Cri du Chat: The Cat’s Cry

1. Cri du Chat: The Cat’s Cry Kelsey Fasteland

2. 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

3. CdC- Phenotypes • Cat-like cry

4. CdC- Phenotype • Facial Dysmorphisms • Including microcephaly, round face, hypertelorism, epicanthal folds, low-set ears, and micrognathia. Bradley, www.criduchat.asn.au/criduchat/bradley.htm

5. 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.

6. Bradley- 2 yearswww.criduchat.asn.au/criduchat/bradley.htm

7. 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

8. 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

9. Genotype-PhenotypeMainardi et al. 2001. J. Med. Genet. 38: 151-158. • 8o patients with 5p deletion • Each patient underwent clinical, developmental, and genetic evaluation

10. 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

11. 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

12. 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.

13. What does this mean? • This highlights a progressive severity of clinical manifestations and psychomotor/mental retardation as the size of the deletion increases.

14. 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.

15. 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

16. 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.

17. 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

18. 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.

19. 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

20. hTERTZhang 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

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

22. hTERTZhang et al. 2003. Am. J. Hum. Genet.72: 940-948. • Haploinsufficiency in CdC patients

23. Postnatal Diagnosis Cat-like cry Karyotyping FISH analysis Prenatal Diagnosis Amniocentesis Chorionic villus sampling (CVS) In vitro fertilization Diagnosis

24. Treatment • No methods of treating disease directly • Several ways to treat medical problems associated with Cri du Chat • Physical therapy • Speech therapy • Behavioral management

25. 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. 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.