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Systematic Analysis of Brain MRI Findings in Adaptor Protein Complex 4-Associated Hereditary Spastic Paraplegia
Darius Ebrahimi-Fakhari1, Julian E Alecu2, Marvin Ziegler2
1From 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.
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.
Insights
AP-4-associated hereditary spastic paraplegia (AP-4-HSP) is a brain disorder affecting gray and white matter. Key MRI findings like a thin corpus callosum and absent anterior commissure aid in early diagnosis and understanding disease progression.
Area of Science:
- Neuroimaging
- Genetics
- Neurology
Background:
- AP-4-associated hereditary spastic paraplegia (AP-4-HSP) presents in childhood, mimicking cerebral palsy.
- It is an emerging cause of hereditary spastic paraplegia.
Purpose of the Study:
- To define the spectrum of brain MRI findings in AP-4-HSP.
- To investigate correlations between imaging findings and clinical presentation.
Main Methods:
- Systematic qualitative and quantitative analysis of 107 brain MRI scans from 76 individuals.
- Correlation of MRI findings with clinical data, including disease severity.
Main Results:
- AP-4-HSP involves gray and white matter abnormalities, with common myelination issues and reduced white matter volume correlating with motor symptoms.
- A diagnostic imaging signature includes a thin splenium of the corpus callosum, absent anterior commissure, "ears of the grizzly sign" in the forceps minor, and periventricular white matter abnormalities.
- The combination of these findings has high sensitivity for AP-4-HSP diagnosis; absent anterior commissure may be specific.
Conclusions:
- The study defines the MRI spectrum of AP-4-HSP, enabling earlier diagnosis and risk identification.
- Findings offer insights into the AP-4 complex's role in brain development and neurodegeneration.
- A subset of patients with polymicrogyria showed increased seizure prevalence, highlighting AP-4's role in early brain development.
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