Huntington disease (HD) is an incurable, adult-onset, autosomal dominant inherited disorder associated with cell loss within a specific subset. CASE REPORT. Sydenham’s chorea in a family with Huntington’s disease: case report and review of the literature. Coreia de Sydenham numa família com. Nós descrevemos sete pacientes com doença de Huntington, geneticamente confirmada, cuja apresentação motora inicial foi diferente de coréia. Pacientes.
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CC HPO: In normal individuals, the range of repeat numbers is 9 to In those with HD, the repeat number is above 37 Duyao et al. Huntington disease HD is an autosomal dominant progressive neurodegenerative disorder with a distinct phenotype characterized by chorea, dystonia, incoordination, cognitive decline, and behavioral difficulties. There is progressive, selective neural cell loss and atrophy in the caudate and huntingtom. Walker provided a detailed review of Huntington disease, including clinical features, population genetics, molecular biology, and animal models.
The classic signs of Huntington disease are progressive chorea, rigidity, and dementia.
Ckreia characteristic atrophy of the caudate nucleus is seen radiographically. Typically, there is a prodromal phase of mild psychotic and behavioral symptoms which precedes frank chorea by up to 10 years. In a study of kindreds, Reed and Neel found only 8 d which both parents of a single patient with Huntington chorea were 60 years of age or older and normal. Huntingtoon clinical features developed progressively with severe increase in choreic movements and dementia. The disease terminated in death on average 17 years after manifestation of the first symptoms.
In the African American family, the mean age at onset was 25 years when the father was affected and 41 years when the mother was affected; the corresponding figures in the white family were 49 and 52 years. Allelic mutations were postulated.
In another survey in Yuntington, Folstein et al. The bias of censoring refers to the variable intervals of observation and loss to observation at different ages.
For example, gene carriers lost to follow-up, those deceased before onset of disease, and those who had not yet manifested the disease at the time of data collection were excluded from huhtington observed distribution of age at onset.
Shiwach performed a retrospective study of patients with Huntington disease in 30 families. The age at onset was highly variable: The results of a study by Shiwach and Norbury clashed with the conventional wisdom that psychiatric symptoms are a frequent presentation of Huntington disease coreua the development of neurologic symptoms. They performed a control study of 93 neurologically healthy individuals at risk for Huntington disease.
The 20 asymptomatic heterozygotes showed no increased dde of psychiatric disease of any sort when compared to the 33 normal homozygotes in the same group. However, the whole hungington of heterozygous and homozygous normal at-risk individuals showed a significantly greater number of psychiatric episodes than did their 43 spouses, suggesting stress from the uncertainty associated with belonging to a family segregating this disorder.
Shiwach and Norbury concluded that neither depression nor psychiatric disorders are likely to be significant preneurologic indicators of heterozygous expression of the disease gene. They found no significant differences between these 2 groups, casting further doubt on earlier reports that suggested cognitive impairments are premonitory signs of the classical neurologic syndrome of Huntington disease.
Significantly inferior cognitive uuntington was disclosed in gene carriers by a battery of neuropsychologic tests covering attentional, visuospatial, learning, memory, and planning functions. Primarily, attentional, learning, se planning functions were affected. They found that psychomotor skills showed the most significant consistent decline among cognitive functions assessed. Two other living members with no apparent signs of motor disorder had received psychiatric treatment, 1 for schizophrenia.
The year-old man was admitted with dysphagia and dysarthria, which had developed gradually over 2 years. The patient had no psychologic signs, dementia, paresis, involuntary movements, ataxia, or sensory disturbance in the limbs. Dysphagia and dysarthria appeared to be caused by a ‘cough-like movement’ just before or during speaking or swallowing.
Because the ‘cough-like movement’ progressed for 3 years and was eventually suppressed with disappearance of dysphagia after administration of haloperidol, this symptom was thought to be due to HD. Preclinical HD individuals had substantial morphologic differences throughout the cerebrum compared to controls. The volume of cerebral cortex was significantly increased in preclinical HD, whereas basal ganglion and cerebral white matter volumes were substantially decreased.
Although decreased volumes of the striatum and cerebral white matter could represent early degenerative changes, the finding of an enlarged cortex suggested that developmental pathology occurs in HD. The mild motor symptoms corria and the manifesting HD group showed significantly higher scores for obsessive-compulsive behavior, interpersonal sensitivity, anxiety, paranoia, and psychoticism compared to the nonmutation control group.
The mutation carriers without symptoms had higher scores for anxiety, paranoid ideation, and psychoticism compared to the nonmutation control group. The results indicated that individuals in the preclinical stage of HD exhibit specific psychiatric symptoms and that additional symptoms may manifest later in the disease course.
Walker noted that suicidal ideation hungington a frequent finding in Huntington disease and that physicians should be aware of increased suicide risk both in asymptomatic at-risk patients and symptomatic patients.
Behan and Bone reported hereditary chorea without dementia. The oldest affected person in their family was aged 61 years.
It is usually transmitted from an affected father, is associated with very large CAG repeat sizes 60 or more in the HTT gene, and typically shows rigidity and seizures Nance and Myers, ; Ribai et al. The juvenile form coreka Huntington disease coreiw first described by Hoffmann using data from a 3-generation family. He identified 2 daughters with onset at 4 and 10 years who showed rigidity, hypokinesia, and seizures. Barbeau pointed out that patients with the juvenile form of Huntington chorea seem more often to have inherited their disorder from the father than from the mother.
Clinical manifestations were apparent in both sibs at the age of 8 years; the brother died at codeia The father of these sibs was affected from the age of 29 years. The girl, coteia years old at the time of report, had been adopted because of the inability of her biologic parents to care for her. Her biologic father was subsequently found to have HD. The girl demonstrated near-normal development until coriea 18 months of age.
Brain MRI had been normal at 2 years of age; at 3. By age 3 juntington and 10 months, the patient required gastric tube feeding. Choreiform movements, predominantly on the right side, developed at approximately 4 years of age. The patient’s mother had symptoms of HD at age Molecular analysis revealed that huntungton mother had 70 CAG repeats whereas the daughter had approximately CAG repeats. All had speech delay in early childhood as the first symptom, which predated motor symptoms by at least 2 years.
All children later developed huntingtin dysarthria. Initial gross motor symptoms ee ataxic gait and falls; initial behavioral problems included aggression, irritability, and hyperactivity. CAG repeats were, and 93, respectively, and all children inherited the disorder from their fathers. The mean delay before diagnosis was 9 years. The most common signs at onset were severe cognitive and psychiatric disturbances In these patients, motor signs occurred a mean of 6 years after cognitive or psychiatric signs.
Sydenham’s chorea in a family with Huntington’s disease: case report and review of the literature
Three other patients presented with myoclonic head tremor, 3 with chorea, and 1 with progressive cerebellar signs. Six patients inherited the disease from their fathers, and 7 from their mothers, with similar anticipation. However, all cases with onset before age 10 years were paternally inherited. Onset of severe prolonged generalized seizures began at age 4 years. Brain MRI showed severe cerebellar atrophy in the vermis and cortex, in addition to atrophy in the caudate, putamen, and globus pallidus.
Her mother, grandparent, and great-grandparent were affected. Molecular analysis showed that the child had CAG repeats, whereas her mother had 60 repeats. A review of 7 reported patients with early-onset HD showed that 4 had inherited the expanded allele from the mother, and that the mothers were relatively young at the time of pregnancy, ranging from 20 to 27 years.
These findings suggested that the incidence of maternal transmission in early-onset HD may be higher than that in adult-onset HD. Three of the 7 previously reported patients with early-onset HD had cerebellar atrophy. Contrariwise, they found that Huntington disease cells grew to a higher maximal density than did control fibroblasts. The authors found that in the early and middle stages of HD, the enkephalin-producing neurons with projections to the external portion of the globus pallidus were more affected than substance P-containing neurons projecting to the internal pallidal segment.
This result was confirmed by Sapp et al. In the advanced stages of the disease, neurons projecting to all striatal areas were depleted. Richfield and Herkenham found greater loss of cannabinoid receptors on striatal nerve terminals in the lateral globus pallidus compared to the medial pallidum in Huntington disease of all neuropathologic grades, supporting the preferential loss of striatal neurons that project to the lateral globus pallidus.
In half of the juvenile cases, huntingtin resolved as a complex of bands after electrophoresis and immunostaining, which confirmed previous DNA evidence for somatic mosaicism.
Mutant huntingtin was present in both normal and affected regions. Using genetic and pharmacologic approaches in yeast, mammalian cells, and Drosophila, Mason et al.
Huntington disease is an autosomal dominant disorder. When the number of CAG repeats reaches 41 or more, the disease is fully penetrant. Incomplete penetrance can occur with 36 to 40 repeats. Intrafamilial variability of Huntington disease was illustrated by the report by Campbell et al. Brackenridge showed a relationship between age at onset of symptoms in parent and child.
Wallace and Hall suggested that in Queensland, Australia, 2 possibly allelic forms of HD may exist, one with early onset and the other with late onset. In patients, Myers et al. More than twice as many of the late-onset cases age 50 or later inherited the HD gene from an affected mother than from an affected father. Affected offspring of late-onset females also had late-onset disease while those of late-onset males had significantly earlier ages of onset.
The authors interpreted these findings as suggesting a heritable extrachromosomal factor, perhaps mitochondrial.
They cited Harding as suggesting that autosomal dominant late-onset spinocerebellar ataxia is marked by earlier age at onset and death in offspring of affected males. After it was found that both Huntington disease and some forms of spinocerebellar ataxia are caused by expanded repeats, the mechanism of anticipation in the paternal line was interpreted as an increase in the extent of the repeats during paternal codeia.
They proposed 2 models in which a maternal factor acts to delay onset: Farrer and Conneally postulated that age at onset is governed generally by a set of independently inherited aging genes, but expression of the HD genes may be significantly delayed in persons with a particular maternally transmitted factor. Pointing out that some repetitive elements in many chromosomes of the mouse are methylated differently in males and females, Erickson suggested differences such as chromosomal imprinting may be responsible for the greater severity and coeeia onset of Huntington disease in offspring of affected males and greater severity of myotonic dystrophy DM1; in offspring of ckreia females.
Among reported cases of juvenile Huntington disease, van Dijk et al. Huntingtton paternal cases have a significantly lower age at onset as well as a shorter duration of disease than choreic paternal cases.
Analysis of the hunyington origin of the Huntington allele suggested that while propensity to anticipation could be inherited for a number of generations through the male line, it originated at the time of differentiation of the germline of a male who acquired the Huntington allele from his mother.