{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T07:49:52Z","timestamp":1753861792304,"version":"3.41.2"},"reference-count":18,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2024,9,26]],"date-time":"2024-09-26T00:00:00Z","timestamp":1727308800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["K23NS119666","K08NS123552\u201001"],"award-info":[{"award-number":["K23NS119666","K08NS123552\u201001"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100017026","name":"Spastic Paraplegia Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100017026","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Frataxin is an evolutionarily conserved mitochondrial protein responsible for iron homeostasis and metabolism. A deficiency of frataxin (encoded by <jats:italic>FXN<\/jats:italic>) leads to Friedreich's ataxia (FRDA), a progressive disorder that affects both the central and peripheral nervous systems, most commonly via a pathogenic GAA trinucleotide expansion. In contrast, pathogenic variants in <jats:italic>ALG1<\/jats:italic> in humans cause a form of congenital disorder of glycosylation. Here, we present a 15\u2010year\u2010old boy with a clinical presentation that raised concern for complex hereditary spastic paraplegia (HSP), with motor features including progressive spastic paraparesis, cervical dystonia, cerebellar dysfunction, and diminished lower extremity reflexes. The proband was initially found to have a novel compound heterozygous variant in <jats:italic>ALG1<\/jats:italic> on exome sequencing, along with N\u2010glycan profiling revealing evidence of defective mannosylation and Western blot analysis demonstrating an 84% reduction in ALG1 expression. Although several of his clinical features could be explained by the <jats:italic>ALG1<\/jats:italic> variant specifically or considered as part of the presentation of CDGs in general, there were additional phenotypes that suggested an alternative, or additional, genetic diagnosis. Subsequently, he was found to have biallelic pathogenic GAA repeat expansions in <jats:italic>FXN<\/jats:italic> on genome sequencing, leading to a diagnosis of FRDA. Given that FRDA explained all his clinical features, the <jats:italic>ALG1<\/jats:italic> variant may have been a hypomorphic form and\/or a biochemical phenotype. Our findings underscore the importance of considering FRDA as a differential diagnosis in cases of complex HSP and demonstrate the utility of unbiased genome sequencing approaches that include detection of trinucleotide repeat expansions for progressive motor disorders.<\/jats:p>","DOI":"10.1002\/ajmg.a.63890","type":"journal-article","created":{"date-parts":[[2024,9,26]],"date-time":"2024-09-26T10:22:19Z","timestamp":1727346139000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Case Report of Friedreich's Ataxia and <scp><i>ALG1<\/i><\/scp>\u2010Related Biochemical Abnormalities in a Patient With Progressive Spastic Paraplegia"],"prefix":"10.1002","volume":"197","author":[{"given":"Aisling","family":"Quinlan","sequence":"first","affiliation":[{"name":"Department of Neurology Boston Children's Hospital  Boston Massachusetts USA"},{"name":"Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2392-6688","authenticated-orcid":false,"given":"Lance","family":"Rodan","sequence":"additional","affiliation":[{"name":"Department of Genetics Boston Children's Hospital  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth","family":"Barkoudah","sequence":"additional","affiliation":[{"name":"Department of Neurology Boston Children's Hospital  Boston Massachusetts USA"},{"name":"Cerebral Palsy and Spasticity Center Boston Children's Hospital  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amy","family":"Tam","sequence":"additional","affiliation":[{"name":"Department of Neurology Boston Children's Hospital  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Afshin","family":"Saffari","sequence":"additional","affiliation":[{"name":"Department of Neurology Boston Children's Hospital  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ibrahim","family":"Shammas","sequence":"additional","affiliation":[{"name":"Division of Laboratory Genetics and Genomics, Department of Laboratory Medicine and Pathology Mayo Clinic  Rochester Minnesota USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wasantha","family":"Ranatunga","sequence":"additional","affiliation":[{"name":"Division of Laboratory Genetics and Genomics, Department of Laboratory Medicine and Pathology Mayo Clinic  Rochester Minnesota USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eva","family":"Morava\u2010Kozicz","sequence":"additional","affiliation":[{"name":"Division of Laboratory Genetics and Genomics, Department of Laboratory Medicine and Pathology Mayo Clinic  Rochester Minnesota USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Devin","family":"Oglesbee","sequence":"additional","affiliation":[{"name":"Division of Laboratory Genetics and Genomics, Department of Laboratory Medicine and Pathology Mayo Clinic  Rochester Minnesota USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gerald","family":"Berry","sequence":"additional","affiliation":[{"name":"Department of Genetics Boston Children's Hospital  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0026-4714","authenticated-orcid":false,"given":"Darius","family":"Ebrahimi\u2010Fakhari","sequence":"additional","affiliation":[{"name":"Department of Neurology Boston Children's Hospital  Boston Massachusetts USA"},{"name":"Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7008-1879","authenticated-orcid":false,"given":"Siddharth","family":"Srivastava","sequence":"additional","affiliation":[{"name":"Department of Neurology Boston Children's Hospital  Boston Massachusetts USA"},{"name":"Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital  Boston Massachusetts USA"},{"name":"Cerebral Palsy and Spasticity Center Boston Children's Hospital  Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,9,26]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/bmb\/ldx034"},{"volume-title":"GeneReviews\u00ae [online]","year":"1993","author":"Bidichandani S. 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