{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T09:58:48Z","timestamp":1771581528426,"version":"3.50.1"},"reference-count":11,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,1,17]],"date-time":"2022-01-17T00:00:00Z","timestamp":1642377600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:sec><jats:title>Background:<\/jats:title><jats:p>Mast syndrome is a rare disorder belonging to the group of hereditary spastic paraplegias (HSPs). It is caused by bi-allelic mutations in the <jats:italic>ACP33<\/jats:italic> gene, and is originally described in Old Order Amish. Outside this population, only one Japanese and one Italian family have been reported. Herein, we describe five subjects from the first three <jats:italic>SPG21<\/jats:italic> families of German and Austrian descent.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods:<\/jats:title><jats:p>Five subjects with complicated HSP were referred to our centers. The workup consisted of neurological examination, neurophysiological and neuropsychological assessments, MRI, and genetic testing.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results:<\/jats:title><jats:p>Onset varied from child- to adulthood. All patients exhibited predominant spastic para- or tetraparesis with positive pyramidal signs, pronounced cognitive impairment, ataxia, and extrapyramidal signs. Neurophysiological workup showed abnormal motor and sensory evoked potentials in all the patients. Sensorimotor axonal neuropathy was present in one patient. Imaging exhibited thin corpus callosum and global brain atrophy. Genetic testing revealed one heterozygous compound and two homozygous mutations in the <jats:italic>ACP33<\/jats:italic> gene.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion:<\/jats:title><jats:p>Herein, we report the first three Austrian and two German patients with <jats:italic>SPG21<\/jats:italic>, presenting a detailed description of their clinical phenotype and disease course. Our report adds to the knowledge of this extremely rare disorder, and highlights that <jats:italic>SPG21<\/jats:italic> must also be considered in the differential diagnosis of complicated HSP outside the Amish community.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fneur.2021.799953","type":"journal-article","created":{"date-parts":[[2022,1,17]],"date-time":"2022-01-17T07:14:23Z","timestamp":1642403663000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Mast Syndrome Outside the Amish Community: SPG21 in Europe"],"prefix":"10.3389","volume":"12","author":[{"given":"Matthias","family":"Amprosi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisabetta","family":"Indelicato","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wolfgang","family":"Nachbauer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Hussl","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudia","family":"Stendel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas","family":"Eigentler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Constanze","family":"Gallenm\u00fcller","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sylvia","family":"Boesch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Klopstock","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,1,17]]},"reference":[{"key":"B1","article-title":"Hereditary spastic paraplegia overview","volume-title":"GeneReviews","author":"Hedera","year":"1993"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1151","DOI":"10.1016\/S0140-6736(83)92879-9","article-title":"Classification of the hereditary ataxias and paraplegias","volume":"1","author":"Harding","year":"1983","journal-title":"Lancet."},{"key":"B3","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1002\/ana.24611","article-title":"Hereditary spastic paraplegia: clinicogenetic lessons from 608 patients","volume":"79","author":"Sch\u00fcle","year":"2016","journal-title":"Ann Neurol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1147","DOI":"10.1086\/379522","article-title":"Maspardin is mutated in mast syndrome, a complicated form of hereditary spastic paraplegia associated with dementia","volume":"73","author":"Simpson","year":"2003","journal-title":"Am J Hum Genet."},{"key":"B5","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1007\/s10048-009-0172-6","article-title":"Interaction of the SPG21 protein ACP33\/maspardin with the aldehyde dehydrogenase ALDH16A1","volume":"10","author":"Hanna","year":"2009","journal-title":"Neurogenetics."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1001\/archneur.1967.00470190005001","article-title":"The mast syndrome. A recessively inherited form of presenile dementia with motor disturbances","volume":"16","author":"Cross","year":"1967","journal-title":"Arch Neurol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1038\/jhg.2013.139","article-title":"Molecular epidemiology and clinical spectrum of hereditary spastic paraplegia in the Japanese population based on comprehensive mutational analyses","volume":"59","author":"Ishiura","year":"2014","journal-title":"J Hum Genet."},{"key":"B8","doi-asserted-by":"publisher","first-page":"2021","DOI":"10.1007\/s00415-017-8558-0","article-title":"Exome sequencing reveals a novel homozygous mutation in ACP33 gene in the first Italian family with SPG21","volume":"264","author":"Scarlato","year":"2017","journal-title":"J Neurol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1530\/ey.17.14.3","article-title":"The mutational constraint spectrum quantified from variation in 141,456 humans","volume":"581","author":"Karczewski","year":"2020","journal-title":"Nature."},{"key":"B10","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1002\/ana.20771","article-title":"Genotypic and phenotypic spectrum of PANK2 mutations in patients with neurodegeneration with brain iron accumulation","volume":"59","author":"Hartig","year":"2006","journal-title":"Ann Neurol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1111\/j.1467-8306.1978.tb01194.x","article-title":"Diffusion and Growth","volume":"68","author":"Crowley","year":"1978","journal-title":"Ann Assoc Am Geogr."}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2021.799953\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,17]],"date-time":"2022-01-17T07:14:24Z","timestamp":1642403664000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2021.799953\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,17]]},"references-count":11,"alternative-id":["10.3389\/fneur.2021.799953"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2021.799953","relation":{},"ISSN":["1664-2295"],"issn-type":[{"value":"1664-2295","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,17]]},"article-number":"799953"}}