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.

Pregnancy outcome after insemination of frozen-thawed bovine semen packaged in two straw sizes: a meta-analysis.

The 0.25-mL French straw has been thoroughly studied and compared with the 0.5-mL French straw for about 40 yr. The 0.25-mL straw has some distinct advantages over the 0.5-mL straw in terms of storage efficiency and extender usage. The 0.25-mL straw is more sensitive to temperature change, which may be an advantage in some freezing systems with a slow freezing rate, but provides no advantage when the freezing rate is accelerated to optimize freezing in 0.5-mL straws. Disadvantages of the 0.25-mL straw include increased sensitivity to post-thaw temperature change, slightly more difficult handling, and inferior readability. Fertility of cattle inseminated with extended semen packaged in 0.25-mL straws assessed in 13 studies (>770,000 inseminations) had a weighted advantage of 0.9% (0.7% unweighted advantage) compared with semen packaged in 0.5-mL straws. In 2 studies in which palpated conception rates were obtained, the weighted advantage of the 0.25-mL versus the 0.5-mL straw was 0.2% (0.4% unweighted advantage). Paired t-tests did not detect a significant difference in pregnancy outcome between straw sizes. Logistic regression of all 15 studies (>780,000 inseminations) detected large variation among studies and tended to detect a small advantage for the 0.25-mL straw. Meta-analyses applied to fixed- or random-effect models of all 15 studies indicated the average odds of having a greater pregnancy outcome with the 0.25-mL straw were either 3 or 4% greater. Based on these odds ratios, the expected proportion of difference in pregnancy outcome translated into a difference of 0.74%. These small differences in pregnancy outcomes do not provide compelling evidence that a transition from 0.50- to 0.25-mL straws in the United States is warranted, especially given the added negative aspects of semen handling and the greater potential for technician x straw type interactions among herdsman inseminators.

Effects of feeding L-carnitine to gilts through day 70 of gestation on litter traits and the expression of insulin-like growth factor system components and L-carnitine concentration in foetal tissues.

We investigated the influence of supplemental L-carnitine on foetal blood metabolites, litter characteristics, L-carnitine concentration in skeletal muscle and insulin-like growth factor (IGF) axis components in foetal hepatic and skeletal muscle tissues at day 40, 55 and 70 of gestating gilts. A total of 59 gilts (body weight = 137.7 kg) received a constant feed allowance of 1.75 kg/day and a top-dress containing either 0 or 50 ppm of L-carnitine starting on the first day of breeding through the allotted gestation length. Foetuses from the gilts fed diets with L-carnitine tended to be heavier (p = 0.06) and the circulating IGF-II tended to be lower (p = 0.09) at day 70, compared with the foetuses from the control gilts. Insulin-like growth factor-I messenger RNA (mRNA) was lower (p = 0.05) in hepatic tissue in the foetuses collected from gilts fed L-carnitine. Free and total carnitine concentration increased (p < 0.05) in the skeletal muscle from the foetuses collected from gilts fed supplemental L-carnitine. This study showed that L-carnitine had beneficial effects on the average foetal weight at day 70 of gestation, associated with changes in the foetal IGF system.

Effects of potassium lactate, sodium chloride, sodium tripolyphosphate, and sodium acetate on colour, colour stability, and oxidative properties of injection-enhanced beef rib steaks.

This study determined the effects of potassium lactate (KL), sodium chloride, sodium tripolyphosphate, and sodium acetate on colour, colour stability, and oxidative properties of injection-enhanced beef rib steaks. Enhancement solutions (8.5% pump) contained combinations of KL (0% or 1.5%), sodium chloride (0.3% or 0.6%), sodium tripolyphosphate (0% or 0.3%), and sodium acetate (0% or 0.1%). Steaks were packaged in a high-oxygen modified atmosphere (80% O(2)/20% CO(2)). Steaks with KL or KL and sodium acetate were darker but more colour stable (P<0.05) than control steaks. Steaks had less glossy surfaces when they contained acetate (P<0.05) and KL (P<0.11). Increasing sodium chloride content resulted in darker, less colour-stable steaks (P<0.05). Removing phosphate had little impact on colour (P>0.05). Both KL and sodium acetate improved visual appearance of injection-enhanced beef rib steaks, whereas the greater salt level were detrimental.

Effects of potassium lactate, sodium chloride, and sodium acetate on surface shininess/gloss and sensory properties of injection-enhanced beef strip-loin steaks.

The objective was to determine the effects of potassium lactate (0% or 1.5%; KL), sodium chloride (0.3% or 0.6%), and sodium acetate (0% or 0.1%) on injection-enhanced (8.5% pump), beef strip-loin steaks. All treatments contained 0.3% phosphate and 0.058% rosemary. Steaks were packaged in a high-oxygen modified atmosphere (80% O(2)/20% CO(2)) and were evaluated on d 2, 9, and 14 for surface shininess/gloss, shear force, and descriptive sensory attributes. As time in MAP progressed, oxidized, stale, and rancid flavours increased (P<0.05) and surface shininess/gloss decreased (P<0.05). Brown-roasted and beef flavours were most intense (P<0.05) on d 9. Using KL increased (P<0.05) brown-roasted and beef flavours and limited rancid flavour. Sodium acetate decreased (P<0.05) shear force. Adding more salt increased salty and rancid flavours (P<0.05). Sodium acetate and KL both improve sensory attributes of injection-enhanced beef.

Effects of crystalline menthol on blood metabolites in Holstein steers and in vitro volatile fatty acid and gas production.

Fifty-two Holstein steers (573 ± 9.92 kg BW) were used to determine if oral administration of crystalline menthol would induce changes in endogenous secretions of IGF-1 and circulating concentrations of glucose, lactate, and plasma urea nitrogen (PUN). Steers were blocked by BW and assigned within block to treatment. Treatments consisted of 0, 0.003, 0.03, or 0.3% crystalline menthol (DM basis) added to the diet. Animals were housed in individual, partially covered pens equipped with feed bunks and automatic water fountains. On d 1 of the experiment, blood samples were obtained via jugular venipuncture at 0, 6, 12, 18, and 24 h after feeding. Treatment administration commenced on d 2, and blood samples were again drawn at 0, 6, 12, 18, and 24 h after feeding. This blood-sampling schedule was repeated on d 9, 16, 23, and 30. Plasma was analyzed for PUN, glucose, and lactate concentrations. Serum was used to analyze IGF-1 concentration. Body weights were measured on d 1, 9, 16, 23, and 30. To accompany the live animal phase, in vitro fermentations were performed using ruminal fluid cultures. Measurements included VFA concentrations and fermentative gas production for cultures containing crystalline menthol at 0, 0.003, 0.03, or 0.3% of substrate DM. Addition of menthol to the diet of steers resulted in a treatment × day interaction ( < 0.01) for concentrations of IGF-1, PUN, and plasma glucose. Cattle fed 0 and 0.003% menthol had greater serum IGF-1 concentrations on d 2 compared with steers fed 0.03% menthol. Steers fed 0% menthol had greater serum IGF-1 concentrations on d 9 compared with steers fed 0.03 and 0.3% menthol, whereas no differences were observed on d 23 or 30. Plasma glucose was similar among treatments until d 23, when steers supplemented with 0.03% menthol had lower glucose concentrations. Plasma urea nitrogen concentrations were not different among treatments; however, PUN concentrations varied by day. A linear response was detected for BW ( = 0.03), with steers consuming 0% menthol having the greatest BW and steers that consumed 0.3% menthol having the lightest BW until d 30. A menthol × day interaction was observed for daily feed deliveries ( < 0.01): cattle fed 0.3% menthol consumed less feed from d 5 through 12. Furthermore, in vitro gas production and VFA concentrations were unaffected by addition of menthol ( > 0.21). In conclusion, menthol supplementation minimally affected blood parameters associated with growth or ruminal fermentative activity.

An autosomal recessive disorder with posterior column ataxia and retinitis pigmentosa.

We report an autosomal recessive form of ataxia that is not allelic to Friedreich's disease in six individuals from a large kindred with family origins traced to a common founder of German-Swiss descent. The disorder begins during early childhood with a concentric contraction of the visual fields and proprioceptive loss. Eventually blindness, a severe sensory ataxia, achalasia, scoliosis, and inanition develop by third decade. Inversion recovery MRIs of the spinal cord in affected individuals demonstrate a hyperintense signal in the posterior columns. Finding the gene responsible for this disorder may aid in our understanding of the mechanisms that cause sensory neuronal degeneration.

Posterior column ataxia with retinitis pigmentosa (AXPC1) maps to chromosome 1q31-q32.

OBJECTIVE: To establish a genetic linkage between highly polymorphic microsatellite loci and the disease locus responsible for an autosomal recessive neurodegenerative syndrome that causes posterior column ataxia and retinitis pigmentosa. BACKGROUND: The authors reported previously a genetic syndrome that causes visual impairment, proprioceptive loss, sensory ataxia, and areflexia in affected individuals from a large, inbred family belonging to a sectarian population that has been genetically semi-isolated from mainstream society for several centuries. METHODS: To find the disease locus responsible for this condition, the authors performed a genome-wide search using genetic loci spaced at 10 to 20-cM intervals spanning human chromosomes (chr) 1-22. Pairwise linkage analysis, multipoint linkage analysis, and haplotype reconstruction were used to delineate the candidate region containing the disease gene. RESULTS: After testing 226 loci that covered the entire genome, the authors identified a maximum lod score of 8.94 at a recombination fraction of 0.00 for locus D1S2692. Additional analyses placed the disease gene, AXPC1, in an 8.3-cM interval flanked by markers D1S2692 and D1S414 on chr 1q31-q32. CONCLUSIONS: This study suggests that a single genetic mutation can cause selective degeneration of the posterior columns of the spinal cord and retina. Finding the gene responsible for this syndrome may increase our understanding of the molecular basis of diseases that affect sensory neurons.

A lack of the R406W tau mutation in progressive supranuclear palsy and corticobasal degeneration.

Linkage disequilibrium studies suggest that progressive supranuclear palsy (PSP) is an autosomal recessive condition that maps to a polymorphism in the tau gene. These results provide evidence that homozygous mutations in the tau gene may cause PSP. Recently, a missense mutation in exon 13 of one tau allele (R406W) was found in a single family with an atypical clinicopathologic form of dominantly inherited PSP. The authors report that the R406W mutation is lacking in 25 unrelated individuals with PSP and in six unrelated individuals with another tauopathy-corticobasal degeneration.

Mutational analysis of the tau gene in progressive supranuclear palsy.

OBJECTIVE: To identify genetic mutations in the coding regions and the splice-donor sites of the tau gene on chromosome 17q in individuals with progressive supranuclear palsy (PSP). BACKGROUND: Several studies provide evidence for linkage disequilibrium between a PSP disease gene and allelic variants of the tau gene. However, a causative mutation has not been identified. METHODS: We designed a study to search for genetic mutations in 15 coding regions of the tau gene including the splice-donor sites in 22 patients with PSP by comparing the mobility shifts on single-strand conformation analysis with those of age-matched controls. Fragments with altered migration were sequenced directly and compared for differences in nucleotide composition. Restriction enzyme digests were used to confirm single base-pair substitutions. RESULTS: Significant differences in mobility shifts were found in exons 1, 4A, and 8 between affected individuals and age-matched controls. All individuals with PSP had a common extended haplotype characterized by a homozygous polymorphism in the 5' splice site untranslated region of exon 1, two missense mutations in exon 4A (Asp285Asn, Ala289Val), and a nonsense mutation in the 5' splice site of exon 8. CONCLUSIONS: This study demonstrates that 22 unrelated progressive supranuclear palsy (PSP) patients have four identical sequence variants within the tau gene that are not present in 24 age-matched controls. Although the functional significance of these results on tau protein expression is unknown, the presence of this "susceptibility" haplotype in individuals may place them at risk for developing PSP.

Pyridoxine-responsive hyper-beta-alaninemia associated with Cohen's syndrome.

We report intermittent seizures, lethargy, and Cohen's syndrome in a 4-year-old girl with hyper-beta-alaninemia and a partial deficiency of beta-alanyl-alpha-ketoglutarate transaminase (AKT). To examine the role of beta-alanine (beta ALA) in cellular metabolism, we cultured her skin fibroblasts in medium containing increasing amounts of beta ALA. At concentrations of 10 to 25 mM, beta ALA caused more than a 50% reduction in the growth of her cells compared with normal control skin fibroblasts. The addition of 0.1 mM of pyridoxine to the culture medium abolished these toxic effects and increased her skin fibroblast AKT enzyme activity more than twofold. During a 2-year period of clinical observation, there were no further episodes of seizures or somnolence in our patient while she received oral pyridoxine therapy.

A gene for nonsyndromic mental retardation maps to chromosome 3p25-pter.

OBJECTIVE: To establish genetic linkage between polymorphic microsatellite loci and a disease locus responsible for an autosomal recessive type of nonsyndromic mental retardation (MR). BACKGROUND: Although MR is the most common developmental disability in the United States, the etiologies of most nonsyndromic cases are not known. METHODS: A genealogic database provided information to reconstruct the relationships between 32 individuals from five nuclear families in a single pedigree with 10 affected individuals with nonsyndromic MR. To find a MR disease locus in this population, we performed a genome-wide search using genetic loci spaced at 10- to 20-cM intervals. Pairwise linkage analysis, multipoint linkage analysis, and haplotype reconstruction were used to localize the disease gene. RESULTS: Genetic linkage between a MR disease locus and locus D3S3050 on chromosome 3p25-pter was established with a Zmax = 9.18 at theta = 0.00. Fine mapping this region delimited a 13. 47-cM candidate interval defined by key recombinants at loci D3S3525 and D3S1304. Multipoint linkage analysis refined the critical region to a 6.71-cM interval flanked by loci D3S3525 and D3S1560. Evidence that a gene for MR resides in this location is supported by previous breakpoint deletion mapping studies performed in the chromosome 3p- syndrome. CONCLUSIONS: These results suggest that a gene on the subtelomeric region of chromosome 3p contributes to general intelligence. The genes for the cell adhesion L1-like molecule (CALL), the inositol triphosphate receptor (ITPR1), and the AD neuronal thread protein (AD7c-NTP) are leading positional candidates because of their role in brain development, neuronal signaling, and structure.

Progressive supranuclear gaze palsy is in linkage disequilibrium with the tau and not the alpha-synuclein gene.

We studied two candidate genes, tau (tau) and alpha-synuclein (SNCA), for evidence of linkage disequilibrium on a group of unrelated individuals with progressive supranuclear palsy (PSP) and a group of age-matched control subjects. The tau alpha1 allele and the tau alpha1alpha1 genotype were overrepresented in individuals with PSP and the tau polymorphism was in linkage disequilibrium with the PSP disease locus when a recessive inheritance model was employed. We also report a lack of evidence to support linkage disequilibrium between PSP and the SNCA candidate Parkinson's disease gene on chromosome 4q21-q23.

HARP syndrome is allelic with pantothenate kinase-associated neurodegeneration.

HARP (hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration) is a rare syndrome with many clinical similarities to pantothenate kinase-associated neurodegeneration (PKAN, formerly Hallervorden-Spatz syndrome). Despite these common features, lipoprotein abnormalities have not been reported in PKAN. After the recent discovery of the genetic defect in PKAN, we report a homozygous nonsense mutation in exon 5 of the PANK2 gene that creates a stop codon at amino acid 371 (R371X) in the original HARP patient. This finding establishes that HARP is part of the PKAN disease spectrum.

Hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration (HARP syndrome).

We describe the clinical and laboratory studies of an 11-year-old girl with prominent orofacial dyskinesia, dystonia, and progressive dementia. Investigations revealed hypoprebetalipoproteinemia, acanthocytosis, atypical retinitis pigmentosa, and evidence of iron deposition in the pallidal nuclei. Electroneuromyography and skin and sural nerve biopsies were normal. The "eye-of-the-tiger" sign, used to describe the pallidal nuclei in Hallervorden-Spatz syndrome, was present on T2-weighted MRIs (GE Signa, 1.5 T). Phase-contrast microscopy of whole blood showed 80 to 90% acanthocytes whose morphology was confirmed by electron microscopy. High-resolution lipoprotein electrophoresis demonstrated an absence of the pre-beta fraction. This case differs phenotypically from the previous reports of Hallervorden-Spatz disease with acanthocytosis by the presence of prominent orofacial dyskinesia and abnormal serum lipoproteins.

A clinical staging classification for type C Niemann-Pick disease.

Analysis of the temporal sequence of neurologic events, neurophysiologic abnormalities, and longevity in 36 Niemann-Pick type C patients revealed two clinical subgroups with five stages of severity within each group. Patients with a preschool onset (group I; n = 18) had a higher mortality than did patients with a school-age onset (group II; n = 18). An asymptomatic phase (stage 0) was defined by biochemical and histopathologic evidence of disease. The initial manifestations of stage 1 were a movement disorder (group I) and cognitive difficulties (group II) accompanied by impaired vertical saccadic eye movements and abnormal acoustic reflexes. Stage 2 was characterized by the sequential occurrence of vertical supranuclear gaze palsy (VSGP), cognitive difficulties, and dysarthria in group I and a movement disorder, VSGP, and dysarthria in group II. Pyramidal tract signs and abnormal brainstem auditory evoked responses defined stage 3 in both groups. Stage 4 culminated in a nonambulant, vegetative state.

An extended 5'-tau susceptibility haplotype in progressive supranuclear palsy.

OBJECTIVE: To confirm the association of an extended 5'-tau haplotype on chromosome 17q with the disease phenotype in clinically ascertained individuals with sporadic progressive supranuclear palsy (PSP). BACKGROUND: PSP is a neurodegenerative disease with parkinsonian signs accompanied by vertical supranuclear palsy and tau pathologic features. Previously, we documented the complete segregation of an extended 5'-tau haplotype consisting of four single nucleotide polymorphisms (SNP) with the disease phenotype in sporadic PSP. This study was conducted in an independent cohort to confirm these results and to improve the statistical power of the data. DESIGN AND METHODS: Direct sequencing and restriction enzyme digests were used to analyze four SNP in tau Exons 1, 4A, and 8. These contiguous SNP were used to reconstruct an extended 5'-tau haplotype in 52 affected and 54 age-matched control individuals. RESULTS: The four SNP formed two homozygous 5'-tau haplotypes (HapA and HapC) or a heterozygous genotype. Fifty-one (98%) patients with PSP had HapA; one (2%) with a later onset was heterozygous; and none had HapC. These PSP haplotype frequencies were different (p < 0.00001) from those of the age-matched control group, in which 18 (33%) people had HapA; 26 (48%) were heterozygous; and 10 (19%) had HapC. The extended 5'-tau haplotype, HapA, had a high sensitivity (98%) and a moderate specificity (67%) as a marker for PSP. CONCLUSIONS: A 5'-tau susceptibility haplotype may be a sensitive marker for sporadic PSP and a genetic defect in, or closely linked to, tau may contribute to the cause of PSP.

An atypical intronic deletion widens the spectrum of mutations in hereditary spastic paraplegia.

OBJECTIVE: To identify the genetic mutation responsible for autosomal dominant spastic paraplegia (HSP) in a large family with a "pure" form of the disorder. BACKGROUND: The disease locus in most families with HSP is genetically linked to the SPG4 locus on chromosome 2p21-p22. Some of these families have mutations in the splice-site or coding regions of the spastin gene (SPAST). METHODS: Linkage and mutational analyses were used to identify the location and the nature of the genetic defect causing the disorder in a large family. After the disease phenotype was linked to the SPG4 locus, all 17 coding regions and flanking intronic sequences of SPAST were analyzed by single-strand conformation polymorphism analysis (SSCP) and compared between affected and normal individuals. Direct sequencing and subcloning methods were used to investigate incongruous mobility shifts. RESULTS: The genomic sequence of SPAST showed a heterozygous four--base pair deletion (delTAAT) near the 3' splice-site of exon three in all 11 affected individuals but not in 21 normal family members or in 50 unrelated controls (100 chromosomes). CONCLUSIONS: This study identifies an atypical intronic microdeletion in SPAST that causes HSP and widens the spectrum of genetic abnormalities that cause the disorder.

Mutations in American families with spinocerebellar ataxia (SCA) type 3: SCA3 is allelic to Machado-Joseph disease.

We identified an expansion of the CAG trinucleotide repeat in the coding region of the Machado-Joseph disease gene in 7 of 24 American families diagnosed with autosomal dominant ataxia. All affected individuals were heterozygous for an expanded allele that ranged from 67 to more than 200 CAG repeats, whereas the normal allele had 14 to 33 repeats. In contrast to the Azorean-Portuguese origins of Machado-Joseph disease, the two largest American families were of German and Dutch-African descent. Clinical, pathologic, and genetic evaluations suggest that American families with spinocerebellar ataxia type 3 differ from those with Machado-Joseph disease by their ethnic origins, predominant spinopontine atrophy, lack of dystonic features, and larger CAG repeat expansion.

The effect of cholesterol-lowering agents on hepatic and plasma cholesterol in Niemann-Pick disease type C.

Niemann-Pick disease type C (NP-C) is a neurovisceral lipidosis characterized by defective intracellular trafficking of cholesterol and lysosomal accumulation of unesterified cholesterol, believed to be an offending metabolite. We studied the effect of cholesterol-lowering agents on hepatic and plasma cholesterol levels in NP-C by randomly assigning 25 patients with NP-C to one of five treatment regimens containing different combinations of cholestyramine, lovastatin, nicotinic acid, or dimethyl sulfoxide (DMSO). Unesterified cholesterol content was measured in liver biopsies before and after 4 months' treatment. All drug regimens except DMSO alone reduced hepatic and plasma cholesterol levels. Toxicity was limited and did not prevent any patient from completing the study. The combination of cholestyramine, lovastatin, and nicotinic acid lowered cholesterol levels in liver and blood with minimal side effects. A controlled clinical study will be necessary to determine if this regimen influences the rate of neurologic progression.