The tau A0 allele in Parkinson's disease.

Parkinson's disease (PD) is primarily an alpha-synucleinopathy, rather than a tauopathy, but there is evidence for an indirect association of tau with the pathogenetic process in PD. We therefore assessed the frequency in PD of the tau A0 allele, a dinucleotide repeat marker that has been associated with a sporadic tauopathy, progressive supranuclear palsy (PSP). We found the A0 allele to comprise 79.2% of 758 alleles from PD patients and 71.2% of 264 control alleles (P = 0.008). We also performed a meta-analysis of three previous reports, two of which failed to produce statistically significant results. Taken together, they also support a PD/A0 allelic association, even after correction for misdiagnosis of PSP as PD (P< 0.001). The A0/A0 genotype frequency in our patients (62.3%) did not differ significantly from that in controls (53.0%, P = 0.062), but the meta-analysis, even after correction for misdiagnosis, showed a significant result, with P = 0.002. The frequency of A0 allele and the A0/A0 genotype were compatible with Hardy-Weinberg equilibrium. The frequency of the A0 allele and the A0/A0 genotype in our patients with familial PD was not significantly greater than in those with sporadic PD. We conclude that the tau protein may play a small role in the pathogenesis of PD and that biochemical characterization of this role may suggest opportunities for PD prophylaxis.

Distribution of alleles of the methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism in familial spina bifida.

Spina bifida cystica (SB) is one of the most common and disabling of birth defects. Folic acid supplementation in mothers during the periconceptional period has been shown to prevent more than 70% of neural tube defects (NTD) including SB. However, the mechanism is unknown. We tested a series of multicase SB families in which 224 individuals were genotyped and a group of 215 unrelated unaffected (external) control individuals for association of SB with the T allele of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism that produces a heat-labile enzyme protein. The data were analyzed using first the transmission/disequilibrium test (TDT) and second a modified case-control study design with Monte Carlo sampling methods. No association of SB with the MTHFR T allele was found by either method. Presently, association between SB and the T allele has been found in four studies, a Dutch study, an Irish study, a North American study, and an Italian study. But no association was found in four other studies, a British study, a French study, a Turkish study, and a German study. A California population-based study found only modestly increased risk of SB with this allele that was not significant at the P < 0.05 level. The present study finds no evidence of the association. Only one other study, the German study, has used TDT analysis. The present study is the first to use a modified case-control study design with Monte Carlo sampling methods to test this association. Thus, it appears that the MTHFR T allele is a risk factor for SB in some populations but not others. Major genetic risk factors for folate-related SB remain to be found.

Studies of penetrance and anticipation in five autosomal-dominant restless legs syndrome pedigrees.

Restless legs syndrome (RLS) can occur with an autosomal-dominant mode of inheritance. To determine if there are distinguishing features of RLS pedigrees which might clarify molecular mechanisms of pathogenesis, five pedigrees with 81 affected members were analyzed for age of onset, sex ratio, and transmission pattern. One-factor analysis of variance of ages of onset between generations was carried out, and segregation ratios were calculated for each generation. These kindreds showed an autosomal-dominant mode of inheritance and a male:female ratio of 1:1.4 (p = 0.15). One of the five analyzed pedigrees shows some evidence of reduced penetrance. In two of the five analyzed pedigrees, there is statistical support for anticipation (p<0.05). These variations in penetrance and anticipation suggest possible genetic heterogeneity.

Hereditary febrile seizures: phenotype and evidence for a chromosome 19p locus.

The occurrence of febrile seizures (FSs) in large autosomal dominant FS kindreds makes possible accurate delineation of the pure clinical phenotype of hereditary FS among secondary FS cases, and the identification of gene loci causing susceptibility to FS. Recently FS gene loci on chromosomes 8 and 19 were identified. We studied the phenotype of FS in four large families in which FS is an autosomal dominant trait. Among 30 affected secondary FS cases, mean age of onset was 16.3 months (range 4 to 36 months), sex ratio was equal, and 43% were complex (13 of 30). Among these 30 secondary FS cases, the mean number of FSs was 2.1, half had only a single FS, and none had afebrile seizures. Penetrance was 0.67, approximately the same as in our previous larger group of 40 multicase FS families (0.64). The occurrence of DPT encephalopathy in a sib of a patient with FS raises the possibility that these two etiologies are related. Linkage studies showed that one of the four families (Family 1) was linked to chromosome 19p markers, none of the families was linked to chromosome 8q markers, and the largest FS family (Kindred 6) was unlinked to either 19p or 8q markers, supporting the hypothesis of genetic heterogeneity for FS.

Compound heterozygous genotype is associated with protracted juvenile neuronal ceroid lipofuscinosis.

We present a clinicopathological study and the first molecular genetic analysis of a family with 2 siblings affected by a rare, protracted form of juvenile neuronal ceroid lipofuscinosis (JNCL). Molecular genetic studies showed that both siblings, in addition to being heterozygous for the 1.02-kb CLN3 deletion, a common mutation in JNCL, also had a G-to-A missense mutation at nucleotide 1,020 of the CLN3 cDNA sequence on the non-1.02-kb deletion chromosomes. This point mutation resulted in a substitution of glutamic acid by lysine at position 295 of the CLN3 protein. Thus, a single point mutation at residue 295 of the CLN3 protein in protracted JNCL may underlie the phenotype in this form, which differs from that in classic JNCL.

Pelizaeus-Merzbacher-like disease: exclusion of the proteolipid protein locus and documentation of a new locus on Xq.

A large X-linked kindred with Pelizaeus-Merzbacher like disease (Pelizaeus-Merzbacher disease [PMD] lacking a proteolipid protein [PLP] mutation) was studied for linkage to 34 X-chromosome short tandem repeat polymorphism markers. Recombinational events excluded linkage to PLP and supported linkage to a 9.4-cM critical region more than 10 cM away from PLP on the X chromosome. A maximum 2-point lod score of 3.91 was observed for DXS441 at theta = 0.0. Neuropathologic study of one affected male showed intact myelin. The data thus support a different etiology for a disease that clinically resembles PMD, distinguishable phenotypically only by degree of myelin involvement. Other patients with the clinical diagnosis of PMD but without PLP mutations could have mutations at this new locus.

Mutation in the alpha-synuclein gene identified in families with Parkinson's disease.

Parkinson's disease (PD) is a common neurodegenerative disorder with a lifetime incidence of approximately 2 percent. A pattern of familial aggregation has been documented for the disorder, and it was recently reported that a PD susceptibility gene in a large Italian kindred is located on the long arm of human chromosome 4. A mutation was identified in the alpha-synuclein gene, which codes for a presynaptic protein thought to be involved in neuronal plasticity, in the Italian kindred and in three unrelated families of Greek origin with autosomal dominant inheritance for the PD phenotype. This finding of a specific molecular alteration associated with PD will facilitate the detailed understanding of the pathophysiology of the disorder.

Mapping of a gene for Parkinson's disease to chromosome 4q21-q23.

Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease, affecting approximately 1 percent of the population over age 50. Recent studies have confirmed significant familial aggregation of PD and a large number of large multicase families have been documented. Genetic markers on chromosome 4q21-q23 were found to be linked to the PD phenotype in a large kindred with autosomal dominant PD, with a Zmax = 6.00 for marker D4S2380. This finding will facilitate identification of the gene and research on the pathogenesis of PD.

Pedigree analysis in families with febrile seizures.

Febrile seizures are the most common form of seizures, occurring in an estimated 2-5% of North American children. We carried out a systematic pedigree study of febrile seizure probands. Forty of 52 probands (77%) in a referral population selected for increased severity had more than one case per family: one family had 10 cases, one family had 7, 3 families had 6, 2 had 5, 3 had 4, 13 had 3, and 17 had 2 cases. Mode of inheritance in the multicase families best fit the hypothesis of autosomal dominance with reduced penetrance. Polygenic inheritance could not be excluded for some of the smaller families. There was no support for X-linked or mitochondrial inheritance. Penetrance was calculated to be 0.64. Because the cases were selected for increased severity, this represents a useful estimate of the upper limit of penetrance and is in agreement with twin studies. Simulated lod scores showed adequate power for a linkage study in the absence of heterogeneity. Individual families had simulated average lod scores as high as 2.1. However, with potential heterogeneity, assuming only 70% of families share the same disease locus, average lod scores were marginal, and a high density map of marker loci and additional families would be required to document linkage.

No evidence for association of familial Parkinson's disease with CAG repeat expansion.

In some kindreds, familial Parkinson's disease (PD) exhibits genetic anticipation. Thus, we postulated that familial PD in certain kindreds may be associated with a CAG repeat expansion. However, using the repeat expansion detection method, we found no significant increase in the frequency of CAG repeat expansion among 46 unrelated PD probands compared with controls. Nor did we find evidence for CAG repeat expansion between generations in 11 different PD families that exhibit anticipation in age at onset.

Short tandem repeat polymorphism linkage studies in a new family with X-linked mental retardation (MRX20).

A family with X-linked recessive mental retardation (XLMR) without other obvious manifestations (MRX20) was studied with 14 short tandem repeat polymorphism (STRP) markers. Two-point lod scores above 3 were obtained with DXS1003, DXYS1, DXS3, and DXS458. A multipoint lod score of 4.25 was obtained with peak at DXS1003. Recombination events identify a 55.6 cM interval between DXS1068 and DXS454, while a one unit support interval identifies 40 cM between MAOA and DXS458.

Absence of linkage between familial neural tube defects and PAX3 gene.

Neural tube defects (NTD) are among the most common and disabling birth defects. The aetiology of NTD is unknown and their genetics are complex. The majority of NTD cases are sporadic, isolated, nonsyndromic, and generally considered to be multifactorial in origin. Recently, PAX3 (formerly HuP2, the human homologue of mouse Pax-3), on chromosome 2q35-37, was suggested as a candidate gene for NTD because mutations of Pax-3 cause the mouse mutant Splotch (Sp), an animal model for human NTD. Mutations in PAX3 were also identified in patients with Waardenburg syndrome type 1 (WS1). At least eight patients with both WS1 and NTD have been described suggesting pleiotropy or a contiguous gene syndrome. Seventeen US families and 14 Dutch families with more than one affected person with NTD were collected and 194 people (50 affected) from both data sets were genotyped using the PAX3 polymorphic marker. The data were analysed using affecteds only linkage analysis. The lod scores were -7.30 (US), -3.74 (Dutch), and -11.04 (combined) at theta = 0.0, under the assumption of the autosomal dominant model. For the recessive model, the lod scores were -3.30 (US), -1.46 (Dutch), and -4.76 (combined) at theta = 0.0. Linkage between PAX3 and familial NTD was excluded to 9.9 cM on either side of the gene for the dominant model and to 3.63 cM on either side of the gene for the recessive model in the families studied. No evidence of heterogeneity was detected using the HOMOG program. Our data indicate that PAX3 is not a major gene for NTD.

Linkage analysis of a candidate locus (HLA) in autosomal dominant sacral defect with anterior meningocele.

Sacral defect with anterior meningocele (SDAM) is a type of caudal dysgenesis. It is present at birth and becomes symptomatic later in life, usually because of obstructive labor in females, chronic constipation, rectal fistula and abscess, or meningitis. The inheritance is autosomal dominant. HLA has been implicated in caudal dysgenesis because of analogy with disorders of the T-locus complex, a tail length determining gene in mice which is linked to the major histocompatibility complex, H-2. Members of a 5-generation family with sacral defect and anterior meningocele (SDAM) were typed with polymorphic markers (dinucleotide repeats D6S89, D6S105, D6S109, and TCTE1) linked to HLA. Two-point and multipoint analysis exclude the HLA region as the location for the SDAM gene in this family.