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Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a triplet (CAG) expansion mutation. The length of the triplet repeat is the most important factor in determining age of onset of HD, although substantial variability remains after controlling for repeat length. The Venezuelan HD kindreds encompass 18,149 individuals spanning 10 generations, 15,409 of whom are living. Of the 4,384 immortalized lymphocyte lines collected, 3,989 DNAs were genotyped for their HD alleles, representing a subset of the population at greatest genetic risk. There are 938 heterozygotes, 80 people with variably penetrant alleles, and 18 homozygotes. Analysis of the 83 kindreds that comprise the Venezuelan HD kindreds demonstrates that residual variability in age of onset has both genetic and environmental components. We created a residual age of onset phenotype from a regression analysis of the log of age of onset on repeat length. Familial correlations (correlation +/- SE) were estimated for sibling (0.40 +/- 0.09), parent-offspring (0.10 +/- 0.11), avuncular (0.07 +/- 0.11), and cousin (0.15 +/- 0.10) pairs, suggesting a familial origin for the residual variance in onset. By using a variance-components approach with all available familial relationships, the additive genetic heritability of this residual age of onset trait is 38%. A model, including shared sibling environmental effects, estimated the components of additive genetic (0.37), shared environment (0.22), and nonshared environment (0.41) variances, confirming that approximately 40% of the variance remaining in onset age is attributable to genes other than the HD gene and 60% is environmental.

The epilepsies are a common, clinically heterogeneous group of disorders defined by recurrent unprovoked seizures. Here we describe identification of the causative gene in autosomal-dominant partial epilepsy with auditory features (ADPEAF, MIM 600512), a rare form of idiopathic lateral temporal lobe epilepsy characterized by partial seizures with auditory disturbances. We constructed a complete, 4.2-Mb physical map across the genetically implicated disease-gene region, identified 28 putative genes (Fig. 1) and resequenced all or part of 21 genes before identifying presumptive mutations in one copy of the leucine-rich, glioma-inactivated 1 gene (LGI1) in each of five families with ADPEAF. Previous studies have indicated that loss of both copies of LGI1 promotes glial tumor progression. We show that the expression pattern of mouse Lgi1 is predominantly neuronal and is consistent with the anatomic regions involved in temporal lobe epilepsy. Discovery of LGI1 as a cause of ADPEAF suggests new avenues for research on pathogenic mechanisms of idiopathic epilepsies.

Evidence for linkage between bipolar affective disorder (BP) and 21q22 was first reported by our group in a single large pedigree with a lod score of 3.41 with the PFKL locus. In a subsequent study, with denser marker coverage in 40 multiplex BP pedigrees, we reported supporting evidence with a two-point lod score of 2.76 at the D21S1260 locus, about 6 cM proximal to PFKL. For cost-efficiency, the individuals genotyped in that study comprised a subset of our large pedigree sample. To augment our previous analysis, we now report a follow-up study including a larger sample set with an additional 331 typed individuals from the original 40 families, improved marker coverage, and an additional 16 pedigrees. The analysis of all 56 pedigrees (a total of 862 genotyped individuals vs. the 372 genotyped previously), the largest multigenerational BP pedigree sample reportedly analyzed to date, supports our previous results, with a two-point lod score of 3.56 with D21S1260. The 16 new pedigrees analyzed separately gave a maximum two-point lod score of 1.89 at D21S266, less than 1 cM proximal to D21S1260. Our results are consistent with a putative BP locus on 21q22., (Copyright 2001 Wiley-Liss, Inc.)

Previously, we demonstrated evidence of linkage to bipolar affective disorder (BP) in a single large, multigenerational family with a LOD score of 3.41 at the PFKL locus on chromosome 21q22.3. Additional families showed little support for linkage to PFKL under homogeneity or heterogeneity, in that study. We have expanded on that analysis, with 31 microsatellite markers at an average marker spacing of

Bipolar affective disorder (BP) is a major neuropsychiatric disorder with high heritability and complex inheritance. Previously reported linkage between BP and DNA markers in the pericentromeric region of chromosome 18, with a parent-of-origin effect (linkage was present in pedigrees with paternal transmission and absent in pedigrees with exclusive maternal inheritance), has been a focus of interest in human genetics. We reexamined the evidence in one of the largest samples reported to date (1,013 genotyped individuals in 53 unilineal multiplex pedigrees), using 10 highly polymorphic markers and a range of parametric and nonparametric analyses. There was no evidence for significant linkage between BP and chromosome 18 pericentromeric markers in the sample as a whole, nor was there evidence for significant parent-of-origin effect (pedigrees with paternal transmission were not differentially linked to the implicated chromosomal region). Two-point LOD scores and single-locus sib-pair results gave some support for suggestive linkage, but this was not substantiated by multilocus analysis, and the results were further tempered by multiple test effects. We conclude that there is no compelling evidence for linkage between BP and chromosome 18 pericentromeric markers in this sample.

Retinitis pigmentosa (RP) is a heterogeneous genetic disorder with autosomal dominant, autosomal recessive, and X-linked forms. We previously mapped an additional arRP locus to chromosome 6p21 (RP14) in a single extended kinship from the Dominican Republic. Aided by a second linked RP pedigree from the same region of the Dominican Republic, we have refined the disease locus to a 2-cM region that is homozygous-by-descent in both pedigrees. A complete YAC, and a partial BAC, contig of the RP14 locus was constructed between the markers D6S1560 and D6S291, encompassing approximately 2.1 Mb. The contig contains 12 YACs and 31 BACs and is characterized by 45 markers including 8 microsatellite markers, 6 gene-derived sequences/ESTs obtained from the databases, and 28 new STSs and 4 new ESTs obtained by BLAST search using DNA sequence from the ends of the BAC and YAC inserts. With a STS density of approximately 1 every 20 kilobases, this contig significantly enhances available maps of the region.

The RP14 autosomal recessive Retinitis pigmentosa (arRP) locus has been mapped to a 2cM region of chromosome 6p21.3. TULP1 (the gene encoding tubby-like protein 1) is a candidate target for the disease mutation because it maps to the RP14 minimum genetic region and because a mutation in the highly homologous mouse tub gene leads to obesity, deafness and early progressive retinal degeneration. Here we report a splice-site mutation (IVS14+1, G-->A) that is homozygous in all affected individuals (N=33) and heterozygous in all obligate carriers (N=50) from two RP14-linked kindreds. The mutation was not observed in 210 unrelated controls. The data indicate that impairment of TULP1 protein function is a rare cause of arRP and that the normal protein plays an essential role in the physiology of the retina.

Wilson disease (WD) is an autosomal recessive disorder characterized by toxic accumulation of copper in the liver and subsequently in the brain and other organs. On the basis of sequence homology to known genes, the WD gene (ATP7B) appears to be a copper-transporting P-type ATPase. A search for ATP7B mutations in WD patients from five population samples, including 109 North American patients, revealed 27 distinct mutations, 18 of which are novel. A composite of published findings shows missense mutations in all exons-except in exons 1-5, which encode the six copper-binding motifs, and in exon 21, which spans the carboxy-terminus and the poly(A) tail. Over one-half of all WD mutations occur only rarely in any population sample. A splice-site mutation in exon 12 accounts for 3% of the WD mutations in our sample and produces an in-frame, 39-bp insertion in mRNA of patients homozygous, but not heterozygous, for the mutation. The most common WD mutation (His1069Glu) was represented in approximately 38% of all the WD chromosomes from the North American, Russian, and Swedish samples. In several population cohorts, this mutation deviated from Hardy-Weinberg equilibrium, with an overrepresentation of homozygotes. We did not find a significant correlation between His1069Glu homozygosity and several clinical indices, including age of onset, clinical manifestation, ceruloplasmin activity, hepatic copper levels, and the presence of Kayser-Fleischer rings. Finally, lymphoblast cell lines from individuals homozygous for His1069Glu and 4 other mutations all demonstrated significantly decreased copper-stimulated ATPase activity.

Spinal muscular atrophy (SMA) is a motor neuron disease presenting with a wide spectrum of phenotypic variations. The primary cause of most, if not all, forms of childhood-onset spinal muscular atrophy appears to be the homozygous loss of the telomeric copy of the survival motor neuron (SMNT) gene. It is interesting that approximately half of all affected patients are likewise homozygous nulls for the neuronal apoptosis inhibitory protein (NAIP) gene and a somewhat lesser fraction for the basal transcription factor, p44 subunit (BTF2p44) gene. It has been proposed that homozygous loss of SMNT is the primary cause of spinal muscular atrophy while the loss of NAIP and perhaps other genes primarily affects the severity of disease manifestation. We explored this hypothesis by evaluating the extent of gene deletions in three multigenerational families with spinal muscular atrophy exhibiting dramatic intrafamilial phenotypic variation. Using somatic cell hybrid lines to sequester individual spinal muscular atrophy homologues, we show that homologues missing several contiguous genes correlate with "severe" disease alleles and homologues missing only SMNT correlate with "mild" disease alleles. These observations support the hypothesis that phenotypic severity among the childhood-onset spinal muscular atrophies is directly correlated with the extent of disease-specific deletions.

Spinal Muscular Atrophy (SMA) is an inherited degenerative disorder of anterior horn cells that results in progressive muscle weakness and atrophy. The autosomal recessive forms of childhood-onset SMA have been mapped to chromosome 5q11.2-13.3, in a number of studies examining different populations. A total of 9 simple sequence repeat markers were genotyped against 32 Polish families with SMA. The markers span an approximately 0.7 cM region defined by the SMA flanking markers D5S435 and MAP1B. Significant linkage disequilibrium (corrected P < .05) was detected at four of these markers, with D/Dmax values of < or = .89. Extended haplotype analysis revealed a predominant haplotype associated with SMA. The apparently high mutation rate of some of the markers has resulted in a number of haplotypes that vary slightly from this predominant haplotype. The predominant haplotype and these closely related patterns represent 25% of the disease chromosomes and none of the nontransmitted parental chromosomes. This predominant haplotype is present both in patients with acute (type I) and in chronic (types II and III) forms of SMA and occurs twice in a homozygous state, both times in children with chronic SMA.

Paternal isodisomy for chromosome 5 was detected in a 2-year-old boy with type III spinal muscular atrophy (SMA), an autosomal recessive degenerative disorder of alpha motor neurons, known to map to 5q11.2-13.3. Examination of 17 short-sequence repeat polymorphisms spanning 5p15.1-15.3 to 5q33.3-qter produced no evidence of maternally inherited alleles. Cytogenetic analysis revealed a normal male karyotype, and FISH with probes closely flanking the SMA locus confirmed the presence of two copies of chromosome 5. No developmental abnormalities, other than those attributable to classical childhood-onset SMA, were present. While the absence of a maternally derived chromosome 5 could have produced the symptoms of SMA through the mechanisms of genomic imprinting, the lack of more global developmental abnormalities would be unusual. Paternal transmission of two copies of a defective gene at the SMA locus seems to be the most likely cause of disease, but proof of this will have to await the identification of the SMA gene. While uniparental isodisomy is a rare event, it must be considered as a possible mechanism involved in SMA when conducting prenatal testing and counseling for this disorder.

We have previously reported the mapping of the chronic (type II/intermediate and type III/mild/Kugelberg-Welander) form of the childhood-onset spinal muscular atrophies (SMA) to chromosome 5q11.2-13.3, with evidence for nonallelic genetic heterogeneity within a small sample of seven families [Brzustowicz et al., Nature 1990;344:540-541]. We now report the results of linkage analysis and heterogeneity testing on a set of 38 families with chronic SMA. Significant evidence for nonallelic heterogeneity was detected among these families, with the predominant locus for chronic SMA mapping to a 0.51-cM region on 5q, between the loci D5S6 and MAP1B. The estimated proportion of linked families, alpha, was 0.91, with a 2.3-unit support interval of 0.75 to 0.98. The indication that some families diagnosed with chronic SMA are not linked to chromosome 5q must be considered in strategies to map the SMA locus. The relevance of these findings to acute SMA (SMA type I, severe, Werdnig-Hoffmann disease) is still unknown.

The childhood-onset SMA locus has been mapped to chromosome 5q13, in a region bounded by the proximal locus, D5S6, and the closely linked distal loci, D5S112 and MAP1B. We now describe a highly polymorphic, tightly linked microsatellite marker (D5S435) that is very likely the closest proximal marker to the SMA locus. Multipoint linkage analysis firmly establishes the following order of markers at 5q13: centromere-D5S76-D5S6-D5S435-MAP1B/D5S112- D5S39-telomere. The data indicate that SMA resides in an approximately 0.7-cM (range 0.1-2.1) region between D5S435 and MAP1B. This finding reduces by approximately fourfold the genetic region that most likely harbors the SMA locus and will facilitate the physical mapping and cloning of the disease gene region.

The microtubule-associated protein 1B (MAP1B) locus has been mapped in close proximity to spinal muscular atrophy (SMA) on chromosome 5q13. We have identified a second microsatellite within a MAP1B intron, which increases the heterozygosity of this locus to 94%. Two unambiguous recombination events establish MAP1B as a closely linked, distal flanking marker for the disease locus, while a third recombinant establishes D5S6 as the proximal flanking marker. The combination of key recombinants and linkage analysis place the SMA gene in an approximately 2-cM interval between loci D5S6 and MAP1B. Physical mapping and cloning locate MAP1B within 250 kb of locus D5S112. The identification and characterization of a highly polymorphic gene locus tightly linked to SMA will facilitate isolation of the disease gene, evaluation of heterogeneity, and development of a prenatal test for SMA.

Persons symptomatic and at risk for Huntington's disease (HD) from a large extended family in the state of Zulia, Venezuela, have been followed prospectively for 7 years. Between 1981 and 1988, 593 people were examined, of whom 128 had symptomatic HD and 171 persons at risk had examination abnormalities that were insufficient to meet criteria for diagnosis. The remaining 294 had normal examinations. Abnormalities of saccadic eye movement and slowness of rapid alternating movements were the most common abnormalities found in at-risk individuals. Thirty persons who did not meet criteria for diagnosis at their first examination have subsequently been diagnosed with symptomatic HD. Their average age at diagnosis was 33.5 +/- 8.3 (SD) years. The likelihood of developing symptomatic HD within 3 years was 3% for those persons with normal first examinations, 23% for those with mildly abnormal first examinations, and 60% for those with highly abnormal first examinations. The rate of disease progression in early symptomatic cases were 1.4 +/- 0.1 (SEM) points per year on the Shoulson-Fahn functional capacity scale. Paternal or maternal inheritance did not appear to affect the rate of progression in this group of individuals. The data suggest that there is not a discrete age of onset but rather a prolonged period of time during which symptoms unfold.

A total of 63 families with Huntington disease (HD) were examined for linkage between HD and G8 (D4S10). The families included 57 Caucasian, four Black American, and two Japanese. The combined maximum lod score was 87.69 at theta = 0.04 (99% confidence interval 0.018-0.071). The maximum frequency of recombination was 0.03 in males and 0.05 in females. Fifty-seven families gave positive lod scores; five small families gave mildly negative lod scores. The maximum likelihood estimate of alpha, the proportion of linked loci, was 1.0 with a lower 99% confidence interval of 0.88. These data suggest that there is only one HD locus, although a second rare locus cannot be ruled out.

Specific and nonspecific cell-mediated effector mechanisms have been simultaneously assayed in 15 aged humans. 8 were female and 7 male, including a 114-year-old male in remarkably good health. Proliferative response to alloantigens, the generation of T killer cells and the ability to express cell-mediated lympholysis as well as the presence of natural cell-mediated cytotoxicity against K562 tumor cell line and the capacity to mount an ADCC response to RhD+ human red blood cell sensitized with anti-D antisera, revealed that in the human aged, while T function significantly declines, nonspecific cell-mediated effector mechanisms are operative.

Huntington's disease is generally considered to be a late-onset neurodegenerative disorder, which follows a protracted course of deteriorating motor control and cognitive impairment. However, in a minority of cases, the onset of symptoms occurs early in life. A preponderance of the juvenile-onset HD victims have inherited the genetic defect from their fathers. This variation in age of onset, based on the sex of the affected parent, has suggested that maternally inherited genes may influence expression of the disorder. We describe a portion of a large Venezuelan HD pedigree in which both the mother and father of three juvenile-onset HD patients share a common maternal lineage. Scanning of mtDNA from members of this family with 43 restriction endonucleases failed to reveal any differences in the mitochondrial genotype that could account for the difference in age of onset between the affected father and his progeny. Members of a related family with an affected father but no juvenile-onset progeny also appeared to share the same mitochondrial genotype. In addition, the mitochondrial gene products from lymphoblast cell lines of these family members were analyzed on polyacrylamide gels after incubation of cells with [35S]methionine, but no detectable alterations were seen. Taken together, these data suggest that the maternally inherited mitochondrial genome does not play a crucial role in determining in age of onset in HD.