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Neuroradiologic Features of CASK Mutations

Neuroradiologic Features of CASK Mutations. (1) Shota Yuasa ， Jun- ichi Takanashi (2 ) Hiroshi Arai ( 3 ) Johji Inazawa (4) Nobuhiko Okamoto (5) A. James. Barkovich (1) Dept of Pediatrics, Kameda Medical Center (2) Dept of Pediatric Neurology, Morinomiya Hospital

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Neuroradiologic Features of CASK Mutations

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  1. Neuroradiologic Features of CASK Mutations (1) ShotaYuasa，Jun-ichiTakanashi (2)Hiroshi Arai (3)JohjiInazawa (4)Nobuhiko Okamoto (5)A. James. Barkovich (1) Deptof Pediatrics, Kameda Medical Center (2) Dept of Pediatric Neurology, Morinomiya Hospital (3)Deptof Molecular Cytogenetics, Tokyo Medical and Dental University (4)Dept of Medical Genetics, Osaka Medical Center and Research Institute for Maternal and Child Health (5)Deptof Radiology and Biomedical Imaging, University of California San Francisco

  2. CASK(calcium/calmodulin-dependenet serine protein kinase) • regulates expression of genes involved in cortical development • Mutations of the CASK gene are associated with X-linked mental retardation microcephaly disproportionate brain stem cerebellar hypoplasia female

  3. MRI (2-year-old) T1WI T1WI T2WI

  4. Case Series 5 Japanese girls with CASK Mutations ( 1–4 years of age) with • histories of developmental retardation • microcephaly • characteristicfacial appearances (large pupils, large ears, and small jaw)

  5. Normal controls 67 female patients (0.5–180 months of age) • mild neurologic symptoms ( headache, hypotonia, seizures, febrile delirium) No parenchymal lesions ( MRI) No genetic abnormalities or syndromes No neurodevelopmental abnormalities

  6. Disease controls 5 patients with pontine hypoplasia (other than CASK mutations) • PEHO syndrome • 5p-syndrome • Trisomy of chromosome 18 • Complex chromosomal abnormalities

  7. Measuring the areas (pons, midbrain tegmentum, cerebellar vermis, corpus callosum) T2WI T1WI T1WI

  8. Cerebrum Cerebellum Pons Corpus callosum

  9. Cerebrum/Corpus callosum

  10. Discussion • Mutations of the CASK gene are associated with X-linked mental retardation microcephaly disproportionate brain stem cerebellar hypoplasia female

  11. Discussion CASK • belongs to the membrane-associated guanylate kinase protein family. • has an important function during neuronal development. Inactivating mutations of CASKin humans have recently been reported to be associated with microcephaly and midhindbrain hypoplasia.

  12. Barkovich AJ, Millen KJ, Dobyns WB. A developmental and genetic classification for midbrain-hindbrain malformations. Brain 2009;132:3199–230

  13. MRI PEHO syndrome: 16-month-old CASK: 24-month-old

  14. Conclusions The normal sizeof the corpus callosum, which gives an impression of callosal thickening at first glance, may be an imaging clue to detect female patients with CASK mutations.

  15. Acknowledgments Ithank Dr Shinichiro Hamano at Saitama Children’s MedicalCenter for referring a patient, and the patients and families for their contribution to this study.

  16. Case：2-year-8-month-old girl [Case Scenario/History] Shewas born at 41 weeks of gestation by caesarean delivery after an uneventful pregnancy.Apgar scores were 9, 9 at 1, 5 minutes. Birth weight 2860g (-0.3 SD), height 48.0cm (-0.2 SD), and head circumference 31.8cm (-0.8SD). At 9 month she was noted to have growth retardation and microcephaly with head circumference 38.0cm (－3.9 SD). she was referred to our pediatric outpatient clinicfor further assessment.

  17. Physical Exam (9-month-old) weight 6775g(-1.6 SD), height 65.2cm(-2.0 SD), head circumference 38.0cm（－3.9 SD） Head & neck: ocular hypertelorism, large pupils, epicanthal folds, large ears, broad nasal bridge, high arched palate, and small jaw Chest: clear breath sounds, bilaterallynomurmurs Abdomen: soft, nondistended, normal bowel sounds no hepatosplenomegaly Extremities: no edema, no syndactyly

  18. Neurological exam Cranial nerves: normal (hearing intact) Cerebellar signs: normal Power: normal Tone: decreased Sensory: normal Reflexes: increased (lower extremity)

  19. Laboratory tests CBC, serum biochemistry: normal lactate , pyruvic acid, thyroid test: normal viral antibody titer: normal Urinalysis: normal Plasma/Urine amino acid, organic acids: normal CSF: normal

  20. Gene analysis Patient: • Chromosome analysis: • aCGH: Parents: • FISH analysis: mutations in the patient’s CASK : normal heterozygous deletion of CASK normal de novo

  21. MRI (9-month-old) T1WI T2WI T1WI

  22. MRI (CASK mutations) normal size corpus callosum reduced size cerebrum, pons, midbrain, cerebellum

  23. The most important outcome in this study is that MR imaging findings of mid-hindbrain hypoplasia and a normal- or large appearing corpus callosum in a girl with microcephaly and neurodevelopmental retardation should suggest the possibility of a CASK mutation, particularly if the cerebrum/corpus callosum ratio is low.

  24. Growth curve height Head circumference weight

  25. [Psychomotor development] Motor development: head control/rolling over at 4 months, sitting/crawling at 1 year, standing at 2 years walking not yet Speech and Language development: one-word phrase at 1 year two-word phrases not yet [Past medical history] None [Family history] Cousin:21trisomy

  26. 入院時検査所見 血算，一般生化学 ： 異常なし 尿検 髄液，アミノ酸，有機酸，ｳｨﾙｽ抗体価：正常範囲内

  27. MCGX-tilingArray

  28. FISH

  29. PEHO症候群

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