Subcortical heterotopic gray matter brain malformations: Classification study of 107 individuals

Abstract

Objective: To better evaluate the imaging spectrum of subcortical heterotopic gray matter brain malformations (subcortical heterotopia [SUBH]), we systematically reviewed neuroimaging and clinical data of 107 affected individuals.

Methods: SUBH is defined as heterotopic gray matter, located within the white matter between the cortex and lateral ventricles. Four large brain malformation databases were searched for individuals with these malformations; data on imaging, clinical outcomes, and results of molecular testing were systematically reviewed and integrated with all previously published subtypes to create a single classification system.

Results: Review of the databases revealed 107 patients with SUBH, the large majority scanned during childhood (84%), including more than half before 4 years (59%). Although most individuals had cognitive or motor disability, 19% had normal development. Epilepsy was documented in 69%. Additional brain malformations were common and included abnormalities of the corpus callosum (65/102 [64%]), and, often, brainstem or cerebellum (47/106 [44%]). Extent of the heterotopic gray matter brain malformations (unilateral or bilateral) did not influence the presence or age at onset of seizures. Although genetic testing was not systematically performed in this group, the sporadic occurrence and frequent asymmetry suggests either postzygotic mutations or prenatal disruptive events. Several rare, bilateral forms are caused by mutations in genes associated with cell proliferation and polarity (EML1, TUBB, KATNB1, CENPJ, GPSM2).

Conclusion: This study reveals a broad clinical and imaging spectrum of heterotopic malformations and provides a framework for their classification.

Figure 1. Representative MRI from group 1: subcortical heterotopia in peritrigonal regions

Each row depicts images from the same patient. (A.a, B.a) Midline sagittal. (A.b, B.b) Axial at the level of the basal ganglia. (A.c) Axial. (B.c) Coronal. (A.d, B.d) Coronal. LR07-197 has bilateral, left larger than right, peritrigonal optic pathway heterotopic gray matter brain malformations (HET) (arrows: A.b and A.d). The genu of the corpus callosum and brainstem are hypoplastic (A.a), the cerebellum is dysplastic (A.c). This individual was found to have a de novo TUBB mutation c.860C>G (p.Pro287Arg). GM-R06 has bilateral peritrigonal optic pathway HET (arrows: B.b, B.c, and B.d). She also has profound microcephaly (−11 SD). She is compound heterozygous for CENPJ mutations c.1805_1808del (p.Glu602fs) and c.289dupA (p.Thr97fs).

Figure 2. Representative MRI from group 2: diffuse ribbon-like heterotopic gray matter brain malformations (HET) and mesial parasagittal HET

Each row depicts images from the same patient. (A.a, B.a, C.a, D.a) Midline sagittal. (A.b, B.b, C.b, D.b) Axial at the level of the basal ganglia. (A.c, B.c, C.c, D.c) Axial. (A.d, C.d, D.d) Axial. (B.d) Coronal. (A, B) LP98-117 and LR13-260 both show complete agenesis of the corpus callosum and a bilateral single undulating ribbon-like HET throughout the white matter (arrows: A.b and B.b). The cortex is polymicrogyria-like. Both individuals are megalencephalic. The lateral ventricles are enlarged in LP98-117 (asterisks: A.b). LR13-260 received a ventriculoperitoneal drain shortly after birth for treatment of hydrocephalus. A homozygous EML1 mutation was identified in LR13-260. DNA was not available for LP98-117. (C, D) LR03-112 and LR03-246 have partial agenesis of the corpus callosum and longitudinal HET in the parasagittal plane (arrows: C.b and C.c); on more upwards cuts the HET connects to the highly dysplastic mesial cortex (not shown). The cerebellum is dysplastic (C.d and D.d). Note also enlarged lateral ventricles and midline cyst in LR03-246 (asterisks: D.b). Both individuals had hearing loss. This pattern is associated with Chudley-McCullough syndrome.

Figure 3. Representative MRI from individuals from group 2: curvilinear and transmantle heterotopic gray matter brain malformations (HET)

Each row depicts images from the same patient. (A.a, B.a, C.a, D.a, E.a) Midline sagittal. (A.b, B.b, C.b, D.b, E.b) Axial. (A.c, B.c, C.c, D.c, E.c) Axial. (A.d, C.d, D.d) Coronal. (B.d, E.d) Axial images. (A–C) Curvilinear subcortical band heterotopia (SUBH) with CSF-like spaces. (D) Curvilinear SUBH with agenesis of the corpus callosum (ACC)–interhemispheric (IHEM) cysts. (E) Transmantle columnar HET. Images from individual LR05-282 show extensive giant HET with curvilinear CSF-like spaces in the right hemisphere (arrows: A.b–A.d). The HET connects to both the overlying cortex and the ependyma in several instances. The left hemisphere crosses the midline. The right frontal horn and right caudate nucleus cannot be identified; instead, a large heterotopic mass is seen (asterisk: A.b). LR01-079 shows HET with curvilinear and nodular SUBH (arrowheads: B.b–B.d) with extensive involvement of the right hemisphere. Also here the right frontal horn and right caudate nucleus cannot be identified (asterisk: B.b). The cerebellum is hypoplastic with a Dandy-Walker configuration (asterisk: B.a and B.d). LR13-408 has extensive involvement of both hemispheres with both curvilinear HET connecting to the cortex and multiple nodular SUBH (examples: C.a–C.d). LR03-395: bilateral asymmetric HET with IHEM. The cysts are denoted with asterisks (D.b–D.d). Note also ACC and hypoplastic pons and cerebellar vermis (arrow: D.a). CSF-like spaces are identifiable (arrowheads: D.c). LR08-415: transmantle columnar HET in the left frontal lobe (arrows: E.c and E.d). The overlying cortex is dysplastic (asterisks: E.b, E.c, E.d), and the lateral ventricles are mildly enlarged.

Figure 4. Representative MRI from individuals from group 3: transmantle columnar and fan-like heterotopic gray matter brain malformations (HET) and deeply infolded HET

Each row depicts images from the same patient. (A.a, B.a, C.a, D.a, E.a) Midline sagittal. (A.b, C.b, D.b, E.b) Axial at the level of the basal ganglia. (B.b) Axial. (A.c) Coronal. (B.c, C.c, D.c, E.c) Axial. (A.d, C.d, D.d, E.d) Coronal. (B.d) Axial. (A) Partial agenesis of the corpus callosum, transmantle columnar subcortical band heterotopia (SUBH) (arrow: A.b) and fan-like SUBH (arrowhead: A.c and A.d) and bilateral clefts (asterisks: A.b). (B, C) Deeply infolded HET–parieto-occipital subtype was identified in LP97-007 and LR12-324, originating posteriorly in the perisylvian areas with an oblique orientation relative to the sagittal plane (circles [B.b] and arrowheads [C.b–C.d]). (D, E) Deeply infolded–parasagittal subtype. Images show a highly similar pattern of bilateral parasagittal deep infolded HET touching the ependyma (arrowheads: D.c, D.d, E.c, E.d). Both individuals are microcephalic (occipital frontal circumference −3 SD and −5 SD, respectively). Other brain structures are relatively preserved.

Figure 5. Representative MRI from individuals from group 4: microventriculy and brain-in-brain malformation

(A.a, B.a, C.a, D.a, E.a) Midline sagittal. (A.b, B.b, C.b, D.b, E.b) Axial at the level of the basal ganglia. (A.c, B.c, C.c, D.c, E.c) Axial. (A.d, B.d, D.d, E.d) Axial images of cerebellum. (C.d) Coronal. (A, B): Microventriculy with heterotopic gray matter brain malformations (HET). (C–E) Brain-in-brain malformation. The latter has similarities to microventriculy and has in addition a midline mass of gray and white matter signal intensity. We did not identify normal lateral ventricles (LV) in any individual. In LP99-240, however, CSF-filled spaces were seen in the region where the LV are expected (asterisks: D.c). The HET are bilateral and resemble disorganized sulci deeply infiltrating the white matter (arrows: D.c). LR00-237, LR05-320, and LR13-329 have high occipital encephalocele, and LR05-320 and LR13-202 have turricephaly with high parietal interhemispheric cyst (arrows: A.a, B.a, C.a, D.a, E.a). Thalamic fusion is suspected in all (asterisks: A.b, B.b, C.b, D.b, E.b) and in addition, alobar holoprosencephaly in LR00-237 and middle interhemispheric fusion in LR99-240 (C.c and D.c). The cerebellum is hypoplastic in all and severe dysplastic in all but LR13-329 (A.d, C.b, C.c, D.d, E.d).