Cri du Chat: The Cat’s Cry

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

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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 First described in 1963 by French pediatrician Lejeune and his associates. - PowerPoint PPT Presentation

Transcript of Cri du Chat: The Cat’s Cry

  • Cri du Chat: The Cats Cry

    Kelsey Fasteland

  • 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

  • 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

  • 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// Mendelian Inheritance in Man, OMIM . Johns Hopkins University, Baltimore, MD. MIM Number: 187270 TERT: May 25, 2004:. World Wide Web URL: http// Mendelian Inheritance in Man, OMIM . Johns Hopkins University, Baltimore, MD. MIM Number: 604275 Catenin, Delta-2: May 8, 2003:. World Wide Web URL: http//, 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 phenotype of the syndrome. The cat-like cry has been localized to 5p15.3, and the critical region for facial dysmorphisms and psychomotor/mental retardation has been localized to 5p15.2. Two different studies done in the early nineties showed similar results, however, they could not agree on exactly where the critical regions were located in the bands. Were going to look at a study published in 2001 by Mainardi et al. that revisits genotype-phenotype correlation and also compares the two earlier studies.80 patients with a 5p deletion from the Italian CdCS register. Clinical evaluation included evaluation of dysmorphisms that remain stable throughout life. Psychomotor development was evaluated using the Denver Developmental Screening Tests and by obtaining the ages at which the patient was able to complete skills in the four areas of development, gross motor, fine-motor, personal-social, and language.Blood cultures of patients and parents were set up. In order to determine the extent of the deletion and to detect any interstitial deletions, FISH experiments were performed using 136 single locus DNA lambda phage probes spanning the 5p arm. DNA was extracted and PCR amplified, then typed with highly polymorphic PCR based microsatellite markers in order to determine the parental origin of the rearranged chromosome.There were also an additional 7 patients with translocations and three patients with mosaicism that were not included in the study due to the misleading effects of partial trisomies and different cell lines.Figure one shows the molecular analysis of 62 patients with terminal deletions. Percentages refer to the frequency of dysmorphism in the patients of different groups. Classical CdC was observed in all cases (meaning that both cat cry and facial dysmorphisms and psychomotor/mental retardation). Distribution of dymorphisms increased between groups A and D, as well as the frequency and severity of microcephaly. There were statistical differences in the ability of patients to walk alone and feed self between groups D and A, and differences in the ability of patient in groups C and A for first words, combining two words, and toilet trained. We can look at figure 5 from the study and see that there was also a trend in the mean age that patients were able to master different skills depending on the size of their deletion. Statistical significance was seen between groups A and D for first words, combining two words, and toilet trained. Note that due to the compexity of quantitative traits, many of these differences may be an interaction between genetic background and environmental factors.*Looking at the analysis of patients 1 and 80 (who did not show CdC dysmorphism) and patient 76 (who did show classical CdC dysmorphism), it suggests that there is a correlation between dysmorphism and CdCCR as defined by Overhauser rather than Church.**Existence for a separate region for the cat-like cry was also confirmed by patients 19, 25, 76, and 80, who maintained the cat cry region and did not have the cry, and patient 75, who lacked the region and did exhibit the cry. Also, when you look at patient 77, you can see that he is only missing part of the cat cry region as suggested by Overhauser, which distally narrows the region for the cat cry down from D5S13 to D5S731, which is supportive of the cat cry region as suggested Church et al.Used natural deletion panel, chromosome specific radiation hybrid panel, and YAC, BAC, and PAC genomic clones to order more than 60 STSs within the regionResearchers identified 17 candidate genes through exon amplification and trapping rather than cDNA selectio (due to the numerous repetitive element in the region).It is now up to researchers to isolate and study these genes in order to obtain a better understanding of their function and how or if they are related to phenotypic manifestations of Cri du Chat. Recently, there has been some research to do exactly that. Im going to briefly describe two studies for you.Delta catenin was first identified during a yeast 2-hybrid screen to identify proteins interacting with Presenilin-1, which is a gene that is commonly mutated in Alheimers disease. FISH analysis was used to map the gene to 5p15 region.Researchers generated mice with a targeted homozygous mutation in the d-catenin gene. Mutant mice and normal mice were compared in several cognitive tests, including water maze, Pavlovian fear conditioning, Rota-rod, and Open field testing.Synaptic plasticity and synaptic structure were also evaluated. Researchers found that the mutant mice were severely deficient in spatial learning and other learning abilities (pavlovian fear conditioning), and also had abnormalities in short-term and long-term synaptic plasticity. These data show that delta-catenin plays a critical role in brain function, and may therefore be associated with the mental retardation seen in cri du chat.It has been shown the hTERT expression is required for telomerase activation in various human cells. Due to the significance of hTERT in cell immortalization and tumorigenesis, it is important to understand the role of hTERT in humans. Researchers basically used Cri du chat patients as a human model of in vivo hTERT regulation and function. They used an hTERT specific probe and performed FISH analysis on cri du chat patients metaphase fibroblasts and lymphocytes to determine that each patient had only one hTERT allele. They measured telomere length of affected and unaffected individuals using quantitative FISH analysis. They did this by hybridizing a labled probe to the telomeres and then measuring the fluorescence. They also used competetive RT-PCR for hTERT mRNA to determine the level of mRNA being expressed.This is the deletion of one hTERT allele. The marker for 5q31 is in green and the marker for hTERT is in redB) And C) telomeres of affected and age-matched unaffected individuals (q-FISH)D) Telomere length expressed as the total fluorescence intensity in affected and unaffected age-matched individualsE) Telomere length as determined by Southern blotResearchers concluded that one copy of the hTERT gene is incapable of maintaining telomere length in CdC patients, and that CdC patients display progressive telomere attrition with cellular proliferation. They are not sure how exactly the deletion of hTERT contributes to the clinical features of CdC, Since hTERT and telomerase are normally highly activated early development, haploinsuffieciency may contribute to growth retardation and mental deficiencies. It also may contribute to phenotypes seen in older CdC patients, such as premature grey hair and small testes.Diagnosis of CdC can occur either prenatally or post-natally. Postnatally, Cri du chat is highly suspected if the catlike cry is heard, however, as shown earlier, the cry does not always indicate Cri du chat, so karyotyping can be used for detection of large deletions, or FISH analysis can be used for smaller deletions. Cri du chat can be diagnosed prenatally using amniocentesis, which is when cells are obtained from amniotic fluid surrounding the fetus, or by Chorionic villus sampling, which is when a small sample of placenta is collected and tested.Normally this is not done unless the couple already has one child with cri du chat, or if it is known that the parent has a balanced translocation. Gene therapy for a deletion of this size does not exist at the moment