Dementia Due to Huntington’s Disease
Susan Folstein
Russell L. Margolis
Introduction
Huntington’s disease (HD) was first described in 1872 by an American physician living on Long Island, New York. His father and grandfather practised medicine in the same community, so he had access to case notes from several generations of families who lived there. This long period of record keeping allowed him to document a hereditary form of chorea, similar to ‘common (Sydenham’s) chorea’, but progressing over many years to death. Its sufferers had a tendency to insanity and suicide. Huntington’s brief essay, which also included a clear description of autosomal dominant inheritance, remains one of the classical descriptions of a medical disorder.(1)
Clinical features and course of illness
Huntington’s disease is an inherited neuropsychiatric disorder mainly affecting the striatum and its direct connections. It is characterized by a triad of clinical features that are common to diseases of this region: a non-aphasic dementia, depression and other disorders of mood, and a variety of dyskinesias, most typically chorea.(2,3) Chorea, from the Greek word for ‘dance’, describes involuntary non-stereotyped jerky movements. The illness, insidious in onset, may begin with all or any one of these three features. Patients who present initially to psychiatrists usually have dementia, loss of temper, or depression, often with suicidal thoughts or attempts. Symptoms may appear at any time from early childhood to old age, most frequently between 35 and 45 years of age. Once the illness begins, sufferers gradually deteriorate over many years in their cognitive and motor functioning and end in a persistent vegetative state with almost complete loss of voluntary motor
function. Death occurs after about 16 years and is usually caused by inanition or aspiration pneumonia. Some patients die earlier from suicide or subdural haematoma caused by a fall. Patients with early onset progress more rapidly than those whose symptoms begin later in life.
function. Death occurs after about 16 years and is usually caused by inanition or aspiration pneumonia. Some patients die earlier from suicide or subdural haematoma caused by a fall. Patients with early onset progress more rapidly than those whose symptoms begin later in life.
Pathology and genetics
The earliest visible neuropathology is in the striosomes of the caudate/putamen,(4) followed by a dorsal-to-ventral progressive loss of almost all striatal output neurones. The deep layers of multiple cortical regions are also prominently affected, and there can also be milder neuronal loss in some brainstem nuclei. Protein aggregates, most easily detectable in neuronal nuclei, are prominent. Neuroimaging studies have shown that neuropathological changes typically begin before the onset of clinically detectable disease. In particular, the extent of striatal loss in presymptomatic individuals, as measured by MRI, correlates with the predicted time until disease onset.(5) Cortical thinning(6) and white matter loss and disorganization(7,8) have also been detected in presymptomatic gene carriers. Subtle changes that may be related to abnormal brain development have also been reported.
The disorder, with a point prevalence of about 6/100 000,(9) is caused by the expansion of an unstable triplet repeat sequence (CAG) in the first exon of a gene near the telomere of chromosome 4p.(10) It is transmitted as an autosomal dominant trait; if one parent is affected, each offspring (regardless of sex) has an independent 50 per cent chance of inheriting the abnormal gene. Normal repeat lengths range from about 7 to 28 triplets. Individuals with 29-35 triplets will not develop HD but may pass an expanded allele to an offspring, while individuals with 40 or more triplets will develop HD. Repeat lengths of 36-39 triplets may or may not cause disease. The rate of mutation from a normal-length allele to an expanded one is low, so that most patients have an affected parent. Family history, however, can be obscured by multiple factors, including misdiagnosis of the parent, death of the parent before disease onset, adoption, and incorrect paternity. The repeat length does not remain stable at meiosis. In HD, the number of CAG triplets is more likely to increase when the gene is transmitted by fathers. As the number of repeats increases, the age at onset is earlier. Thus, paternal transmission is often associated with ‘anticipation’, earlier onset in the subsequent generation; most individuals with childhood onset have affected fathers.(11)
The pathogenesis of HD is not well understood but appears to be multifaceted. The gene, huntingtin, with the expanded repeat is expressed as a protein, huntingtin. The CAG repeat expansion is translated as an expanded polyglutamine tract, which appears to have neurotoxic properties. The region of the huntingtin protein with the polyglutamine tract may be cleaved from the rest of the protein and adopt an abnormal configuration. This in turn is thought to lead to disruption of cellular functions, including transcriptional machinery, protein degradation processes, and cellular transport. It is also possible that the expansion mutation results in a partial loss of the normal functions of huntingtin, one of which is the stimulation of the neurotrophic factor BDNF; decreased BDNF may contribute to neurotoxicity.(12)
Diagnosis
The most difficult aspect of diagnosis is to think of HD in the differential. Diagnosis remains dependent on a thorough psychiatric history, including a detailed family history and history of changes in social adjustment, mental state examination, including a cognitive examination, and neurological examination. The features vary, depending on how long the patient has been ill.(13) Once the disease is suspected, genetic testing, available through many commercial laboratories, provides the definitive diagnosis.
Diagnosis of patients with early symptoms
Patients with HD who initially consult psychiatrists present with a variety of psychiatric syndromes, including depression, bipolar disorder, obsessive-compulsive disorder, schizophrenia, or excessive anxiety. Irritability is common with any of these or may appear outside the context of another syndrome. These psychiatric syndromes are clinically indistinguishable from idiopathic disorders and may be the only manifestation of HD for several years. It is during this prodromal phase that patients often commit suicide; this may occur even if the patient is unaware of his risk for HD.(14) Presenting symptoms and problems with functioning at work or at home must often be elicited from an informant; the patient may minimize them, be embarrassed, or even unaware of them. These include declines in work speed or accuracy, which may have resulted in demotion or warnings from superiors; a tendency to become irritated or physically aggressive in response to annoying stimuli that would not have elicited such a response in the past; and a decreased interest in activities. Most of these symptoms and behaviours are common in psychiatric disorders, but the cognitive inefficiency and irritability may seem to be out of proportion, relative to the patient’s other symptoms. On cognitive examination, the patient may have difficulty recalling dates of important life events and more difficulty than expected with ‘serial sevens’. Usually, the cognitive changes are easier to notice after the psychiatric disorder is treated, which can usually be accomplished using standard medications. However, unlike idiopathic disorders, cognitive inefficiency and difficulties at work, apathy (if present), and sometimes irritability remain even after the patient’s mood, energy, and sleep patterns have improved. When this happens in the course of treatment of depression, a dementia work-up should be considered and the family history further scrutinized through hospital records and other family informants.
On neurological examination, motor restlessness is usually present but is easily misinterpreted as a manifestation of anxiety. Motor signs may be subtle: slightly slow saccadic eye movements,(15) writhing movements of the protruded tongue or of the fingertips when the arms are held at 90?, or mild disdiadochokinesis.
Diagnosis can be further complicated by the apparent lack of a family history of HD. The family may not have been informed about the affected parent’s diagnosis, or may know only that a parent died in a psychiatric institution or committed suicide. In other cases the paternity is uncertain. If the family history is actually negative (this is quite uncommon) or unobtainable (often the case for adopted individuals who frequently present in childhood), the diagnosis may be confirmed by testing for the HD gene expansion.
(a) Diagnosis in childhood and adolescence
When HD starts in childhood or early adolescence,(16) motor signs include parkinsonian-like motor slowness of voluntary movement, with lead pipe or cogwheel rigidity and very slow saccades. Occasional children have a coarse tremor; later myoclonus is seen. Cognitively, the rate of learning in school slows, handwriting
deteriorates, and interest in school and social activities declines.(17) Of the patients who present with a schizophrenic syndrome, most are adolescents. Psychosis and loss of cognitive capacity may be the only clinical features for several years before motor impairment begins. Children with HD often have seizures, which are usually grand mal. Sometimes myoclonus is mistaken for seizures.
deteriorates, and interest in school and social activities declines.(17) Of the patients who present with a schizophrenic syndrome, most are adolescents. Psychosis and loss of cognitive capacity may be the only clinical features for several years before motor impairment begins. Children with HD often have seizures, which are usually grand mal. Sometimes myoclonus is mistaken for seizures.
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