Cri du Chat: The Cat’s Cry

Kelsey Fasteland
 Cri du Chat (CdC)- History
 Relatively rare genetic disorder that affects
1:20,000 to 1:50,000

 First described in 1963 by French pediatrician

Lejeune and his associates.

 Karyotyped individuals with the disorder, found

that they all were missing a piece of
chromosome 5
 CdC- Phenotypes
 Cat-like cry
 CdC- Phenotype
 Facial Dysmorphisms
Including
microcephaly, round
face, hypertelorism,
epicanthal folds, low-
set ears, and
micrognathia.

Bradley,
www.criduchat.asn.au/criduchat/bradley.htm
 CdC- Phenotype
 Severe psychomotor and mental
retardation

 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
 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
 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
 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
 Molecular-Cytogenetic Analysis-
Results
 62 patients had a terminal 5p deletion
with break points from p13 to 5p15.2

 7 patients with interstitial 5p deletions

 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?
 This highlights a progressive severity of
clinical manifestations and
psychomotor/mental retardation as the
size of the deletion increases.
Seven patients with interstitial deletions
 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
 What do we do now?
 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
 Delta-catenin
Israely et al. 2004. Current Biology. 14: 1657-1663.

 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
 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
 hTERT
Zhang et al. 2003. Am. J. Hum. Genet. 72: 940-948.
 hTERT
Zhang et al. 2003. Am. J. Hum. Genet. 72: 940-948.

 Haploinsufficiency in
CdC patients
 Diagnosis
 Postnatal Diagnosis  Prenatal Diagnosis
Cat-like cry Amniocentesis
Karyotyping Chorionic villus
FISH analysis sampling (CVS)
In vitro fertilization
 Treatment
 No methods of treating disease directly
 Several ways to treat medical problems
associated with Cri du Chat
Physical therapy
Speech therapy
Behavioral management
 References
 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: 1857-
1663.
 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: genotype-
phenotype 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.
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 Van Buggenhout, G. J. C. M., E. Pijkels, M. Holvoet, C. Schaap, B. C. J. Hamel, and J. P. Fryns. 2000. Cri du chat
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 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.