Systematic Analysis of Brain MRI Findings in Adaptor Protein Complex 4-Associated Hereditary Spastic Paraplegia.

Adaptor Protein Complex 4 / metabolism Corpus Callosum / diagnostic imaging Humans Magnetic Resonance Imaging / methods Neuroimaging Spastic Paraplegia, Hereditary / diagnostic imaging

Journal

Neurology
ISSN: 1526-632X
Titre abrégé: Neurology
Pays: United States
ID NLM: 0401060

Informations de publication

Date de publication:
09 11 2021
Historique:
received: 19 04 2021
accepted: 23 08 2021
pubmed: 22 9 2021
medline: 7 4 2022
entrez: 21 9 2021
Statut: ppublish

Résumé

AP-4-associated hereditary spastic paraplegia (AP-4-HSP: SPG47, SPG50, SPG51, SPG52) is an emerging cause of childhood-onset hereditary spastic paraplegia and mimic of cerebral palsy. This study aims to define the spectrum of brain MRI findings in AP-4-HSP and to investigate radioclinical correlations. We performed a systematic qualitative and quantitative analysis of 107 brain MRI studies from 76 individuals with genetically confirmed AP-4-HSP and correlation with clinical findings including surrogates of disease severity. We define AP-4-HSP as a disorder of gray and white matter and demonstrate that abnormal myelination is common and that metrics of reduced white matter volume correlate with severity of motor symptoms. We identify a common diagnostic imaging signature consisting of (1) a thin splenium of the corpus callosum, (2) an absent or thin anterior commissure, (3) characteristic signal abnormalities of the forceps minor ("ears of the grizzly sign"), and (4) periventricular white matter abnormalities. The presence of 2 or more of these findings has a sensitivity of ∼99% for detecting AP-4-HSP; the combination of all 4 is found in ∼45% of cases. Compared to other HSPs with a thin corpus callosum, the absent anterior commissure appears to be specific to AP-4-HSP. Our analysis identified a subset of patients with polymicrogyria, underscoring the role of AP-4 in early brain development. These patients displayed a higher prevalence of seizures and status epilepticus, many at a young age. Our findings define the MRI spectrum of AP-4-HSP, providing opportunities for early diagnosis, identification of individuals at risk for complications, and a window into the role of the AP-4 complex in brain development and neurodegeneration.

Sections du résumé

BACKGROUND AND OBJECTIVES
AP-4-associated hereditary spastic paraplegia (AP-4-HSP: SPG47, SPG50, SPG51, SPG52) is an emerging cause of childhood-onset hereditary spastic paraplegia and mimic of cerebral palsy. This study aims to define the spectrum of brain MRI findings in AP-4-HSP and to investigate radioclinical correlations.
METHODS
We performed a systematic qualitative and quantitative analysis of 107 brain MRI studies from 76 individuals with genetically confirmed AP-4-HSP and correlation with clinical findings including surrogates of disease severity.
RESULTS
We define AP-4-HSP as a disorder of gray and white matter and demonstrate that abnormal myelination is common and that metrics of reduced white matter volume correlate with severity of motor symptoms. We identify a common diagnostic imaging signature consisting of (1) a thin splenium of the corpus callosum, (2) an absent or thin anterior commissure, (3) characteristic signal abnormalities of the forceps minor ("ears of the grizzly sign"), and (4) periventricular white matter abnormalities. The presence of 2 or more of these findings has a sensitivity of ∼99% for detecting AP-4-HSP; the combination of all 4 is found in ∼45% of cases. Compared to other HSPs with a thin corpus callosum, the absent anterior commissure appears to be specific to AP-4-HSP. Our analysis identified a subset of patients with polymicrogyria, underscoring the role of AP-4 in early brain development. These patients displayed a higher prevalence of seizures and status epilepticus, many at a young age.
DISCUSSION
Our findings define the MRI spectrum of AP-4-HSP, providing opportunities for early diagnosis, identification of individuals at risk for complications, and a window into the role of the AP-4 complex in brain development and neurodegeneration.

Identifiants

DOI: 10.1212/WNL.0000000000012836 PMID: 34544818 PMC: PMC8601212
pubmed: 34544818
pii: WNL.0000000000012836
doi: 10.1212/WNL.0000000000012836
pmc: PMC8601212
doi:

Substances chimiques

Adaptor Protein Complex 4 0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

e1942-e1954

Subventions

Organisme : NICHD NIH HHS
ID : P50 HD105351
Pays : United States
Organisme : NINDS NIH HHS
ID : R25 NS070682
Pays : United States
Organisme : NINDS NIH HHS
ID : K08 NS123552
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007753
Pays : United States
Organisme : NICHD NIH HHS
ID : U54 HD090255
Pays : United States

Investigateurs

Saskia Bulk (S)
Fr Ed Erique Depierreux (FEE)
Parham Habibzadeh (P)
Anand S Iyer (AS)
Margaret Kaminska (M)
Soyoung Kim (S)
Staci D King (SD)
Hanna Mierzewska (H)
Agathe Roubertie (A)
Filippo M Santorelli (FM)
Moneef Shoukier (M)
Krzysztof Szczałuba (K)
Sanem P Uysal (SP)
Conny M A van Ravenswaaij-Arts (CMA)

Informations de copyright

© 2021 American Academy of Neurology.

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Auteurs

Darius Ebrahimi-Fakhari (D)

From the Department of Neurology (D.E.-F., J.E.A., M.Z., G.G., C.J., A.D., A.S., M.S.), and Division of Neuroradiology, Department of Radiology (S.P.P., E.Y.), The Manton Center for Orphan Disease Research (D.E.-F., R.C.Y., S.K.A.), Rosamund Stone Zander Translational Neuroscience Center (M.S.), and Division of Genetics and Genomics (D.E.-F., R.C.Y., S.K.A.), Boston Children's Hospital, Harvard Medical School, MA. darius.ebrahimi-fakhari@childrens.harvard.edu.
ORCID: 0000-0002-0026-4714

Julian E Alecu (JE)

From the Department of Neurology (D.E.-F., J.E.A., M.Z., G.G., C.J., A.D., A.S., M.S.), and Division of Neuroradiology, Department of Radiology (S.P.P., E.Y.), The Manton Center for Orphan Disease Research (D.E.-F., R.C.Y., S.K.A.), Rosamund Stone Zander Translational Neuroscience Center (M.S.), and Division of Genetics and Genomics (D.E.-F., R.C.Y., S.K.A.), Boston Children's Hospital, Harvard Medical School, MA.
ORCID: 0000-0002-1420-9775

Marvin Ziegler (M)

From the Department of Neurology (D.E.-F., J.E.A., M.Z., G.G., C.J., A.D., A.S., M.S.), and Division of Neuroradiology, Department of Radiology (S.P.P., E.Y.), The Manton Center for Orphan Disease Research (D.E.-F., R.C.Y., S.K.A.), Rosamund Stone Zander Translational Neuroscience Center (M.S.), and Division of Genetics and Genomics (D.E.-F., R.C.Y., S.K.A.), Boston Children's Hospital, Harvard Medical School, MA.
ORCID: 0000-0002-0504-7815

Gregory Geisel (G)

From the Department of Neurology (D.E.-F., J.E.A., M.Z., G.G., C.J., A.D., A.S., M.S.), and Division of Neuroradiology, Department of Radiology (S.P.P., E.Y.), The Manton Center for Orphan Disease Research (D.E.-F., R.C.Y., S.K.A.), Rosamund Stone Zander Translational Neuroscience Center (M.S.), and Division of Genetics and Genomics (D.E.-F., R.C.Y., S.K.A.), Boston Children's Hospital, Harvard Medical School, MA.

Catherine Jordan (C)

From the Department of Neurology (D.E.-F., J.E.A., M.Z., G.G., C.J., A.D., A.S., M.S.), and Division of Neuroradiology, Department of Radiology (S.P.P., E.Y.), The Manton Center for Orphan Disease Research (D.E.-F., R.C.Y., S.K.A.), Rosamund Stone Zander Translational Neuroscience Center (M.S.), and Division of Genetics and Genomics (D.E.-F., R.C.Y., S.K.A.), Boston Children's Hospital, Harvard Medical School, MA.

Angelica D'Amore (A)

From the Department of Neurology (D.E.-F., J.E.A., M.Z., G.G., C.J., A.D., A.S., M.S.), and Division of Neuroradiology, Department of Radiology (S.P.P., E.Y.), The Manton Center for Orphan Disease Research (D.E.-F., R.C.Y., S.K.A.), Rosamund Stone Zander Translational Neuroscience Center (M.S.), and Division of Genetics and Genomics (D.E.-F., R.C.Y., S.K.A.), Boston Children's Hospital, Harvard Medical School, MA.
ORCID: 0000-0003-4960-2689

Rebecca C Yeh (RC)

From the Department of Neurology (D.E.-F., J.E.A., M.Z., G.G., C.J., A.D., A.S., M.S.), and Division of Neuroradiology, Department of Radiology (S.P.P., E.Y.), The Manton Center for Orphan Disease Research (D.E.-F., R.C.Y., S.K.A.), Rosamund Stone Zander Translational Neuroscience Center (M.S.), and Division of Genetics and Genomics (D.E.-F., R.C.Y., S.K.A.), Boston Children's Hospital, Harvard Medical School, MA.

Shyam K Akula (SK)

From the Department of Neurology (D.E.-F., J.E.A., M.Z., G.G., C.J., A.D., A.S., M.S.), and Division of Neuroradiology, Department of Radiology (S.P.P., E.Y.), The Manton Center for Orphan Disease Research (D.E.-F., R.C.Y., S.K.A.), Rosamund Stone Zander Translational Neuroscience Center (M.S.), and Division of Genetics and Genomics (D.E.-F., R.C.Y., S.K.A.), Boston Children's Hospital, Harvard Medical School, MA.
ORCID: 0000-0003-2334-591X

Afshin Saffari (A)

From the Department of Neurology (D.E.-F., J.E.A., M.Z., G.G., C.J., A.D., A.S., M.S.), and Division of Neuroradiology, Department of Radiology (S.P.P., E.Y.), The Manton Center for Orphan Disease Research (D.E.-F., R.C.Y., S.K.A.), Rosamund Stone Zander Translational Neuroscience Center (M.S.), and Division of Genetics and Genomics (D.E.-F., R.C.Y., S.K.A.), Boston Children's Hospital, Harvard Medical School, MA.
ORCID: 0000-0003-4119-7519

Sanjay P Prabhu (SP)

From the Department of Neurology (D.E.-F., J.E.A., M.Z., G.G., C.J., A.D., A.S., M.S.), and Division of Neuroradiology, Department of Radiology (S.P.P., E.Y.), The Manton Center for Orphan Disease Research (D.E.-F., R.C.Y., S.K.A.), Rosamund Stone Zander Translational Neuroscience Center (M.S.), and Division of Genetics and Genomics (D.E.-F., R.C.Y., S.K.A.), Boston Children's Hospital, Harvard Medical School, MA.
ORCID: 0000-0003-0871-115X

Mustafa Sahin (M)

From the Department of Neurology (D.E.-F., J.E.A., M.Z., G.G., C.J., A.D., A.S., M.S.), and Division of Neuroradiology, Department of Radiology (S.P.P., E.Y.), The Manton Center for Orphan Disease Research (D.E.-F., R.C.Y., S.K.A.), Rosamund Stone Zander Translational Neuroscience Center (M.S.), and Division of Genetics and Genomics (D.E.-F., R.C.Y., S.K.A.), Boston Children's Hospital, Harvard Medical School, MA.
ORCID: 0000-0001-7044-2953

Edward Yang (E)

From the Department of Neurology (D.E.-F., J.E.A., M.Z., G.G., C.J., A.D., A.S., M.S.), and Division of Neuroradiology, Department of Radiology (S.P.P., E.Y.), The Manton Center for Orphan Disease Research (D.E.-F., R.C.Y., S.K.A.), Rosamund Stone Zander Translational Neuroscience Center (M.S.), and Division of Genetics and Genomics (D.E.-F., R.C.Y., S.K.A.), Boston Children's Hospital, Harvard Medical School, MA.

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Protéines du transport vésiculaire › Protéines adaptatrices du transport vésiculaire › Complexe protéique adaptateur 4 › Systematic Analysis of Brain MRI Findings in...
questionsmedicales.fr › Système nerveux › Système nerveux central › Encéphale › Prosencéphale › Télencéphale › Commissures du télencéphale › Corps calleux › Systematic Analysis of Brain MRI Findings in...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Systematic Analysis of Brain MRI Findings in...
questionsmedicales.fr › Diagnostic › Techniques et procédures diagnostiques › Imagerie diagnostique › Tomographie › Imagerie par résonance magnétique › Systematic Analysis of Brain MRI Findings in...
questionsmedicales.fr › Techniques d'investigation › Neuroimagerie › Systematic Analysis of Brain MRI Findings in...
questionsmedicales.fr › Malformations et maladies congénitales, héréditaires et néonatales › Maladies génétiques congénitales › Maladies neurodégénératives héréditaires › Neuropathie héréditaire motrice et sensitive › Paraplégie spasmodique héréditaire › Systematic Analysis of Brain MRI Findings in...