Huntington’s disease is a neurodegenerative condition transmitted in an autosomal dominant fashion. The onset is usually in midlife and the symptoms progress over several years.

Huntington’s disease is a rare condition with a prevalence of 5–10 individuals per 100,000 in Europe. In Japan, Huntington’s disease is extremely rare, with a prevalence of less than 0.5 per 100,000.

Initially patient may develop anxiety, behavioral changes, sleep disturbances, depression, general restlessness, and hygienic neglect. Motor signs usually appear after but can occur at the onset of the disease and include involuntary movements which cannot be suppressed by the patient. The characteristic facial movements and postures include raising eyebrows, leading to the facial expression of an astonished appearance. Patients have clumsiness upon rapid alternating hand movements or finger tapping. Uncontrolled finger and truncal movements are also apparent. The chorea usually exacerbates during stress, walking, and concentration. Most patients are more aware of their mood swings than choreiform movements.

With the evolution of the disease, chorea becomes worse and impairs voluntary movements and gait balance. Rigidity and bradykinesia are common in juvenile cases where chorea may be absent. Dystonic postures of the limbs, trunk, and neck are common. Gait and motor speed are both affected with the increasing risk of falls. In some cases, there is evidence of cerebellar dysfunction, and eye movements are always abnormal. Individuals generally have trouble initiating saccades and decrease in saccade velocity. The eye movement abnormalities can be seen in presymptomatic stages.

Patients usually have hyperreflexia with extensor plantar responses, and dysarthria is frequent, and speech disturbance is usually mixed, occasionally cerebellar in nature. Weight loss and sleep disturbances are also common.

As the condition advances, motor disability becomes severe, the patient becoming incontinent and dependent upon others for activities of daily life. The average survival time after the diagnoses of HD usually varies from 5 to 30 years.

Behavior disorders differentiate Huntington’s disease from other causes of chorea. Patients usually have anxiety that can be disabling and accompanied with depression. In early stages, patients have decreased mood, loss of energy, interest, and appetite. With the progression of disease, patients may develop impulsivity, irritability, and untreated anxiety which can lead to violent and aggressive behavior. Low self-esteem with feelings of hopelessness is not uncommon, and the risk of suicide is also increased. The psychiatric symptoms respond well to pharmacological treatment.

Cognitive changes may be present in the early stages of Huntington’s disease and may precede motor symptoms and depression. The usual cognitive changes include reduced mental flexibility, memory problems, impaired working memory, and slowness of execution. Planning and organization of sequential activities affects everyday tasks. Decreased attention capacities and global inertia with subcortical dementia are frequent.

The diagnosis of Huntington’s disease can be established clinically due to the presence of affective and cognitive changes associated with progressive motor dysfunction, family history consistent with autosomal dominant transmission, and behavioral problems.

The diagnosis of Huntington’s disease is supported by the atrophy of the caudate nucleus, although MRI is used more commonly to rule out other neurological conditions. Pathologic studies show severe and progressive atrophy of the putamen and caudate. Proteins with lengthened polyglutamine tracts aggregate to form intraneuronal inclusions and may appear before other symptoms of disease.

The HD gene mutation with trinucleotide CAG repeat expansion is the main gene abnormality in Huntington’s disease. The HDL2 gene mutation is a rare gene abnormality causing Huntington’s disease with similar phenotype.

For an extensive period of time, Huntington’s disease was considered a genetically homogenous disorder with a single gene (HD gene or IT15) mutation on chromosome 4p, leading to CAG repeat expansion. Although this mutation is responsible for the vast majority of cases of Huntington’s disease, presently genetic heterogeneity is known due to mutation involving Junctophilin 3 gene or HDL2 gene, causing a typical Huntington’s disease phenotype in a small number of patients.

Juvenile Huntington’s disease is considered with onset before the age of 21 and is responsible for nearly 5–15 % of all Huntington’s disease cases. In majority of cases the transmission of juvenile Huntington’s disease is paternal, and the number of CAG repeats in the HD gene is larger than 60. Maternal transmission of juvenile Huntington’s disease with abnormally large expansions has also been reported. These patients have seizures and prominent rigidity with dystonia, while the chorea is minimal.

Huntington’s disease gene is located on chromosome 4p16.3 with CAG trinucleotide repeat above the threshold of 36 in a heterozygous state in individuals. Individuals with 36–38 CAG repeats have a reduced penetrance and may not exhibit HD during a regular life-span. In many cases the size of the expansion increases even more during transmission, resulting in an average increase of the expansion size in successive generations. Paternal transmissions are associated with the greatest tendency to increase in size and instability. There are also intermediate sizes of repeats which range from 27 to 35, although not linked with the disease, but are commonly susceptible to expansion, even if the estimated risk is very rare. However, very few patients with CAG repeats falling within the intermediate allele size develop clinical signs of HD. Intermediate alleles can also display instability during paternal transmissions, which indicates that the offspring of a male intermediate allele carrier risks the inheritance of a larger allele which can be linked to Huntington’s disease. On the contrary, no expansion of intermediate alleles has been observed maternally. Although the abnormal repeat size varies from 36 to 200 units, alleles with 40 to 45 repeats are predominant in most patients affected with Huntington’s disease.

Huntington’s disease was originally believed to be monogenetic with one responsible gene and one single mutation in the HD gene. However, the association of HDL2 or Junctophilin 3 located on chromosome 1 6q confirmed genetic heterogeneity in Huntington’s disease. The observed mutation is an expanded CAG repeat, which varies from 44 to 57 repeats. HDL2 gene may be more common in populations from black African ancestry. Several patients with HDL2 have prominent hypokinetic syndrome, thus resembling a juvenile form of HD.

Dentatorubropallidoluysian atrophy is transmitted in an autosomal dominant fashion with anticipation responsible for the differences in juvenile- and adult-onset cases. The genetic defect is trinucleotide repeat of CAG located on chromosome 12p, causing mutations in a protein called atrophin-1. It is a rare condition and initial cases were described from Japan, but other families from North America and Europe have been reported as well. There is neuronal loss and gliosis in the dentate nucleus, red nucleus, external globus pallidus, and subthalamic nucleus. There is diversity in the phenotype including chorea, myoclonus, seizures, cerebellar ataxia, and dementia.

Neuroacanthocytosis is characterized by cognitive dysfunction, movement disorder such as chorea, and behavioral changes. The gene for neuroacanthocytosis is located on chromosome 9q21. Although neuroacanthocytosis is an autosomal recessively transmitted condition, as well, some families are affected by autosomal dominant forms of inheritance. Amyotrophy and areflexia are frequent and nerve conduction studies may show peripheral neuropathy. More than half of individuals affected by neuroacanthocytosis have a self-mutilating oro-mandibulo-lingual dystonia which involves biting of the tongue. Tonic-clonic generalized seizures are not uncommon and some patients may have vocal tics as well. There may be increased serum level of creatine kinase, and about 10 % or more of the peripheral red cells in patients with neuroacanthocytosis consist of acanthocytes although this level may vary as the disease progresses. Parkinsonism can be the sole movement disorder in neuroacanthocytosis, whereas in Huntington’s disease this is not the case.

The clinical features of McLeod syndrome can be difficult to differentiate from neuroacanthocytosis. Self-mutilating tongue dystonia and seizures are frequent in patients affected by neuroacanthocytosis, whereas more patients with McLeod syndrome have cardiomyopathy and myopathy. McLeod syndrome and neuroacanthocytosis can however both be accurately distinguished by observing the gene CHAC in neuroacanthocytosis and the low reactivity of Kell erythrocyte antigens, the universal sign of McLeod syndrome. Patients with McLeod syndrome with seizure disorder may require antiepileptic drugs as valproic acid or carbamazepine. For self-mutilating lingual dystonia, botulinum toxin is considered an effective treatment.

The clinical features of benign hereditary chorea manifest before the age of 5 years and include chorea, autosomal dominant transmission, and ataxia in minority of the patients. Their course may be static or with spontaneous improvement after childhood. After the discovery of a mutation of the TITF-1 gene mutation on chromosome 14q, it is considered independent nosologic entity.

The neurological signs of this rare autosomal recessive condition are caused by a mutation in the ATP7B gene on chromosome 13q. This condition results in deposition of copper in the brain, predominantly in the upper brainstem and basal ganglia. Because Wilson’s disease can be treated effectively with agents that chelate copper and prevent its absorption, it should be included in differential diagnosis of patients of 40 years of age or younger with movement disorders. A fatal outcome is associated with cases of Wilson’s disease, if left untreated. The clinical phenotype of Wilson’s disease is rather varied, with chorea, tremor, parkinsonism, and dystonia. It should be noted, however, that isolated chorea is seldom observed in these patients. The diagnosis of Wilson’s disease is normally based on the distinctive biochemical abnormalities such as elevated urine copper, low serum ceruloplasmin, and the identification of the Kayser-Fleischer rings.

Sydenham chorea is an autoimmune condition occurring in approximately one fourth of patients with rheumatic fever. Despite its declining incidence, Sydenham chorea remains one of the most frequent causes of acute chorea in children worldwide.

The usual age of onset of Sydenham chorea is around 8 years, although there have been reports of individuals developing Sydenham chorea in their 30s. Sydenham chorea is rarely seen before the age of 5 years. Usually, patients develop choreiform movements a few weeks after an episode of group A β-hemolytic streptococcus (GABHS) pharyngitis. In some cases, although choreiform movements may become generalized, in one fifth of patients, it is localized to one side of body. Individuals affected with Sydenham chorea show motor impersistence, particularly noticeable during ocular fixation and tongue protrusion. These patients may have decreased muscle tone, in rare cases making patients bedridden as a result.

Choreiform movements in patients with Sydenham chorea may be difficult to differentiate from simple tics. Vocal tics may be found in some patients with Sydenham chorea, the exact cause of which is unclear.

Peripheral nervous system is believed not to be involved in Sydenham chorea. Sydenham chorea is a major manifestation of rheumatic fever. More than two thirds of patients with Sydenham chorea exhibit cardiac involvement, especially mitral valve dysfunction. The association of Sydenham chorea with arthritis is less common and may be observed in one third of the patients.

The pathogenesis of Sydenham chorea is believed to be due to existence of molecular imitation between central nervous system and streptococcal antigens. Group A β-hemolytic streptococcal infection in genetically predisposed patients leads to the formation of antibodies which are cross-reactive with the basal ganglia. Numerous studies have shown the presence of such circulating antibodies in more than half of the individuals with Sydenham chorea.

The current criteria for the diagnosis of Sydenham chorea include chorea with lack of evidence of alternative causes of chorea. The diagnosis is supported even further by the presence of additional minor or major signs of rheumatic fever. The goal of the diagnostic work-up in patients suspected to be affected with Sydenham chorea is to rule out alternative causes of Sydenham chorea, identify evidence of recent streptococcal infection or acute phase reaction in the individual affected with SC, and rule out any cardiac injury associated with rheumatic fever.