Living Family Members Research Articles

Alexander S. Wiener: The Man and His Work

To mark the 100th anniversary of the birth of Alexander Solomon Wiener, a lecture was presented before the 2007 Wiener Award winner's talk at the New York Blood Center. This article is based on that talk. Dr Wiener was very committed to his career and very devoted to his family, and living family members remember him with fondness. He had numerous personal and professional interests. He used his knowledge of blood groups in forensics, parentage studies, testing and monitoring mothers, and treating their babies for erythroblastosis fetalis (now known as hemolytic disease of the fetus and newborn). Dr Wiener's method for exchange transfusion was highly efficient. He appreciated the value of collecting plasma from women whose babies had hemolytic disease and making reagents with it. Indeed, the US National Institutes of Health license he obtained for this function was one before that obtained by ortho diagnostics. He was a stickler for doing tests correctly and insisted on the use of appropriate controls. Toward the end of his career, Dr Wiener became obsessed by the terminology for antigens in the Rh blood group system, but that should not distract from his contributions.

Psychopathological features of obsessive–compulsive disorder in an Italian family with Gilles de la Tourette syndrome not linked to the SLITRK1 gene

We report the psychopathological features in a large Italian family with Gilles de la Tourette syndrome not linked to the SLITRK1 gene. Of the 23 living family members, 14 were evaluated using the Structured Clinical Interview for DSM-IV, the Yale–Brown Obsessive–Compulsive Scale, the Clinical Global Impression and the Global Assessment of Functioning scale. Ten patients were found to have obsessive–compulsive disorder in which tic-like compulsions predominated. The distinctive feature of this family is the high frequency of obsessive–compulsive disorder with various clinical phenotypes.

Clinical Presentation and Genetic Analysis of a Five Generation Chinese Family with Isolated Left Ventricular Noncompaction

Isolated left ventricular noncompaction (ILVNC) is a rare congenital cardiomyopathy characterized by numerous excessive trabeculations and deep intertrabecular recesses. To date, the clinical features and genetic causes of ILVNC remain unclear. Here, we report the clinical presentation and genetic analysis of a five generation Chinese family with ILVNC. For this study, 21 living family members were recruited. Each individual underwent a detailed clinical examination for ILVNC. Peripheral blood samples were collected for direct gene sequencing to determine any mutations in the known disease-causing genes of ILVNC, which include the genes TAZ, DTNA, LDB3, LMNA and FKBP12. Classic echocardiographic presentation of ILVNC was identified in the proband who had his first onset of heart failure at age 52. His 28-year-old son and 26-year-old daughter showed similar heart anomalies as their father. Although they had no symptoms to date, depressed ventricular systolic function was noted in both of them. Pedigree analysis suggested an autosomal domain mode of inheritance. DNA sequencing found no mutation in the known disease-causing genes of ILVNC. Interestingly, two other members of the family, the proband's wife (also his first cousin) and her sister had classic echocardiographic presentation of hypertrophic cardiomyopathy (HCM). A single Chinese family with ILVNC associated with HCM is reported; no mutations in TAZ, DTNA, LDB3, LMNA and FKBP12 was found.

Case studies of minority student placement in special education

This book features vivid case studies that bring to life real children, school personnel, and family members from the bestselling book, Why Are So Many Minority Students in Special Education?. Once again addressing the disproportionate placement of minority students in special education programs, this new book includes the voices and perspectives of all stakeholders to show the tremendous complexity of the issues and the dilemmas faced by professionals, family members, and children. Challenging questions and scenarios are offered at the end of each case study to provide thoughtful follow-up activities and topics for further study. This collection of cases can be used - on its own or as a companion to the main volume - in elementary and special education courses and professional development workshops.

A novel DSPPmutation is associated with type II dentinogenesis Imperfecta in a chinese family

BackgroundHereditary defects of tooth dentin are classified into two main groups: dentin dysplasia (DD) (types I and II) and dentinogenesis imperfecta (DGI) (types I, II, and III). Type II DGI is one of the most common tooth defects with an autosomal dominant mode of inheritance. One disease-causing gene, the dentin sialophosphoprotein (DSPP) gene, has been reported for type II DGI.MethodsIn this study, we characterized a four-generation Chinese family with type II DGI that consists of 18 living family members, including 8 affected individuals. Linkage analysis with polymorphic markers D4S1534 and D4S414 that span the DSPP gene showed that the family is linked to DSPP. All five exons and exon-intron boundaries of DSPP were sequenced in members of type II DGI family.ResultsDirect DNA sequence analysis identified a novel mutation (c.49C→T, p.Pro17Ser) in exon 1 of the DSPP gene. The mutation spot, the Pro17 residue, is the second amino acid of the mature DSP protein, and highly conserved during evolution. The mutation was identified in all affected individuals, but not in normal family members and 100 controls.ConclusionThese results suggest that mutation p.Pro17Ser causes type II DGI in the Chinese family. This study identifies a novel mutation in the DSPP gene, and expands the spectrum of mutations that cause DGI.

X-Linked Hyper-Immunoglobulin M Syndrome: Molecular Genetic Study and Long-Time Follow-Up of Three Generations of a Chinese Family

Background: X-linked hyper-immunoglobulin M (IgM) syndrome (XHIGM) is a rare immunodeficiency disease caused by mutations of the CD40 ligand gene. Patients are subject to recurrent infections and have normal or elevated levels of IgM but markedly decreased serum IgG. Objective: We describe molecular genetic studies and clinical manifestations in three generations of one family, as well as results of long-term treatment of 2 young men with the disorder. Methods: Of 37 living family members, mutational analysis of the CD40 ligand gene was performed in 36 members. Laboratory data for patients and carriers were reviewed. Results: Four male family members had died of unexplained causes. The 3 patients with XHIGM syndrome and the 5 carriers all had a novel mutation located at Tyr 169 Asn (T526A) in exon 5, the tumor necrosis factor domain of the CD40 ligand gene. In the 3 patients, CD40 ligand expression in activated CD4+ T cells was below 1%. In the carriers, about half of activated CD4+ cells expressed CD40 ligand. One carrier had malignant lymphoma. Long-term (>20 years) intravenous immunoglobulin therapy in 2 patients improved IgG levels but did not fully suppress the high levels of IgM, nor did it prevent late complications (bronchiectasis and sclerosing cholangitis). Conclusions: Diagnosis of a genetic immunodeficiency, especially an X-linked disease such as XHIGM syndrome, should prompt a survey of the entire family.

Baby Think It Over: Evaluation of an Infant Simulation Intervention for Adolescent Pregnancy Prevention

In an intervention aimed at showing students the amount of responsibility involved in caring for an infant, 353 predominantly ninth-grade and Latino students carried the Baby Think It Over simulation doll in an intervention and completed matched pre- and posttest measures. Statistically significant gains were found on the total score and the impact of having a baby on academics, social life, and other family members; emotional risks; understanding and handling an infant's crying; and apprehension of the amount of responsibility involved in infant care. On a posttest-only measure, 108 participants reported statistically significant differences before and after carrying the doll with regard to the age at which they wished to have a child, their career and education plans, and the perceived interference of an infant with those education and career plans and their social life.

Cardiac arrhythmias and sudden death in infancy: implication for the medicolegal investigation

Genetically transmitted diseases are an important cause of juvenile sudden cardiac death (SCD). In a considerable proportion of individuals in which a medicolegal investigation is performed, structural heart disease is absent, and the medical examiner fails to discover an adequate cause of death. In such cases, an inherited arrhythmogenic disease should be considered, which manifests with life-threatening ventricular tachycardia or SCD. Molecular diagnosis is progressively becoming an important tool for these questions. Therefore, postmortem genetic testing ("molecular autopsy") should be considered as a part of the comprehensive medicolegal investigation in SCD cases without apparent structural heart disease. It will have implications not only for the deceased individual but also for living family members in preventing (further) cardiac events by expert counseling, appropriate lifestyle adjustment, and adequate treatment, if available.

CDH1 associated gastric cancer: a report of a family and review of the literature

Aims Hereditary diffuse gastric cancer (HDGC) is an autosomal-dominant inherited form of gastric cancer associated with inactivating germline mutations in the CDH1 gene. We set out to outline the role of CDH1 in HDGC. Investigation of a family suspected as having HDGC is discussed. The role of surgery in the management of affected individuals is then examined. Methods A search was conducted of Medline and the National Library of Medicine to identify key articles concerning CDH1 gene mutations, familial gastric cancer and gastrectomy. Further, relevant articles were obtained by manual scanning of the reference lists of identified papers. Mutation-specific CDH1 genetic testing was performed on six living family members and on gastric tissue obtained from two deceased members. Results CDH1 mutations cause inactivation of the cell adhesion protein E-cadherin. Carriers of the CDH1 germline gene mutation develop an aggressive, diffuse, submucosal gastric cancer at an early age. Current endoscopic screening is ineffective at detecting HDGC. The presence of a CDH1 germline gene mutation was confirmed in both deceased family members and also in four of the six living members tested. Conclusion Genetic counselling and CDH1 gene mutation testing is indicated in families with suspected HDGC. In the absence of a satisfactory surveillance mechanism, prophylactic total gastrectomy would appear to be an appropriate therapeutic option in mutation carriers.

Aberrant <I>p16</I> Methylation, a Possible Epigenetic Risk Factor in Familial Esophageal Squamous Cell Carcinoma

Detection of methylation in the p16 gene, an inhibitor of cyclin D-dependent protein kinase, as a new tumor marker for early detection of esophageal squamous cell carcinoma (ESCC) in DNA derived from blood and serum. A large family with clustering of ESCC was assessed in Khorasan province in northeastern Iran. The family had three histologically proven cases of ESCC in two consecutive generations and several other deceased cases with histories of ESCC. DNA from blood of 28 living family members in three consecutive generations, 30 sporadic ESCC cases (from serum, blood, and tumor tissues), and 30 healthy volunteers (from blood) were examined for the methylation status of p16 promoter using methylation-specific PCR (MSP). Aberrant p16 promoter methylation was found in 64.3% (n = 28) of ESCC family members and none (n = 30) of our normal volunteers. Five of the 28 family members with esophageal cancer symptoms had negative endoscopy results for ESCC, while four of these members had p16 hypermethylation in their blood. The family members with negative endoscopy and positive p16 promoter methylation are being monitored closely for signs of ESCC development through regular check-ups and chromoendoscopies. In sporadic ESCC in northeastern Iran, 73.3% (n = 30) of tumor tissue samples had p16 hypermethylation. Serum and blood samples from the same patients showed p16 hypermethylation in 26.6% and 43.3% of the samples, respectively. Aberrant p16 methylation may be a valuable diagnostic tool as a tumor marker for the early identification of individuals in high risk ESCC families.

Ethics. Constructing ethical guidelines for biohistory.

Increasingly, biohistorical analysis is being used to answer questions about historic figures9 behavior, disease, cause of death, and lineage, as well as for purposes of authentication of remains or artifacts. Such investigations raise social, legal, ethical, and scientific concerns for the historic figure, living family members, affected groups, and society in general. This Policy Forum analyzes relevant considerations and proposes a framework for regulating biohistorical research through professional guidelines.

Extensive investigation of a large Brazilian pedigree of 11778/haplogroup J Leber hereditary optic neuropathy

Purpose To conduct systematic epidemiologic, neuro-ophthalmologic, psychophysical, and mitochondrial DNA (mtDNA) genetic examinations on a newly identified pedigree with Leber hereditary optic neuropathy (LHON). Design Observational population cohort study. Methods A prospective investigation of an entire Brazilian LHON family. Setting A field investigation by an international team conducted in a remote part of Brazil. Study population We evaluated 265 (both eyes) of the 328 living family members of this LHON pedigree. Only members of this pedigree were studied. Those entering the pedigree as spouses were used as controls. Observation procedures We conducted epidemiologic interviews emphasizing possible environmental risk factors, comprehensive neuro-ophthalmologic examinations, psychophysical tests, Humphrey visual field studies, fundus photography, and blood testing for mitochondrial genetic analysis. Results We reconstructed a seven-generation maternal lineage descended from a common ancestor dating to the 1870s. All maternally related family members were invariably homoplasmic 11778 with a haplogroup J mtDNA, 33 being affected, of which 22 are still living. With each subsequent generation, there was a progressive decrease of penetrance, and only males were affected in the last two generations. A significant exposure (greater than 95% confidence intervals) to a variety of environmental risk factors characterized the affected individuals, with smoking as the most common ( P < .01). Both affected and carriers (95% confidence intervals) presented with a significantly lower incidence of hypertension and high cholesterol compared with the control group ( P < .05). Conclusions Almost 95% of a 328-living-member pedigree with LHON 11778/J haplogroup was comprehensively studied. Our initial results indicate the strong influence of environmental risk factors. The remarkably reduced incidence of cardiovascular risk in the maternal lineage is discussed. Further genetic analysis may reveal a role for the nuclear genome.

A Naturally Occurring Nonpolymerogenic Mutant of α1-Antitrypsin Characterized by Prolonged Retention in the Endoplasmic Reticulum

The classical form of alpha 1-antitrypsin (alpha 1-AT) deficiency is associated with a mutant alpha 1-ATZ molecule that polymerizes in the endoplasmic reticulum (ER) of liver cells. A subgroup of individuals homozygous for the protease inhibitor (PI) Z allele develop chronic liver injury and are predisposed to hepatocellular carcinoma. In this study we evaluated the primary structure of alpha 1-AT in a family in which three affected members had severe liver disease associated with alpha 1-AT deficiency. We discovered that one sibling was a compound heterozygote with one PI Z allele and a second allele, the PI Z + saar allele, bearing the mutation that characterizes alpha 1-ATZ as well as the mutation that characterizes alpha 1-AT Saarbrucken (alpha 1-AT saar). The mutation in PI saar introduces a premature termination codon resulting in an alpha 1-AT protein truncated for 19 amino acids at its carboxyl terminus. Studies of a second sib with severe liver disease and other living family members did not reveal the presence of the alpha 1-AT saar mutation and therefore do not substantiate a role for this mutation in the liver disease phenotype of this family. However, studies of alpha 1-AT saar and alpha 1-ATZ + saar expressed in heterologous cells show that there is prolonged intracellular retention of these mutants even though they do not have polymerogenic properties. These results therefore have important implications for further understanding the fate of mutant alpha 1-AT molecules, the mechanism of ER retention, and the pathogenesis of liver injury in alpha 1-AT deficiency.

Frequency of the R3500Q mutation of the apolipoprotein B-100 gene in a sample screened clinically for familial hypercholesterolemia in Hungary

Familial hypercholesterolemia (FH) and familial defective apolipoprotein B-100 (FDB) cause early onset of coronary heart diseases (CHD). According to the recommendations of the international MEDPED program, we tried to find FH cases. We analyzed 73 FH probands and their 304 first-degree relatives. A total of 39 probands were found from the 21 000 subjects screened (1:538) from family doctors’ registers recording all citizens, while the remaining 34 were derived from screened patients from lipid clinics. In our FH probands, four cases of FDB (R3500Q mutation) were diagnosed with allele-specific PCR, and the mutation was also detectable in five cases out of seven living family members. In the remaining 69 FH families, 156 people were diagnosed clinically with FH, and 31.8% of the males (against 13% of the not clinically diagnosed FH males, P<0.01), and 32.4% of the females (against 13.5% of the not clinically diagnosed FH females, P<0.01) suffered from early onset CHD. The plasma total cholesterol level of the FDB patients, especially in the younger patients, was very close to normal values. Therefore, the FDB patients seem to be under-represented in this type of survey. Because FDB is one of the independent causes of early onset CHD, the R3500Q mutation should be considered in families with a high frequency of cardiovascular diseases.

High incidence of sudden death with conduction system and myocardial disease due to lamins A and C gene mutation.

We studied 54 living relatives from a large French kindred, among which 17 members presented with a cardiomyopathy transmitted on an autosomal dominant mode. Five of these individuals had clinical manifestations of muscle disease phenotypically consistent with Emery-Dreifuss muscular dystrophy. Genetic analysis of this kindred had demonstrated a nonsense mutation in the LMNA gene located on chromosome 1q11-q23. This gene encodes lamins A and C, proteins of the nuclear lamina located on the inner face of the nuclear envelope. We retrospectively determined the cause of death of 15 deceased family members, 8 of whom had died suddenly, 2 as a first and single manifestation of the disease. The six other cases had histories of arrhythmias and left ventricular dysfunction before dying suddenly, and three of them died despite the prior implantation of a permanent pacemaker. The mean age of onset of cardiac symptoms among affected living family members was 33 years (range 15-47 years), and the first symptoms were due to marked atrioventricular conduction defects or sinus dysfunction, requiring the implantation of permanent pacemakers in seven cases. Myocardial dysfunction accompanied by ventricular arrhythmias developed rapidly in the course of the disease and resulted in severe dilated cardiomyopathy requiring cardiac transplantation in three cases. In conclusion, in patients presenting a life-threatening familial or sporadic cardiac restricted phenotype similar to that described here, mutations in the lamins A and C gene should be looked for. In the genotypically affected individuals, cardiological and electrophysiological follow-up should be performed to prevent sudden death that could occur rapidly in the evolution of such disease.

Two independent mutations in a family with neurofibromatosis type 1 (NF1)

We report on two independent alterations of the NF1 gene in a three-generation kindred with neurofibromatosis type 1 (NF1). Using temperature gradient gel electrophoresis (TGGE) in a mutation analysis of exon 31 of the NF1 gene we detected the previously reported nonsense mutation R1947X. This C-to-T transition at codon 1947 in exon 31 is considered to represent a mutation “ot spot” of the NF1 gene due to 5mCpG deamination. All living family members together with their genomic DNA were included in this investigation. However, the mutation R1947X was absent from two undoubtedly affected siblings of the propositus. Another NF1 mutation (889-2A→G) was identified in the two sibs by the protein truncation test (PTT). The novel splice site mutation 889-2A→G results in a skip of NF1 exon 7 during splicing and protein truncation due to frameshift. The two NF1 alterations are linked to different paternal haplotypes. In our study of a three-generation kindred, R1947X represents a de novo mutation whereas 889-2A→G is an inherited splice mutation. Implications for phenotype variation are discussed. Am. J. Med. Genet. 83:6–12, 1999. © 1999 Wiley-Liss, Inc.

Two independent mutations in a family with neurofibromatosis type 1 (NF1)

We report on two independent alterations of the NF1 gene in a three-generation kindred with neurofibromatosis type 1 (NF1). Using temperature gradient gel electrophoresis (TGGE) in a mutation analysis of exon 31 of the NF1 gene we detected the previously reported nonsense mutation R1947X. This C-to-T transition at codon 1947 in exon 31 is considered to represent a mutation "hot spot" of the NF1 gene due to 5mCpG deamination. All living family members together with their genomic DNA were included in this investigation. However, the mutation R1947X was absent from two undoubtedly affected siblings of the propositus. Another NF1 mutation (889-2A-->G) was identified in the two sibs by the protein truncation test (PTT). The novel splice site mutation 889-2A-->G results in a skip of NF1 exon 7 during splicing and protein truncation due to frameshift. The two NF1 alterations are linked to different paternal haplotypes. In our study of a three-generation kindred, R1947X represents a de novo mutation whereas 889-2A-->G is an inherited splice mutation. Implications for phenotype variation are discussed.

Genetic studies of a family with hereditary hyperparathyroidism-jaw tumour syndrome.

Familial hyperparathyroidism may occur as familial isolated hyperparathyroidism (FIHP) or as part of an inherited syndrome, in particular multiple endocrine neoplasia types 1 and 2A (MEN1, MEN2A) and hyperparathyroidism-jaw tumour (HPT-JT) syndrome. The localization of the genes responsible for these syndromes has enabled genetic screening of families with primary hyperparathyroidism (PHPT) to be carried out. This has important clinical implications in terms of individual follow-up and management. We previously reported a large FIHP family with an increased risk of parathyroid cancer and excluded its linkage to MEN1, MEN2 and PTH genes. Here we re-analysed this family and performed genetic linkage to the HPT-JT locus in chromosome 1q21-q32. Loss of heterozygosity studies of 1q21-q32, 11q13 and X chromosome were also performed. We studied 19 family members, aged 6-63 years. High molecular weight DNA was isolated from peripheral blood samples from 17 family members. For the two deceased individuals, DNA was extracted from normal paraffin embedded tissues. All individuals (except two deceased patients) had serum corrected calcium, inorganic phosphate, intact PTH, prolactin and various pancreatic hormones, measured on fasting blood samples. Twenty microsatellite markers were examined for the 1q21-q32 region, the locus for the HPT-JT gene. Genetic polymorphisms were determined by polymerase chain reaction amplification of genomic DNA and genetic linkage analysis was performed. Loss of heterozygosity studies were performed using paraffin-embedded parathyroid tissues from four affected members. Seven of the eight affected family members included in this study had biochemical evidence of PHPT and surgically proven parathyroid tumours. Indication of linkage of the disease to the HPT-JT locus was demonstrated with a maximum lod score of 2.32 by two-points linkage analysis. Linkage data were supported by multi-point analysis which gave a maximum lod score of 2.7. Meiotic recombinations detected in one affected individual narrowed the region to 26 cM. As a result of the genetic findings, we re-screened the living family members by orthopantomograph and renal ultrasound, and identified two jaw lesions in two gene carriers. One affected family member demonstrated polycystic kidney disease, thus establishing the association between the two conditions. A reduced penetrance of HPT in females was evident, in agreement with our previous study. No allelic deletion was detected in any tumour at 1q21-q32, 11q13 or X chromosome. This study illustrates the usefulness and importance of genetic studies in familial isolated hyperparathyroidism families. Our clinical and genetic findings indicate that this previously reported familial isolated hyperparathyroidism family has hyperparathyroidism-jaw tumour syndrome.

Prostate Cancer Susceptibility Locus on Chromosome 1q: A Confirmatory Study

Background: Recent recognition that a predisposition to prostate cancer can be inherited has led to a search for specific genes associated with the disease. Through a study of families with three or more affected first-degree relatives, a region on the long arm of chromosome 1 (i.e., 1q24-25) has been tentatively identified as containing a gene, HPC1, involved in the development of hereditary prostate cancer. Confirmation of this finding is needed, however, before attempts are made to isolate and characterize the putative HPC1 gene. Purpose: To confirm that chromosome 1q24-25 contains a gene relevant to hereditary prostate cancer, we analyzed an independent set of families, each with two or more affected individuals. Methods: Fifty-nine unrelated families were selected for analysis on the sole criterion that more than one living family member was affected by prostate cancer. DNA samples were subsequently isolated from 130 individuals with the disease. These samples were genotyped at six polymorphic marker sequences (D1S215, D1S2883, D1S466, D1S158, D1S518, and D1S2757) covering the chromosomal region proposed to contain HPC1. The resulting data were analyzed by nonparametric multipoint linkage (NPL) methods, yielding NPL Z scores and corresponding one-sided P values. Results: When the entire set of 59 families was considered, the occurrence of prostate cancer (and, presumably, the HPC1 gene) was most tightly linked to marker D1S466 (NPL Z score = 1.58; P = .0574). Analysis of the 20 families (51 affected individuals) fulfilling one or more of the proposed clinical criteria for hereditary prostate cancer (i.e., three or more affected individuals within one nuclear family; affected individuals in three successive generations [maternal or paternal lineage]; and/or clustering of two or more individuals affected before the age of 55 years) revealed more convincing evidence of disease linkage to chromosome 1q24-25 (maximum NPL Z score [at marker D1S466] = 1.72; P = .0451). The 39 families (79 affected individuals) that did not meet the clinical criteria for hereditary prostate cancer exhibited no significant evidence of disease linkage to DNA sequences at chromosome 1q24-25 (maximum NPL Z score [at marker D1S466] = 0.809; P = .208). The six African-American families in our study contributed disproportionately to the observation of linkage, with a maximum NPL Z score at marker D1S158 of 1.39 (P = .0848) for these families. Conclusions and Implications: Our data confirm that chromosome 1q24-25 is likely to contain a prostate cancer susceptibility gene. Future efforts at positional cloning of the HPC1 gene should focus on families who meet the proposed clinical criteria for hereditary prostate cancer. [J Natl Cancer Inst 1997;89:955-9]

A clinical, echocardiographic and genetic characterization of a Danish kindred with familial amyloid transthyretin methionine 111 linked cardiomyopathy.

To identify carriers and non-carriers of the mutant transthyretin methionine 111 linked familial amyloid disease, to detect early signs of the restrictive cardiomyopathy and other clinical manifestations characteristic of this inheritable disease. Out of 125 living family members 99 were available for clinical, echocardiographic and genetic examination. Twenty-five family members were heterozygous carriers of the mutant transthyretin methionine 111 genotype, while 74 were non-carriers. Among the 25 carriers, none had overt clinical signs of heart disease. Eight carriers, all above the age of 35, showed echocardiographic abnormalities suggestive of developing or manifest restrictive cardiomyopathy. Three had biopsy-verified transthyretin-related amyloid cardiomyopathy. None of the 15 carriers in the younger age group exhibited aberrant echocardiographic patterns. Nine carriers had carpal tunnel syndrome as opposed to none of the non-carriers. For early detection of familial amyloid cardiomyopathy, echocardiography is the investigation of choice. The first sign is diastolic dysfunction detected as an abnormal relaxation pattern. The appearance of echocardiographic aberrations solely in the older age group suggests that the cardiomyopathy is a late onset disease. Carpal tunnel syndrome appears to be the earliest presenting clinical symptom. A curative treatment seems to be an early liver transplantation.