{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T10:50:52Z","timestamp":1783075852204,"version":"3.54.6"},"reference-count":14,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2023,10,13]],"date-time":"2023-10-13T00:00:00Z","timestamp":1697155200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"TIRCON"},{"name":"European Commission 7th Framework Programme","award":["FP7\/2007-2013"],"award-info":[{"award-number":["FP7\/2007-2013"]}]},{"name":"European Commission 7th Framework Programme","award":["HEALTHF2-2011"],"award-info":[{"award-number":["HEALTHF2-2011"]}]},{"name":"ApoPharma Inc"},{"name":"CoA Therapeutics"},{"name":"Retrophin, Inc"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,4,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Mitochondrial membrane protein-associated neurodegeneration (MPAN) is an ultraorphan neurogenetic disease from the group of neurodegeneration with brain iron accumulation (NBIA) disorders. Here we report cross-sectional and longitudinal data to define the phenotype, to assess disease progression and to estimate sample sizes for clinical trials.<\/jats:p>\n               <jats:p>We enrolled patients with genetically confirmed MPAN from the Treat Iron-Related Childhood-Onset Neurodegeneration (TIRCON) registry and cohort study, and from additional sites. Linear mixed-effect modelling (LMEM) was used to calculate annual progression rates for the Unified Parkinson\u2019s Disease Rating Scale (UPDRS), Barry\u2013Albright Dystonia (BAD) scale, Schwab and England Activities of Daily Living (SE-ADL) scale and the Pediatric Quality of Life Inventory (PedsQL).<\/jats:p>\n               <jats:p>We investigated 85 MPAN patients cross-sectionally, with functional outcome data collected in 45. Median age at onset was 9\u2005years and the median diagnostic delay was 5\u2005years. The most common findings were gait disturbance (99%), pyramidal involvement (95%), dysarthria (90%), vision disturbances (82%), with all but dysarthria presenting early in the disease course. After 16\u2005years with the disease, 50% of patients were wheelchair dependent. LMEM showed an annual progression rate of 4.5 points in total UPDRS. The total BAD scale score showed no significant progression over time. The SE-ADL scale and the patient- and parent-reported PedsQL showed a decline of 3.9%, 2.14 and 2.05 points, respectively. No patient subpopulations were identified based on longitudinal trajectories.<\/jats:p>\n               <jats:p>Our cross-sectional results define the order of onset and frequency of symptoms in MPAN, which will inform the diagnostic process, help to shorten diagnostic delay and aid in counselling patients, parents and caregivers. Our longitudinal findings define the natural history of MPAN, reveal the most responsive outcomes and highlight the need for an MPAN-specific rating approach. Our sample size estimations inform the design of upcoming clinical trials.<\/jats:p>","DOI":"10.1093\/brain\/awad357","type":"journal-article","created":{"date-parts":[[2023,10,13]],"date-time":"2023-10-13T17:16:41Z","timestamp":1697217401000},"page":"1389-1398","source":"Crossref","is-referenced-by-count":9,"title":["Phenotype and natural history of mitochondrial membrane protein-associated neurodegeneration"],"prefix":"10.1093","volume":"147","author":[{"given":"Vassilena","family":"Iankova","sequence":"first","affiliation":[{"name":"Department of Neurology with Friedrich-Baur-Institute, University Hospital of Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen , 80336 Munich , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9160-0794","authenticated-orcid":false,"given":"Peter","family":"Sparber","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics , 115522 Moscow , Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5409-1804","authenticated-orcid":false,"given":"Mohammad","family":"Rohani","sequence":"additional","affiliation":[{"name":"Department of Neurology, Rasoul Akram Hospital, School of Medicine, Iran University of Medical Sciences , 1449614535 Tehran , Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petr","family":"Dusek","sequence":"additional","affiliation":[{"name":"Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital , 121 08 Prague , Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boriana","family":"B\u00fcchner","sequence":"additional","affiliation":[{"name":"Department of Neurology with Friedrich-Baur-Institute, University Hospital of Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen , 80336 Munich , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Karin","sequence":"additional","affiliation":[{"name":"Department of Neurology with Friedrich-Baur-Institute, University Hospital of Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen , 80336 Munich , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne A","family":"Schneider","sequence":"additional","affiliation":[{"name":"Department of Neurology with Friedrich-Baur-Institute, University Hospital of Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen , 80336 Munich , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan M","family":"Gorriz","sequence":"additional","affiliation":[{"name":"Data Science and Computational Intelligence Institute, University of Granada , Granada CP 18071 , Spain"},{"name":"Department of Psychiatry, University of Cambridge , Cambridge CB2 0SZ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomasz","family":"Kmiec","sequence":"additional","affiliation":[{"name":"Children\u2019s Memorial Health Institute, Child Neurology Department , 04-730 Warsaw , Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Klopstock","sequence":"additional","affiliation":[{"name":"Department of Neurology with Friedrich-Baur-Institute, University Hospital of Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen , 80336 Munich , Germany"},{"name":"German Center for Neurodegenerative Diseases (DZNE) , 81377 Munich , Germany"},{"name":"Munich Cluster for Systems Neurology , 81377 Munich , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,10,13]]},"reference":[{"key":"2024040418392889800_awad357-B1"},{"key":"2024040418392889800_awad357-B2","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1016\/j.ajhg.2011.09.007","article-title":"Absence of an orphan mitochondrial protein, c19orf12, causes a distinct clinical subtype of neurodegeneration with brain iron accumulation","volume":"89","author":"Hartig","year":"2011","journal-title":"Am J Hum Genet"},{"key":"2024040418392889800_awad357-B3","doi-asserted-by":"crossref","first-page":"103869","DOI":"10.1016\/j.ebiom.2022.103869","article-title":"Lifetime risk of autosomal recessive neurodegeneration with brain iron accumulation (NBIA) disorders calculated from genetic 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