Clinical and radiological features of Japanese patients with a severe phenotype due to CASK mutations
Jun-ichi Takanashi1, Nobuhiko Okamoto, Yuto Yamamoto
1Department of Pediatrics, Kameda Medical Center, Kamogawa, Japan. jtaka44@hotmail.co.jp
Insights
CASK gene mutations in females cause intellectual disability (ID) and microcephaly with pontine and cerebellar hypoplasia (MICPCH). Longitudinal studies reveal early normal growth followed by severe microcephaly and developmental delays in affected individuals.
Area of Science:
- Genetics
- Neurology
- Developmental Biology
Background:
- Heterozygous loss-of-function mutations in the CASK gene are linked to severe intellectual disability (ID) and microcephaly with pontine and cerebellar hypoplasia (MICPCH) in females.
- The longitudinal clinical and radiological progression, including postnatal growth patterns, of patients with CASK-related ID and MICPCH remains underdescribed.
Purpose of the Study:
- To describe the longitudinal clinical and radiological course of patients with intellectual disability and MICPCH associated with CASK mutations.
- To characterize postnatal growth patterns and neurodevelopmental trajectories in affected individuals.
Main Methods:
- Retrospective analysis of neurodevelopmental and imaging data from 16 Japanese patients (15 female, 1 male) with CASK mutations.
- Evaluation of growth patterns, neurological development, clinical signs, facial features, and MRI findings.
Main Results:
- Female patients exhibited similar phenotypes, with normal birth head circumference in about half, followed by severe postnatal microcephaly and growth retardation.
- Motor delays were observed after typically normal head control acquisition (3-6 months); epilepsy affected over half of the females.
- MRI revealed microcephaly, brainstem/cerebellar hypoplasia, and a normal/large corpus callosum; the male patient presented a more severe phenotype.
Conclusions:
- Uniform clinical and radiological features associated with CASK mutations in females facilitate early diagnosis.
- Understanding the longitudinal course aids in providing appropriate medical care for females with ID and MICPCH due to CASK mutations.
Abstract:
Heterozygous loss of function mutations of CASK at Xp11.4 in females cause severe intellectual disability (ID) and microcephaly with pontine and cerebellar hypoplasia (MICPCH). However, the longitudinal clinical and radiological course of affected patients, including patterns of postnatal growth, has not been described. Neurodevelopmental and imaging information was retrospectively accrued for 16 Japanese (15 female and 1 male) patients with ID and MICPCH associated with CASK mutations. All records were analyzed; patient age ranged from 2 to 16 years at the time of the most recent examinations. The growth pattern, neurological development, neurological signs/symptoms, and facial features were similar in the 15 female patients. Their head circumference at birth was within the normal range in about half, and their height and weight were frequently normal. This was followed by early development of severe microcephaly and postnatal growth retardation. The patients acquired head control almost normally between 3 and 6 months, followed by motor delay. More than half of the female patients had epilepsy. Their MRIs showed microcephaly, brainstem, and cerebellar hypoplasia in early infancy, and a normal or large appearing corpus callosum. The male patient showed a more severe clinical phenotype. These uniform clinical and radiological features should facilitate an early diagnosis and be useful for medical care of females with ID and MICPCH associated with CASK mutations.
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