Trinucleotide Repeat Disorder (Fragile X Syndrome, Huntington's disease)

Human genetics is a very interesting part of science. It not only helps us to to understand the lineage of a disease but also helps us to understand then at a genetic level. The human body has over 20000+ Genes present. There are two main parts of a Gene: 

1. Exon, which is the Coding region
2. Intron which is the Non-coding region 

Introns comprise 98.5% of the Genome, & Exons are roughly 1.5% of the Genome.

The are also some other important terms one needs to understand when studying genetics. Locus is defined as the location of a gene on a Chromosome. Every chromosome has a short arm (p) and a long arm (q).

For example, P⁵³ Gene is present in Chromosome 17p(short arm) 

Every gene has two alternative forms, and these alternative forms are known as Alleles.

Dominant Allele is represented by the capital form A, and Recessive Allele is represented by the small form a. Same alleles (AA, aa) are known as Homozygous, while Different alleles (Aa) are known as Heterozygous. Dominant Allele Expresses in Homozygous & Heterozygous conditions. Recessive Allele Expresses in Homozygous Conditions.

The is another important concept in genetics known as Codominance, and It means both the dominant alleles will be expressed. Eg, AB Blood Group & HLA Gene. We have A

(Dominant), B (Dominant), and o(recessive) in our blood.

Chromosomal disorders can be classified mainly as Mendelian disorders and non-medallion disorders.

As the name suggests, Non-Mendelian disorders are those that do not follow the

Mendelian rules. There are four categories or types of Non-

Mendelian disorders, which include:

1. Mitochondrial inheritance

2. Trinucleotide repeat disorders

3. Genomic imprinting

4. Gonadal mosaicism

This blog mainly focuses on Trinucleotide Repeat Disorders, which involve excessive repetition of trinucleotides. They can be further classified on the basis of the regions where the disorder occurs:

i. Intron or non-coding region

1. FRAGILE X SYNDROME- CGGis the repeated segment
2. Myotonic dystrophy- CTG is the repeated segment
3. Fredreich's Ataxia- GAA is the repeated segment

ii. Exon or coding region

1. Huntington's disease- CAG is the repeated segment
2. Kennedy CAG is the repeated segment

Let us start with a very volatile topic for NEET-PG and FMGE examination, that is Fragile X syndrome. This disorder is related to the chromosome Xq. The problem is caused due to the FMR 1 gene (Familial Mental Retardation Gene) on the x chromosome. The trinucleotide segment repeated is CGG. This disorder is called fragile because of its appearance in a folate-deficient media as an unstained area.

In a normal human, there are around 5 to 55 CGG repeats. If the CGG repeat is between 55 and 200, then that is known as the Permutation stage. In this stage, there is usually no peculiar clinical manifestations except in females, where it has been shown to cause premature ovarian failure. If CGG repeats are between 200 and 4000, then it is considered a Mutation. This is when it results in FRAGILE X SYNDROME. This is explained by Sherman's Paradox /Anticipation, which says that with each generation, the number of repeats and severity of disease increases.

When the chromosome of Fragile X syndrome is stained in a folate-stained media, there is a particular area in the chromosome that will be unstained. This unstained area gives an appearance as that area of the chromosome is falling off, and thus the name fragile is derived.

This disorder is mainly seen in males, and females are generally the carriers. The following are the Clinical Features:

· Mental Retardation (IQ= 20-60)

· Long face

· Large ears

· Large Jaw/mandible

· The most characteristic feature of fragile X syndrome is Macro-orchidism (large testicular size)

This disease has some very serious clinical manifestations, and therefore, it becomes very important to make a clinical Diagnosis. The Diagnosis of choice is PCR, but if it fails, southern blotting is used. 

A review of important blotting techniques is crucial. This also becomes a direct question for major examinations like NEET-PG, NEXT, and FMGE. Southern blotting is used for DNA detection; northern blotting is used for RNA detection; western blotting is used for Protein detection, and Eastern blotting is used for Post-translational modifications.

Myotonic dystrophy is the second intron or non-coding trinucleotide repeat. It has CTG sequence repeats. This patient has a strong grip, and They will not terminate the

Grip. The patient will have characteristic "Hatchet Facies." A very peculiar cataract, the Christmas tree cataract, is also seen with Myotonic dystrophy. Testicular Atrophy is also seen.

In the blood, we can see decreased gamma-type globulins known as Hypogammaglobulinemia.

Next, we can discuss the exon or coding type of trinucleotide disorder—Huntington's disease. This is a CAG sequence defect seen on chromosome 4. It has an autosomal dominant type of inheritance. There will be Increased Huntintin and Ubiquitin proteins.

These topics, as well as other important topics like mendalian and nonmendalian disorders, can be studied through our PrepLadder app, where Dr. Preeti has discussed them in detail. 

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