Jun-ichi Takanashi

CASK belongs to the membrane-associated guanylate kinase protein family, which transfers phosphorus-containing groups (phosphotransferases) with a phosphate group as an acceptor; this is an important function during neuronal development. CASK regulates gene expression by interacting with a nucleosome assembly protein (CINAP) and the transcription factor TBR1 to form a complex that induces the transcription of genes containing TBR1 binding sequences, such as RELN. The CASK-TBR1-RELN cascade is essential for the normal development of the cerebrum, brain stem, and cerebellum.

We were consulted concerning a 2-year-old girl with an intellectual disability, microcephaly (-4SD), and MR imaging showing microcephaly with pontine and cerebellar hypoplasia (MICPCH). Sagittal T1-weighted images gave an impression of thickening of the corpus callosum, an unusual finding in pontocerebellar hypoplasia (the corpus callosum is usually thin). She was later given a diagnosis of MICPCH due to the CASK mutation. A subsequent evaluation of MR imaging in 5 patients with CASK mutations revealed a normal size of the corpus callosum and a reduced size of the cerebrum, leading to a low ratio of cerebrum to corpus callosum.¹ This finding of relative callosal thickening in a patient with microcephaly is an imaging clue to detect patients with CASK mutations, and is useful for pediatricians in the detection of patients with CASK mutations among those with MICPCH.

After our publication in AJNR, we continued our studies of the clinical and radiologic features of CASK mutations in a study of 16 Japanese patients, supported by the Research Grant for Nervous and Mental Disorders from the Ministry of Health, Labor and Welfare of Japan (Chief Researcher, Masayuki Sasaki, MD, PhD). This report described a uniform pattern of growth, neurologic development, and neurologic symptoms among affected patients¹: head circumference at birth was within the normal range in about half, but was followed by the early development of severe microcephaly. They acquired head control almost normally between the ages of 3 and 6 months, followed by motor delay. More than half of the girls developed epilepsy.

An analysis of their MR imaging studies confirmed the findings reported in AJNR. We presented our findings at the 2012 European Society of Neuroradiology Annual Meeting in Edinburgh, Scotland, and the 2013 Japanese Society of Pediatric Radiology Annual Meeting in Shimonoseki, Japan.

Our colleagues, Dr. Shin Hayashi and Professor Johji Inazawa, found intragenic duplications and mutations of the CASK gene in 10 of the patients. We have hypothesized that these mutations resulted in an aberrant transcript that caused a nonfunctional protein product, resulting in CASK null mutations.² We believe that this may explain the similarity of the phenotypes of patients with mutations of CASK, regardless of the specific type of CASK aberration. Similar findings reported in a study by Moog et al³ confirmed our findings.

References

1. Takanashi J, Okamoto N, Yamamoto Y, et al. Clinical and radiological features of Japanese patients with a severe phenotype due to CASK Mutations. Am J Med Genet Part A 2012;158A:3112–8.
2. Hayashi S, Okamoto N, Chinen Y, et al. Novel intragenic duplications and mutations of CASK in patients with mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH). Hum Genet 2012;131:99–110.
3. Moog U, Bierhals T, Brand K, et al. Phenotypic and molecular insights into CASK-related disorders in males. Orphanet J Rare Dis 2015;10:44.

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