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Adult-Onset Genetic Central Nervous System Disorders Masquerading as Acquired Neuroinflammatory DisordersA Review

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Importance  Adult-onset genetic disorders may present with clinical and magnetic resonance imaging (MRI) features suggestive of acquired inflammatory diseases. An ever-growing number of potentially treatable adult-onset genetic neuroinflammatory disorders have been described in the past few years that need to be rapidly identified.

Observations  Adult-onset acquired neuroinflammatory disorders encompass a large group of central nervous system (CNS) diseases with varying presentation, MRI characteristics, and course, among which the most common is multiple sclerosis. Despite recent progress, including the discovery of specific autoantibodies, a significant number of adult-onset neuroinflammatory disorders with progressive or relapsing course still remain without a definite diagnosis. In addition, some patients with genetic disorders such as leukodystrophies, hemophagocytic lymphohistiocytosis, or genetic vasculopathies can mimic acquired neuroinflammatory disorders. These genetic disorders, initially described in pediatric populations, are increasingly detected in adulthood thanks to recent progress in molecular genetics and the larger availability of high-throughput sequencing technologies.

Conclusions and Relevance  Genetic adult-onset neuroinflammatory diseases are at the border between primary CNS inflammatory diseases and systemic disorders with multiorgan involvement and predominantly neurologic manifestations. Neurologists must be aware of the main clues and red flags so they can confirm a diagnosis early, when some of these genetic disorders can be successfully treated.

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Article Information

Accepted for Publication: June 10, 2022.

Published Online: August 15, 2022. doi:10.1001/jamaneurol.2022.2141

Corresponding Author: Xavier Ayrignac, MD, PhD, Department of Neurology, Montpellier University Hospital, 80 rue Augustin Fliche, 34295 Montpellier, Cedex 05, France (xavier.ayrignac@yahoo.fr).

Author Contributions: Dr Ayrignac had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: All authors.

Acquisition, analysis, or interpretation of data: Carra-Dalliere, Marelli, Taieb.

Drafting of the manuscript: All authors.

Critical revision of the manuscript for important intellectual content: Ayrignac, Carra-Dalliere, Marelli, Taieb.

Administrative, technical, or material support: Carra-Dalliere, Taieb, Labauge.

Supervision: Ayrignac, Marelli.

Conflict of Interest Disclosures: Dr Marelli reported board participation with Roche and travel grants from BioMarin Pharmaceutical and Nutricia outside the submitted work. No other disclosures were reported.

Additional Contributions: We thank Fanny Mochel, MD, PhD, and Romain Deschamps, MD, who provided MRIs of patients with X-ALD and biotinidase deficiency.

Reich  DS , Lucchinetti  CF , Calabresi  PA .  Multiple sclerosis.   N Engl J Med. 2018;378(2):169-180. doi:10.1056/NEJMra1401483PubMedGoogle ScholarCrossref
Hardy  TA , Reddel  SW , Barnett  MH , Palace  J , Lucchinetti  CF , Weinshenker  BG .  Atypical inflammatory demyelinating syndromes of the CNS.   Lancet Neurol. 2016;15(9):967-981. doi:10.1016/S1474-4422(16)30043-6PubMedGoogle ScholarCrossref
Marignier  R , Hacohen  Y , Cobo-Calvo  A ,  et al.  Myelin-oligodendrocyte glycoprotein antibody-associated disease.   Lancet Neurol. 2021;20(9):762-772. doi:10.1016/S1474-4422(21)00218-0PubMedGoogle ScholarCrossref
Wingerchuk  DM , Banwell  B , Bennett  JL ,  et al; International Panel for NMO Diagnosis.  International consensus diagnostic criteria for neuromyelitis optica spectrum disorders.   Neurology. 2015;85(2):177-189. doi:10.1212/WNL.0000000000001729PubMedGoogle ScholarCrossref
Flanagan  EP , Hinson  SR , Lennon  VA ,  et al.  Glial fibrillary acidic protein immunoglobulin G as biomarker of autoimmune astrocytopathy: analysis of 102 patients.   Ann Neurol. 2017;81(2):298-309. doi:10.1002/ana.24881PubMedGoogle ScholarCrossref
Hajj-Ali  RA , Singhal  AB , Benseler  S , Molloy  E , Calabrese  LH .  Primary angiitis of the CNS.   Lancet Neurol. 2011;10(6):561-572. doi:10.1016/S1474-4422(11)70081-3PubMedGoogle ScholarCrossref
Hoitsma  E , Faber  CG , Drent  M , Sharma  OP .  Neurosarcoidosis: a clinical dilemma.   Lancet Neurol. 2004;3(7):397-407. doi:10.1016/S1474-4422(04)00805-1PubMedGoogle ScholarCrossref
Al-Araji  A , Kidd  DP .  Neuro-Behçet’s disease: epidemiology, clinical characteristics, and management.   Lancet Neurol. 2009;8(2):192-204. doi:10.1016/S1474-4422(09)70015-8PubMedGoogle ScholarCrossref
Wildner  P , Stasiołek  M , Matysiak  M .  Differential diagnosis of multiple sclerosis and other inflammatory CNS diseases.   Mult Scler Relat Disord. 2020;37:101452. doi:10.1016/j.msard.2019.101452PubMedGoogle ScholarCrossref
Wells  E , Hacohen  Y , Waldman  A ,  et al; Attendees of the International Neuroimmune Meeting.  Neuroimmune disorders of the central nervous system in children in the molecular era.   Nat Rev Neurol. 2018;14(7):433-445. doi:10.1038/s41582-018-0024-9PubMedGoogle ScholarCrossref
McCreary  D , Omoyinmi  E , Hong  Y ,  et al.  Development and validation of a targeted next-generation sequencing gene panel for children with neuroinflammation.   JAMA Netw Open. 2019;2(10):e1914274. doi:10.1001/jamanetworkopen.2019.14274PubMedGoogle ScholarCrossref
Hardy  TA , Young  S , Sy  JS ,  et al.  Tumefactive lesions in retinal vasculopathy with cerebral leucoencephalopathy and systemic manifestations (RVCL-S): a role for neuroinflammation?   J Neurol Neurosurg Psychiatry. Published online August 9, 2017. doi:10.1136/jnnp-2017-316142PubMedGoogle ScholarCrossref
Weisfeld-Adams  JD , Katz Sand  IB , Honce  JM , Lublin  FD .  Differential diagnosis of Mendelian and mitochondrial disorders in patients with suspected multiple sclerosis.   Brain. 2015;138(pt 3):517-539. doi:10.1093/brain/awu397PubMedGoogle ScholarCrossref
Ayrignac  X , Goulabchand  R , Jeziorski  E ,  et al.  Two neurologic facets of CTLA4-related haploinsufficiency.   Neurol Neuroimmunol Neuroinflamm. 2020;7(4):e751. doi:10.1212/NXI.0000000000000751PubMedGoogle ScholarCrossref
Taieb  G , Kaphan  E , Duflos  C ,  et al.  Hemophagocytic lymphohistiocytosis gene mutations in adult patients presenting with CLIPPERS-like syndrome.   Neurol Neuroimmunol Neuroinflamm. 2021;8(3):e970. doi:10.1212/NXI.0000000000000970PubMedGoogle ScholarCrossref
Stam  AH , Kothari  PH , Shaikh  A ,  et al.  Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations.   Brain. 2016;139(11):2909-2922. doi:10.1093/brain/aww217PubMedGoogle ScholarCrossref
Schindler  MK , Pittaluga  S , Enose-Akahata  Y ,  et al.  Haploinsufficiency of immune checkpoint receptor CTLA4 induces a distinct neuroinflammatory disorder.   J Clin Invest. 2020;130(10):5551-5561. doi:10.1172/JCI135947PubMedGoogle ScholarCrossref
Miller  WP , Mantovani  LF , Muzic  J ,  et al.  Intensity of MRI gadolinium enhancement in cerebral adrenoleukodystrophy: a biomarker for inflammation and predictor of outcome following transplantation in higher risk patients.   AJNR Am J Neuroradiol. 2016;37(2):367-372. doi:10.3174/ajnr.A4500PubMedGoogle ScholarCrossref
Meier  K , Gärtner  J , Huppke  P .  Tumefactive inflammatory lesions in juvenile metachromatic leukodystrophy.   Neurol Neuroimmunol Neuroinflamm. 2020;8(1):e922. doi:10.1212/NXI.0000000000000922PubMedGoogle ScholarCrossref
Loes  DJ , Fatemi  A , Melhem  ER ,  et al.  Analysis of MRI patterns aids prediction of progression in X-linked adrenoleukodystrophy.   Neurology. 2003;61(3):369-374. doi:10.1212/01.WNL.0000079050.91337.83PubMedGoogle ScholarCrossref
Deschamps  R , Savatovsky  J , Vignal  C ,  et al.  Adult-onset biotinidase deficiency: two individuals with severe, but reversible optic neuropathy.   J Neurol Neurosurg Psychiatry. 2018;89(9):1009-1010. doi:10.1136/jnnp-2017-316644PubMedGoogle ScholarCrossref
Chung  TW .  CNS involvement in hemophagocytic lymphohistiocytosis: CT and MR findings.   Korean J Radiol. 2007;8(1):78-81. doi:10.3348/kjr.2007.8.1.78PubMedGoogle ScholarCrossref
Staels  F , Collignon  T , Betrains  A ,  et al.  Monogenic adult-onset inborn errors of immunity.   Front Immunol. 2021;12:753978. doi:10.3389/fimmu.2021.753978PubMedGoogle ScholarCrossref
Köhler  W , Curiel  J , Vanderver  A .  Adulthood leukodystrophies.   Nat Rev Neurol. 2018;14(2):94-105. doi:10.1038/nrneurol.2017.175PubMedGoogle ScholarCrossref
Lynch  DS , Wade  C , Paiva  ARB ,  et al.  Practical approach to the diagnosis of adult-onset leukodystrophies: an updated guide in the genomic era.   J Neurol Neurosurg Psychiatry. 2019;90(5):543-554. doi:10.1136/jnnp-2018-319481PubMedGoogle ScholarCrossref
Hardy  TA , Chataway  J .  Tumefactive demyelination: an approach to diagnosis and management.   J Neurol Neurosurg Psychiatry. 2013;84(9):1047-1053. doi:10.1136/jnnp-2012-304498PubMedGoogle ScholarCrossref
Engelen  M , Kemp  S , de Visser  M ,  et al.  X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management.   Orphanet J Rare Dis. 2012;7:51. doi:10.1186/1750-1172-7-51PubMedGoogle ScholarCrossref
Liu  C , Cao  Y , Bu  B .  Teaching NeuroImages: frontal lobe involvement in adult-onset cerebral X-linked adrenoleukodystrophy.   Neurology. 2019;93(13):e1326-e1327. doi:10.1212/WNL.0000000000008181PubMedGoogle ScholarCrossref
Kumar  AJ , Köhler  W , Kruse  B ,  et al.  MR findings in adult-onset adrenoleukodystrophy.   AJNR Am J Neuroradiol. 1995;16(6):1227-1237.PubMedGoogle Scholar
Mallack  EJ , Askin  G , van de Stadt  S ,  et al.  A longitudinal analysis of early lesion growth in presymptomatic patients with cerebral adrenoleukodystrophy.   AJNR Am J Neuroradiol. 2021;42(10):1904-1911. doi:10.3174/ajnr.A7250PubMedGoogle ScholarCrossref
Melhem  ER , Loes  DJ , Georgiades  CS , Raymond  GV , Moser  HW .  X-linked adrenoleukodystrophy: the role of contrast-enhanced MR imaging in predicting disease progression.   AJNR Am J Neuroradiol. 2000;21(5):839-844. PubMedGoogle Scholar
Bouquet  F , Dehais  C , Sanson  M , Lubetzki  C , Louapre  C .  Dramatic worsening of adult-onset X-linked adrenoleukodystrophy after head trauma.   Neurology. 2015;85(22):1991-1993. doi:10.1212/WNL.0000000000002173PubMedGoogle ScholarCrossref
Lund  TC , Stadem  PS , Panoskaltsis-Mortari  A ,  et al.  Elevated cerebral spinal fluid cytokine levels in boys with cerebral adrenoleukodystrophy correlates with MRI severity.   PLoS One. 2012;7(2):e32218. doi:10.1371/journal.pone.0032218PubMedGoogle ScholarCrossref
Mahmood  A , Raymond  GV , Dubey  P , Peters  C , Moser  HW .  Survival analysis of haematopoietic cell transplantation for childhood cerebral X-linked adrenoleukodystrophy: a comparison study.   Lancet Neurol. 2007;6(8):687-692. doi:10.1016/S1474-4422(07)70177-1PubMedGoogle ScholarCrossref
Fitzpatrick  AS , Loughrey  CM , Johnston  P ,  et al.  Haematopoietic stem-cell transplant for adult cerebral adrenoleukodystrophy.   Eur J Neurol. 2008;15(3):e21-e22. doi:10.1111/j.1468-1331.2007.02048.xPubMedGoogle ScholarCrossref
Huffnagel  IC , van Ballegoij  WJC , van Geel  BM , Vos  JMBW , Kemp  S , Engelen  M .  Progression of myelopathy in males with adrenoleukodystrophy: towards clinical trial readiness.   Brain. 2019;142(2):334-343. doi:10.1093/brain/awy299PubMedGoogle ScholarCrossref
Weisfeld-Adams  JD , Katz Sand  IB , Honce  JM , Lublin  FD .  Differential diagnosis of Mendelian and mitochondrial disorders in patients with suspected multiple sclerosis.   Brain. 2015;138(pt 3):517-539. doi:10.1093/brain/awu397PubMedGoogle ScholarCrossref
Kohlschütter  A .  Lysosomal leukodystrophies: Krabbe disease and metachromatic leukodystrophy.   Handb Clin Neurol. 2013;113:1611-1618. doi:10.1016/B978-0-444-59565-2.00029-0PubMedGoogle ScholarCrossref
Müller vom Hagen  J , Karle  KN , Schüle  R , Krägeloh-Mann  I , Schöls  L .  Leukodystrophies underlying cryptic spastic paraparesis: frequency and phenotype in 76 patients.   Eur J Neurol. 2014;21(7):983-988. doi:10.1111/ene.12423PubMedGoogle ScholarCrossref
Benzoni  C , Moscatelli  M , Fenu  S , Venerando  A , Salsano  E .  Metachromatic leukodystrophy with late adult-onset: diagnostic clues and differences from other genetic leukoencephalopathies with dementia.   J Neurol. 2021;268(5):1972-1976. doi:10.1007/s00415-020-10374-9PubMedGoogle ScholarCrossref
Martin  A , Sevin  C , Lazarus  C , Bellesme  C , Aubourg  P , Adamsbaum  C .  Toward a better understanding of brain lesions during metachromatic leukodystrophy evolution.   AJNR Am J Neuroradiol. 2012;33(9):1731-1739. doi:10.3174/ajnr.A3038PubMedGoogle ScholarCrossref
Nandhagopal  R , Krishnamoorthy  SG .  Neurological picture: tigroid and leopard skin pattern of dysmyelination in metachromatic leucodystrophy.   J Neurol Neurosurg Psychiatry. 2006;77(3):344. doi:10.1136/jnnp.2005.075762PubMedGoogle ScholarCrossref
Xu  L , Zhong  M , Wang  Y ,  et al.  Case report: novel arylsulfatase A (ARSA) gene mutations in a patient with adult-onset metachromatic leukodystrophy misdiagnosed as multiple sclerosis.   Front Neurol. 2021;11:576881. doi:10.3389/fneur.2020.576881PubMedGoogle ScholarCrossref
Boucher  AA , Miller  W , Shanley  R ,  et al.  Long-term outcomes after allogeneic hematopoietic stem cell transplantation for metachromatic leukodystrophy: the largest single-institution cohort report.   Orphanet J Rare Dis. 2015;10:94. doi:10.1186/s13023-015-0313-yPubMedGoogle ScholarCrossref
Ford  AL , Chin  VW , Fellah  S ,  et al.  Lesion evolution and neurodegeneration in RVCL-S: a monogenic microvasculopathy.   Neurology. 2020;95(14):e1918-e1931. doi:10.1212/WNL.0000000000010659PubMedGoogle ScholarCrossref
Hoogeveen  ES , Pelzer  N , de Boer  I , van Buchem  MA , Terwindt  GM , Kruit  MC .  Neuroimaging findings in retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations.   AJNR Am J Neuroradiol. 2021;42(9):1604-1609. doi:10.3174/ajnr.A7194PubMedGoogle ScholarCrossref
Dhamija  R , Schiff  D , Lopes  MBS , Jen  JC , Lin  DD , Worrall  BB .  Evolution of brain lesions in a patient with TREX1 cerebroretinal vasculopathy.   Neurology. 2015;85(18):1633-1634. doi:10.1212/WNL.0000000000002092PubMedGoogle ScholarCrossref
Raynowska  J , Miskin  DP , Pramanik  B ,  et al.  Retinal vasculopathy with cerebral leukoencephalopathy (RVCL): a rare mimic of tumefactive MS.   Neurology. 2018;91(15):e1423-e1428. doi:10.1212/WNL.0000000000006329PubMedGoogle ScholarCrossref
Jacob  J , Robertson  NJ , Hilton  DA .  The clinicopathological spectrum of Rosenthal fibre encephalopathy and Alexander’s disease: a case report and review of the literature.   J Neurol Neurosurg Psychiatry. 2003;74(6):807-810. doi:10.1136/jnnp.74.6.807PubMedGoogle ScholarCrossref
Prust  M , Wang  J , Morizono  H ,  et al.  GFAP mutations, age at onset, and clinical subtypes in Alexander disease.   Neurology. 2011;77(13):1287-1294. doi:10.1212/WNL.0b013e3182309f72PubMedGoogle ScholarCrossref
Graff-Radford  J , Schwartz  K , Gavrilova  RH , Lachance  DH , Kumar  N .  Neuroimaging and clinical features in type II (late-onset) Alexander disease.   Neurology. 2014;82(1):49-56. doi:10.1212/01.wnl.0000438230.33223.bcPubMedGoogle ScholarCrossref
Ayaki  T , Shinohara  M , Tatsumi  S , Namekawa  M , Yamamoto  T .  A case of sporadic adult Alexander disease presenting with acute onset, remission and relapse.   J Neurol Neurosurg Psychiatry. 2010;81(11):1292-1293. doi:10.1136/jnnp.2009.178079PubMedGoogle ScholarCrossref
Moser  HW .  Alexander disease: combined gene analysis and MRI clarify pathogenesis and extend phenotype.   Ann Neurol. 2005;57(3):307-308. doi:10.1002/ana.20436PubMedGoogle ScholarCrossref
Farina  L , Pareyson  D , Minati  L ,  et al.  Can MR imaging diagnose adult-onset Alexander disease?   AJNR Am J Neuroradiol. 2008;29(6):1190-1196. doi:10.3174/ajnr.A1060PubMedGoogle ScholarCrossref
Pareyson  D , Fancellu  R , Mariotti  C ,  et al.  Adult-onset Alexander disease: a series of eleven unrelated cases with review of the literature.   Brain. 2008;131(Pt 9):2321-2331. doi:10.1093/brain/awn178PubMedGoogle ScholarCrossref
Walker  LSK , Sansom  DM .  The emerging role of CTLA4 as a cell-extrinsic regulator of T cell responses.   Nat Rev Immunol. 2011;11(12):852-863. doi:10.1038/nri3108PubMedGoogle ScholarCrossref
Schwab  C , Gabrysch  A , Olbrich  P ,  et al.  Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects.   J Allergy Clin Immunol. 2018;142(6):1932-1946. doi:10.1016/j.jaci.2018.02.055PubMedGoogle ScholarCrossref
Egg  D , Schwab  C , Gabrysch  A ,  et al.  Increased risk for malignancies in 131 affected CTLA4 mutation carriers.   Front Immunol. 2018;9:2012. doi:10.3389/fimmu.2018.02012PubMedGoogle ScholarCrossref
Kolcava  J , Litzman  J , Bednarik  J , Stulik  J , Stourac  P .  Neurological manifestation of immune system dysregulation resulting from CTLA-4 receptor mutation: a case report.   Mult Scler Relat Disord. 2020;45:102313. doi:10.1016/j.msard.2020.102313PubMedGoogle ScholarCrossref
van Leeuwen  EM , Cuadrado  E , Gerrits  AM , Witteveen  E , de Bree  GJ .  Treatment of intracerebral lesions with abatacept in a CTLA4-haploinsufficient patient.   J Clin Immunol. 2018;38(4):464-467. doi:10.1007/s10875-018-0511-1PubMedGoogle ScholarCrossref
Pittock  SJ , Debruyne  J , Krecke  KN ,  et al.  Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS).   Brain. 2010;133(9):2626-2634. doi:10.1093/brain/awq164PubMedGoogle ScholarCrossref
Taieb  G , Duran-Peña  A , de Chamfleur  NM ,  et al.  Punctate and curvilinear gadolinium enhancing lesions in the brain: a practical approach.   Neuroradiology. 2016;58(3):221-235. doi:10.1007/s00234-015-1629-yPubMedGoogle ScholarCrossref
Taieb  G , Mulero  P , Psimaras  D ,  et al; in cooperation with the French CLIPPERS Group.  CLIPPERS and its mimics: evaluation of new criteria for the diagnosis of CLIPPERS.   J Neurol Neurosurg Psychiatry. 2019;90(9):1027-1038. doi:10.1136/jnnp-2018-318957PubMedGoogle ScholarCrossref
Tobin  WO , Guo  Y , Krecke  KN ,  et al.  Diagnostic criteria for chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS).   Brain. 2017;140(9):2415-2425. doi:10.1093/brain/awx200PubMedGoogle ScholarCrossref
Benson  LA , Li  H , Henderson  LA ,  et al.  Pediatric CNS-isolated hemophagocytic lymphohistiocytosis.   Neurol Neuroimmunol Neuroinflamm. 2019;6(3):e560. doi:10.1212/NXI.0000000000000560PubMedGoogle ScholarCrossref
Wolf  B .  Biotinidase deficiency should be considered in individuals exhibiting myelopathy with or without and vision loss.   Mol Genet Metab. 2015;116(3):113-118. doi:10.1016/j.ymgme.2015.08.012PubMedGoogle ScholarCrossref
Yilmaz  S , Serin  M , Canda  E ,  et al.  A treatable cause of myelopathy and vision loss mimicking neuromyelitis optica spectrum disorder: late-onset biotinidase deficiency.   Metab Brain Dis. 2017;32(3):675-678. doi:10.1007/s11011-017-9984-5PubMedGoogle ScholarCrossref
Santoro  JD , Paulsen  KC .  Biotinidase deficiency as a mimic of neuromyelitis optica spectrum disorder in childhood.   JAMA Neurol. 2020;78(1):118-120. doi:10.1001/jamaneurol.2020.3558PubMedGoogle ScholarCrossref
Desai  S , Ganesan  K , Hegde  A .  Biotinidase deficiency, a reversible metabolic encephalopathy: neuroimaging and MR spectroscopic findings in a series of four patients.   Pediatr Radiol. 2008;38(8):848-856. doi:10.1007/s00247-008-0904-zPubMedGoogle ScholarCrossref
Van Iseghem  V , Sprengers  M , De Zaeytijd  J ,  et al.  Biotinidase deficiency: a treatable cause of opticospinal syndrome in young adults.   Mult Scler Relat Disord. 2019;32:64-65. doi:10.1016/j.msard.2019.04.025PubMedGoogle ScholarCrossref
Wiltink  RC , Kruijshaar  ME , van Minkelen  R ,  et al.  Neonatal screening for profound biotinidase deficiency in the Netherlands: consequences and considerations.   Eur J Hum Genet. 2016;24(10):1424-1429. doi:10.1038/ejhg.2016.65PubMedGoogle ScholarCrossref
Gorman  GS , Chinnery  PF , DiMauro  S ,  et al.  Mitochondrial diseases.   Nat Rev Dis Primers. 2016;2:16080. doi:10.1038/nrdp.2016.80PubMedGoogle ScholarCrossref
Salsano  E , Farina  L , Lamperti  C ,  et al.  Adult-onset leukodystrophies from respiratory chain disorders: do they exist?   J Neurol. 2013;260(6):1617-1623. doi:10.1007/s00415-013-6844-zPubMedGoogle ScholarCrossref
Marelli  C , Salsano  E , Politi  LS , Labauge  P .  Spinal cord involvement in adult-onset metabolic and genetic diseases.   J Neurol Neurosurg Psychiatry. 2019;90(2):211-218. doi:10.1136/jnnp-2018-318666PubMedGoogle ScholarCrossref
Roosendaal  SD , van de Brug  T , Alves  CAPF ,  et al.  Imaging patterns characterizing mitochondrial leukodystrophies.   AJNR Am J Neuroradiol. 2021;42(7):1334-1340. doi:10.3174/ajnr.A7097PubMedGoogle ScholarCrossref
Verny  C , Loiseau  D , Scherer  C ,  et al.  Multiple sclerosis-like disorder in OPA1-related autosomal dominant optic atrophy.   Neurology. 2008;70(13 pt 2):1152-1153. doi:10.1212/01.wnl.0000289194.89359.a1PubMedGoogle ScholarCrossref
Pfeffer  G , Burke  A , Yu-Wai-Man  P , Compston  DAS , Chinnery  PF .  Clinical features of MS associated with Leber hereditary optic neuropathy mtDNA mutations.   Neurology. 2013;81(24):2073-2081. doi:10.1212/01.wnl.0000437308.22603.43PubMedGoogle ScholarCrossref
Matthews  L , Enzinger  C , Fazekas  F ,  et al; MAGNIMS Network.  MRI in Leber’s hereditary optic neuropathy: the relationship to multiple sclerosis.   J Neurol Neurosurg Psychiatry. 2015;86(5):537-542. doi:10.1136/jnnp-2014-308186PubMedGoogle ScholarCrossref
Codjia  P , Ayrignac  X , Mochel  F ,  et al.  Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia: an MRI study of 16 French cases.   AJNR Am J Neuroradiol. 2018;39(9):1657-1661. doi:10.3174/ajnr.A5744PubMedGoogle ScholarCrossref
Lakshmanan  R , Adams  ME , Lynch  DS ,  et al.  Redefining the phenotype of ALSP and AARS2 mutation-related leukodystrophy.   Neurol Genet. 2017;3(2):e135. doi:10.1212/NXG.0000000000000135PubMedGoogle ScholarCrossref
Wolf  NI , Toro  C , Kister  I ,  et al.  DARS-associated leukoencephalopathy can mimic a steroid-responsive neuroinflammatory disorder.   Neurology. 2015;84(3):226-230. doi:10.1212/WNL.0000000000001157PubMedGoogle ScholarCrossref
Zhou  Q , Yang  D , Ombrello  AK ,  et al.  Early-onset stroke and vasculopathy associated with mutations in ADA2.   N Engl J Med. 2014;370(10):911-920. doi:10.1056/NEJMoa1307361PubMedGoogle ScholarCrossref
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Credit Designation Statement: The American Medical Association designates this Journal-based CME activity activity for a maximum of 1.00  AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to:

  • 1.00 Medical Knowledge MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program;;
  • 1.00 Self-Assessment points in the American Board of Otolaryngology – Head and Neck Surgery’s (ABOHNS) Continuing Certification program;
  • 1.00 MOC points in the American Board of Pediatrics’ (ABP) Maintenance of Certification (MOC) program;
  • 1.00 Lifelong Learning points in the American Board of Pathology’s (ABPath) Continuing Certification program; and
  • 1.00 CME points in the American Board of Surgery’s (ABS) Continuing Certification program

It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting MOC credit.

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