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)
T1WI
T1WI
T2WI
Case Series
5 Japanese girls with CASK Mutations
( 1–4 years of age)
with
histories of developmental retardation
 microcephaly
characteristic 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 syndromes
No neurodevelopmental abnormalities
Disease controls
5 patients
with
pontine hypoplasia (other than CASK mutations)
PEHO syndrome
5p-syndrome
Trisomy of chromosome 18
Complex chromosomal abnormalities
Measuring the areas
(pons, midbrain tegmentum, cerebellar vermis,
corpus callosum)
T2WI
T1WI
T1WI
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
CASK
belongs 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 classification
for midbrain-hindbrain malformations. Brain 2009;132:3199–230
MRI
CASK:
PEHO syndrome:
24-month-old
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 jaw
Chest: clear breath sounds, bilaterallyno murmurs
Abdomen: soft, nondistended, normal bowel sounds
no hepatosplenomegaly
Extremities: no edema, no syndactyly
Neurological exam
Cranial nerves: normal (hearing intact)
Cerebellar signs: normal
Power: normal
Tone: decreased
Sensory: normal
Reflexes: increased (lower extremity)
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
Patient:
 Chromosome analysis:
 aCGH:
normal
heterozygous deletion of CASK
Parents:
 FISH analysis:
normal
mutations in the patient’s CASK :
de novo
MRI (9-month-old)
T1WI
T1WI
T2WI
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.
Growth curve
height
Head circumference
weight
[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
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)
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
乳酸
ピルビン酸
TSH
異常なし
異常なし
13.1mg/dl
0.85mg/dl
5.4μIU/ml
フリ－T4
1.4ng/dl
フリ－T3
4.9pg/ml
MCG X-tiling Array
FISH
PEHO症候群