Overview

Cri du Chat syndrome (translated literally from French as call/cry of the cat), is a genetic disease, named after the cat-like cry that an infant will typically make.¹ The genetic disease stems from a partial deletion in a chromosome (contains our DNA and genetic material) specifically chromosome number 5, which leads to developmental delays and (moderate to severe) intellectual disabilities.¹ Statistically, the disease is considered rare, with an occurrence rate of 1 in 15,000 to 1 in 50,000 infants.² In order to manage symptoms and prevent social difficulties once your child grows older, it is important for parents to implement early prevention strategies through the form of occupational therapy. Below, this article aims to explore the causes of Cri du Chat syndrome, its symptoms, and the use of occupational therapy in improving the quality of life of children with Cri du Chat syndrome.

Biological background

Deoxyribonucleic acid, more commonly shortened and known as DNA, is the double-stranded molecule found in our cells that holds the genetic information necessary for us to function. Due to the amount of information it holds, these long strands need to be packed and compartmentalised in order for our cells to remain organised.³ Our DNA is found in the nucleus and is packed into structures called chromosomes. Every living being will need some sort of genetic information in their bodies in order to carry out specific functions. These functions, on a biological level, require the production of proteins that are produced from ‘reading’ DNA (in humans). This theory, known as the ‘central dogma of molecular biology’ is a necessary process, and mutations (either random or inherited) that disrupt the process can lead to diseases. There are ways for humans to repair damaged DNA or ‘mistakes’ that the processes make, but depending on the complexity of the error can still lead to the onset of disease.⁴

Central dogma of molecular biology

In order to carry out essential functions in the body, three processes must occur, these are DNA replication, transcription, and translation.⁵ In order for the body to develop and grow, cells must divide (i.e., our DNA needs to be replicated). During transcription, the DNA is ‘read.’ During this reading process a ribonucleic acid (RNA) molecule/strand that is complementary to one of the DNA strands is made.⁵ This RNA molecule is processed to make messenger RNA (mRNA). Translation is where the mRNA is then taken and ‘translated’ into amino acids and turned into proteins.⁵ The proteins are then used in many other functions such as providing structural support and acting as catalysts or enzymes.⁶ 

• The whole process can be summarised as: DNA → RNA → Protein

Mutations

Mutations can occur anywhere and can either be by random chance (i.e. novel) or through inheritance (received from both parents or one parent).⁷ There are also factors that may influence novel mutations to occur. These factors, known as mutagens, include examples such as UV radiation, which is used as a common example of the cause of skin cancer. In inherited mutations, a parent or both parents may have genes (i.e. segments of DNA that code for a protein) that may be dysfunctional that is then passed onto their child(ren).⁸ 

Cri du Chat biology

Our chromosomes are numbered (23 pairs in total, or 46 chromosomes) and have particular labelled structures. These labelled structures are the centromere, the p-arm (short arm), q-arm (longer arm), and telomeres. In patients that have Cri du Chat syndrome, chromosome 5 either has a missing or deleted p-arm, commonly denoted as 5p- (5: chromosome number, p: relevant arm, ‘-’: a minus sign indicating a deletion).² 

Further numbering can be used on chromosomes designating broad gene locations within chromosome bands.⁹ For Cri du Chat syndrome, the most relevant locations on chromosome 5 include 5p15.33 (read: band 15.33 on chromosome 5’s p-arm), and 5p15.2.² On 5p15.33 and 5p15.2, there are three incredibly relevant genes that are necessary towards neuronal development. The genes that are responsible for encoding the proteins needed for development are: the telomerase reverse transcriptase gene (hTERT) [located in 5p15.33], Semaphorin 5A (SEMA5A), and delta (δ)-catenin (CTNND2) [both located in 5p15.2].² With the deletion of the 5p arm, the DNA that is needed to transcribe and translate these proteins no longer exists.

Telomerase reverse transcriptase (hTERT)

Telomeres on chromosomes are important structures that contain repetitive DNA and telomere-associated proteins.¹⁰ They provide stability by preventing any possible breakdown of the chromosome ends and preventing the ends from fusing with other chromosomes.¹⁰ Just through ageing, telomeres naturally shorten and eventually stop cellular growth.¹⁰ Telomerase reverse transcriptase (TERT) is a protein/enzyme that synthesises telomeric DNA that would account for the loss of the telomeres that happens due to age or due to the nature of the replication cycle.¹¹ Consequently, patients with Cri du Chat syndrome that have a deletion of hTERT would have decreased telomere development, leading to lack of cell growth,² and therefore, possible developmental delays. 

Semaphorin 5A (SEMA5A)

SEMA5A, previously/alternatively known as SEMAF (protein: Semaphorin F)¹² has been shown to span 10% of the 5p15.2 region, and therefore physical characteristics can possibly be attributed to the deletion of the SEMA5A gene.² SEMA5A encodes for the Semaphorin 5A protein, which in mice has been shown to guide parts of nerve cells (axons) during brain development.² Other studies show that Semaphorin 5A (and other semaphorins) can be involved in preventing cancer progression by activating immune response.^2,13,14 

Delta (δ)-catenin (CTNND2)

As a protein, δ-catenin is used during early development due to its ability to aid in cell-to-cell adhesion, an important characteristic in tissue development.¹⁵ Patients who have a total deletion of this particular area show signs of intellectual disability. This was further evidenced in mice, where scientists knocked out the CTNND2 gene in lab mice and found a severe decline in cognitive development and function.² 

Symptoms

Many infants with Cri du Chat syndrome have a mortality rate of 75% within the first few months and up to 90% within the first year. However, the survival rates after the first few years of life are high.² Symptoms may change over the course of the child’s age, which include:

In babies:

• Unusually small head 
• Abnormally round face
• Wide nose
• Widely set eyes 
• Crossed eyes 
• Downward slanting eyelid folds 
• Monolid eyes
• Low-set ears
• Abnormally small jaw
• Unusually short distance from your child’s upper lip to their nose 

While growing, the baby may lose its facial roundness and will start to have a more long and narrow face.

Other symptoms:

• Low birth weight
• Delayed growth
• Feeding difficulties, such as poor sucking, difficulty swallowing and GERD
• Weak muscle tone
• Curvature of the spine 
• Heart defects
• Developmental delays, such as head control, sitting up and walking.
• Speech and language delays
• Moderate to severe intellectual disability

Early intervention

Cri du Chat syndrome is not typically attributed to inheritance, and in most cases is due to a novel mutation.² Parents of children with novel mutations will typically have normal chromosomes and are not at risk of conceiving another child with Cri du Chat syndrome (NORD). However, genomic counselling may still be advised. This is because, in 10–15% of cases, a parent may have a balanced translocation. Translocation is where parts of the chromosome move to another chromosome, but no detrimental effect is shown. This may cause issues when conceiving a child. This is because during meiosis (the process of producing eggs or sperm), chromosomes undergo a process called random assortment. During this process, chromosomes are randomly oriented and can therefore lead to a random distribution of genetic information, which can cause the balanced translocation to become unbalanced.²

After confirmation of Cri du Chat syndrome, a series of therapies may be offered or discussed with you and your child. These include speech therapy, behavioural therapy (if needed), physical therapy and occupational therapy.² Physical therapy is generally given within the first few weeks of the baby being born to help the baby suckle.² Speech and occupational therapy are also recommended due to the possible neurological problems from lack of neuronal development.² Occupational therapy specifically focuses on giving your child activities to complete to give them a sense of purpose, including acts of self-service such as cleaning, using the toilet, eating and socialising. Often children with Cri du Chat will develop their own way of communicating through signs thanks to occupational and speech therapy.

Summary

Cri du Chat syndrome is a genetic disease often stemming from novel mutations within chromosome number 5. Within chromosome number 5, Cri du Chat has been found to be attributed to deletions of the p-arm, specifically from deletions of the telomerase reverse transcriptase gene (hTERT), Semaphorin 5A (SEMA5A), and delta (δ)-catenin (CTNND2). These genes encode proteins that are necessary for neuronal development and growth, and therefore their deletion can cause developmental delays found in Cri du Chat patients. Therapies are available for your child, including speech, physical, occupational, and behavioural therapy. These therapies can make your child healthier and enhance their quality of life.