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 Relatively

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  • Slide 1
  • Cri du Chat: The Cats Cry Kelsey Fasteland
  • Slide 2
  • Cri du Chat (CdC)- History Relatively rare genetic disorder that affects 1:20,000 to 1:50,000 Relatively rare genetic disorder that affects 1:20,000 to 1:50,000 First described in 1963 by French pediatrician Lejeune and his associates. 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 Karyotyped individuals with the disorder, found that they all were missing a piece of chromosome 5
  • Slide 3
  • CdC- Phenotypes Cat-like cry Cat-like cry
  • Slide 4
  • CdC- Phenotype Facial Dysmorphisms Facial Dysmorphisms Including microcephaly, round face, hypertelorism, epicanthal folds, low- set ears, and micrognathia. Bradley, www.criduchat.asn.au/criduchat/bradley.htm
  • Slide 5
  • CdC- Phenotype Severe psychomotor and mental retardation Severe psychomotor and mental retardation Other health problems associated with CdC: 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.
  • Slide 6
  • Bradley- 2 years www.criduchat.asn.au/criduchat/bradley.htm
  • Slide 7
  • CdC- Cytogenetics Arises from a partial terminal or interstitial deletion of the short arm of chromosome 5 (5p). 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
  • Slide 8
  • CdC- Cytogenetics Multigenic Multigenic Researchers have found two critical regions for CdC 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
  • Slide 9
  • Genotype-Phenotype Genotype-Phenotype Mainardi et al. 2001. J. Med. Genet. 38: 151-158. 8o patients with 5p deletion 8o patients with 5p deletion Each patient underwent clinical, developmental, and genetic evaluation Each patient underwent clinical, developmental, and genetic evaluation
  • Slide 10
  • Molecular-Cytogenetic Analysis Blood cultures of patients and parents Blood cultures of patients and parents FISH experiments were performed using 136 single locus DNA lambda phage probes 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 DNA was extracted and PCR amplified, then typed with highly polymorphic PCR based microsatellite markers
  • Slide 11
  • Molecular-Cytogenetic Analysis- Results 62 patients had a terminal 5p deletion with break points from p13 to 5p15.2 62 patients had a terminal 5p deletion with break points from p13 to 5p15.2 7 patients with interstitial 5p deletions 7 patients with interstitial 5p deletions Also found that 90.2% of de novo deletions were paternal in origin Also found that 90.2% of de novo deletions were paternal in origin
  • Slide 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.
  • Slide 13
  • What does this mean? This highlights a progressive severity of clinical manifestations and psychomotor/mental retardation as the size of the deletion increases. This highlights a progressive severity of clinical manifestations and psychomotor/mental retardation as the size of the deletion increases.
  • Slide 14
  • Seven patients with interstitial deletions Patient 1*: Cat cry, no typical dysmorphisms, mild psychomotor retardation Patient 1*: Cat cry, no typical dysmorphisms, mild psychomotor retardation Patients 19, 25, 76*: No cat cry, typical dysmorphisms, mild to severe 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 45:?, typical dysmorphisms, moderate/severe psychomotor retardation Patient 77: cat cry**, typical dysmorphisms, moderate 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. 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.
  • Slide 15
  • Conclusions Highlight progessive severity of clinical manifestations and psychomotor retardation with increase in deletion size 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) Confirm presence of two critical regions for classical CdC (5p15.3 and 5p15.2) Narrow Cat-cry region to D5S731 Narrow Cat-cry region to D5S731 Stress difficulties in defining specific critical regions for mental retardation Stress difficulties in defining specific critical regions for mental retardation
  • Slide 16
  • What do we do now? High resolution physical mapping and transcript map of 5p15.2 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.
  • Slide 17
  • Delta-catenin (5p15.2) -catenin is a neuron-specific catenin involved in adhesion and cell motility. It is expressed early in development -catenin is a neuron-specific catenin involved in adhesion and cell motility. It is expressed early in development First identified through interaction with PS1 First identified through interaction with PS1
  • Slide 18
  • Delta-catenin Israely et al. 2004. Current Biology. 14: 1657-1663. Generated knockout mice (-catenin -/- ) Generated knockout mice (-catenin -/- ) Mutant mice were compared to normal mice in several cognitive tests. Synaptic plasticity and structure were also evaluated. 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. Researchers found that -catenin -/- mice severe BUT SPECIFIC deficits in some areas learning and in synaptic plasticity.
  • Slide 19
  • Telomerase Reverse Transcriptase Gene (hTERT) Localized to 5p15.33 Localized to 5p15.33 hTERT is the rate-limiting component for telomerase activity that is essential for telomere length maintenance and cell proliferation hTERT is the rate-limiting component for telomerase activity that is essential for telomere length maintenance and cell proliferation
  • Slide 20
  • hTERT Zhang et al. 2003. Am. J. Hum. Genet. 72: 940-948. Cri du Chat- human model of hTERT Cri du Chat- human model of hTERT FISH analysis of metaphase fibroblasts and lymphocytes FISH analysis of metaphase fibroblasts and lymphocytes Quantitative FISH analysis to measure telomere length Quantitative FISH analysis to measure telomere length Competitive RT-PCR to determine level of hTERT mRNA Competitive RT-PCR to determine level of hTERT mRNA
  • Slide 21
  • hTERT Zhang et al. 2003. Am. J. Hum. Genet. 72: 940-948.
  • Slide 22
  • Haploinsufficiency in CdC patients Haploinsufficiency in CdC patients
  • Slide 23
  • Diagnosis Postnatal Diagnosis Postnatal Diagnosis Cat-like cry Karyotyping FISH analysis Prenatal Diagnosis Prenatal Diagnosis Amniocentesis Chorionic villus sampling (CVS) In vitro fertilization
  • Slide 24
  • Treatment No methods of treating disease directly No methods of treating disease directly Several ways to treat medical problems associated with Cri du Chat Several ways to treat medical problems associated with Cri du Chat Physical therapy Speech therapy Behavioral management
  • Slide 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. 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. 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. Dykens, E. M., R. M. Hodapp, and B. M. Finucane. 2000. Genetics and Mental Retardation Syndromes. Paul H.

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