“Huntington’s disease caused by mutations in the HTT gene inherited in an autosomal dominant pattern.”


In autosomal dominant disease condition, only a single allele of a gene is sufficient to cause disease. 

Huntington’s disease is a progressive neurological-brain disorder causes cognitive problems, loss of thinking and uncontrolled movement. Further, emotional problems are one of the factors in it. 

Huntington’s disease is caused by a special type of mutation called triplet repeat explanation disorder or trinucleotide expansion disorder in which the expansion of unusual triple repeat codon causes disease condition. 

Especially, in the CpG island of a gene is responsible for triplet repeat expansion disorder. In the case of Huntington’s disease, an abnormal expansion of CAG triplet codon causes the neurodegenerative disorder. 

The condition of the disease is based on the length of the CAG repeat in the HTT gene. The repeat length of more than ~40 causes the full penetrance of the disease in which the severity of the disease is very extreme. 

The number of the repeat is directly proportional to the severity of the disease. This phenomenon is known as anticipation. 

Interestingly, Huntington’s disease is previously known as “dancing disorder” or “epidemic dance”.

The disease was first reported by George Huntington in 1872. The global prevalence of it is 1 in 10,000, however, it is most prevalent in the caucasian population. 

The CAG triplet encodes for the glutamine amino acid thus the disease is often known as polyQ tract disorder or polyglutamine disorder. 

The number of the repeat and the severity of the disease is shown into the table below, 

Table 1:

Number of CAG repeats Disease status
<27  Normal 
~27 to 35 Premutation (at risk of developing the disease)
35- 39 Premutation at high risk
>39 Full mutation 
40- 50  Adult-onset of the disease
>60  Juveline form of the disease

The HTT gene encodes for the huntingtin protein which supposes to function in neurons development in the brain. 

The gene is located on chromosome 4 at the short “p” arm at 16.3 (4p16.3). 

Although, huntignin present in many tissues in our body, the highest activity of it is reported in the brain cells. 

The structure of a gene is interesting and different from other genes as it contains the major portion of cytosine- adenine and guanine rich region called trinucleotides. 

The HTT gene also known as the IT15 gene is located on chromosome 4 while the CAG repeat is located on 5’ untranslated region of it. 

Other triplet repeat expansion disorders are given into the table below, 

Table 2:

Disease  Gene  Location  Repeat  Normal range  Full mutation 
Huntington Disease  IT15 Exon 1  CAG  6-29 38-180
DRPL ATN1 Exon 5  CAG 6-35 49-88
SCA1 ATXN1 Exon 8 CAG 6-39 41-83
SCA2 ATXN2  Exon 1  CAG <31 32-200
SCA3  ATXN3 Exon 8 CAG 12-40 52-86
SCA6 CACNA1A Exon 47 CAG <18 20-33
SCA7 ATXN7 Exon 3 CAG 4-17 36- >460
SCA17 TBP Exon 3 CAG 25-42 45-66
SMBA AR Exon 3 CAG 13-31 >40
Synpolydactyly II HOXD 13 Exon 1 GCG 1-15 >21
Cleidocranial dysplasia  RUNX2 Exon1 GCG 2-17 >26
HFGS HOXA13 Exon 1 GCG 12 >17
XLMR ARX Exon 2 GCG 16 >17
OPMD PABPN1 Exon 1 GCG 10 >11

As we discussed above, the CAG repeats located on after another is responsible for Huntington’s disease. 

Symptoms of Huntington’s disease: 

  • Uncontrolled body movements 
  • Huntington’s chorea- involuntary jerking movements. 
  • Dystonia- rigid muscle
  • In-coordinative movements 
  • Speech and swallowing problems 
  • Depression- anxiety- anger- apathy 
  • Uncontrolled emotions 
  • Learning and memory problem 
  • Slow or abnormal eye movements 
  • Frequent thoughts of suicide, death and dying.
  • Difficulty on focusing particular task, prioritizing and organizing. 
  • Lack of impulse control
  • Insomnia 
  • Energy loss and fatigue
  • Seizure

How is Huntington’s disease inherited? 

Huntington’s disease is an autosomal dominant genetic disorder in which the mutation in a single dominant allele of the HTT gene is capable of causing the disease. 

Two alleles of the HTT gene are located on two different 4 number of chromosomes. If a single mutated allele is present on chromosome number 4, the individual suffers from the disease. 

If one of the two parents are affected, the chance of the inheritance of the disease is 50% in offspring. 

See image 1 below:

Image 1: graphical illustration of inheritance Huntington's disease.

Image 1: graphical illustration of inheritance Huntington’s disease.

Two different conditions of the Huntington’s disease is shown into the figures below, 

If both the parents carry a single dominant allele, the chance of occurrence of the disease is 75%.

Image 2: graphical illustration of inheritance Huntington's disease.

Image 2: graphical illustration of inheritance Huntington’s disease.

 

In another condition, if a single parents carry two dominant alleles, the occurrence of the disease in progenies is 100%.

Image 3: graphical illustration of inheritance Huntington's disease.

Image 3: graphical illustration of inheritance Huntington’s disease.

Although the disease is often characterised under non-mendelian inheritance, still the dominant allele is capable of causing full mutation.  

Javelina Huntington’s disease occurs in childhood while adult-onset Huntington’s disease occurs in either thirties or forties of a person. 

However, the juvenile form of the disease is very rare and the number of triplet repeat in full mutation is more than 60.

Huntington’s disease facts:

Anticipation- the process of anticipation plays an important role in the development of the disease which observed rarely in other disorders. the severity of the disease is proportional to the number of the repeats present in a gene is called anticipation.

Dancing disease the disease is also known as a dancing disease due to the imbalanced and in-coordinative body movement.

Occurrence- the occurrence of the disease reported since the 16th century.

Mutation- the disease originated due to an unusual mutation of triplet repeat expansion in which a triplet CAG codon (which encodes glutamine protein) expanded abnormally.

Conclusion:

Genetic testing is one of the best methods for knowing “how is Huntington’s disease inherited.” larger the amplicon band in a gel indicates higher the number of repeats in a sample. An autosomal dominant- single gene Huntington’s disease is one of the commonest motor and neurodegenerative disorder.  

Sources:

  1. Roos RA. Huntington’s disease: a clinical review. Orphanet J Rare Dis. 2010;5:40. Published 2010 Dec 20. doi:10.1186/1750-1172-5-40.
  2. Nopoulos PC. Huntington disease: a single-gene degenerative disorder of the striatum. Dialogues Clin Neurosci. 2016;18(1):91–98.

Quiz:

The location of the IT15 gene

  1. chromosomes 1
  2. chromosome 4
  3. chromosome X
  4. chromosome 2

Answer

2. chromosome 4

The inheritance pattern of Huntington’s disease-

  1. Autosomal dominant
  2.  Autosomal recessive
  3. X linked dominant
  4. X linked recessive

Answer

1. Autosomal dominant

The tripler repeat in Huntington’s disease is

  1. GCG
  2. GAA
  3. CAG
  4. GAC

Answer

3. CAG