Incomplete hippocampal inversion in patients with mutations in genes involved in sonic hedgehog signaling

Abstract

Sonic hedgehog (Shh) signaling pathways are known to play an important role in the morphological development of the hippocampus in vivo, but their actual roles in humans have not been clarified. Hypothalamic hamartoma (HH) is known to be associated with germline or somatic gene mutations of Shh signaling. We hypothesized that patients with HH and mutations of Shh-related genes also show hippocampal maldevelopment and an abnormal hippocampal infolding angle (HIA). We analyzed 45 patients (age: 1-37 years) with HH who underwent stereotactic radiofrequency thermocoagulation and found Shh-related gene mutations in 20 patients. In addition, 44 pediatric patients without HH (age: 2-25 years) who underwent magnetic resonance imaging (MRI) examinations under the same conditions during the same period were included in this study as a control group. HIA evaluated on MRI was compared between patients with gene mutations and the control group. The median HIA at the cerebral peduncle slice in patients with the gene mutation was 74.36° on the left and 76.11° on the right, and these values were significantly smaller than the corresponding values in the control group (80.46° and 80.56°, respectively, p < 0.01). Thus, mutations of Shh-related genes were correlated to incomplete hippocampal inversion. The HIA, particularly at the cerebral peduncle slice, is a potential indicator of abnormalities of the Shh-signaling pathway.

Keywords: Genetic mutation; Hippocampal infolding angle; Hippocampal inversion; Hypothalamic hamartoma; Sonic hedgehog.

Fig. 1

Genetic analysis and assigned group. Blood samples were analyzed in all 45 cases. Specimens of hypothalamic hamartoma (HH) were obtained from 27 patients. Seven patients showing mutations in blood samples were classified into the germline mutation group (GM group). In the analyses of the HH samples of 20 patients without germline mutations, 13 patients showed mutations in HH samples and were classified into the somatic mutation group (SM group).

Fig. 2

Measurement of the hippocampal infolding angle (HIA). A. HIAs were measured at the coronal section reconstructed perpendicular to the long axis of the hippocampus. B. HIAs were defined as the angle between the line connecting the medial superior margin of the subiculum (arrowhead) with the lateral margin of the cornu ammonis (arrow) and the vertical midline of the cerebral hemisphere. HIA was measured on the cerebral peduncle (CP) section (C) and superior cerebellar peduncle (SCP) section (D).

Fig. 3

Comparisons among the GM, SM, and control groups. A, B. The CP section showed no difference between the GM and SM groups, but both groups showed significantly smaller HIAs than the control group. C, D. The SCP section showed a significant difference only between the SM group on the right side and the control group. **:p < 0.01, *: P < 0.05.

Fig. 4

HIA of CP sections in the illustrative cases for the mutation and control groups. A. Mutation group (HIA: 63°). B. Control group (HIA: 82°). HIA was significantly smaller in the GM and SM groups than in the C group, HIA was significantly smaller in the GM and SM groups than in the C group. The arrowhead indicates HH.

Fig. 5

Relationship between HIA and age. A. Left CP section. B. Right CP section. C. Left SCP section. D. Right SCP section. The upper panel shows the control group and the lower panel shows the gene mutation group. In the control group, HIA showed a mild correlation with age, but in the gene mutation group, no correlation with age was observed.

Fig. 6

Diagram representing the differentiation from stem cells to hippocampus and hypothalamus. The somatic mutation may have occurred around the time of differentiation from neuroectoderm to prosencephalon, The somatic mutation may have occurred around the time of differentiation from neuroectoderm to prosencephalon (gray area).