Cri du Chat: The Cats 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, lowset 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

Mainardi et al. 2001. J. Med. Genet. 38: 151-158.

Genotype-Phenotype

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 AnalysisResults

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)
-catenin is a neuron-specific catenin involved in adhesion and cell motility. It is expressed early in development First identified through interaction with PS1

Israely et al. 2004. Current Biology. 14: 1657-1663.

Delta-catenin

Generated knockout mice (-catenin-/-) Mutant mice were compared to normal mice in several cognitive tests. Synaptic plasticity and structure were also evaluated. Researchers found that -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

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

hTERT

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

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

hTERT

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

hTERT

Haploinsufficiency in CdC patients

Diagnosis

Postnatal Diagnosis
Cat-like cry Karyotyping FISH analysis

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

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: 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.