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Page 1: Cri du Chat:  The Cat’s Cry

Cri du Chat: The Cat’s Cri du Chat: The Cat’s CryCry

Kelsey FastelandKelsey Fasteland

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Cri du Chat (CdC)- HistoryCri du Chat (CdC)- History

Relatively rare genetic disorder that affects Relatively rare genetic disorder that affects 1:20,000 to 1:50,0001:20,000 to 1:50,000

First described in 1963 by French First described in 1963 by French pediatrician Lejeune and his associates.pediatrician Lejeune and his associates.

Karyotyped individuals with the disorder, Karyotyped individuals with the disorder, found that they all were missing a piece of found that they all were missing a piece of chromosome 5 chromosome 5

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CdC- PhenotypesCdC- Phenotypes

Cat-like cryCat-like cry

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CdC- PhenotypeCdC- Phenotype Facial Facial

DysmorphismsDysmorphisms– Including Including

microcephaly, round microcephaly, round face, hypertelorism, face, hypertelorism, epicanthal folds, low-epicanthal folds, low-set ears, and set ears, and micrognathia.micrognathia.

Bradley, Bradley, www.criduchat.asn.au/criduchat/bradley.htwww.criduchat.asn.au/criduchat/bradley.htmm

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CdC- PhenotypeCdC- Phenotype

Severe psychomotor and mental Severe psychomotor and mental retardationretardation

Other health problems associated with CdC:Other health problems associated with CdC:– Poor-suck, hypotonia, respitory and heart defects, Poor-suck, hypotonia, respitory and heart defects,

growth retardation, and cleft palate and/or lip.growth retardation, and cleft palate and/or lip.– CdC patients are generally very sociable, but may CdC patients are generally very sociable, but may

exhibit maladaptive behaviors such as exhibit maladaptive behaviors such as inattentiveness, hyperactivity, temper-tantrums, inattentiveness, hyperactivity, temper-tantrums, and self injury.and self injury.

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Bradley- 2 yearsBradley- 2 yearswww.criduchat.asn.au/criduchat/bradley.htmwww.criduchat.asn.au/criduchat/bradley.htm

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CdC- CytogeneticsCdC- Cytogenetics

Arises from a partial terminal or Arises from a partial terminal or interstitial deletion of the short arm interstitial deletion of the short arm of chromosome 5 (5p).of chromosome 5 (5p).– De novo deletionDe novo deletion– Parental translocationParental translocation– Other rare cytogenetic aberrationsOther rare cytogenetic aberrations

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CdC- CytogeneticsCdC- Cytogenetics

MultigenicMultigenic Researchers have Researchers have

found two critical found two critical regions for CdCregions for CdC– Cat-like cry localized at Cat-like cry localized at

5p15.35p15.3– Facial dysmorphisms Facial dysmorphisms

and and psychomotor/mental psychomotor/mental retardation localized at retardation localized at 5p15.25p15.2

Figure from www.criduchat.asn.au/criduchatFigure from www.criduchat.asn.au/criduchat

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Genotype-PhenotypeGenotype-PhenotypeMainardi et al. 2001. J. Med. Genet. 38: 151-158.

8o patients with 5p deletion8o patients with 5p deletion Each patient underwent clinical, Each patient underwent clinical,

developmental, and genetic developmental, and genetic evaluationevaluation

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Molecular-Cytogenetic Molecular-Cytogenetic AnalysisAnalysis

Blood cultures of patients and parents Blood cultures of patients and parents FISH experiments were performed FISH experiments were performed

using 136 single locus DNA lambda using 136 single locus DNA lambda phage probesphage probes

DNA was extracted and PCR DNA was extracted and PCR amplified, then typed with highly amplified, then typed with highly polymorphic PCR based microsatellite polymorphic PCR based microsatellite markersmarkers

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Molecular-Cytogenetic Molecular-Cytogenetic Analysis- ResultsAnalysis- Results

62 patients had a terminal 5p deletion 62 patients had a terminal 5p deletion with break points from p13 to 5p15.2with break points from p13 to 5p15.2

7 patients with interstitial 5p deletions7 patients with interstitial 5p deletions

Also found that 90.2% of de novo Also found that 90.2% of de novo deletions were paternal in origindeletions were paternal in origin

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62 patients with terminal 5p 62 patients with terminal 5p deletionsdeletions

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.

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What does this mean?What does this mean?

This highlights a progressive severity This highlights a progressive severity of clinical manifestations and of clinical manifestations and psychomotor/mental retardation as psychomotor/mental retardation as the size of the deletion increases.the size of the deletion increases.

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Seven patients with interstitial Seven patients with interstitial deletionsdeletions

Patient 1*: Cat cry, no typical Patient 1*: Cat cry, no typical dysmorphisms, mild dysmorphisms, mild psychomotor retardationpsychomotor retardation

Patients 19, 25, 76*: No cat cry, Patients 19, 25, 76*: No cat cry, typical dysmorphisms, mild to typical dysmorphisms, mild to severe psychomotor retardationsevere psychomotor retardation

Patient 45:?, typical Patient 45:?, typical dysmorphisms, moderate/severe dysmorphisms, moderate/severe psychomotor retardationpsychomotor retardation

Patient 77: cat cry**, typical Patient 77: cat cry**, typical dysmorphisms, moderate dysmorphisms, moderate psychomotor retardationpsychomotor retardation

Patient 80*: No cat cry, no Patient 80*: No cat cry, no classical CdC phenotype, did classical CdC phenotype, did have microcephaly and speech have microcephaly and speech delay.delay.

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

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ConclusionsConclusions

Highlight progessive severity of clinical Highlight progessive severity of clinical manifestations and psychomotor manifestations and psychomotor retardation with increase in deletion sizeretardation with increase in deletion size

Confirm presence of two critical regions Confirm presence of two critical regions for classical CdC (5p15.3 and 5p15.2)for classical CdC (5p15.3 and 5p15.2)

Narrow Cat-cry region to D5S731Narrow Cat-cry region to D5S731 Stress difficulties in defining specific Stress difficulties in defining specific

critical regions for mental retardationcritical regions for mental retardation

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What do we do now?What do we do now? High resolution physical High resolution physical

mapping and transcript mapping and transcript map of 5p15.2map of 5p15.2– Church Church et al. et al. 1997. 1997. Genome Res. Genome Res. 7:7: 787-801. 787-801.

Researchers were able to identify 17 candidate genes in the CdCCR of 5p15.2. Most of these are of unknown function.

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Delta-catenin (5p15.2)Delta-catenin (5p15.2)

δδ-catenin is a neuron-specific catenin -catenin is a neuron-specific catenin involved in adhesion and cell motility. It is involved in adhesion and cell motility. It is expressed early in developmentexpressed early in development

First identified through interaction with First identified through interaction with PS1PS1

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Delta-catenin Delta-catenin Israely Israely et al.et al. 2004. 2004. Current Biology.Current Biology. 14: 14: 1657-1663.1657-1663.

Generated knockout mice (Generated knockout mice (δδ-catenin-catenin-/--/-)) Mutant mice were compared to normal mice in Mutant mice were compared to normal mice in

several cognitive tests. Synaptic plasticity and several cognitive tests. Synaptic plasticity and structure were also evaluated.structure were also evaluated.

Researchers found that Researchers found that δδ-catenin-catenin-/--/- mice severe mice severe BUT SPECIFIC deficits in some areas learning and BUT SPECIFIC deficits in some areas learning and in synaptic plasticity. in synaptic plasticity.

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Telomerase Reverse Transcriptase Gene Telomerase Reverse Transcriptase Gene (hTERT)(hTERT)

Localized to 5p15.33Localized to 5p15.33 hTERT is the rate-limiting component hTERT is the rate-limiting component

for telomerase activity that is for telomerase activity that is essential for telomere length essential for telomere length maintenance and cell proliferationmaintenance and cell proliferation

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

Cri du Chat- human model of hTERTCri du Chat- human model of hTERT FISH analysis of metaphase FISH analysis of metaphase

fibroblasts and lymphocytesfibroblasts and lymphocytes Quantitative FISH analysis to Quantitative FISH analysis to

measure telomere lengthmeasure telomere length Competitive RT-PCR to determine Competitive RT-PCR to determine

level of hTERT mRNAlevel of hTERT mRNA

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

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

Haploinsufficiency Haploinsufficiency in CdC patientsin CdC patients

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DiagnosisDiagnosis

Postnatal DiagnosisPostnatal Diagnosis– Cat-like cryCat-like cry– KaryotypingKaryotyping– FISH analysisFISH analysis

Prenatal DiagnosisPrenatal Diagnosis– AmniocentesisAmniocentesis– Chorionic villus Chorionic villus

sampling (CVS)sampling (CVS)– In vitro fertilization In vitro fertilization

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TreatmentTreatment

No methods of treating disease No methods of treating disease directlydirectly

Several ways to treat medical Several ways to treat medical problems associated with Cri du Chatproblems associated with Cri du Chat– Physical therapyPhysical therapy– Speech therapySpeech therapy– Behavioral managementBehavioral management

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ReferencesReferences Church, D. M., J. Yang, M. Bocian, R. Shiang, and J. J. Wasmuth. 1997. A high-resolution physical and Church, D. M., J. Yang, M. Bocian, R. Shiang, and J. J. Wasmuth. 1997. A high-resolution physical and

transcript transcript map of the cridu chat region of human chromosome 5p. map of the cridu chat region of human chromosome 5p. Genome Res. Genome Res. 7: 787-801. 7: 787-801. Cornish, K. and D. Bramble. 2002. Cri du chat syndrome: genotype-phenotype correlations and Cornish, K. and D. Bramble. 2002. Cri du chat syndrome: genotype-phenotype correlations and

recommendations recommendations for clinical management. for clinical management. Developmental Medicine and Child Neurology. Developmental Medicine and Child Neurology. 44: 494-44: 494-497.497.

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Marinescu, R. M., E. M. Johnson, D. Grady, X. N. Chen, and J. Overhauser. 1999. FISH analysis of terminal 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. deletions in patients diagnosed with cri-du-chat syndrome. Clin. Genet. Clin. Genet. 56: 282-288.56: 282-288.

Online Mendelian Inheritance in Man, OMIM ™. Johns Hopkins University, Baltimore, MD. MIM Number: Online Mendelian Inheritance in Man, OMIM ™. Johns Hopkins University, Baltimore, MD. MIM Number: 123450 123450 Cri du Chat Syndrome: April 23, 2003:. World Wide Web URL: Cri du Chat Syndrome: April 23, 2003:. World Wide Web URL: http//www.ncbi.nlm.nih.gov/omim/http//www.ncbi.nlm.nih.gov/omim/

Online Mendelian Inheritance in Man, OMIM ™. Johns Hopkins University, Baltimore, MD. MIM Number: Online Mendelian Inheritance in Man, OMIM ™. Johns Hopkins University, Baltimore, MD. MIM Number: 187270 187270 TERT: May 25, 2004:. World Wide Web URL: http//www.ncbi.nlm.nih.gov/omim/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: Online Mendelian Inheritance in Man, OMIM ™. Johns Hopkins University, Baltimore, MD. MIM Number: 604275 604275 Catenin, Delta-2: May 8, 2003:. World Wide Web URL: http//www.ncbi.nlm.nih.gov/omim/Catenin, Delta-2: May 8, 2003:. World Wide Web URL: http//www.ncbi.nlm.nih.gov/omim/

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