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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

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neuroradiologic features of cask mutations

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

cask calcium calmodulin dependenet serine protein kinase
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

slide3

MRI (2-year-old)

T1WI

T1WI

T2WI

case series
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)

normal controls
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

disease controls
Disease controls

5 patients

with

pontine hypoplasia (other than CASK mutations)

  • PEHO syndrome
  • 5p-syndrome
  • Trisomy of chromosome 18
  • Complex chromosomal abnormalities
slide7

Measuring the areas

(pons, midbrain tegmentum, cerebellar vermis,

corpus callosum)

T2WI

T1WI

T1WI

slide8

Cerebrum

Cerebellum

Pons

Corpus callosum

discussion
Discussion
  • Mutations of the CASK gene are associated with

X-linked mental retardation

microcephaly

disproportionate brain stem

cerebellar hypoplasia

female

discussion1
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.

slide12

Barkovich AJ, Millen KJ, Dobyns WB. A developmental and genetic classification

for midbrain-hindbrain malformations. Brain 2009;132:3199–230

slide13
MRI

PEHO syndrome:

16-month-old

CASK:

24-month-old

conclusions
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.

acknowledgments
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.

case 2 year 8 month old girl
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.

physical exam 9 month old
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

neurological exam
Neurological exam

Cranial nerves: normal (hearing intact)

Cerebellar signs: normal

Power: normal

Tone: decreased

Sensory: normal

Reflexes: increased (lower extremity)

laboratory tests
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

gene analysis
Gene analysis

Patient:

  • Chromosome analysis:
  • aCGH:

Parents:

  • FISH analysis:

mutations in the patient’s CASK :

normal

heterozygous deletion of CASK

normal

de novo

slide22

MRI (9-month-old)

T1WI

T2WI

T1WI

mri cask mutations
MRI (CASK mutations)

normal size

corpus callosum

reduced size

cerebrum, pons, midbrain, cerebellum

slide25

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.

slide26

Growth curve

height

Head circumference

weight

slide27

[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

slide28
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