Markku Ryynänen

Familial intracranial aneurysms

BACKGROUND We set out to determine the prevalence of incidental intracranial aneurysms in first-degree relatives aged 30 years or more of people with intracranial aneurysms, and to see if polycystic kidney disease contributes to the aggregation of familial intracranial aneurysms. METHODS 91 families with two or more affected members had previously been identified from a 14 year series of 1150 intracranial aneurysm patients treated at the University Hospital of Kuopio, Finland. Magnetic resonance angiography was used as a preliminary screening method, followed by conventional four-vessel angiography to verify suspected aneurysms. Participants were also screened for polycystic kidneys by ultrasonography. FINDINGS Incidental aneurysms were detected in 40 individuals: 38 of 438 individuals from 85 families without polycystic kidney disease or other diagnosed heritable disorders, and two of 22 individuals from six families known to have polycystic kidney disease. The crude and age-adjusted prevalence of incidental intracranial aneurysms among screened first-degree relatives was 8.7 (SE 1.3)% (95% CI 6.2-11.7) and 9.1 (1.4)% (6.2-11.7), respectively, for the familial group and the crude prevalence for the polycystic kidney group was 9.1 (6.1)% (1.1-29.2). INTERPRETATION Our results demonstrate a high prevalence of incidental intracranial aneurysms among first-degree relatives aged 30 years or older of patients with the condition and indicate that the risk of having an aneurysm is about four times higher for a close relative than for someone from the general population. Also, polycystic kidney disease families are a small fraction of the familial intracranial aneurysm families.

Familial Subarachnoid Hemorrhage in East Finland, 1977–1990

The familial occurrence of cerebral aneurysms in a defined clinical group of 1150 patients from a defined catchment area was studied. Two or more proven aneurysmal subarachnoid hemorrhage (SAH) patients within the same family were included. Of these 1150 patients, 113 (10%) had a proven familial occurrence of aneurysmal SAH. These 113 patients form 91 SAH families with a total of 203 aneurysm patients. Fifty-four percent of the patients were female, and the mean age in female patients was 49 years and in male patients was 44 years. In 23% of the families, three or more members were identified as having cerebral aneurysms. Middle cerebral artery aneurysms were the most common type (47%). Based on the high incidence (10%) of familial intracranial aneurysms among SAH patients, a prospective study of healthy family members for incidental intracranial aneurysms was performed, with positive findings of 12%.

Search for intracranial aneurysm susceptibility gene(s) using Finnish families

BackgroundCerebrovascular disease is the third leading cause of death in the United States, and about one-fourth of cerebrovascular deaths are attributed to ruptured intracranial aneurysms (IA). Epidemiological evidence suggests that IAs cluster in families, and are therefore probably genetic. Identification of individuals at risk for developing IAs by genetic tests will allow concentration of diagnostic imaging on high-risk individuals. We used model-free linkage analysis based on allele sharing with a two-stage design for a genome-wide scan to identify chromosomal regions that may harbor IA loci.MethodsWe previously estimated sibling relative risk in the Finnish population at between 9 and 16, and proceeded with a genome-wide scan for loci predisposing to IA. In 85 Finnish families with two or more affected members, 48 affected sibling pairs (ASPs) were available for our genetic study. Power calculations indicated that 48 ASPs were adequate to identify chromosomal regions likely to harbor predisposing genes and that a liberal stage I lod score threshold of 0.8 provided a reasonable balance between detection of false positive regions and failure to detect real loci with moderate effect.ResultsSeven chromosomal regions exceeded the stage I lod score threshold of 0.8 and five exceeded 1.0. The most significant region, on chromosome 19q, had a maximum multipoint lod score (MLS) of 2.6.ConclusionsOur study provides evidence for the locations of genes predisposing to IA. Further studies are necessary to elucidate the genes and their role in the pathophysiology of IA, and to design genetic tests.

Proteinuria and prenatal diagnosis of congenital nephrosis in fetal carriers of nephrin gene mutations

High concentrations of alpha-fetoprotein (AFP) are used for prenatal diagnosis of the Finnish type of congenital nephrotic syndrome (NPHS1). We investigated the validity of this test. We retrospectively established fetal NPHS1 genotype and assessed renal pathology in 21 pregnancies that had been terminated because of raised concentrations of AFP in amniotic fluid. 12 fetuses were homozygous and nine were heterozygous (carriers) for NPHS1 mutations. Raised concentrations of AFP and similar proteinuric features in fetal kidneys were seen in both groups, indicating that these signs are unreliable for prenatal diagnosis of congenital nephrosis. We strongly recommend the use of mutation analysis of the NPHS1 gene to confirm the AFP results in prenatal diagnosis of NPHS1.

A ten percent prevalence of asymptomatic familial intracranial aneurysms: preliminary report on 110 magnetic resonance angiography studies in members of 21 Finnish familial intracranial aneurysm families.

The population in eastern Finland has been stable for generations, causing a high degree of genetic isolation and providing excellent possibilities for follow-up studies. Of 91 families with familial intracranial aneurysms, 21 were randomly selected for prospective magnetic resonance angiography studies for intracranial aneurysms. Sixteen intracranial aneurysms were detected in 11 asymptomatic family members of a total of 110 studied. The prevalence of intracranial aneurysms among these familial intracranial aneurysm families is 10%, approximately 10 times higher than in the average population. Our findings suggest that family members of familial intracranial aneurysm families should be examined for intracranial aneurysms. Familial intracranial aneurysm may be a genetic disorder.

A Ten Percent Prevalence of Asymptomatic Familial Intracranial Aneurysms

: The population in eastern Finland has been stable for generations, causing a high degree of genetic isolation and providing excellent possibilities for follow-up studies. Of 91 families with familial intracranial aneurysms, 21 were randomly selected for prospective magnetic resonance angiography studies for intracranial aneurysms. Sixteen intracranial aneurysms were detected in 11 asymptomatic family members of a total of 110 studied. The prevalence of intracranial aneurysms among these familial intracranial aneurysm families is 10%, approximately 10 times higher than in the average population. Our findings suggest that family members of familial intracranial aneurysm families should be examined for intracranial aneurysms. Familial intracranial aneurysm may be a genetic disorder.

A 15 base-pair AT-Rich Variable Number Tandem Repeat in the Type III Procollagen Gene (COL3A1) as an Informative Marker for 2q31-2q32.3

Segments of repeating DNA, termed variable number tandem repeats, within the genome are often used as polymorphic markers. Here we report such a repeat in the intervening sequence 25 of the type III procollagen gene (COL3A1) located at 2q31-q32.3. The region containing intervening sequence 25 of the COL3A1 gene was amplified using the polymerase chain reaction and the products were analyzed by agarose gel electrophoresis and dideoxynucleotide sequencing. The repeat consisted of an AT-rich unit of 15 base-pairs (ATATATATATGAGAC). Seven different alleles were identified containing between three and nine repeats of the 15 base-pair unit. The allele heterozygosity was 73% in 117 unrelated individuals. The alleles were shown to be inherited in a Mendelian fashion in three large families. This marker should prove useful in linkage studies for COL3A1, and for linkage studies of other genes on the long arm of chromosome 2. The information extends and complements a report on the same repeat recently published by Lee et al. (J. Biol. Chem. 266: 5256, 1991 a).

Bullous pemphigoid antigens (BPAGs): identification of RFLPs in human BPAG1 and BPAG2, and exclusion as candidate genes in a large kindred with dominant epidermolysis bullosa simplex.

Bullous pemphigoid antigens (BPAGs) are defined as autoantigens in a blistering skin disease, bullous pemphigoid. Two of the BPAGs, a 230-kD (BPAG1) and a 180-kD (BPAG2) protein, have been localized to hemidesmosomes, attachment structures at the basal keratinocyte-basement membrane interphase. We have recently cloned cDNAs corresponding to human BPAG1 and BPAG2, and mapped the corresponding genes to human chromosomes 6p and 10q, respectively. These cDNAs have now been used in a search for RFLPs in the corresponding genes. Southern hybridizations of genomic DNA from normal unrelated individuals with a BPAG1 cDNA detected an informative MspI RFLP, and similar hybridizations with a BPAG2 cDNA revealed an informative TaqI RFLP. These RFLPs were applied to a large kindred with epidermolysis bullosa simplex (EBS), generalized (Koebner) type, consisting of 14 affected and 12 unaffected individuals in three generations. Linkage analysis excluded the EBS locus in this pedigree approximately 9 cM and approximately 5 cM on either side of the BPAG1 and BPAG2 loci, respectively, when a lod score of -2.0 was taken as the limit of exclusion. This study demonstrates that mutations in the BPAG1 or BPAG2 genes are not the primary genetic defect in this family with EBS.