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(3) Dept of Molecular Cytogenetics, Tokyo Medical and Dental University(4) Dept of Medical Genetics, Osaka Medical Center and Research Institute for Maternal and Child Health(5) Dept of Radiology and Biomedical Imaging, University of California San Francisco

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

　　　　　 MRI (2-year-old)

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Case Series

5 Japanese girls with CASK Mutations ( 1–4 years of age) with histories of developmental retardation microcephalycharacteristic 　 facial appearances (large pupils, large ears, and small jaw)

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 syndromesNo neurodevelopmental abnormalities

Disease controls 5 patients with pontine hypoplasia (other than CASK mutations)

PEHO syndrome5p-syndromeTrisomy of chromosome 18Complex chromosomal abnormalities

Measuring the areas (pons, midbrain tegmentum, cerebellar vermis,

corpus callosum)

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Cerebrum Cerebellum

Pons Corpus callosum

Cerebrum / Corpus callosum

Discussion

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

Discussion

CASKbelongs to the membrane-associated guanylate

kinase protein family.has an important function during neuronal

development.

Inactivating mutations of CASK in humans have recently been reported to be associated with microcephaly and midhindbrain hypoplasia.

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

MRI

CASK:24-month-old

PEHO syndrome:16-month-old

Conclusions

　 The normal size of 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.

Acknowledgments

I thank Dr Shinichiro Hamano at Saitama Children’s Medical Center for referring a patient, and the patients and families for their contribution to this study.

　　　　　　　　　　　　　　　　　　　　　　　　　

Case ： 2-year-8-month-old girl[Case Scenario/History]She was 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 31.8 cm (-0.8 SD). 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 clinic for further assessment.

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 jawChest: clear breath sounds, bilaterallyno murmursAbdomen: soft, nondistended, normal bowel sounds no hepatosplenomegalyExtremities: no edema, no syndactyly

Neurological exam 　Cranial nerves: normal (hearing intact)Cerebellar signs: normalPower: normalTone: decreasedSensory: normal Reflexes: increased (lower extremity)

Laboratory tests

CBC, serum biochemistry: normallactate , pyruvic acid, thyroid test: normalviral antibody titer: normal

Urinalysis: normalPlasma/Urine amino acid, organic acids: normalCSF: normal

Gene analysisPatient: Chromosome analysis: 　 aCGH: 　Parents: FISH analysis: 　　

mutations in the patient’s CASK :

heterozygous deletion of CASK normal

normal

de novo

　　　　　 MRI (9-month-old)

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MRI (CASK mutations)

normal size corpus callosum

reduced size cerebrum, pons, midbrain, cerebellum

• 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.

height

weight

Head circumference

Growth curve

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

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：正常範囲内アミノ酸分析 (血清・尿・髄液 ) 異常なしﾄｷｿﾌﾟﾗｽﾞﾏ・ｻｲﾄﾒｶﾞﾛｳｨﾙｽ・風疹・単純ﾍﾙﾍﾟｽ抗体価 異常なし乳酸 13.1mg/dl

ピルビン酸 0.85mg/dlTSH 5.4μIU/ml

フリ－ T4 1.4ng/dl 　

フリ－ T3 4.9pg/ml 　

MCG X-tiling Array 　

FISH

PEHO 症候群