Two pairs of proven monozygotic twins discordant for familial amyloid neuropathy (FAP) TTR Met 30.

J Med Genet. 1999 Aug;36(8):629-32. Two pairs of proven monozygotic twins discordant for familial amyloid neuropathy (FAP) TTR Met 30. Munar-Qués M, Pedrosa JL, Coelho T, Gusmão L, Seruca R, Amorim A, Sequeiros J. Grupo de Estudio de la PAF, Palma de Mallorca, Spain. Abstract Twin studies are an important tool in medical genetics for the evaluation of the relative roles of genetic and non-genetic factors in several diseases. Familial amyloidotic polyneuropathy type I (FAP-I), TTR Met 30, was present in two sets of proven monozygotic (MZ) twins, one from Majorca and the other from Portugal. Monozygosity was established by analysis of DNA polymorphisms. Both pairs were discordant for age at onset and some clinical manifestations of FAP-I. We reviewed the differences in age at onset and clinical features in both sets and in two other pairs of presumed MZ twins with FAP-I and compared them with those in MZ twin pairs with other Mendelian disorders, such as neurofibromatosis type 1, Huntington's disease, facioscapulohumeral muscular dystrophy, and myotonic dystrophy. We conclude that, in addition to the postulated modifying genes, there must be a significant contribution from non-genetic factors to the phenotypic variability of FAP-I (age at onset and clinical expression), either because of environmental differences or stochastic events during (or after) the twinning process. PMID: 10465115 [PubMed - indexed for MEDLINE]PMCID: PMC176297

A Trans-acting Factor May Modify Age at Onset in Familial Amyloid Polyneuropathy ATTRV30M in Portugal

Although all familial amyloid polyneuropathy (FAP) ATTRV30M patients carry the same causative mutation, early (<40) and late-onset forms (≥50 years) of FAP may coexist in the same family. However, this variability in age at onset is still unexplained. To identify modifiers closely linked to the TTR locus that may in part be associated with age at onset of FAP ATTRV30M, in particular in a group of very early-onset patients (≤30 years) when compared with late-onset individuals. A clinical genetic study at a referral center comprising a sample of 910 Portuguese individuals includes 589 Val30Met carriers, 102 spouses, and 189 controls from the general population. Haplotype analysis was performed, using eight intragenic single nucleotide polymorphisms (SNPs) at the TTR locus. We compared haplotypes frequency in FAP samples and controls and in parent-offspring pairs using appropriated statistical analysis. Haplotype A was the most common in the general population. Noteworthy, haplotype C was more frequent in early-onset (<40) than in late-onset patients (≥50 years) (p = 0.012). When comparing allelic frequencies of each SNP within haplotype C between "very early" (≤30 years) and late-onset (≥50 years) cases, the A allele of rs72922947 was associated with an earlier onset (p = 0.009); this remained significant after a permutation-based correction. Also, the heterozygous genotype (GA) for this SNP was associated with a decrease in mean age at onset of 8.6 years (p = 0.014). We found a more common haplotype (A) linked to the Val30Met variant and a possible modulatory trans effect on age at onset. These findings may lead to potential therapeutical targets.This work was supported by grants of Fundação para a Ciência eTecnologia,FCT[PTDC/SAU-GMG/100240/2008andPEsT], cofunded byERDF andCOMPETE; and byFinanciamentoPlurianual de Unidades de Investigação (FCT). Conflict of Interest M.A.F. and D. S. have received research support from a FCT fellowship (SFRH/BD/101352/2014 and SFRH/BD/91160/2012, respectively). T.C.’sinstitution hasreceived support from FoldRx Pharmaceuticals, which was acquired by Pfizer Inc. in October 2010; T. C. hasserved on the scientific advisory board of PfizerInc. and received funding from Pfizer Inc. for scientific meeting expenses (travel, accommodations,and registration).ShecurrentlyservesontheTHAOS(natural historydiseaseregistry)scientific advisory board.J.S.,I.A.,A.S.,and C. L. report no disclosures

Life paths of patients with transthyretin-related familial amyloid polyneuropathy Val30Met: a descriptive study

Transthyretin-related familial amyloid polyneuropathy Val30Met is a fatal progressive disease. It is a rare hereditary amyloidosis, manifesting as a sensorimotor neuropathy and autonomic dysfunction. It begins during adulthood and is a disabling disease, posing a great psychological burden to patients and their families. Our aim was to describe and characterize life events related to the disease and discuss its psychosocial implications. Social and demographic data and a questionnaire on history of family and personal disease, and biographic events, were applied to 209 subjects attending an outpatient specialized clinic. Descriptive and statistical analyses were performed. They were 84 men and 127 women belonging to three groups: pre-symptomatic carriers, patients, and subjects with no established diagnosis. Most subjects were married/lived with a partner and had children (mean of 4). Most (96.3%) had contact with the disease before having a diagnosis; the affected or at-risk parent was the mother in 53.8% and the father in 43.3%; 71.8% of these had deceased. At their parent’s death, many subjects were aged under 10 (9.9%), 10–14 (15.5%), or 15–24 years (31.7%). Most were under age 14 (44.9%) at their parent’s disease onset; 37.2% referred this brought life changes with psychological and familial impact; most had been parent’s caregivers; 7.5% had not been raised by the parents. Some (8.4%) declined to know their genetic tests results for over 1 year. Parent’s disease and death are very common early in these patient’s lives. During childhood or youth, many subjects became caregivers, implying changes in family roles. This disease and its life implications pose a significant psychosocial burden since childhood. TTR-FAP patients and their relatives are highly vulnerable to emotional stress and psychopathology during their lifetime. Psychological and psychiatric support, implying a multidisciplinary group, must thus be available for all of them

Familial amyloid polyneuropathy in Portugal: New genes modulating age-at-onset

OBJECTIVES: Familial amyloid polyneuropathy (FAP ATTRV30M) shows a wide variation in age-at-onset (AO) between clusters, families, and among generations. We will now explore some candidate genes involved in altered disease pathways in order to assess their role as genetic modifiers of AO, using a family-centered approach. METHODS: We analyzed 62 tagging SNPs from nine genes-NGAL,MMP-9,BGN,MEK1,MEK2,ERK1,ERK2,HSP27, and YWHAZ - in a sample of 318 V30M Portuguese patients (106 families), currently under follow-up. A generalized estimating equation analysis was used to take into account nonindependency of AO between relatives. Also, an in silico analysis was performed in order to assess the functional impact of significant variants associated with AO. RESULTS: We found for the first time variants from six genes (NGAL,BGN (in the female group), MEK1,MEK2,HSP27, and YWHAZ) that were significantly associated with early- and/or late-onset. Then, we confirmed a strong synergistic interaction between NGAL and MMP-9 genes. Additionally, by an in silico analysis, we found some variants for MEK1 gene that may alter binding of the transcription factors and that influence the regulation of gene expression regarding microRNA binding sites and splicing regulatory factors. INTERPRETATION: These findings showed that different genetic factors can modulate differently the onset of disease's symptoms and revealed new mechanisms with clinical implications in the genetic counseling and follow-up of mutation carriers and could contribute for development of potential therapeutical targets.info:eu-repo/semantics/publishedVersio

Large Normal Alleles of ATXN2 Decrease Age at Onset in Transthyretin Familial Amyloid Polyneuropathy Val30Met Patients

Objective: Transthyretin (TTR)-related familial amyloid polyneuropathy (FAP) is an autosomal dominant neurological disease, caused most frequently by a Val30Met (now classified as Val50Met) substitution in TTR. Age at onset (AO) ranges from 19 to 82 years, and variability exists mostly between generations. Unstable oligonucleotide repeats in various genes are the mechanism behind several neurological diseases, found also to act as modifiers for other disorders. Our aim was to investigate whether large normal repeat alleles of 10 genes had a possible modifier effect in AO in Portuguese TTR-FAP Val30Met families. Methods: We analyzed 329 Portuguese patients from 123 families. Repeat length (at ATXN1, ATXN2, ATXN3, ATXN7, TBP, ATN1, HTT, JPH3, AR, and DMPK) was assessed by single and multiplex polymerase chain reaction, using fluorescently labeled primers, followed by capillary electrophoresis. We used a family-centered approach, and generalized estimating equations were used to account for AO correlation between family members. Results: For ATXN2, the presence of at least 1 allele longer than 22 CAGs was significantly associated with an earlier onset in TTR-FAP Val30Met, decreasing mean AO by 6 years (95% confidence interval = -8.81 to -2.19, p = 0.001). No association was found for the remaining repeat loci. Interpretation: Length of normal repeats at ATXN2 may modify AO in TTR-FAP Val30Met and may function as a risk factor. This can be due to the role of ATXN2 in RNA metabolism and as a modulator of various cellular processes, including mitochondrial stress. This may have relevant implications for prognosis and the follow-up of presymptomatic carriers. ANN NEUROL 2019;85:251-258.This work was supported by the Fundação para a Ciência e Tecnologia (FCT; PTDC/SAUGMG/100240/2008 and PEsT), and co-funded by ERDF, COMPETE, and Multi- annual Financing of Research Units (FCT). D.S. and M.A.-F. are the recipients of an FCT fellowship (SFRH/BD/91160/2012 and SFRH/BD/101352/2014, respectively). We thank all patients for participating in this study and V. Costa for help assembling family data

C1QA and C1QC modify age-at-onset in familial amyloid polyneuropathy patients

Objectives: Transthyretin (TTR) familial amyloid polyneuropathy (FAP) (OMIM 176300) shows a variable age-at-onset (AO), including within families. We hypothesized that variants in C1QA and C1QC genes, might also act as genetic modifiers of AO in TTR-FAP Val30Met Portuguese patients. Methods: We analyzed DNA samples of 267 patients (117 families). To search for variants, all exons and flanking regions were genotyped by automated sequencing. We used generalized estimating equations (GEEs) to take into account the nonindependency of AO among relatives. Intensive in silico analyses were performed, using various software to assess miRNAs target sites, splicing sites, transcription factor binding sites alterations, and gene–gene interactions. Results: Two variants for C1QA gene, GA genotype of rs201693493 (P < 0.001) and CT genotype of rs149050968 (P < 0.001), were significantly associated with later AO. In silico analysis demonstrated, that rs201693493 may alter splicing activity. Regarding C1QC, we found three statistically significant results: GA genotype of rs2935537 (P = 0.003), GA genotype of rs201241346 (P < 0.001) and GA genotype of rs200952686 (P < 0.001). The first two were associated with earlier AO, whereas the third was associated with later-onset. Interpretation: C1QA was associated with later onset, whereas C1QC may have a double role: variants may confer earlier or later AO. As found in a study in Cyprus, we confirmed the role of complement C1Q genes (and thus of inflammation) as modulator of AO in Portuguese patients with TTR-FAP Val30Met.We would like to thank FEDER funds, through the Programa Operacional Factores de Competitividade – COMPETE 2020 and by Nacional funds through the FCT – Fundação para a Ciência e a Tecnologia [COMPETE: POCI-01-0145-FEDER-007440]. This work was supported by grants of Fundação para a Ciência e Tecnologia, FCT [PTDC/SAU GMG/100240/2008 and PEsT], co-funded by ERDF and COMPETE; and by Financiamento Plurianual de Unidades de Investigac¸a˜ o (FCT). DS is the recipient of a FCT fellowship [SFRH/BD/91160/2012]. MAF is recipient of a FCT fellowship [SFRH/BD/101352/2014]

Nonnegative rank-preserving operators

AbstractAnalogues of characterizations of rank-preserving operators on field-valued matrices are determined for matrices witheentries in certain structures S contained in the nonnegative reals. For example, if S is the set of nonnegative members of a real unique factorization domain (e.g. the nonnegative reals or the nonnegative integers), M is the set of m×n matrices with entries in S, and min(m,n)⩾4, then a “linear” operator on M preserves the “rank” of each matrix in M if and only if it preserves the ranks of those matrices in M of ranks 1, 2, and 4. Notions of rank and linearity are defined analogously to the field-valued concepts. Other characterizations of rank-preserving operators for matrices over these and other structures S are also given

mtDNA copy number associated with age of onset in familial amyloid polyneuropathy

background Transthyretin-related familial amyloid polyneuropathy (TTR-Fap Val30Met) shows a wide variation in age-at-onset (aO) between generations and genders, as in portuguese families, where women display a later onset and a larger anticipation (>10 years). Mitochondrial DNa (mtDNa) copy number was assessed to clarify whether it has a modifier effect on aO variability in portuguese patients. Methods The mtDNa copy number of 262 samples (175 Val30Met TTR carriers and 87 controls (proven Val30Val)) was quantified by quantitative real-time pcR. statistical analysis was performed using IBM spss V.23 software. results This study shows that Val30Met TTR carriers have a significantly higher (p<0.001) mean mtDNa copy number than controls. Furthermore, the highest mtDNa copy number mean was observed in early-onset patients (aO <40 years). Importantly, early-onset offspring showed a significant increase (p=0.002) in the mtDNa copy number, when compared with their late aO parents. Conclusions The present findings suggest, for the first time, that mtDNa copy number may be associated with earlier events and may therefore be further explored as a potential biomarker for follow-up of TTR-Fap Val30Met carriers.DS and MA-F are recipients of an FCT fellowship (SFRH/BD /91160/2012 and SFRH/BD/101352/2014, respectively). Our funding sources supported the data collection and analysis, but did not play a role in the study design, in interpretation of data, in the writing of the report or in the decision to submit the paper for publication

Mutations in PNKP cause recessive ataxia with oculomotor apraxia type 4

Hereditary autosomal-recessive cerebellar ataxias are a genetically and clinically heterogeneous group of disorders. We used homozygosity mapping and exome sequencing to study a cohort of nine Portuguese families who were identified during a nationwide, population-based, systematic survey as displaying a consistent phenotype of recessive ataxia with oculomotor apraxia (AOA). The integration of data from these analyses led to the identification of the same homozygous PNKP (polynucleotide kinase 3′-phosphatase) mutation, c.1123G>T (p.Gly375Trp), in three of the studied families. When analyzing this particular gene in the exome sequencing data from the remaining cohort, we identified homozygous or compound-heterozygous mutations in five other families. PNKP is a dual-function enzyme with a key role in different pathways of DNA-damage repair. Mutations in this gene have previously been associated with an autosomal-recessive syndrome characterized by microcephaly; early-onset, intractable seizures; and developmental delay (MCSZ). The finding of PNKP mutations associated with recessive AOA extends the phenotype associated with this gene and identifies a fourth locus that causes AOA. These data confirm that MCSZ and some forms of ataxia share etiological features, most likely reflecting the role of PNKP in DNA-repair mechanisms

Comprehensive feature selection for classifying the treatment outcome of high-intensity ultrasound therapy in uterine fibroids

The study aim was to utilise multiple feature selection methods in order to select the most important parameters from clinical patient data for high-intensity focused ultrasound (HIFU) treatment outcome classification in uterine fibroids. The study was retrospective using patient data from 66 HIFU treatments with 89 uterine fibroids. A total of 39 features were extracted from the patient data and 14 different filter-based feature selection methods were used to select the most informative features. The selected features were then used in a support vector classification (SVC) model to evaluate the performance of these parameters in predicting HIFU therapy outcome. The therapy outcome was defined as non-perfused volume (NPV) ratio in three classes: 80%. The ten most highly ranked features in order were: fibroid diameter, subcutaneous fat thickness, fibroid volume, fibroid distance, Funaki type I, fundus location, gravidity, Funaki type III, submucosal fibroid type and urinary symptoms. The maximum F1-micro classification score was 0.63 using the top ten features from Mutual Information Maximisation (MIM) and Joint Mutual Information (JMI) feature selection methods. Classification performance of HIFU therapy outcome prediction in uterine fibroids is highly dependent on the chosen feature set which should be determined prior using different classifiers