Huntington Disease

Alternative Names

  • HD
  • Huntington Chorea
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WHO-ICD-10 version:2010

Diseases of the nervous system

Systemic atrophies primarily affecting the central nervous system

OMIM Number

143100

Mode of Inheritance

Autosomal dominant

Gene Map Locus

4p16.3

Description

Huntington Disease (HD) is a progressive neurodegenerative disease characterized by chorea, emotional disturbances, and cognitive problems. Most common is the adult-onset form of the disease, which presents itself in the third or fourth decade of the affected individual's life. Initially, the disease may start off as mild balance problems, clumsiness, mood swings, mild uncontrolled movements in the fingers and toes, and involuntary facial movements. However, as the disease progresses, the severity of the problems increases, and affected patients show severe gait, balance and co-ordination problems, impaired judgment, memory and cognition, severe chorea, slurred speech, and difficulty in swallowing and eating. Most patients survive up to 10 to 15 years after the symptoms appear. There is also a juvenile form of the disease, although rare, which manifests itself at as early as 3-years of age. This form is usually more severe and progresses faster than the adult-onset form. About 30-50% of patients affected by the juvenile form display seizures in addition to the general symptoms of HD.

The disease is more common among Caucasian populations, where 7-10 of every 100,000 individuals are affected. Genetic analysis of the Huntingtin gene is used to diagnose the disease. In fact, screening of this gene can also identify at-risk individuals. Management of the disease is difficult. Imaging techniques show a distinctive pattern with loss of neurons, especially in the caudate and putamen. Tranquilizers, anti-psychotic drugs, and anti-depression medications can help. However, most of these medications have a number of side effects including fatigue, restlessness, and imparting rigidity and stiffness. Speech, physical, and occupational therapy may help in later stages of the disease. Long-term care services may also be required in later stages.

HD is caused due to a specific type of mutation in the Huntingtin gene. The gene is located on the short arm of chromosome 4, where it spans a length of approximately 17 kb of DNA. The normal gene codes for a protein with 3144 amino acids, weighing approximately 347 kDa. Although the exact function of this protein is not known, it is speculated that it plays major roles in intracellular organelle or axonal transport, and in the generation and expression of hematopoietic cells.

The HD gene contains an unstable CAG repeat toward the 5' end of the coding region, which in normal cases, extends to a length of 10 to 35 repeats. In individuals affected with HD however, this repeat occurs from 36 to 120 times. The protein produced by such abnormal genes, therefore, contains a long stretch of glutamine, which interferes with the normal functioning of the protein. The effect is most severe in neuronal cells, where loss of function of this protein results in cell death, and resulting in the signs and symptoms typical of HD. Interestingly, this repeat length is commonly seen to expand in successive generations, but has also been in some cases to contract.

Molecular Genetics

HD is caused due to a specific type of mutation in the Huntingtin gene. The gene is located on the short arm of chromosome 4, where it spans a length of approximately 17 kb of DNA. The normal gene codes for a protein with 3144 amino acids, weighing approximately 347 kDa. Although the exact function of this protein is not known, it is speculated that it plays major roles in intracellular organelle or axonal transport, and in the generation and expression of hematopoietic cells.

The HD gene contains an unstable CAG repeat toward the 5' end of the coding region, which in normal cases, extends to a length of 10 to 35 repeats. In individuals affected with HD however, this repeat occurs from 36 to 120 times. The protein produced by such abnormal genes, therefore, contains a long stretch of glutamine, which interferes with the normal functioning of the protein. The effect is most severe in neuronal cells, where loss of function of this protein results in cell death, and resulting in the signs and symptoms typical of HD. Interestingly, this repeat length is commonly seen to expand in successive generations, but has also been in some cases to contract.

Epidemiology in the Arab World

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Other Reports

Bahrain

Al-Arrayed (personal communication, 2006) reviewed 7000 admissions to the Salmaniya Medical Complex between years 1988 and 2005. Huntington disease occurred in 65 patients. However, further studies are needed to determine its exact prevalence.

Morocco

Among 74 patients with an HD-like phenotype but without CAG repeat expansions in the IT15 gene, Stevanin et al. (2002) identified one patient with a pure uninterrupted 50 CAG/CTG repeat in the junctophilin-3 gene, causing Huntington disease-like-2 (HDL2). The patient was a 44-year-old Moroccan woman with subcortical dementia, mild choreic movements, and atrophy of the cerebral cortex. Stevanin et al. (2002) noted that, in their study, expansion at the HDL2 locus accounted for only 2% of typical HD cases not caused by expansion in the IT15 gene, suggesting further genetic heterogeneity.

[See also: Saudi Arabia > Bohlega et al., 1995].

Oman

Kumar et al. (1998) reported two cases of Huntington disease with typical CT/MRI features of the disease. The first case was a six-year-old Omani girl with unrelated parents, who presented with one year history of progressive intellectual deterioration, grimacing, dysarthria, dystonic positioning of the hands, and ataxia with falls. CT scan and MRI revealed marked atrophy of both caudate nuclei, and DNA studies showed 92 CAG repeats in the HD gene. The other case was that of a 23-year old Omani female with four years history of progressive choreoathetosis, and early dementia of recent onset. Her father who died at the age of 62 years had features suggestive of HD, such as cerebellar dysfunction and dementia. CT scan of her brain revealed atrophy of both caudate nuclei, and DNA studies confirmed the diagnosis of HD, as it revealed 54 CAG repeats in the HD gene. [Kumar SD, Koul RL, Scrimgeour EM, Chand P. Atrophy of caudate nuclei- A CT/MRI finding in Huntington's disease. Oman Med J. 1998; 15(1):15-6.]

Koul (2007) reported a family in which all the three children (two girls and a boy) as well as the father were affected with Huntington's Disease. The children were born to consanguineous parents. Early symptoms in all the children were grimacing, dysarthria, and gait problems in the boy. The symptoms later developed into generalized tonic-clonic seizures in the girls. The elder girl died the age of 8-years due to status epilepticus. The younger girl was alive at the time of reporting, but had refractory seizures and was on multiple epileptic drugs. The boy presented with early symptoms at 12-years, a later age than the girls. Upon examination, he was found to have oculomotor apraxia, generalized rigidity, and stooped gait with hyperreflexia. CT brain of the children revealed bicaudate atrophy. DNA analysis showed 92 CAG repeats in one of the alleles of the Huntingtin gene, and 18 repeats in the second allele. Two years prior, the father had also begun to show symptoms of the disease, including grimacing and emotional changes. The mother's side of the family had a history of abnormal jerky movements.

Saudi Arabia

Scrimgeour et al. (1994) reported two unrelated Saudi Arabian kindreds with classical HD. Both pedigrees indicated an autosomal dominant mode of inheritance. The proband in the first kindred was a 55-year old woman with a decade old history of grimacing, choreoathetosis, dysarthria, ataxia, and progressive mental deterioration. At the time of examination, she was emaciated, mute, and had dementia with incontinence. MRI Brain showed advanced atrophy of the caudate nucleus and putamina, and generalized cortical atrophy. Her 35-year old son was suspected to have early onset HD. Also, his 10-year old son had developed signs of mental impairment associated with generalized seizures. Three of the proband's siblings, two brothers and a sister, were similarly affected. One of these brothers had died of tuberculosis. In the second kindred, the proband was a 48-year old woman, who presented with psychiatric symptoms during her last pregnancy at 37-years of age. These included suicidal tendencies, as well as paranoia with delusions of persecution. She later developed grimacing, and choroathetoid movements. Upon examination, she was found to have marked dementia, dysarthria, generalized choreoathetosis, and ataxia. MRI brain suggested early cortical atrophy. Her mother was reported to have had HD. In addition, her maternal aunt had also been diagnosed with HD at the age of 50-years. Both families did not allow for genetic counseling, and refused to accept the diagnosis. Although European ancestry was not reported in either of the families, Scrimgeour et al. (1994) suggested that the defective gene could have been introduced to them in the previous century by foreigners visiting the Red Sea or the Arabian Gulf ports. Bohlega et al. (1995), on the other hand, thought that this would be extremely unlikely, and that a novel mutation could be responsible for the condition in these families. Bohlega et al. (1995) described four Saudi Arabian families that were diagnosed with HD over a period of six years at the KFSH&RC. This included the first kindred described by Scrimgeour et al. (1994). The second family was from Qatif, the third was a Bedouin family from the mid-northern region of the peninsula, while the fourth family was from Qassim. In all the families, the disease manifestation started around early adulthood and featured mood and personality changes, clumsiness and chorea. MRI brain revealed striking caudate atrophy and increased bicaudate diameter. The first family was reported to have a Moroccan grandmother.

Sudan

Scrimgeour et al. (1995) described a case of apparently typical HD in a 40-year-old Sudanese man from Khartoum, in whom the HD gene showed 51 CAG repeats. It was suspected that his mother and his deceased 16-year-old son were also affected.

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