Periventricular nodular heterotopia in 22q11.2 deletion and frontal lobe migration

Abstract

Objective: We aimed to delineate the distribution of periventricular nodular heterotopia (PNH) in patients with 22q11.2 microdeletion syndrome (22q11.2DS) and place this in the context of other genetic forms of PNH.

Methods: We retrospectively analyzed brain imaging and postmortem data available for adult patients with 22q11.2DS. We included only those with good quality MRI data (n = 29) in addition to two patients with PNH identified through postmortem studies. We also reviewed the pattern of PNH in all genetic conditions reported with this phenotype.

Results: Of the total seven patients (M = 4, F = 3; age: 19-61 years) identified to have PNH, six had a history of seizures, six had schizophrenia, six had variable levels of intellectual disability, and two had obsessive compulsive disorder. In all seven patients, the nodules were located over the dorsal pole of the frontal horn of the lateral ventricles. The nodules were small, noncontiguous, and ranged in number from 1 to 10 per individual. Our review identified 37 genetic conditions associated with PNH. With the cases reported here, 22q11.2DS becomes the fifth most commonly reported genetic condition, and the third most common copy number variation, associated with PNH.

Interpretation: The neuropsychiatric manifestations in our patients with PNH support other data indicating abnormal neurodevelopment as part of the pathogenesis of 22q11.2DS.The location and cellular characteristics of PNH in 22q11.2DS overlaps with a group of migrating postnatal interneurons termed Arc cells, although more research is needed to confirm that PNH in 22q11.2DS represents Arc cells arrested in their migratory pathway.

Figure 1

Brain MRIs of six patients with 22q11.2DS. (A) Patient 1: A single, small periventricular nodule (arrow) overlying the dorsal pole of the left frontal horn of the lateral ventricle. (B) Patient 2: single nodule of gray matter adjacent to the dorsal pole of the right frontal horn of the lateral ventricle (arrow). (C) Patient 3: Few small nodules of gray matter over the dorsal pole of the left frontal horn of the lateral ventricle. (D) Patient 4. A single nodule of gray matter adjacent to the dorsal pole of the right frontal horn of the lateral ventricle (arrow). (E) Patient 5: A single nodule of gray matter adjacent to the dorsal pole of the right frontal horn of the lateral ventricle (arrow). (F) Patient 7: Few small nodules of gray matter adjacent to the dorsal poles of the frontal horns of the lateral ventricles (arrows).

Figure 2

Neuropathologic features in patients with 22q11.2DS (A–C from Patient 6, D–F from Patient 7). (A) Macroscopic image of coronal section through the brain showed bilateral PNH adjacent to the lateral ventricles in the white matter of both frontal lobes. Size of heterotopias was approximately 4 mm. (B) Histologic sections of the PNH (arrows) revealed disorganized aggregates of gray matter containing haphazardly arranged neurons. (C) Frequent individual heterotopic neurons were detected in the white matter surrounding the heterotopias. Magnification (insets) reveals cytologic details, such as pyramidal shapes. (D) Immunohistochemistry for synaptophysin in a section containing two heterotopic nodules underlines the fact that the nodules are composed of gray matter. (E) Immunohistochemistry for NeuN labels the neurons in the nodule, suggesting that they are fully differentiated. (F) Higher magnification of nodule with immunostain for Calretinin, a marker of cortical interneurons.

Figure 3

Unilateral schematic representation of Arc cells surrounding the dorsal pole of the anterior horn of the lateral ventricles, with the four tiers of cells migrating toward the cortex.