Alda Sousa

Familial Amyloidotic Polyneuropathy in Sweden: Geographical Distribution, Age of Onset, and Prevalence

Familial amyloidotic polyneuropathy (FAP) in Swedish patients is associated with the same transthyretin mutation (TTRMet30) as in Portuguese, Japanese, Brazilian and Majorcan patients. Yet, the age of onset of FAP is much later in Sweden than in other populations. We have studied 239 cases of FAP from northern Sweden, their geographical distribution, differences in age of onset, and estimated prevalence and incidence rates. Cases and families concentrate mainly in two areas, around the towns of Skellefteå and Piteå. Mean age of onset was found to be later in the Piteå (58.8 +/- 10.8) than in the Skellefteå area (54.4 +/- 13.5). Unusually high figures were found for prevalence rates (91 x 10(-5) and 104 x 10(-5), respectively) in 1985. Mean yearly incidences were 3.1 x 10(-5) and 4.4 x 10(-5), respectively, over the period 1985-1989.

Familial amyloidotic polyneuropathy in Sweden: a pedigree analysis.

Extended genealogical studies were performed on the heredity patterns in Swedish patients with familial amyloidotic polyneuropathy (FAP) using Swedish historical archives. The population studied included 239 patients: 109 patients were linked to five large pedigrees and 80 patients belonged to 30 smaller pedigrees or nuclear families. In the remaining 50 cases, no genealogical links were found. Differences in mean ages of onset between the different pedigrees were found, although a considerable variation within the pedigrees was also present. There was a tendency for later ages of onset among older generations than younger ones: descendants of affected mothers seem to be more prone to anticipation in age of onset than descendants of affected fathers. Furthermore, there seems to be a tendency for earlier ages of onset among patients with a carrier mother than a carrier father. Some extended pedigrees, from the Skellefteå and Piteå areas, are presented in detail. The former go back into the middle of the 17th century. One important conclusion is that the mutational event may have occurred in late mediaeval times.

Haplotypes and DNA sequence variation within and surrounding the transthyretin gene: genotype-phenotype correlations in familial amyloid polyneuropathy (V30M) in Portugal and Sweden

Familial amyloid polyneuropathy (FAP) is a lethal autosomal dominant disorder in which fibrils derived from mutant forms of transthyretin (TTR), the normal plasma carrier of thyroxine (T4) and retinol-binding protein, are deposited in tissues. Over 80 TTR sequence variants are associated with FAP, but the amino-acid substitutions alone do not completely explain the variability in disease penetrance, pathology and clinical course. To analyze the factors possibly contributing to this phenotypic variability, we characterized the variations within the wild-type and mutant (Val30Met) TTR genes and their flanking sequences by performing extended microsatellite haplotype analyses, sequencing and single-nucleotide polymorphism haplotyping of genomic DNA from Portuguese and Swedish carriers of V30M. We identified 10 new polymorphisms in the TTR untranslated regions, eight resulting from single-base substitutions and two arising from insertion/deletions in dinucleotide repeat sequences. The data suggest that the onset of symptoms of FAP V30M may be modulated by an interval downstream of TTR on the accompanying noncarrier chromosome (defined by microsatellites D18S457 and D18S456), but not by the immediately 5′- and 3′-flanking sequences of TTR. During the course of these studies, we also encountered the first instance in which the previously described intragenic haplotype III may be associated with V30M FAP in the Portuguese population.

Large normal and reduced penetrance alleles in Huntington disease: instability in families and frequency at the laboratory, at the clinic and in the population

Sequeiros J, Ramos EM, Cerqueira J, Costa MC, Sousa A, Pinto‐Basto J, Alonso I. Large normal and reduced penetrance alleles in Huntington disease: instability in families and frequency at the laboratory, at the clinic and in the population.

End-stage renal disease and dialysis in hereditary amyloidosis TTR V30M: presentation, survival and prognostic factors.

Classical familial amyloid polyneuropathy may have a course with progressive renal impairment. We studied 62 patients (24 males, 38 females) with FAP, transthyretin variant V30M, and end-stage renal disease (ESRD) treated with hemodialysis, all referred to a single center over a period of 11 years. Clinical course, morbidity and survival after dialysis were analyzed. Patients mean age at first dialysis was 51.5 ± 10.7 years, and mean duration of neuropathy was 10.2 ± 3.8 years. The most frequent form of presentation of FAP nephropathy was nephrotic proteinuria with renal dysfunction. In the year prior to dialysis, renal function declined rapidly, and fluid overload was the main indication to initiate treatment. The presence of decubitus ulcers, significant disability, venous catheter for definitive vascular access for long-term treatment, and permanent bladder catheter, were related to death during the first year of dialysis. The mean duration of renal replacement therapy was 21 months, with a 54.5% one year, and 38.4% two year treatment survival. However, when the duration of neurological symptoms at first dialysis exceeded 10 years, survival was significantly lower. Infections, (41% were decubitus ulcers with sepsis) were the cause of early, as well as late mortality. Early creation of vascular access for hemodialysis, surveillance of skin wounds, and intervention on neurogenic bladder are essential to improve the prognosis of ESRD in FAP.

Vitreous involvement in familial amyloidotic neuropathy a genealogical and genetic study

Extended genealogical studies stretching back to the 17th century were performed concerning the heredity patterns of vitreous involvement in Swedish patients with familial amyloidotic polyneuropathy (FAP). FAP is an autosomal dominant inherited disorder, characterized by extracellular deposition of amyloid and a clinical syndrome of peripheral and autonomic neuropathy. In addition, some patients show typical vitreous opacities. All patients had their origin in a restricted geographical area. Some main patterns arose from this study: 1) Patients who had vitreous opacities as the first symptom of FAP seem to form a separate group, with a distinct age of onset distribution; 2) The familial occurrence of vitreous opacities raises the possibility that other familial factors modify the expression of the FAP gene; 3) The mean age of onset for vitreous opacities is lower for homozygous than for heterozygous patients.

BDNF and CGRP interaction: implications in migraine susceptibility.

Objectives: Migraine pathophysiology involves several pathways. Our aims were to explore a possible role of the brain-derived neurotrophic factor gene (BDNF) in migraine susceptibility; to study, for the first time, the calcitonin gene-related peptide gene (CGRP); and a possible interaction between the two. Methods: Using a case-control approach, four tagging single nucleotide polymorphisms (SNPs) (rs7124442, rs6265, rs11030107, and rs2049046) of BDNF and one tagging SNP—rs1553005—of CGRP were analyzed in 188 cases and 287 controls. A multivariable logistic regression was performed, adjusting for gender. Allelic and haplotypic frequencies were estimated. Interaction was assessed by a stepwise multivariable-logistic regression and confirmed by a multifactor dimensionality reduction analysis. Results: No significant main effects were found; however, a significant interaction was found between BDNF and CGRP, showing an increased risk for the AT-genotype of rs2049046 and the GC-genotype of rs1553005 (odds ratio = 1.88, 95% confidence interval: 1.20–2.93) for migraineurs. Conclusion: Our data support the hypothesis of an interaction between BDNF and CGRP in migraine susceptibility that should be further explored.

Genetic anticipation in Portuguese kindreds with familial amyloidotic polyneuropathy is unlikely to be caused by triplet repeat expansions

Abstract Familial amyloidotic polyneuropathy (FAP) is a lethal autosomal dominant type of amyloidosis resulting from the deposition of transthyretin (ATTR) variants in the peripheral and autonomic nervous systems. ATTR V30M-associated FAP exhibits marked genetic anticipation in some families, with clinical symptoms developing at an earlier age in successive generations. The genetic basis of this phenomenon in FAP is unknown. Anticipation has been associated with the dynamic expansion of trinucleotide repeats in several neurodegenerative disorders, such as Huntington disease, myotonic dystrophy, and fragile X syndrome. We have used the repeat expansion detection (RED) assay to screen affected members of Portuguese FAP kindreds for expansion of any of the ten possible trinucleotide repeats. Nine generational pairs with differences in their age of onset greater than 12 years and a control pair with identical ages of onset were tested. No major differences were found in the lengths of the ten trinucleotide repeats analyzed. The distribution of the maximal repeat sizes was consistent with reported studies in unrelated individuals with no known genetic disease. The present data do not support a role for trinucleotide repeat expansions as the molecular mechanism underlying anticipation in Portuguese FAP.

Familial Aggregation of Maxillary Lateral Incisor Agenesis

In spite of recent developments, data regarding the genes responsible for the less severe forms of hypodontia are still scarce and controversial. This study addressed the hypothesis that agenesis of maxillary lateral incisors (MLIA) is a distinct type of hypodontia, by evaluating its familial aggregation and the occurrence of other types of ageneses or microdontia in probands’ relatives. Sixty-two probands with MLIA were identified, and information was collected on 142 first-degree relatives. Relative risk (RR) was calculated and compared by re-assessment of data previously published for the Swedish, Utah, and Israeli populations, for the same trait. A RR of 15 was obtained in the Portuguese, 16 in the Swedish, 12 in Utah, and 5 in the Israeli population. Our results support a significant familial aggregation of MLIA, show that MLIA almost never segregates with other forms of agenesis, and suggest that microdontia of maxillary lateral incisors is part of the same phenotype.

Population Genetics of Wild-Type CAG Repeats in the Machado-Joseph Disease Gene in Portugal

Objective: To gain insights on the molecular mechanisms of mutation that led to the emergence of expanded alleles in the MJD gene, by studying the behavior of wild-type alleles and testing the association of its distribution with the representation of the disease. Methods: The number of CAG motifs in the MJD gene was determined in a representative sample of 1000 unrelated individuals. Associations between the repeat size and the epidemiological representation of MJD were tested. Results: The allelic profile of the total sample was in the normal range (13–41 repeats), with mode (CAG)23. No intermediate alleles were present. Allelic size distribution showed a negative skew. The correlation between the epidemiological representation of MJD in each district and the frequency of small, medium and large normal alleles was not significant. Further correlations performed grouping the districts also failed to produce significant results. Conclusions: The absence of association between the size of the repeats and the representation of MJD demonstrates that prevalence is not an indirect reflection of the frequency of large normal alleles. Globally the results obtained are in accordance with a model that postulates the occurrence of a few mutations on the basis of most of the MJD cases worldwide.