Huntington's disease: two families with differing clinical features show linkage to the G8 probe.

To test the hypothesis that interfamily variability in Huntington's Disease (HD) is due to mutation at different loci, linkage analysis was undertaken in two large HD kindreds that differed in ethnicity, age-at-onset, and neurologic and psychiatric features. Both families showed linkage of the HD locus to the G8 probe. Several recombinants were documented in each family, and the best estimate of the recombination fraction for the two families was 6 percent with a 95 percent confidence interval of 0 to 12 percent. Although the data support the existence of a single HD locus, use of the G8 probe for presymptomatic testing in these kindreds would have resulted in a 12 percent error rate in genotype assignment at the HD locus.

Huntington's disease gene (IT15) is widely expressed in human and rat tissues.

Huntington's Disease (HD) is notable for selective neuronal vulnerability in the basal ganglia and cerebral cortex. We have investigated in human and rodent tissues the expression of the gene (IT15) whose mutation causes HD. IT15 is widely expressed, with highest levels of expression in brain, but also in lung, testis, ovary, and other tissues. Within the brain, expression is widespread with a neuronal pattern and is not enriched in the basal ganglia. Expression of IT15 is not reduced in the brain of HD patients when corrected for actin (though it is slightly decreased in the striatum when uncorrected, consistent with neuronal loss). Thus, the widespread distribution of IT15 expression does not correspond with the restricted distribution of neuropathologic changes in HD. We suggest that pathophysiology may relate to abnormal cell type-specific protein interactions of the HD protein.

A potential diagnostic method for food allergy: clinical application and immunogenicity evaluation of an elemental diet.

The use of a simple, hypoallergenic elemental diet would appear well suited for diagnosing food allergy. Vivonex was used in 21 patients (5 to 40 years old) suspected of food allergy or those who had failed to respond to the usual management of inhalant allergy. To study immunogenicity, five New Zealand rabbits were immunized with Vivonex, milk, and egg and were evaluated for the production of precipitin and passive cutaneous anaphylactic antibodies, the latter was evaluated in three Hartley guinea pigs. The clinical study was conducted over a 2- to 3-week period with evaluation of symptom and medication scores, physical examination, and hematological and biochemical measurements made before and after the Vivonex trial, which was a minimum of 1 week. No consistent, significant improvement of allergic manifestations were seen while patients received Vivonex. On the other hand, there were no serious side effects noted either clinically or by laboratory measurements, although four patients discontinued the study because of Vivonex palatibility. Vivonex was not immunogenic by either the precipitin reaction or passive cutaneous anaphylactic response. Although Vivonex did not prove helpful in these severe, refractory allergic individuals, we were encouraged by its safety and acceptance in the outpatient setting. Further studies in young allergic children who are more likely to have clear-cut food sensitivity are being planned.

Patients with features similar to Huntington's disease, without CAG expansion in huntingtin.

OBJECTIVE: To describe characteristics of gene-negative patients with clinical features of Huntington's disease (HD), exploring likely etiologies. BACKGROUND: When a direct gene test became definitive for diagnosis of HD, we discovered a number of patients in our clinics in Baltimore, MD, and Cambridge, UK, believed or suspected to have HD who did not have the triplet repeat expansion. METHODS: Patients were examined using standardized instruments, and given full neurologic and psychiatric evaluations. Those negative for HD were tested for dentatorubro-pallidoluysian atrophy, SCA-1, SCA-3, SCA-2, SCA-6, and other conditions as indicated. RESULTS: Of 15 patients, 7 received specific diagnoses or appear to be sporadic cases, 4 have a possible but uncertain relation to HD, and 4 have unknown familial progressive movement disorders. CONCLUSIONS: This last group of patients might be properly described as phenocopies of HD, some of which may be caused by unidentified triplet repeat expansions.

Familial influence on age of onset among siblings with Huntington disease.

In order to provide data relevant to a search for modifying genes for age of onset in Huntington disease, we examined the relationship between CAG number and age of onset in a total of 370 individuals from 165 siblingships, in two cohorts of siblings with Huntington disease: an American group of 144 individuals from 64 siblingships, and a Canadian population of 255 individuals from 113 siblingships. Using a logarithmic model to regress the age of onset on the number of CAG triplets, we found that CAG number alone accounted for 65%-71% of the variance in age of onset. The siblingship an individual belonged to accounted for 11%-19% of additional variance. This adds to the previous evidence that there are familial modifiers of the age of onset, independent of the CAG number. Such modifiers may consist of additional genes, which could be the target of a linkage study. A linkage study is feasible with the cooperation of a number of major centers and may be made more efficient by concentrating on sibling pairs that are highly discordant for age of onset.

Recent advances in bronchial asthma.

Bronchial asthma in childhood is a major pediatric problem for the physician, both as an acute emergency and as a chronic disease. To adequately manage asthma, one must have a firm understanding of its pathogenesis, and the clinical aspects of diagnosis and therapy. We review important developments in the area of the basic mechanisms causing bronchial obstruction, and methods of measuring the abnormalities present. This presentation includes the fields of neuropharmacology, biochemistry, immunology, and pulmonary physiology. With this background, the clinical aspects of diagnosis and therapy are explored. The role of the allergy history, skin testing, measurement of serum IgE antibodies, and target organ provocation testing are placed in perspective. Therapy involving avoidance measures, use of pharmacologic agents and injection therapy with inhalant allergens are discussed in detail.

Sexual disorders in Huntington's disease.

This study assessed the frequency and type of sexual disorders associated with Huntington's disease (HD) in an unbiased sample. Of 39 HD patients and 32 of their partners, 82% and 66%, respectively, had one or more sexual disorders by DSM-III-R criteria. The most frequent for both groups was hypoactive sexual disorder. Significantly more patients who had both inhibited orgasm and increased sexual interest also had paraphilic disorders. Findings support the hypotheses that sexual disorders are frequent among HD patients and their partners and that sexual disorders among HD patients may take the form of increased sexual interest or paraphilias. The association between inhibited orgasm, increased sexual interest, and paraphilic disorders will require further investigation but suggests a possible etiology for some paraphilias.

Correlation between the onset age of Huntington's disease and length of the trinucleotide repeat in IT-15.

Huntington's disease (HD) is an autosomal dominant disorder with a variable age of onset that is influenced by the sex of the affected parent. The recent recognition that HD is caused by an expanded triplet repeat suggests the possibility that the onset age may be predicted by the length of the repeat. This hypothesis was tested by assaying the length of the repeat in 114 individuals who were clinically diagnosed with HD and had a known onset age. Every individual had an expanded allele. The range was from 36 to 82 repeats (mean = 48.4 +/- 9.51) and larger than the normal range (6 to 31). The size of the expanded allele was correlated with the age of onset (r = -0.65 p < .0001). Despite the highly significant correlation, the repeat size explains less than half of the variance in onset age. Furthermore, the age of onset cannot be predicted from the size of the triplet repeat, particularly if the number of repeats is in the smaller end of the expanded range. If the repeat is < or = 50 triplets, the amount of variation in the age of onset explained by the length of the triplet repeat is less than 10%. As an illustration, the onset age of individuals with 39 repeats ranges from 30 to 65 years old. The sex of the affected parent had no effect in our sample beyond the effect of the length of the repeat. Affected offspring of affected fathers had longer repeats and a larger variance in allele size than offspring of affected mothers, perhaps reflecting greater instability in paternal transmission.

Conduct disorder and affective disorder among the offspring of patients with Huntington's disease.

The rate of occurrence of conduct disorder and affective illness was studied for a sample of 112 offspring of 34 Huntington's Disease (HD) patients. Psychiatric disorder in the offspring was assessed as a function of: (1) age of the parent at the onset of symptoms of HD; (2) family disorganization; and (3) psychiatric disorder in either parent. The findings indicated an increased frequency of conduct disorder in disrupted families, most especially in those where the HD parent had an early onset of symptoms and the non-HD parent showed psychiatric disorder. Affective disorder in the offspring was most strongly associated with the presence of similar symptoms in the HD parent. Affective disorder, but not conduct disorder, may be an early manifestation of the HD gene. The implication of these findings for genetic counselling is discussed.

Phenotypic heterogeneity in Huntington disease.

Two Huntington disease (HD) pedigrees are presented which differ according to mean and distribution of the age at onset, the effect of paternal transmission on the age at onset, presence of manic-depressive symptoms, and type of presenting symptoms. Together with previous reports, the data suggest clinical heterogeneity between HD kindreds which may imply some kind of genetic heterogeneity, most likely subsequent mutation at a single HD locus. The possibility of genetic heterogeneity has important consequences, both in research, and in the counseling and care of families and patients with differing manifestations of the disease.

Unstable expansion of the CAG trinucleotide repeat in MAB21L1: report of a second pedigree and effect on protein expression.

MAB21L1, originally termed CAGR1, is the human homologue of the C. elegans cell fate determining gene mab21. MAB21L1, mapped to 13q13, contains a highly polymorphic 5' untranslated CAG repeat that normally ranges from six to 31 triplets in length. A pedigree has been previously reported in which the repeat length is expanded to 45-50 triplets and is transmitted unstably between generations; the expansion did not correlate to a clinical phenotype but did exhibit somatic mosaicism. We now report a second pedigree with an expanded and unstably transmitted MAB21L1 CAG repeat of similar length. The expansion is not clearly associated with a clinical phenotype, though the complexity of the pedigree renders any conclusion concerning phenotype-genotype relationships speculative. The expansion did not result in decreased expression of MAB21L1 protein. The length, C-G rich composition, somatic mosaicism, and unstable transmission of the expanded CAG repeat in MAB21L1 resemble the premutations observed in other genes, such as FMR1 and MDPK, in which longer expanded repeats are associated with a clinical phenotype. This raises the possibility that longer expansions in the MAB21L1 repeat may also be associated with a clinical phenotype.

A disorder similar to Huntington's disease is associated with a novel CAG repeat expansion.

Huntington's disease (HD) is an autosomal dominant disorder characterized by abnormalities of movement, cognition, and emotion and selective atrophy of the striatum and cerebral cortex. While the etiology of HD is known to be a CAG trinucleotide repeat expansion, the pathways by which this mutation causes HD pathology remain unclear. We now report a large pedigree with an autosomal dominant disorder that is clinically similar to HD and that arises from a different CAG expansion mutation. The disorder is characterized by onset in the fourth decade, involuntary movements and abnormalities of voluntary movement, psychiatric symptoms, weight loss, dementia, and a relentless course with death about 20 years after disease onset. Brain magnetic resonance imaging scans and an autopsy revealed marked striatal atrophy and moderate cortical atrophy, with striatal neurodegeneration in a dorsal to ventral gradient and occasional intranuclear inclusions. All tested affected individuals, and no tested unaffecteds, have a CAG trinucleotide repeat expansion of 50 to 60 triplets, as determined by the repeat expansion detection assay. Tests for the HD expansion, for all other known CAG expansion mutations, and for linkage to chromosomes 20p and 4p were negative, indicating that this mutation is novel. Cloning the causative CAG expansion mutation for this new disease, which we have termed Huntington's disease-like 2, may yield valuable insight into the pathogenesis of HD and related disorders.

A disorder similar to Huntington's disease is associated with a novel CAG repeat expansion.

Huntington's disease (HD) is an autosomal dominant disorder characterized by abnormalities of movement, cognition, and emotion and selective atrophy of the striatum and cerebral cortex. While the etiology of HD is known to be a CAG trinucleotide repeat expansion, the pathways by which this mutation causes HD pathology remain unclear. We now report a large pedigree with an autosomal dominant disorder that is clinically similar to HD and that arises from a different CAG expansion mutation. The disorder is characterized by onset in the fourth decade, involuntary movements and abnormalities of voluntary movement, psychiatric symptoms, weight loss, dementia, and a relentless course with death about 20 years after disease onset. Brain magnetic resonance imaging scans and an autopsy revealed marked striatal atrophy and moderate cortical atrophy, with striatal neurodegeneration in a dorsal to ventral gradient and occasional intranuclear inclusions. All tested affected individuals, and no tested unaffecteds, have a CAG trinucleotide repeat expansion of 50 to 60 triplets, as determined by the repeat expansion detection assay. Tests for the HD expansion, for all other known CAG expansion mutations, and for linkage to chromosomes 20p and 4p were negative, indicating that this mutation is novel. Cloning the causative CAG expansion mutation for this new disease, which we have termed Huntington's disease-like 2, may yield valuable insight into the pathogenesis of HD and related disorders.

Presymptomatic diagnosis of delayed-onset disease with linked DNA markers. The experience in Huntington's disease.

Clinical medicine in the 21st century is almost certain to include wide-scale use of molecular genetic diagnostic tests. In September 1986, The Johns Hopkins University School of Medicine initiated a voluntary program of presymptomatic genetic testing for Huntington's disease for persons at 50% risk. DNA analyses using the D4S10 (G8), D4S43, and D4S95 locus probes have been performed for 55 people. Twelve of the tests have yielded positive results, 30 were negative, and 13 were uninformative. Initial reactions ranged from joy and relief to disappointment, sadness, and demoralization. Thus far, there have been no severe depressive reactions. Although the sample size is small, our data suggest that people who receive genetic test results cope well, at least over the short term, when the testing is performed in a clinical context that includes education, pretest counseling, psychological support, and regular follow-up.

Anticipation and instability of IT-15 (CAG)n repeats in parent-offspring pairs with Huntington disease.

Huntington disease (HD) is an autosomal dominant degenerative disorder caused by an expanded and unstable trinucleotide repeat (CAG)n in a gene (IT-15) on chromosome 4. HD exhibits genetic anticipation--earlier onset in successive generations within a pedigree. From a population-based clinical sample, we ascertained parent-offspring pairs with expanded alleles, to examine the intergenerational behavior of the trinucleotide repeat and its relationship to anticipation. We find that the change in repeat length with paternal transmission is significantly correlated with the change in age at onset between the father and offspring. When expanded triplet repeats of affected parents are separated by median repeat length, we find that the longer paternal and maternal repeats are both more unstable on transmission. However, unlike in paternal transmission, in which longer expanded repeats display greater net expansion than do shorter expanded repeats, in maternal transmission there is no mean change in repeat length for either longer or shorter expanded repeats. We also confirmed the inverse relationship between repeat length and age at onset, the higher frequency of juvenile-onset cases arising from paternal transmission, anticipation as a phenomenon of paternal transmission, and greater expansion of the trinucleotide repeat with paternal transmission. Stepwise multiple regression indicates that, in addition to repeat length of offspring, age at onset of affected parent and sex of affected parent contribute significantly to the variance in age at onset of the offspring. Thus, in addition to triplet repeat length, other factors, which could act as environmental factors, genetic factors, or both, contribute to age at onset. Our data establish that further expansion of paternal repeats within the affected range provides a biological basis of anticipation in HD.

Dentatorubral and pallidoluysian atrophy (DRPLA). Clinical and neuropathological findings in genetically confirmed North American and European pedigrees.

Dentatorubral and pallidoluysian atrophy (DRPLA) is an autosomal dominant disorder that clinically overlaps with Huntington's disease (HD) and manifests combinations of chorea, myoclonus, seizures, ataxia, and dementia. DRPLA is caused by a CAG triplet repeat (CTG-B37) expansion coding for polyglutamine on chromosome 12 and exhibits the genetic phenomenon of anticipation. This neurodegenerative disease has only rarely been reported in non-Japanese pedigrees, and there are only a few neuropathological studies in genetically confirmed patients. We report 10 cases of DRPLA from two North American and two British pedigrees in which CTG-B37 expansions have been demonstrated within each kindred (54-83 repeats), individually in 8 of the 10 cases, and describe the neuropathological findings in 4 cases. Members of DRPLA kindreds have a wide range of clinical phenotypes and markedly variable ages at onset. The neuropathological spectrum is centered around the cerebellifugal and pallidofugal systems, but neurodegenerative changes can be found in many nuclei, tracts, and systems. Evidence of CTG-B37 triplet repeat expansion should be sought in HD-like cases that are negative for expanded triplet repeats within the HD IT15 gene or in autopsy cases with degeneration of the dentatorubral or pallidoluysian systems.

Phenotypic characterization of individuals with 30-40 CAG repeats in the Huntington disease (HD) gene reveals HD cases with 36 repeats and apparently normal elderly individuals with 36-39 repeats.

Abnormal CAG expansions in the IT-15 gene are associated with Huntington disease (HD). In the diagnostic setting it is necessary to define the limits of the CAG size ranges on normal and HD-associated chromosomes. Most large analyses that defined the limits of the normal and pathological size ranges employed PCR assays, which included the CAG repeats and a CCG repeat tract that was thought to be invariant. Many of these experiments found an overlap between the normal and disease size ranges. Subsequent findings that the CCG repeats vary by 8 trinucleotide lengths suggested that the limits of the normal and disease size ranges should be reevaluated with assays that exclude the CCG polymorphism. Since patients with between 30 and 40 repeats are rare, a consortium was assembled to collect such individuals. All 178 samples were reanalyzed in Cambridge by using assays specific for the CAG repeats. We have optimized methods for reliable sizing of CAG repeats and show cases that demonstrate the dangers of using PCR assays that include both the CAG and CCG polymorphisms. Seven HD patients had 36 repeats, which confirms that this allele is associated with disease. Individuals without apparent symptoms or signs of HD were found at 36 repeats (aged 74, 78, 79, and 87 years), 37 repeats (aged 69 years), 38 repeats (aged 69 and 90 years), and 39 repeats (aged 67, 90, and 95 years). The detailed case histories of an exceptional case from this series will be presented: a 95-year-old man with 39 repeats who did not have classical features of HD. The apparently healthy survival into old age of some individuals with 36-39 repeats suggests that the HD mutation may not always be fully penetrant.