Cri du Chat: The Cats Cry
Cri du Chat (CdC)- HistoryRelatively 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- PhenotypesCat-like cry
CdC- PhenotypeFacial DysmorphismsIncluding microcephaly, round face, hypertelorism, epicanthal folds, low-set ears, and micrognathia.
CdC- PhenotypeSevere 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 yearswww.criduchat.asn.au/criduchat/bradley.htm
CdC- CytogeneticsArises from a partial terminal or interstitial deletion of the short arm of chromosome 5 (5p).De novo deletionParental translocationOther rare cytogenetic aberrations
CdC- CytogeneticsMultigenic Researchers have found two critical regions for CdCCat-like cry localized at 5p15.3Facial dysmorphisms and psychomotor/mental retardation localized at 5p15.2
Figure from www.criduchat.asn.au/criduchat
Genotype-PhenotypeMainardi et al. 2001. J. Med. Genet. 38: 151-158.
8o patients with 5p deletionEach patient underwent clinical, developmental, and genetic evaluation
Molecular-Cytogenetic AnalysisBlood cultures of patients and parents FISH experiments were performed using 136 single locus DNA lambda phage probesDNA was extracted and PCR amplified, then typed with highly polymorphic PCR based microsatellite markers
Molecular-Cytogenetic Analysis- Results62 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 deletionsClassical 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 deletionsPatient 1*: Cat cry, no typical dysmorphisms, mild psychomotor retardationPatients 19, 25, 76*: No cat cry, typical dysmorphisms, mild to severe psychomotor retardationPatient 45:?, typical dysmorphisms, moderate/severe psychomotor retardationPatient 77: cat cry**, typical dysmorphisms, moderate psychomotor retardationPatient 80*: No cat cry, no classical CdC phenotype, did have microcephaly and speech delay.Mainardi et al. 2001. J. Med. Genet. 38: 151-158.
ConclusionsHighlight progessive severity of clinical manifestations and psychomotor retardation with increase in deletion sizeConfirm presence of two critical regions for classical CdC (5p15.3 and 5p15.2)Narrow Cat-cry region to D5S731Stress difficulties in defining specific critical regions for mental retardation
What do we do now?High resolution physical mapping and transcript map of 5p15.2Church 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 developmentFirst identified through interaction with PS1
Delta-catenin Israely et al. 2004. Current Biology. 14: 1657-1663.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 5p15.33hTERT is the rate-limiting component for telomerase activity that is essential for telomere length maintenance and cell proliferation
hTERTZhang et al. 2003. Am. J. Hum. Genet. 72: 940-948.Cri du Chat- human model of hTERTFISH analysis of metaphase fibroblasts and lymphocytesQuantitative FISH analysis to measure telomere lengthCompetitive RT-PCR to determine level of hTERT mRNA
hTERTZhang et al. 2003. Am. J. Hum. Genet. 72: 940-948.
hTERTZhang et al. 2003. Am. J. Hum. Genet. 72: 940-948.Haploinsufficiency in CdC patients
DiagnosisPostnatal DiagnosisCat-like cryKaryotypingFISH analysisPrenatal DiagnosisAmniocentesisChorionic villus sampling (CVS)In vitro fertilization
TreatmentNo methods of treating disease directlySeveral ways to treat medical problems associated with Cri du ChatPhysical therapySpeech therapyBehavioral management
ReferencesChurch, 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.
Cri du Chat, which means cry of the cat in French, is also known as Lejeune syndrome and 5p- syndrome. It is a relatively rare genetic disorder that affects 1:20000 to 1:50000. Cri du chat was first described by French paediatrician Lejeune and his associates as a herediary congenital syndrome associated with deletion of part of the short arm of chromosome 5. They discovered this by karyotyping individuals exhibitiing syndrome phenotypes.The most noticeable and distinctive phenotype exhibited in classical cri du chat syndrome is the cat-like cry. It is also where the syndrome gets its name. It is due to abnormal development of the larynx.The third phenotype associated with Cri du Chat syndrome is psychomotor and mental retardation. The severity of psychomotor dysfunction and mental retardation can vary from mild to rare. Other health problems include:It should be noted that some of the clinical characteristics of older patients may be a little different. Often times, a long face, macrostomia, and scoliosis become more prominent, and premature gray hair and small testes are also seen.CdC arises from a partial terminal or interstitial deletion of the short arm of ch. 5. These deletions can arise in several ways. Most cases are due to a de novo deletion. About 10-15% are familial in nature and are normally a result of unbalanced segregation of balanced parental translocations , although some may be due to familial para- or pericentric inversions. Other rare cytogenetic aberrations occur in less than 10%. Since a large deletion is involved in CdC, it is a multigenic disorder. Also, there is a large number of different deletions that may result in CdC Several studies have been performed to develop a better understanding of how the phenotype correlates with the genetic deletions. We will walk through one of these experiments in a moment. What researchers have been able to discern is that there are two critical regions of 5p that must be deleted in order for the individual to show the typical phen