Transcript Cri du Chat: The Cat`s Cry

Cri du Chat: The Cat’s Cry
Kelsey Fasteland
Cri du Chat (CdC)- History
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Relatively rare genetic disorder that affects
1:20,000 to 1:50,000
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First described in 1963 by French pediatrician
Lejeune and his associates.
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Karyotyped individuals with the disorder, found
that they all were missing a piece of
chromosome 5
CdC- Phenotypes
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Cat-like cry
CdC- Phenotype
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Facial Dysmorphisms
– Including
microcephaly, round
face, hypertelorism,
epicanthal folds, lowset ears, and
micrognathia.
Bradley,
www.criduchat.asn.au/criduchat/bradley.htm
CdC- Phenotype
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Severe psychomotor and mental
retardation
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Other health problems associated with CdC:
– Poor-suck, hypotonia, respitory and heart defects,
growth retardation, and cleft palate and/or lip.
– CdC patients are generally very sociable, but may
exhibit maladaptive behaviors such as inattentiveness,
hyperactivity, temper-tantrums, and self injury.
Bradley- 2 years
www.criduchat.asn.au/criduchat/bradley.htm
CdC- Cytogenetics
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Arises from a partial terminal or interstitial
deletion of the short arm of chromosome
5 (5p).
– De novo deletion
– Parental translocation
– Other rare cytogenetic aberrations
CdC- Cytogenetics
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Multigenic
Researchers have found
two critical regions for
CdC
– Cat-like cry localized at
5p15.3
– Facial dysmorphisms and
psychomotor/mental
retardation localized at
5p15.2
Figure from www.criduchat.asn.au/criduchat
Genotype-Phenotype
Mainardi et al. 2001. J. Med. Genet. 38: 151-158.
8o patients with 5p deletion
 Each patient underwent clinical,
developmental, and genetic evaluation
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Molecular-Cytogenetic Analysis
Blood cultures of patients and parents
 FISH experiments were performed using
136 single locus DNA lambda phage
probes
 DNA was extracted and PCR amplified,
then typed with highly polymorphic PCR
based microsatellite markers
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Molecular-Cytogenetic AnalysisResults
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62 patients had a terminal 5p deletion
with break points from p13 to 5p15.2
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7 patients with interstitial 5p deletions
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Also found that 90.2% of de novo
deletions were paternal in origin
62 patients with terminal 5p deletions
Classical CdC observed in all cases
-Distribution of dysmorphism increased
-frequency and severity of
microcephaly increased
-Psychomotor development was more
affected in groups D and C than in
group A
Mainardi et al. 2001. J. Med. Genet. 38: 151-158.
What does this mean?
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This highlights a progressive severity of
clinical manifestations and
psychomotor/mental retardation as the
size of the deletion increases.
Seven patients with interstitial deletions
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Patient 1*: Cat cry, no typical
dysmorphisms, mild psychomotor
retardation
Patients 19, 25, 76*: No cat cry,
typical dysmorphisms, mild to
severe psychomotor retardation
Patient 45:?, typical
dysmorphisms, moderate/severe
psychomotor retardation
Patient 77: cat cry**, typical
dysmorphisms, moderate
psychomotor retardation
Patient 80*: No cat cry, no
classical CdC phenotype, did have
microcephaly and speech delay.
Mainardi et al. 2001. J. Med. Genet. 38: 151-158.
Conclusions
Highlight progessive severity of clinical
manifestations and psychomotor
retardation with increase in deletion size
 Confirm presence of two critical regions
for classical CdC (5p15.3 and 5p15.2)
 Narrow Cat-cry region to D5S731
 Stress difficulties in defining specific
critical regions for mental retardation
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What do we do now?
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High resolution physical
mapping and transcript map of
5p15.2
– Church et al. 1997. Genome Res. 7: 787-801.
Researchers were able to identify 17
candidate genes in the CdCCR of
5p15.2. Most of these are of
unknown function.
Delta-catenin (5p15.2)
δ-catenin is a neuron-specific catenin involved in
adhesion and cell motility. It is expressed early
in development
 First identified through interaction with PS1
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Delta-catenin
Israely et al. 2004. Current Biology. 14: 1657-1663.
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Generated knockout mice (δ-catenin-/-)
Mutant mice were compared to normal mice in several
cognitive tests. Synaptic plasticity and structure were
also evaluated.
Researchers found that δ-catenin-/- mice severe BUT
SPECIFIC deficits in some areas learning and in synaptic
plasticity.
Telomerase Reverse Transcriptase Gene (hTERT)
Localized to 5p15.33
 hTERT is the rate-limiting component for
telomerase activity that is essential for
telomere length maintenance and cell
proliferation
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hTERT
Zhang et al. 2003. Am. J. Hum. Genet. 72: 940-948.
Cri du Chat- human model of hTERT
 FISH analysis of metaphase fibroblasts
and lymphocytes
 Quantitative FISH analysis to measure
telomere length
 Competitive RT-PCR to determine level of
hTERT mRNA
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hTERT
Zhang et al. 2003. Am. J. Hum. Genet. 72: 940-948.
hTERT
Zhang et al. 2003. Am. J. Hum. Genet. 72: 940-948.
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Haploinsufficiency in
CdC patients
Diagnosis
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Postnatal Diagnosis
– Cat-like cry
– Karyotyping
– FISH analysis
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Prenatal Diagnosis
– Amniocentesis
– Chorionic villus
sampling (CVS)
– In vitro fertilization
Treatment
No methods of treating disease directly
 Several ways to treat medical problems
associated with Cri du Chat
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– Physical therapy
– Speech therapy
– Behavioral management
References
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Church, D. M., J. Yang, M. Bocian, R. Shiang, and J. J. Wasmuth. 1997. A high-resolution physical and transcript
map of the cridu chat region of human chromosome 5p. Genome Res. 7: 787-801.
Cornish, K. and D. Bramble. 2002. Cri du chat syndrome: genotype-phenotype correlations and recommendations
for clinical management. Developmental Medicine and Child Neurology. 44: 494-497.
Dykens, E. M., R. M. Hodapp, and B. M. Finucane. 2000. Genetics and Mental Retardation Syndromes. Paul H.
Brooks Publishing Co, MD, pp. 233-240.
Israely, I., R. M. Costa, C. W. Xie, A. J. Silva, K. S. Kosik, and X. Liu. 2004. Deletion of the Neuron-Specific
Protein Delta-Catenin Leads to Severe Cognitive and Synaptic Dysfunction. Current Biology, 14: 18571663.
Mainardi, P. C., C.Perfumo, A. Cali, G. Coucourde, G. Pastore, S. Cavani, F. Zara, J. Overhauser, M. Pierluigi, and
F. D. Bricarelli. 2001. Clinical and molecular characterization of 80 patients with 5p deletion: genotypephenotype correlation. J. Med. Genet. 38: 151-158.
Marinescu, R. M., E. M. Johnson, D. Grady, X. N. Chen, and J. Overhauser. 1999. FISH analysis of terminal
deletions in patients diagnosed with cri-du-chat syndrome. Clin. Genet. 56: 282-288.
Online Mendelian Inheritance in Man, OMIM ™. Johns Hopkins University, Baltimore, MD. MIM Number: 123450
Cri du Chat Syndrome: April 23, 2003:. World Wide Web URL: http//www.ncbi.nlm.nih.gov/omim/
Online Mendelian Inheritance in Man, OMIM ™. Johns Hopkins University, Baltimore, MD. MIM Number: 187270
TERT: May 25, 2004:. World Wide Web URL: http//www.ncbi.nlm.nih.gov/omim/
Online Mendelian Inheritance in Man, OMIM ™. Johns Hopkins University, Baltimore, MD. MIM Number: 604275
Catenin, Delta-2: May 8, 2003:. World Wide Web URL: http//www.ncbi.nlm.nih.gov/omim/
Shprintzen, R. J. 1997. Genetics, Syndromes, and Communication Disorders. Singular Publishing Group, CA, pp.
36-42, 270-271.
Tullu, M. S., M. N. Muranjan, S. V. Sharma, D. R. Sahu, S. R. Swami, C. T. Deshmukh, and B. A. Bharucha. 1998.
Cri-du-chat syndrome: Cinical profile and prenatal diagnosis. J. Postgrad. Med. 44: 101-104.
Van Buggenhout, G. J. C. M., E. Pijkels, M. Holvoet, C. Schaap, B. C. J. Hamel, and J. P. Fryns. 2000. Cri du chat
syndrome: Changing phenotype in older patients. Am. J. Med. Genet. 90: 203-215.
Zhang, A., C. Zheng, M. Hou, C. Lindvall, K. Li, F. Erlandsson, M. Bjorkholm, A. Gruber, E. Blennow, and D. Xu.
2003. Deletion of the Telomerase Reverse Transcriptase gene and haploinsuffieciency of telomere
maintenance in Cri du Chat Syndrome. Am. J. Hum. Genet. 72: 940-948.