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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
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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
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MRI (2-year-old)
T1WI T1WI T2WI
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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)
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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
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Disease controls 5 patients with pontine hypoplasia (other than CASK mutations)
PEHO syndrome5p-syndromeTrisomy of chromosome 18Complex chromosomal abnormalities
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Measuring the areas (pons, midbrain tegmentum, cerebellar vermis,
corpus callosum)
T1WI T1WIT2WI
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Cerebrum Cerebellum
Pons Corpus callosum
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Cerebrum / Corpus callosum
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Discussion
Mutations of the CASK gene are associated with X-linked mental retardation microcephaly disproportionate brain stem cerebellar hypoplasia female
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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.
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Barkovich AJ, Millen KJ, Dobyns WB. A developmental and genetic classificationfor midbrain-hindbrain malformations. Brain 2009;132:3199–230
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MRI
CASK:24-month-old
PEHO syndrome:16-month-old
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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.
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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.
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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.
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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
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Neurological exam Cranial nerves: normal (hearing intact)Cerebellar signs: normalPower: normalTone: decreasedSensory: normal Reflexes: increased (lower extremity)
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Laboratory tests
CBC, serum biochemistry: normallactate , pyruvic acid, thyroid test: normalviral antibody titer: normal
Urinalysis: normalPlasma/Urine amino acid, organic acids: normalCSF: normal
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Gene analysisPatient: Chromosome analysis: aCGH: Parents: FISH analysis:
mutations in the patient’s CASK :
heterozygous deletion of CASK normal
normal
de novo
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MRI (9-month-old)
T1WI T1WI T2WI
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MRI (CASK mutations)
normal size corpus callosum
reduced size cerebrum, pons, midbrain, cerebellum
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• 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.
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height
weight
Head circumference
Growth curve
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[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
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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 ) 異常なしトキソプラズマ・サイトメガロウィルス・風疹・単純ヘルペス抗体価 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
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MCG X-tiling Array
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FISH
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PEHO 症候群