Huntington’s Disease

"HD is caused by a change in the gene that makes the protein huntingtin (HTT). This change causes a section of DNA called CAG to repeat itself many more times than normal, causing production of an abnormal version of huntingtin that damages brain cells" (NINDS). The gene sits on chromosome 4.

Inheritance. "When a parent has HD, each child has a 50% chance of inheriting the genetic variant. If a child does not inherit the variant, they won’t develop the disease and can’t pass it on to future generations" (NINDS). MedlinePlus Genetics: one copy of the altered gene in each cell "is sufficient to cause the disorder."

Repeat length matters (figures differ slightly by source). NINDS: "Most people have fewer than 27 CAG repeats in their HD gene, so they aren’t at risk for the disease." "People who have CAG repeats in the middle range (27 to 35) aren’t likely to develop the disease, but they could still pass it on to future generations." "People with HD may have 36 or more CAG repeats." MedlinePlus Genetics: "People with 36 to 39 CAG repeats may or may not develop the signs and symptoms of Huntington's disease, while people with 40 or more repeats almost always develop the disorder."

Anticipation. As the gene passes down a family, the repeat often grows, and "A larger number of repeats is usually associated with an earlier onset of signs and symptoms" (MedlinePlus Genetics). StatPearls: "In Huntington disease, the anticipation phenomenon is seen mainly in the paternal line of inheritance, which arises due to the instability of the CAG repeats during spermatogenesis." A negative family history does not rule HD out — the parent may have died early, had late-onset disease or never been diagnosed.

"An increase in the size of the CAG segment leads to the production of an abnormally long version of the huntingtin protein. The elongated protein is cut into smaller, toxic fragments that bind together and accumulate in neurons, disrupting the normal functions of these cells" (MedlinePlus Genetics).

The striatum fails first. "The primary feature is the degeneration of neurons of the striatum, ie, the putamen and the caudate." Most striatal projection neurons are GABAergic, and "Throughout Huntington disease, over 90% of these GABAergic neurons degenerate" (StatPearls). The typical MRI finding is caudate atrophy with a "boxcar appearance" (StatPearls, Chorea).

Why the movements happen. "Striatal modulation is mainly inhibitory through GABAergic innervation. Consequently, any striatal lesion can disrupt this inhibitory mechanism, resulting in hyperkinetic movement disorders such as chorea or choreoathetosis." These disorders "are believed to result from increased phasic dopaminergic signaling in the striatum" (StatPearls, Chorea). That is why drugs that deplete dopamine (VMAT2 inhibitors) reduce chorea.

Beyond movement. Neurodegeneration also occurs "throughout the cerebral cortex," and "The involvement of the cingulate gyrus is associated with emotion and mood disturbances" (StatPearls). Brain changes start early: "measurable brain and behavioral changes can be detected up to 15 years before an HD diagnosis" (NINDS).

"The signs and symptoms classically consist of the triad of motor, cognitive, and psychiatric disturbances" (StatPearls). Motor signs are not always first: "Behavioral and psychiatric symptoms are present very early in the disease, often even before the onset of motor manifestations" (StatPearls), and motor symptoms "are frequently preceded by cognitive and behavioral symptoms" (EHDN guideline).

Onset and course (attributed). "Huntington disease commonly affects patients between the ages of 30 to 50" (StatPearls); NHS says symptoms "usually start in adults aged between 30 and 50, but it can happen at any age." Adults "usually live about 15 to 20 years after signs and symptoms begin" (MedlinePlus Genetics). Early chorea is hyperkinetic; "In later stages, however, hypokinesia with bradykinesia and dystonia may predominate" (StatPearls). Juvenile HD (onset before age 20, StatPearls) is rare (NINDS).

Swallowing, weight and the lungs. "Dysarthria and dysphagia develop during the course of the disease, which could lead to aspiration in patients, with pneumonia being a common cause of death" (StatPearls). The EHDN guideline adds that swallowing disorders can become "a major problem in later stages by inducing repeated choking and leading to secondary bronchopulmonary infections or even cardiac arrest." Weight loss "might occur despite normal, or even high calorie intake, due to a significant energy expenditure in HD patients" (EHDN).

Causes of death. "Aspiration pneumonia is the most frequent cause of death, which is followed by suicide" (StatPearls). "Approximately 25% of the patients attempt suicide" (StatPearls).