Kigali 4285, Rwanda"},{"name":"Department of Paediatrics and Clinical Genetics, Rwanda Military Referral and Teaching Hospital, Kigali 3377, Rwanda"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2544-9747","authenticated-orcid":false,"given":"Alype","family":"Rwamatwara","sequence":"additional","affiliation":[{"name":"Centre for Human Genetics, School of Medicine and Pharmacy, College of Medicine and Health Sciences, University of Rwanda, Kigali 4285, Rwanda"},{"name":"Department of Paediatrics and Clinical Genetics, Rwanda Military Referral and Teaching Hospital, Kigali 3377, Rwanda"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8131-095X","authenticated-orcid":false,"given":"Gis\u00e8le","family":"Isingizwe","sequence":"additional","affiliation":[{"name":"Centre for Human Genetics, School of Medicine and Pharmacy, College of Medicine and Health Sciences, University of Rwanda, Kigali 4285, Rwanda"},{"name":"Department of Paediatrics and Clinical Genetics, Rwanda Military Referral and Teaching Hospital, Kigali 3377, Rwanda"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7388-3277","authenticated-orcid":false,"given":"Janvi\u00e8re","family":"Mutamuliza","sequence":"additional","affiliation":[{"name":"Centre for Human Genetics, School of Medicine and Pharmacy, College of Medicine and Health Sciences, University of Rwanda, Kigali 4285, Rwanda"},{"name":"Department of Paediatrics and Clinical Genetics, Rwanda Military Referral and Teaching Hospital, Kigali 3377, Rwanda"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Nsanzabaganwa","sequence":"additional","affiliation":[{"name":"Centre for Human Genetics, School of Medicine and Pharmacy, College of Medicine and Health Sciences, University of Rwanda, Kigali 4285, Rwanda"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Bukuru","sequence":"additional","affiliation":[{"name":"Department of Ear, Nose, and Throat, Rwanda Military Referral and Teaching Hospital, Kigali 3377, Rwanda"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Florent","family":"Rutagarama","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Clinical Genetics, Rwanda Military Referral and Teaching Hospital, Kigali 3377, Rwanda"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Agn\u00e8s","family":"Mukaruziga","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Clinical Genetics, Rwanda Military Referral and Teaching Hospital, Kigali 3377, Rwanda"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Os\u00e9e","family":"Karangwa","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Clinical Genetics, Rwanda Military Referral and Teaching Hospital, Kigali 3377, Rwanda"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Augustin","family":"Ndatinya","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Clinical Genetics, Rwanda Military Referral and Teaching Hospital, Kigali 3377, Rwanda"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6138-5376","authenticated-orcid":false,"given":"Maurice","family":"Nsanzabera","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Clinical Genetics, Rwanda Military Referral and Teaching Hospital, Kigali 3377, Rwanda"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Norbert","family":"Dukuze","sequence":"additional","affiliation":[{"name":"Centre for Human Genetics, School of Medicine and Pharmacy, College of Medicine and Health Sciences, University of Rwanda, Kigali 4285, Rwanda"},{"name":"Department of Paediatrics and Clinical Genetics, Rwanda Military Referral and Teaching Hospital, Kigali 3377, Rwanda"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5308-3706","authenticated-orcid":false,"given":"L\u00e9on","family":"Mutesa","sequence":"additional","affiliation":[{"name":"Centre for Human Genetics, School of Medicine and Pharmacy, College of Medicine and Health Sciences, University of Rwanda, Kigali 4285, Rwanda"},{"name":"Department of Paediatrics and Clinical Genetics, Rwanda Military Referral and Teaching Hospital, Kigali 3377, Rwanda"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1016\/S1474-4422(19)30235-2","article-title":"Hereditary spastic paraplegia: From diagnosis to emerging therapeutic approaches","volume":"18","author":"Brasch","year":"2019","journal-title":"Lancet Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Meyyazhagan, A., and Orlacchio, A. (2022). Hereditary Spastic Paraplegia: An Update. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031697"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Bellofatto, M., De Michele, G., Iovino, A., Filla, A., and Santorelli, F.M. (2019). Management of hereditary spastic paraplegia: A systematic review of the literature. Front. Neurol., 10.","DOI":"10.3389\/fneur.2019.00003"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1002\/ana.24611","article-title":"Hereditary spastic paraplegia: Clinicogenetic lessons from 608 patients","volume":"79","author":"Wiethoff","year":"2016","journal-title":"Ann. Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1580","DOI":"10.1111\/ene.13085","article-title":"Identification of mutations in AP4S1\/SPG52 through next generation sequencing in three families","volume":"23","author":"Tessa","year":"2016","journal-title":"Eur. J. Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1136\/jmg.2010.082263","article-title":"Adaptor protein complex-4 (AP-4) deficiency causes a novel autosomal recessive cerebral palsy syndrome with microcephaly and intellectual disability","volume":"48","author":"Helmers","year":"2011","journal-title":"J. Med. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Trummer, B., Haubenberger, D., and Blackstone, C. (2018). Clinical Trial Designs and Measures in Hereditary Spastic Paraplegias. Front. Neurol., 9.","DOI":"10.3389\/fneur.2018.01017"},{"key":"ref_8","unstructured":"ClinVar (2025, April 21). NM_001128126.3(AP4S1):c.295-3C>A. Accession: RCV001089600.1. National Center for Biotechnology Information Archives, Available online: https:\/\/www.ncbi.nlm.nih.gov\/clinvar\/RCV001089600.1\/."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1002\/humu.23939","article-title":"Utilizing RNA and outlier analysis to identify an intronic splice-altering variant in AP4S1 in a sibling pair with progressive spastic paraplegia","volume":"41","author":"McCullough","year":"2020","journal-title":"Hum. Mutat."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1159\/000358801","article-title":"The Global Epidemiology of Hereditary Ataxia and Spastic Paraplegia: A Systematic Review of Prevalence Studies","volume":"42","author":"Ruano","year":"2014","journal-title":"Neuroepidemiology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e223","DOI":"10.1212\/NXG.0000000000000223","article-title":"ACO2 homozygous missense mutation associated with complicated hereditary spastic paraplegia","volume":"4","author":"Bouwkamp","year":"2018","journal-title":"Neurol. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e273","DOI":"10.1212\/NXG.0000000000000273","article-title":"Splice-site mutation in AP4S1 causing spastic paraplegia type 52 with polymicrogyria: A case report","volume":"4","author":"Carmona","year":"2018","journal-title":"Neurol. Genet."},{"key":"ref_13","unstructured":"Alecu, J., Schierbaum, L., and Ebrahimi-Fakhari, D. (2018). AP-4-Associated Hereditary Spastic Paraplegia. GeneReviews\u00ae, University of Washington."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Mahungu, A.C., Steyn, E., Floudiotis, N., Wilson, L.A., Vandrovcova, J., Reilly, M.M., Record, C.J., Benatar, M., Wu, G., and Raga, S. (2023). The mutational profile in a South African cohort with inherited neuropathies and spastic paraplegia. Front. Neurol., 14.","DOI":"10.3389\/fneur.2023.1239725"},{"key":"ref_15","unstructured":"CENTOGENE (2025). Genetic Testing Offer for Neurology, CENTOGENE."},{"key":"ref_16","unstructured":"Karczewski, K.J., Francioli, L.C., Tiao, G., Cummings, B.B., Alf\u00f6ldi, J., Wang, Q., Collins, R.L., Laricchia, K.M., Ganna, A., and Birnbaum, D.P. (2015, April 23). gnomAD Variant: 14-31080570-C-A. Genome Aggregation Database (gnomAD) v4. Broad Institute. Available online: https:\/\/gnomad.broadinstitute.org\/variant\/14-31080570-C-A?dataset=gnomad_r4."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_18","first-page":"2929","article-title":"Adaptor protein complex 4-associated hereditary spastic paraplegia clinical, molecular and imaging spectrum","volume":"143","author":"Teinert","year":"2020","journal-title":"Brain"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1038\/s41586-022-04558-8","article-title":"A joint NCBI and EMBL-EBI transcript set for clinical genomics and research","volume":"604","author":"Morales","year":"2022","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1007\/s00401-013-1115-8","article-title":"Hereditary spastic paraplegia: Clinico-pathologic features and emerging molecular mechanisms","volume":"126","author":"Fink","year":"2013","journal-title":"Acta Neuropathol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"a036525","DOI":"10.1101\/cshperspect.a036525","article-title":"Predictive genetic counseling for neurodegenerative diseases: Past, present, and future","volume":"10","author":"Goldman","year":"2020","journal-title":"Cold Spring Harb. Perspect. Med."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/5\/542\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:25:00Z","timestamp":1760030700000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/5\/542"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,30]]},"references-count":21,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["genes16050542"],"URL":"https:\/\/doi.org\/10.3390\/genes16050542","relation":{},"ISSN":["2073-4425"],"issn-type":[{"type":"electronic","value":"2073-4425"}],"subject":[],"published":{"date-parts":[[2025,4,30]]}}}