A novel stroke locus identified in a northern Sweden pedigree: linkage to chromosome 9q31-33.

OBJECTIVES: The population of northern Sweden is characterized by reduced genetic diversity and a high incidence of stroke. We sought to reduce genetic variation further, using genealogic analysis in a set of nuclear families affected by stroke, and we subsequently performed a genome-wide scan to identify novel stroke susceptibility loci. METHODS: Through genealogy, 7 nuclear families with a common ancestor, connected over 8 generations, were identified. A genome-wide scan using 449 microsatellite markers was performed with subsequent haplotype analyses. RESULTS: A maximum allele-sharing lod score of 4.81 on chromosome 9q31-q33 was detected. Haplotype analysis identified a common 2.2-megabase interval in the chromosomal region in 4 of the nuclear families, where an overrepresentation of intracerebral hemorrhage was observed. CONCLUSIONS: We have identified a novel susceptibility locus for stroke. Haplotype analysis suggests that a shared genetic factor is of particular importance for intracerebral hemorrhage.

Ocular phenotype of bothnia dystrophy, an autosomal recessive retinitis pigmentosa associated with an R234W mutation in the RLBP1 gene.

OBJECTIVE: To describe the phenotype of Bothnia dystrophy, an autosomal recessive retinal dystrophy with an R234W mutation in the RLBP1 gene encoding cellular retinaldehyde-binding protein. DESIGN: Medical records were reviewed retrospectively. Ophthalmologic examination, including kinetic perimetry and, in selected cases, adaptometry, color vision tests, fluorescein angiography, and electrophysiologic studies, was performed. The study included 24 individuals, all homozygous for an R234W mutation in the RLBP1 gene. RESULTS: Patients typically show night blindness from early childhood. In young adults, retinitis punctata albescens was observed, followed by macular degeneration and a decrease in visual acuity that led to legal blindness in early adulthood. Dark adaptometry and electrophysiologic testing showed an initial loss of rod function followed by a progressive reduction of the cone responses in older ages. CONCLUSIONS: Bothnia dystrophy is a unique retinal dystrophy belonging to the rod-cone dystrophies and has a high prevalence in northern Sweden. Fifty-seven cases of Bothnia dystrophy have been diagnosed, indicating a prevalence as high as 1 per 4500 population in the geographic area studied. A defect ability of mutated cellular retinaldehyde-binding protein to bind retinoid probably explains the defect rod function followed by central and peripheral degeneration. CLINICAL RELEVANCE: Retinal dystrophies associated with other mutations of the RLBP1 gene, including retinitis pigmentosa of Bothnia type, might account for a considerable number of cases of autosomal recessive retinitis pigmentosa in other geographic areas as well.

Heart failure caused by a novel amyloidogenic mutation of the transthyretin gene: ATTR Ala45Ser.

Cardiac failure in transthyretin (TTR) amyloidosis patients has been shown to be caused by different mutations in the TTR gene. In the present case, a 73-year-old man from Northern Sweden was evaluated for heart failure. Amyloid deposits were found in subcutaneous fat and in intestinal biopsies. The presence of a variant form of TTR was detected in the plasma by electrospray ionisation mass spectrometry (ESI-MS). The mutation was located by single-strand conformation polymorphism (SSCP) analysis of the TTR gene where a band shift was seen in exon 2. Direct sequencing of exon 2 revealed a single base-pair substitution (G1724T). This transversion results in an amino acid substitution at codon 45, alanine to serine (ATTR Ala45Ser). Mass spectrometry analysis excluded that the variant is a polymorphism, since no similar shift in molecular weight has been present in more than 200 control samples. Congo red and immunostaining of duodenum biopsy specimens confirmed the presence of systemic ATTR amyloidosis, and clinical examination, including echocardiography, found evidence of a restrictive cardiomyopathy. He had 10 years previously been operated for a bilateral carpal tunnel syndrome, but otherwise no symptoms were present that could be attributed to his systemic amyloidosis. No axonal polyneuropathy was noted at nerve conduction studies. This novel mutation is the second amyloidogenic TTR mutation found in the Swedish population.