Huntington’s Disease (HD, Huntington’s Chorea) — Genetics and Progression

Image : “Neuron with mHtt inclusion” by Dr. Steven Finkbeiner. License: CC BY-SA 3.0

Definition of Huntington’s Disease

Huntington’s disease is a hereditary disease

Huntington’s disease, also known as St. Vitus Dance, is a hyperkinetic disease of autosomal dominant inheritance which manifests in full penetrance, which means that those who have the mutated gene will become diseased at some point. The pathogenic gene is located on the short arm of chromosome 4.

Image: “Autosomal Dominant Pedigree Chart. In Autosomal Dominance the chance of receiving and expressing a particular gene is 50% regardless of the sex of parent or child.” by Jerome Walker. License: CC BY-SA 3.0

Synonymous with Huntington’s disease is the name Chorea major. Chorea major must be strictly distinguished from Chorea minor (Sydenham’s chorea), which has a different pathogenesis (see below).

Epidemiology of Huntington’s Disease

Huntington’s disease in the population

The prevalence of the disease is about 2 – 8 / 100,000. Often, the disease clinically manifests between the ages of 35 and 55, although there is a wide range in age of the disease’s onset.

Men and women are affected almost equally by the disease. This can be explained by the autosomal dominant inheritance of the disease, among other things.

Etiology of Huntington’s Disease

Huntington’s disease at the genetic level

Huntington’s disease is one of several trinucleotide repeat disorders containing multiple CAG triplet repeats. Medical diagnosis is made if a repetition of CAG-triplets of at least 39 times is present. As a matter of fact, the more the count of triplet-repeats, the earlier the disease’s onset.

The fact that the severity of symptoms of Huntington’s disease increases in successive generations or manifests at an earlier age of onset, is called anticipation. In correlation to a gender-specific varying DNA-methylation in the course of gametogenesis, especially in children who inherit the mutation from their father, are affected by the consequence of anticipation. This is referred to as Genomic Imprinting.

The location of the repeats on chromosome 4 is also called “Huntingtin-gene”. This gene provides the genetic information to a protein that is found mostly in the brain, but also present in other types of tissue. The precise function of the protein has not been identified yet.

Pathophysiology of Huntington’s Disease

Huntington’s disease on a neuroanatomical level

Huntington’s disease is characterized by an atrophy of the Corpus striatum. Consequently, GABA-concentration decreases and a state of disequilibrium between GABA and dopamine is induced.

Altogether, dopamine has an excitatory effect on the direct pathway and an inhibiting effect on the indirect pathway of the circuitry of the basal ganglia, which consequently results in an increased activation of the thalamus and the motor cortex.

Clinic of Huntington’s Disease

Initial symptoms of Huntington’s disease

Spontaneous movements caused by the increased activation of the thalamus primarily appears on the patient’s face and in distal parts of the limbs. Orofacial hyperkinesia of the face can occur in the early stages of the disease and is also referred to as “Grimacing“.

Another sign that appears at an early stage in the facial area is the so-called “chameleon tongue”, where the tongue is pulled back immediately after it is stuck out.

Further in the course of the disease, limbs are affected by involuntary arrhythmical movements and the back is often pulled back jerkily (hyper lordosis). During times of emotional stress, symptoms can intensify (“choreatic movement attack“).

Late symptoms of Huntington’s disease

Altogether, patients exhibit a significantly increased calorie consumption rate caused by consistent abrupt movements, and are often cachectic. Food intake is even more hindered if nerve tracts of the caudal cranial nerves are also damaged and if the chewing and tongue muscles are also impaired.

Mental symptoms of Huntington’s disease

Frequently, psychopathological changes precede extrapyramidal movement disorders and partially occur 10 – 15 years before the onset of movement disorders; changes appear as avolition, affective disorders as well as psychosis.

Further as the disease progresses, Huntington’s disease generally leads to dementia with a reduction in cognitive capabilities and attention deficit disorders. This type of dementia is called subcortical dementia.

Image: “Area of the brain most damaged in early Huntington’s disease—striatum (shown in purple)” by John Henkel. License: Public Domain

Diagnosis of Huntington’s Disease

Genetic examinations in Huntington’s disease

Besides using PCR for genetic analysis of gene mutations including a CAG-triplet-repeat, the medical diagnosis of Huntington’s disease is made by looking at the clinical picture (see above) of the disease.

EDTA-blood is used for genetic testing. However, prior to that, the guidelines for molecular genetic diagnostics of the Huntington-self-help group must be fulfilled. This includes prior human genetic counseling conducted by the correspondent institute.

Imaging techniques in Huntington’s disease

Moreover, in some cases atrophies of the Nucleus caudatus can be visible in a CT or MRT scan of the head when the disease is in its advanced stage.

Additionally, a HMPAO-SPECT-examination can be performed if necessary, in which a reduced cerebral perfusion of the striatum appears. Another optional examination is the ¹⁸FDG-PET (positron emission tomography), where by a hypometabolism of the striatum can be detected, possibly even in the early phase of the disease.

Image: “Coronal FSPGR through the brain at the level of the caudate nuclei demonstrating marked reduced volume in keeping with the patient’s known diagnosis of Huntington Disease” by Frank Gaillard. License: CC BY-SA 3.0

Functional diagnostics in Huntington’s disease

More possibilities of diagnostics lie the field of electrophysiology, comprising a SEP (somatosensory evoked potential) as well as ENG (electroneurography). The Medianus– or Tibialis-SEP can show a reduction of the amplitude of central potentials.

The ENG is able to visualize a prolonged latency of saccades or a decelerated speed of saccades as well as a possible optokinetic nystagmus.

Eventually, within the diagnostic setting, possible differential diagnosis (see below) need to be ruled out. Furthermore, a neuropsychological test to record cognitive capabilities may be performed.

Differential Diagnosis of Huntington’s Disease

Diseases similar to Huntington’s disease

Among the most important differential diagnoses of Huntington’s disease is on one hand Chorea minor and on the other hand extrapyramidal motoric disorders with hyperkinesia.

Ballism, hemiballismus, dystonia, dyskinesia, or akathisia (inability to sit still) are considered to be among hyperkinetic diseases.

Medication-induced hyperkinesia is called dyskinesia. A possible drug which can trigger dyskinesia is  L-Dopa, which is used in the treatment of Parkinson’s disease. In this case, dyskinesia usually occurs during the course of long-term therapy.

More possible differential diagnoses from the field of internal medicine are hyperthyreosis, Wilson’s disease, as well as hypoparathyroidism. Within the field of neurology, inflammatory diseases like a neuroacanthocytosis must be ruled out using a spinal tap when indicated.

Chorea minor as differential diagnosis to Huntington’s disease

Chorea minor (Sydenham’s chorea) is a disorder resulting from a pathological immune reaction subsequent to an infection with β-haemolytic group A streptococcus. In about 50 % of the cases symptoms of rheumatic fever precede the choreatic movement disorders, including polyarthritis, carditis, erythema annulare and subcutaneous papules.

School age children are particularly affected by this. In this age group, girls are more often affected than boys. Choreatic hyperkinesia predominantly appears in the areas of mimetic muscles, pharyngeal muscles, the tongue, as well as distal parts of the upper limbs.

Due to the accompanying psychic abnormalities like increased excitability, apathy and labile affect, the children’s peculiar behaviour often becomes noticable at school.

Therapy of chorea minor consists of medication consisting of penicillin G, which should be dosed at sufficiently high amounts and administered for an adequately long period.

Therapy of Huntington’s Disease

Treatment of Huntington’s Disease

The course of the disease cannot be changed using any treatment, which means that there is no cure. However, symptoms can be managed with medications, physical and occupational therapy.  In addition, high caloric nutrition can counteract cachexia.

Drugs commonly used for treating hyperkinesia are  Sulpirid (atypical neuroleptic) or Tiaprid (classicl neuroleptic). Both these drugs are given first choice, whereas Haloperidol is a drug of second choice (see literature for further information).

The above-mentioned Sulpirid is also used for treating feelings of depressions. In this context, further medications for treating depression are Alprazolam (benzodiazepine), Thioridazin (neuroleptic) and tricyclic antidepressants.

Progression of Huntington’s Disease

The disease is chronic and progressive. The earlier its onset, the faster its progression (faster progression when onset < 20 years of age, slower progression when onset > 50 years of age). The average disease duration is about 20 years.

Review Questions

The correct answers are below the list of references.

1. Which statement about the etiology of Huntington’s disease is incorrect?

1. It is a disease of autosomal dominant inheritance.
2. Penetrance adds up to 100 %.
3. It is a trinucleotide repeat disorder.
4. The more the count of triplet repeats, the earlier the onset of the disease.
5. The phenomenon of genomic imprinting exists in a maternal inheritance.

2. Which statement about the symptoms of Huntington’s disease is incorrect?

1. During the early stage of the disease, orofacial hyperkinesia which can be described as “grimacing” occurs regularly.
2. Dysarthrophonia can occur.
3. Dementia only develops in extremely rare cases in the later course of the disease.
4. A pseudobulbar palsy can occur.
5. During times of emotional stress, symptoms can intensify.

3. Which statement about the diagnostics of Huntington’s disease is correct?

1. The gene mutation can be detected using PCR.
2. An MRT of the head can regularly visualize an atrophy of the Nucleus ruber in the later stages of the disease.
3. The HMPAO-SPECT-examination detects an increased perfusion of the striatum.
4. The PET-examination reveals a hypometabolism in the striatum, which only occurs during later stages of the disease.
5. In the ENG an increased speed of the optokinetic nystagmus is conspicuous.