Cri du Chat: The Cat

1
Cri du Chat The Cats Cry

• Kelsey Fasteland

2
Cri du Chat (CdC)- History

• Relatively rare genetic disorder that affects
  120,000 to 150,000
• 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.ht
  m

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/br
adley.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)

• d-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 (d-catenin-/-)
• Mutant mice were compared to normal mice in
  several cognitive tests. Synaptic plasticity and
  structure were also evaluated.
• Researchers found that d-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
Diagnosis

• Postnatal Diagnosis
• Cat-like cry
• Karyotyping
• FISH analysis

• Prenatal Diagnosis
• Amniocentesis
• Chorionic villus sampling (CVS)
• In vitro fertilization

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/omi
  m/
• 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.