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Background
Huntington
disease (HD) is an incurable,
adult-onset, autosomal dominant disorder associated with cell loss within
a specific subset of neurons in the basal ganglia and cortex.
HD is named after George Huntington, the physician who described it as hereditary
chorea in 1872. Characteristic features of HD include involuntary movements, dementia, and behavioral changes.
The most striking neuropathology in HD occurs within the neostriatum, in which
there is gross atrophy of the caudate nucleus and putamen, accompanied by selective neuronal loss and astrogliosis. Marked
neuronal loss also is seen in deep layers of the cerebral cortex.
Other regions, including the globus pallidus, thalamus, sub-thalamic nucleus, substantia
nigra, and cerebellum, show varying degrees of atrophy depending on the pathologic grade.
The extent of gross striatal
pathology, neuronal loss, and gliosis provides a basis for grading the severity of HD pathology (grades 0-4).
No gross striatal atrophy is observed in grades 0 and 1.
Grade 0 cases have no detectable
histological neuropathology in the presence of a typical clinical picture and positive family history suggesting HD.
Grade
1 cases have neuropathological changes that can be detected microscopically but without gross atrophy.
Grade
2 striatal atrophy is present, but the caudate nucleus remains convex.
Grade 3
striatal atrophy is more severe, and the caudate nucleus is flat.
Grade 4 striatal atrophy
is most severe, and the medial surface of the caudate nucleus is concave.
The genetic basis of HD is the expansion
of a cysteine-adenosine-guanine (CAG) repeat encoding a polyglutaminetract in the N-terminus of the protein
product called
huntingtin.
The function of huntingtin is not known. Normally, it is located
in the cytoplasm. The association of huntingtin with the cytoplasmic surface of a variety of organelles, including transport
vesicles, synaptic vesicles, micro-tubules, and mitochondria, raises the possibility of the occurrence of normal cellular
interactions that might be relevant to neuro-degeneration.
N-terminal fragments of mutant huntingtin accumulate and
form inclusions in the cell nucleus in the brains of patients with HD, as well as in various animal and cell models of HD.
The presence of neuronal intranuclear inclusions (NIIs) initially led to the view that they are toxic and, hence,
pathogenic. More recent data from striatal neuronal cultures transfected with mutant huntingtin and transgenic mice carrying
the spino-cerebellar ataxia-1 (SCA-1) gene (another CAG repeat disorder) suggest that NIIs may not be necessary or sufficient
to cause neuronal cell death, but translocation into the nucleus is sufficient to cause neuronal cell death. Caspase inhibition
in clonal striatal cells showed no correlation between the reduction of aggregates in the cells and increased survival.
Furthermore,
postmortem studies reveal that NIIs are quite rare in the striatum of patients with HD as compared to the cortex, and most
of the aggregates within the striatum are observed in populations of interneurons that are typically spared in individuals
with HD.
Frequency
In
the US: Estimates of the prevalence of HD in the US range from 4.1-8.4 per 100,000 people. Accurate estimates of
the incidence of HD are not available.
Internationally:
The frequency of HD in different countries varies greatly. A few isolated
populations of western European origin have an unusually high prevalence of HD that appears to have resulted from a founder
effect.
These include the
- Tasmania (17.4 per 100,000 people
Mortality/Morbidity
HD is a relentlessly progressive disorder, leading to disability and death,
usually from an intercurrent illness. The mean age at death in all major series ranges from 51-57 years, but the range may
be broader. Duration of illness varies considerably, with a mean of approxi-mately 19 years. Most patients survive for 10-25
years after the onset of illness. In a large study, pneumonia and cardiovascular disease were the most common primary causes
of death.
Juvenile HD - (ie, onset
of HD in patients younger than 20 years) account for approximately 5-10% of all
affected patients. Most patients with juvenile HD inherit the disease from their father, whereas patients with onset of the
disease after the age of 20 years are more likely to have inherited the gene from their mother. Inheritance through the father
can lead to earlier onset through succeeding generations, a phenomenon termed anticipation. This is caused by greater instability
of the HD allele during spermato-genesis. CAG repeat length correlates inversely with age of onset, and the correlation is
stronger when the onset of symptoms occurs earlier.
A small number of homozygotes for the HD mutation have been identified,
and they seem to be phenotypically indistinguishable from heterozygotes, making HD a truly autosomal dominant disorder.
Sex: No sex predilection has been reported.
Age: Most studies show a mean age at
onset ranging from 35-44 years. However, the range is large and varies from 2 years to older than 80 years. Onset in patients
younger than 10 years and in patients older than 70 years is rare.
Clinical
History:
The clinical features of HD include a move-ment disorder, a cognitive disorder,
and a behavioral disorder. Patients may present with one or all disorders in varying degrees.
Chorea (derived from the Greek word, which
means to dance) is the most common movement disorder seen in HD.Initially, mild chorea may pass for fidgetiness. Severe chorea
may appear as uncontrollable flailing of the extremities (ie, ballism), which interferes with function.
As the
disease progresses, chorea coexists with and is gradually replaced by dystonia and parkinsonian
features, such as bradykinesia, rigidity, and postural instability, which are usually
more disabling than the choreic syndrome per se.
In advanced disease, patients develop an akinetic-rigid
syndrome, with minimal or no chorea. Other late features are spasticity, clonus,
and extensor plantar responses.
Dysarthria and dysphagia are common. Abnormal eye movements may be seen early in the disease. Other movement disorders,
such as tics and myoclonus, may be seen in patients with HD.
Juvenile HD (Westphal
variant), defined as having an age of onset of younger than 20 years, is characterized by parkinsonian
features, dystonia, long-tract signs, dementia, epilepsy, and mild or even absent
chorea.
Cognitive decline is characteristic of HD, but the rate of progression
among individual patients can vary considerably. Dementia and the psychiatric features of HD are perhaps the earliest and
most important indicators of functional impairment.
The dementia syndrome associated with HD includes early-onset behavioral changes, such as irritability, untidiness, and loss of
interest.
Slowing of cognition, impairment of intellectual function, and memory disturbances are seen later. This pattern corresponds
well to the syndrome of subcortical dementia, and it has been suggested to reflect dysfunction of frontal-subcortical
neuronal
circuitry. (The so-called cortical dementias primarily involve the cerebral cortex and are associated with aphasia,
agnosia, apraxia, and severe amnesia.)
Early stages of HD are characterized by deficits in short-term memory, followed by motor dysfunction
and a variety of cognitive changes in the intermediate stages of dementia. These deficits include diminished verbal
fluency, problems with attention, executive function, visuospatial processing, and abstract reasoning.
Language skills become affected in the
final stages of the illness, resulting in a marked word-retrieval deficit.
The behavioral disorder
of HD is most commonly represented by affective illness.
Depression is more prevalent, with a
small percentage of patients experiencing episodic bouts of mania characteristic of bipolar disorder.
Patients with HD and persons at risk for HD may have an increased rate of suicide.
Patients with HD also can develop psychosis, obsessive-compulsive symptoms, sexual and sleep disorders, and changes in personality.
Physical
Most
patients with HD have a mixed pattern of neurological and psychiatric
abnormalities. Understanding of the clinical signs must
take into account the fact that signs change during the course of the illness and that different patterns may be observed, depend-ing
on the age of onset.
Chorea is a characteristic feature of HD and, until recently,
the disorder was commonly called Huntington chorea. Chorea, as defined by the
World Federation of Neurology, is a state of excessive, spontaneous movements, irregularly timed, randomly distributed, and abrupt.
Severity of chorea may vary from restlessness with mild intermittent exaggeration
of gesture and expression, fidgeting movements of the hands, and unstable dancelike gait to a continuous flow of disabling
violent move-ments.
Chorea in cases of HD usually is generalized.
-
Patients may incorporate involuntary choreiform movements into apparently
purposeful gestures, a phenomenon referred to as parakinesia.
-
Ballism is characterized by large amplitude, usually proximal, flinging
movements of a limb or body part. Ballism is considered to be a severe
form of chorea by most authors.
-
Chorea may coexist with slower, distal, writhing, sinuous movements called
athetosis; it is then described as choreoathetosis.
-
Chorea is less prominent in juvenile HD and in advanced stages of the illness.
Bradykinesia and akinesia are frequent features
of HD and may explain some of the abnormalities of voluntary movement observed
clinically.
- Bradykinesia may be a major source of disability of voluntary movement, though it commonly is overshadowed by the hyper-kinetic movement disorder.
- Other parkinsonian signs, such as rigidity and postural instability, may be seen. Patients may become akinetic and rigid in the terminal stages of the illness.
Dystonia is defined as a syndrome of sustained
muscle contractions, frequently causing twisting and repetitive movements or abnormal postures.
- Mild dystonia, in combination with chorea, may give the writhing appearance of choreoathetosis.
- Sustained dystonic posturing may result in contractures, immobility, and breakdown of skin
- Dystonia may be prominent in juvenile HD.
- Eye movement abnormalities can be seen early in the disease.
- Initiation of saccadic movements is slow and uncoordinated. Patients have difficulty
suppressing head movements or blinking in order to break fixation and generate
saccadic movements.
- Smooth pursuit is interrupted by saccadic intrusions.
- Patients with HD are unable to inhibit saccades toward a peripheral stimulus when instructed to look in the opposite direction.
- Tendon reflexes are variable in HD, ranging from reduced in some patients to pathologically brisk with clonus in other patients. The plantar response usually is flexor, but it may be extensor
in advanced stages of the illness.
- Other hyperkinesias, such as tics and myoclonus, may be seen in HD.
- Dementia, depression, and other psychiatric manifestations may be seen at the time of examination as well.
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Causes
The selective neuronal dysfunction and subsequent loss of neurons in the striatum,
the cerebral cortex, and other parts of the brain can explain the clinical picture seen in cases of HD. Several mechanisms
of neuronal cell death have been proposed for HD, mainly including excitotoxicity, oxidative stress, impaired energy metabolism,
and apoptosis.
Excitotoxicity refers to the neurotoxic effect of excitatory amino acids
in the presence of excessive activation of postsynaptic receptors.
Intrastriatal injections of kainic acid, an
agonist of a subtype of glutamate receptor, produce lesions similar to those seen in HD.
Intrastriatal
injections of quinolinic acid, an N-methyl-D- aspartate (NMDA) receptor agonist, selectively affects medium-sized
GABA-ergic spiny projection neurons, sparing the striatal interneurons and closely mimicking the neuropathology
seen in HD.
NMDA receptors are depleted in the striatum of patients with HD, suggesting a role of NMDA receptor-mediated
excitotoxicity, but no correlation exists between the distribution of neuronal loss and the density of such receptors.
The theory that reduced uptake of glutamate by glial cells may play a role in the
pathogenesis of HD also has been proposed.
Oxidative stress
Oxidative
stress is caused by the presence of free radicals (ie, highly reactive oxygen derivatives) in large amounts. This
may occur as a consequence of mitochondrial or excitotoxicity and can trigger apoptosis.
Striatal damage induced by
quinolinic acid can be ameliorated by the administration of spin-trap
agents, which reduce oxidative stress, providing indirect evidence for the of free radicals in excitotoxic cell death.
Impaired energy metabolism
Impaired energy metabolism reduces the threshold for glutamate toxicity
and can lead to activation of excitotoxic mechanisms as well as an increased production of reactive oxygen species.
Nuclear
magnetic resonance spectroscopy studies have shown elevated lactate levels in the basal ganglia and occipital
cortex of patients with HD.
Patients with HD have an elevated lactate-pyruvate ratio in the cerebrospinal
fluid.
A reduction in the activity of the respiratory chain complex II and III (and less in complex IV)
of mitochondria of caudate neurons in patients with HD has been reported.
In rats, intrastriatal injections of
3-nitroproprionic acid (3-NP), an inhibitor of succinate dehydrogenase or complex II of the respiratory chain, cause a dose-dependent
ATP depletion, increased lactate concentration, and neuronal loss in the striatum. Systemic injections of 3-NP into rats produce
a selective
loss of medium spiny neurons in the striatum.
Apoptosis
Apoptosis is the programmed cell death that is normally activated in the nervous
system during embryogenesis to remove supernumerary neurons as part of the natural
development.
Morphological features
of apoptosis have been well characterized. Oxidative stress, excitotoxicity, and partial energy failure can lead to
apoptosis.
A subset of neurons and glia in the neo-striatum of patients with HD appears to undergo apoptosis, as shown
by in situ DNA nick end labeling (TUNEL) staining, but clear
morphological evidence for an apoptotic process in HD
is still missing
It has been hypothesized that expanded polyglutamine repeats
cause neuronal degeneration through abnormal interactions with other proteins
containing short
polyglutamine tracts. Recent work suggests that polyglutamine interference with transcription of CREB binding protein
(CBP), a major mediator of survival signals in mature neurons, may constitute a genetic gain of
function underlying polyglutamine disorders including HD.
Other Problems to be Considered
- Sydenham chorea
- Antiphospholipid antibody syndrome
- Benign hereditary chorea
- Dentatorubropallidoluysian atrophy (DRPLA)
- Senile chorea
- Vascular chorea, hemichorea, and hemiballismus
- Hyperthyroidism
- Polycythemia vera
- Paroxysmal dyskinesias
- Drugs
Presymptomatic genetic testing for HD is now available. It should only be performed
in specialized centers following strict protocols because of the ethical and legal implications of a positive (or negative)
result.
Workup
Imaging Studies:
No single
imaging technique is necessary or sufficient for diagnosis. Measurement of the bicaudate diameter (ie, the distance between
the heads of the 2 caudate nuclei) by CT scan or MRI is a reliable marker of HD.
Abnormalities in positron emission
tomography (PET) scanning and proton MR spectroscopy have been reported; however, their use in clinical practice
is limited.
Other Tests:
Genetic testing
(reported as the CAG repeat number for each allele) is now commercially available.
Genetic testing may not be necessary
in a patient with a typical clinical picture and a genetically proven family history of HD.
In the absence
of a family history of HD, patients with a suggestive clinical presentation should undergo genetic testing to exclude
or confirm HD.
Persons at risk for HD who request presymptomatic testing should undergo extensive genetic counseling
and neurological and psychiatric evaluation, given the
implications of receiving a positive (or negative) result
for an untreatable, familial, progressive, neurodegenerative disease. Most testing centers follow strict protocols, such as
the one put forth by the Huntington's Disease Society of America (HDSA).
If
the genetic test is negative for HD, then depending on each individual case, it may be reasonable to test for systemic lupus
erythematosus (SLE), antiphospholipid antibody syndrome, thyroid disease, neuroacanthocytosis, DRPLA, Wilson disease,
and other less common causes of chorea.
Staging:
The extent of gross striatal pathology, neuronal loss, and gliosis provides a basis
for grading the severity of HD pathology (grades 0-4). See Pathophysiology.
Treatment
Medical Care:
Consider general safety
measures and nonpharmacologic interventions first.
If chorea is severe
enough to interfere with function, consider treatment with benzo-diazepines, such as clonazepam or diazepam; valproic acid;
dopamine-depleting agents, such as reserpine or tetrabenazine (not available in the US but can be obtained from Canada);
and finally, neuroleptics. Carefully weigh potential adverse effects against the benefits from each drug.
Patients
who have HD and predominant features of bradykinesia and rigidity may benefit from
treatment with L-dopa or dopamine agonists.
Depression in patients with HD is
treatable and should be recognized promptly. Selective serotonin reuptake inhibitors (SSRIs) should be considered as
first-line therapy. Other antidepressants, including bupropion, venlafaxine, nefazodone, and tricyclic anti-depressants,
also can be used.
Electroconvulsive therapy (ECT) can be used in patients with refractory depression.
Antipsychotic
medications may be necessary in patients with hallucinations, delusions, or schizophrenialike
syndromes. As compared to the older agents, the newer agents, such as quetiapine, clozapine, olanzapine, and
risperidone,
are preferred because of the lower incidence of extrapyramidal side effects and the decreased risk for tardive syndromes.
Irritability may be treated with anti-depressants, particularly
the SSRIs; mood stabilizers, such as valproic acid or carbamazepine; and, if
needed, atypical
neuroleptics.
Other less frequent aspects
of HD that may require pharmacologic treatment are mania, obsessive-compulsive disorder, anxiety, sexual disorders,
myoclonus, tics, dystonia, and epilepsy.
Surgical
Care
Ablative surgical procedures and fetal cell transplantation have been attempted in patients with HD. Currently, enough data to
support this type of treatment is not available. It is still experimental.
Consultations
Physical therapist
Occupational therapist
Speech therapist
Psychiatrist
Genetic counselor
Medication
Although no therapy to delay the onset of symptoms or prevent the progression of the disease is currently available, symptomatic
treatment of patients with HD may improve the quality of life and prevent complications.
As is the case with other neurological diseases, HD makes
individuals more vulnerable to side effects from medications, particularly cognitive adverse effects. Avoid
polypharmacy if possible.
Symptomatic treatment for HD can be divided into drugs to treat the movement disorder and drugs to treat psychiatric or behavioral problems.
Experimental therapies
for HD are currently being tested in animal models and human trials. Awareness
of ongoing research to find an effective cure for HD must be a part of the care
plan of an individual patient and the patients family. Therapeutic options include dopamine-depleting agents (eg, reserpine,
tetrabenazine) and dopamine-receptor antagonists (eg, neuroleptics). Long-term use of these drugs may carry a high risk of side effects.
Pharmacologically treat choreic
movements in patients with HD only if they become disabling to the patient. Neuroleptics, may worsen other features
of the disease, such as bradykinesia and rigidity, leading to further functional decline.
Results of some studies
have suggested that valproic acid and clonazepam may be effective in the treatment of chorea, while results of other studies
have been less conclusive.
In the authors experience, it may be worth-while to use valproic acid and clonazepam first
because of their safer adverse-effect profile.
Tetrabenazine is a dopamine-depleting agent, not available in the US,
which can be obtained from the UK through special arrangements. May be more effective in the treatment of chorea and less
likely to cause hypotension than reserpine. Administer 12.5 mg bid or tid initially. May increase dose over several weeks
to maximum 75-100 mg/d in divided doses
Drug Treament Category: See Source Website (medicines) for the information on medicines that are discussed in this article. Scan down
to middle of article.
Micellaneous
Medical/Legal Pitfalls:
The
usual medicolegal pitfalls of missed diagnosis, delayed diagnosis, and compli-cations of medication therapy are pertinent
in those with Huntington disease.
With the increasing amount of genetic -hereditary information available in Huntington disease the question of whether patients and/or family members
should be made aware of the genetic risks is becoming an increasingly important issue
Source:
eMedicine
Journal, September 11 2001, Volume 2, Number 9
Very thorough workup on HD Authored by Fredy J Revilla, MD, Instructor,Department
of Neurology, Washington University in Saint Louis School of Medicine
This is an excellent, more current report on
HD. See website for the information on medicines that are discussed in this article
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