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Eighteen Swedish patients with familial amyloidotic polyneuropathy were tested for the met30 mutation of the transthyretin (TTR) (prealbumin) gene by RFLP analysis of genomic DNA using the restriction enzyme NsiI. The results confirmed previous findings that the Swedish variant of familial polyneuropathy has the same valine by methionine substitution at position 30, as seen in patients with FAP from Japan, Portugal or patients of Swedish descent from USA. However, two of the patients were homozygous, totally lacking the wild type allele. Measurable serum values for the variant transthyretin (TTR) was detected with a RIA-method in all the 18 Swedish FAP patients studied with a mean concentration of 12.1 +/- 5.1 (SD) mg/100 ml, (11.0 +/- 4.1 when the two homozygotes were excluded). In 45 Japanese patients the mean was 9.2 +/- 2.7 mg/100 ml. The variant TTR was not detected in the healthy controls. The value for the variant TTR was nearly twice that high in the two homozygous patients, 21.14 and 21.16 mg/100 ml, respectively. There was no correlation between the serum levels of variant TTR and the duration of disease or levels of serum albumin in the FAP-patients.

Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant inherited disorder characterized by progressive peripheral and autonomic neuropathy, associated with neural and systemic amyloid deposits. The amyloid fibrils contain a variant transthyretin (TTR) molecule (TTR met30), over 90% of which is produced in the liver. After liver transplantation in two patients with severe symptomatic FAP, only normal TTR was detectable in circulation. The two patients are being monitored at regular intervals, and, although in one patient there was no evidence of reduction in the quantity of amyloid present at 6 months, there had been no further progression of the neuropathy.

A syndrome with severe generalized congenital ichthyosis, alopecia, eclabion, ectropion and mental retardation without neurological symptoms or macular changes in the eyes was seen in two sibs and in two aunts and uncles in an inbred North-Swedish family. The clinical picture of the patients in the present family strongly deviated from that seen in the Sjögren-Larsson syndrome found in the same area. This could be a new syndrome with autosomal recessive inheritance.

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.

A series of children with mild mental retardation (171 children, IQ 50-69) born in 1959-1970 in a northern Swedish county and registered by the Board for Provisions and Services to the Mentally Retarded were analysed retrospectively. The mean annual incidence of mild mental retardation in registered children alive at the age of one year decreased during the period 1959-1970 and for the whole period was 4.2 per 1000, compared with 3.9 per 1000 for severe mental retardation in the same period of time and area. Ten children once classified as mildly mentally retarded made considerable intellectual progress and after some time no longer needed special help from the authorities. There was a pronounced male excess in the total series (1.8:1) and in all the main aetiological groups. Only small differences were found in mean birth weights, gestational age and maternal age in the main aetiological groups. In the series as a whole, however, there was an increased frequency of children small for gestational age. Prenatal causes were considered relevant in 43 per cent, perinatal in 7 per cent, and postnatal in 5 per cent. In 2 per cent there was a psychosis. In 43 per cent the aetiology could not be traced. Genetic causes were found in 31 per cent; in 8 per cent there was a chromosomal aetiology, in a further 8 per cent a mutant gene disorder and in 15 per cent the aetiology were considered multifactorial, i.e. at least one first-degree relative also had mental retardation and in both cases the cause of the retardation was unknown. Thirty per cent of the children had associated CNS handicaps, epilepsy (16 per cent) being the most frequent.

A gene (DYT1) for susceptibility to early-onset torsion dystonia in Ashkenazi Jewish and Gentile kindreds is situated on chromosome 9q32-q34 in a 6-7 cM span between markers AK1 and ASS. To determine whether transmission of familial dystonia with myoclonic jerks responsive to alcohol was consistent with a gene in this region, we studied the 37 members of a Swedish family, of whom 20 were so affected. A lod score of-2.00 from a two-point linkage analysis with six DNA markers covering a 30 cM span from D9S26 to D9S10 that included the region of the DYT gene indicated that this gene is not located in this region, and that two or more autosomal loci are responsible for hereditary dystonia in humans.

Four Swedish families in northern Sweden with polycystic lipomembranous osteodysplasia (PLO-SL) were studied genealogically. Historical and genealogical date provided evidence for a Finnish origin. Both parents of two of the families could be traced back to Finnish ancestors, and the other two families had a common origin in a region with a known Finnish influence, but without evidence for Finnish ancestry. PLO-SL is the first rare monogenic disease with an autosomal recessive inheritance in Sweden with a probable Finnish origin.

Two Swedish families with Huntington's disease (HD) have been investigated for linkage with G8 (D4S10). In one family from northern Sweden (Family 1) 48 family members were examined, and in another family from the southwestern part of Sweden (Family 2) 14 family members were examined. The lod scores were 1.531 for Family 1 and 2.057 for Family 2, and the combined lod score was 3.59. The HD gene was segregating with the haplotype C in Family 1 and with haplotype A in Family 2. The predictive value of the test was obvious. Before the testing with the G8 probe, 84.2% of the family members in Family 1 had a theoretical risk of 25% or 50% of having the HD gene. After the testing with the G8 probe, only 23.7% of the family members remained at the same risk, and it could also be certified that 63.2% had no or little risk of having the HD gene. Only one asymptomatic person was predicted to have HD.

In a country-wide screening examination in Sweden, PKU was observed in 75 (4.5 per 1,000) and hyperphenylalaninemia in 14 (0.8 per 1,000) of a total of 16,805 patients in institutions for the mentally retarded. In the national neonatal screening program in 1965-1975, which covered nearly 1 million individuals, PKU was observed in 36 and hyperphenylalaninemia in 19 individuals. The incidences of PKU and hyperphenylalaninemia in newborns are calculated to be 1/26,000 and 1/50,000, respectively. In addition, PKU and hyperphenylalaninemia were diagnosed in 14 and 1 non-institutionalized individuals, respectively, born before September 1965. The total numbers of individuals detected as having PKU and hyperphenylalaninemia in Sweden in the present investigation are 125 and 34, respectively.

The effect of folic acid intake on the frequency of fragile X positive cells and some behavioural characteristics were evaluated in 5 boys and 4 adult males with the fragile X syndrome. The expression of fragile X was nullified in 6 and decreased in 3 of the 9 patients. Behavioural and motor ability were considered to have improved in 4 of the 5 boys but not in the 4 adults with fragile X syndrome.

Sjogren-Larsson syndrome (SLS), originally described in Sweden, has been studied in a countrywide survey. A total of 58 SLS patients in 41 families were traced, 35 of them still alive. Thirty patients, 23 alive and seven deceased, have not been reported earlier. The mean incidences per 100,000 in the years 1901–1977 were 0.6 in the whole of Sweden, 10.2 in the county of Vasterbotten and 2.7 per 100,000 in the county of Norrbotten. In the above-mentioned areas, the prevalence figures for SLS on 31st December 1978 were estimated to be 0.4, 8.3 and 2.6 per 100,000 persons, the frequencies of SLS gene carriers 0.5, 2.0 and 1.0%, and the gene frequencies 0.002, 0.010 and 0.005, respectively. Of the 58 identified Swedish SLS patients, 45 were born in a restricted area in the northeast of Sweden.

The prevalence of diabetes mellitus : a study of children and their relatives in a northern Swedish county.

Although amyloidogenic transthyretin (ATTR) mutations are common in several populations, such as black Americans, the small number of diagnosed patients homozygous for TTR amyloid and the short follow up in most studies has until now prevented an analysis of their phenotype. In Sweden, nine homozygous patients from eight families carrying the ATTR mutation Val30Met, which gives rise to fatal neuropathic amyloidosis (FAP), have been identified and have now been followed for up to 15 years. This has enabled an analysis of the phenotype of homozygous patients. Genetic testing and detection of amyloid deposits in the vitreous body or in intestinal or skin biopsies confirmed the diagnosis in all patients. The patients' symptoms were obtained from medical records. For comparison, we used a group of 35 heterozygous non-transplanted patients with FAP (18 men and 17 women), who had been evaluated at the Department of Medicine, Umeå University Hospital before their deaths. Vitreous amyloidosis was the most prevalent symptom in the homozygous group, and in two patients it was the only manifestation of the disease during their lifetime. The age at onset was not different from that of heterozygous patients, and their survival tended not to be shorter but actually longer than for heterozygotes. Homozygosity for the mutation associated with FAP, ATTR Val30Met, does not implicate a more severe phenotype for Swedish patients. The most common symptom was vitreous opacity, which may be the only manifestation of the disease. These findings point to the possibilities of different pathways for amyloid formation, or the presence of hitherto unknown genes operating in amyloid formation.

Familial amyloidotic polyneuropathy (FAP) designates TTR mutations where the phenotype is dominated by a peripheral sensory-motor polyneuropathy. The most common mutation is ATTR Val30Met. FAP in association with ATTR Phe33Leu has been described previously in two American families, one of Polish-Lithuanian descent and the other of Polish-American. In this study, we report the phenotype of the ATTR Phe33Leu in a Swedish family. The proband is a 48 year-old patient from northern Sweden, whose father died with symptoms suggestive of FAP. Characteristic clinical features included polyneuropathy, carpal tunnel syndrome and asymptomatic, but echocardiographic examination diagnosed cardiomyopathy. The family history supports an early intervention with orthotopic liver transplantation in patients with FAP associated with the TTR Phe33Leu, and the patient was submitted for liver transplantation.

For familial amyloidotic polyneuropathy (FAP) patients, several problems regarding reproduction are present. For males, erectile dysfunction and retrograde ejaculation are well known complications of the disease In addition, the risk of transferring a fatal disease to their offspring is a matter of concern for the patients. For transplanted fertile patients, the risk of side effects of immunosupression therapy causing congenital malformations must be addressed, and for female patients the additional risk of complications during pregnancy and delivery is a case of concern. After delivery, the problem of breast-feeding arises. In the Swedish population of transplanted patients, five successful pregnancies, of which male FAP recipients fathered three, are reported. All patients were on stable immunosuppressive therapy with cyclosporine or tacrolimus and prednisolone. From our experience, successful fatherhood and pregnancy is possible for liver transplanted FAP patients, as it has been reported for patients transplanted for other medical reasons.

Identification of genes associated with pain insensitivity syndromes can increase the understanding of the pathways involved in pain and contribute to the understanding of how sensory pathways relate to other neurological functions. In this report we describe the mapping and identification of the gene responsible for loss of deep pain perception in a large family from northern Sweden. The loss of pain perception in this family is characterized by impairment in the sensing of deep pain and temperature but with normal mental abilities and with most other neurological responses intact. A severe reduction of unmyelinated nerve fibers and a moderate loss of thin myelinated nerve fibers are observed in the patients. Thus the cases in this study fall into the class of patients with loss of pain perception with underlying peripheral neuropathy. Clinically they best fit into HSAN V. Using a model of recessive inheritance we identified an 8.3 Mb region on chromosome 1p11.2-p13.2 shared by the affected individuals in the family. Analysis of functional candidate genes in the disease critical region revealed a mutation in the coding region of the nerve growth-factor beta (NGFB) gene specific for the disease haplotype. This NGF mutation seems to separate the effects of NGF involved in development of central nervous system functions such as mental abilities, from those involved in peripheral pain pathways. This mutation could therefore potentially provide an important tool to study different roles of NGF, and of pain control.

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 (T(4)) 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.

Suhr OB, Svendsen IH, Andersson R, Danielsson A, Holmgren G, Ranlov PJ (Umea University Hospital, Umea, Sweden; Rigshospitalet, Kobenhavn O, Denmark; Ornskoldsviks Hospital, Ornskoldsvik, Sweden; and Horsholm Hospital, Horsholm, Denmark). Hereditary transthyretin amyloidosis from a Scandinavian perspective (Review). J Intern Med 2003; 254: 225–235. Hereditary transthyretin (TTR) amyloidosis is a rare often fatal form of systemic amyloidosis, that until recently was considered intractable, with the patients dying from the disease 5–15 years after onset. The phenotype of the disease varies according to the type of mutation, but generally the heart and/or the nervous system is affected. Liver and in some cases heart transplantation has now been shown to stop the progress of the disease, but the outcome depends on the patients’ status at the time of operation, as no substantial improvement of the patients’ symptoms has been noted after the procedure. Thus an early diagnosis is of importance for the outcome. In the following, we summarize our knowledge of the amyloidogenic TTR mutations found in the Scandinavian countries, their symptoms, how to settle the diagnosis and the outcome of transplantation. Besides, the problems arising from our capability to genetically test asymptomatic members of affected families for the trait will be discussed.

We have identified a large family in the northern part of Sweden with multiple cases of autoimmune diseases, namely type 1 diabetes (T1D), Graves' disease (GD) and Hashimoto's thyroiditis (HT). The family members affected by any of these diseases share a region of 2.4 Mb that comprises among others the CTLA4 gene. We determined that all affected members of the family shared the HLA susceptibility haplotype (DR4-DQA1*0301-DQB1*0302). Analysis of genetic interaction conditioning for HLA haplotype provided strong evidence that the critical region which includes the CTLA4 gene acts together with the HLA locus on the etiology of disease (lodscore 4.20 (theta=0.0). The study of this family allowed us to: (1) reinforce a number of reports on linkage and association of the CTLA4 region to T1D and AITD; (2) demonstrate that a single haplotypic variant in this region constitutes an etiological factor to disease susceptibility in T1D, GD and HT; (3) reveal a strong genetic interaction of the CTLA4 and HLA loci in the genetic architecture of autoimmune disease; (4) emphasise the value of large pedigrees drawn from isolated populations as tools to single out the effect of individual loci in the etiology of complex diseases.

Migraine is the most common type of chronic episodic headache. To find novel susceptibility genes for familial migraine with and without aura, a genomewide screen was performed in a large family from northern Sweden. Evidence of linkage was obtained on chromosome 6p12.2-p21.1, with a maximum two-point lod score of 5.41 for marker D6S452. The patients with migraine shared a common haplotype of 10 Mb between markers D6S1650 and D6S1960.

Spectral karyotyping (SKY) on metaphase spreads from 15 high hyperdiploid (>51 chromosomes) childhood acute lymphoblastic leukemias (ALL), which typically display a poor chromosome morphology, was performed in order to investigate the pattern of numerical abnormalities, reveal the chromosomal origin of marker chromosomes, and identify translocations and other interchromosomal rearrangements not detected by G-banding analysis. In all cases the numerical changes could be fully characterized, and a non-random pattern of chromosomal gain was identified, with chromosomes X, 21, 14, 17, 6, 18, 4, and 10 being most frequently gained. The numerical changes had been partly misinterpreted in 12 of the 15 ALL patients using G-banding, and the present study hence emphasizes the importance of SKY in identifying such anomalies, some of which, i.e. +4 and +10, have been suggested to be prognostically important. The chromosomal origin of all marker chromosomes and of seven structural rearrangements, one of which was the prognostically important Philadelphia chromosome, could be identified. Five rearrangements [der(1)t(1;14)(q32;q21), der(2)t(2;8)(q36;?), der(3)t(2;3)(q21;?), der(8)t(8;14)(?;?), and t(9;21)(q12;q22)] have previously not been reported in ALL, emphasizing the value of SKY in identifying novel chromosomal rearrangements.

A novel Val154-->Ile mutation in the D2 dopamine receptor (DRD2) on chromosome 11q23 has recently been shown to be associated with myoclonus dystonia (M-D) in one large family. Sequence analysis of the DRD2 gene in 5 M-D patients from different families did not reveal any mutations, nor was there evidence of linkage to the 11q23 region in the DRD2 gene in four other families. Receptor binding and signal transduction assays of the DRD2 mutant and wild-type receptors revealed identical agonist and antagonist affinities and functional responses. These studies suggest that M-D is genetically heterogeneous. The molecular mechanisms through which the Val-->Ile mutation may contribute to M-D remain to be determined.

The aim of the present study was to compare the clinical symptoms of Swedish and Japanese patients with familial amyloidotic polyneuropathy (ATTR Val Met), especially gastrointestinal disturbances, and to correlate the findings with survival.Seventy-three Swedish and 47 Japanese patients were available for the study. Thirty-two Swedish and 7 Japanese patients had undergone liver transplantation. The mean age at onset was 50 for Swedish and 35 for Japanese patients (P

Background For all forms of amyloidosis, the amyloid-generating mechanism is unknown. Familial amyloidotic polyneuropathy type I is caused by a variant transthyretin (TTR Met-30). As electrospray ionization mass spectrometry (ESI-MS) discloses both thiol-conjugated and -unconjugated forms of wild-type and variant TTR, we wanted to investigate the relationship between TTR conjugation and clinically overt amyloid disease. Methods Plasma from 35 individuals (12 symptomatic TTR Met-30 carriers, nine asymptomatic and 14 healthy control subjects) were analysed using ESI-MS. Results The total TTR concentration was significantly lower in symptomatic TTR Met-30 carriers than in control subjects. An increased percentage of conjugated TTR Met-30 was found in symptomatic carriers compared with asymptomatic, whereas the percentage conjugated wild-type TTR was similar for control subjects, asymptomatic and symptomatic TTR Met-30 carriers. Conclusion The finding of a decreased ratio of unconjugated to conjugated TTR Met-30 in plasma samples from symptomatic TTR Met-30 carriers indicates that thiol conjugation of TTR could be involved in amyloid formation.

Best macular dystrophy (BMD), also known as vitelliform macular dystrophy (VMD2; OMIM 153700), is an autosomal dominant form of macular degeneration characterized by an abnormal accumulation of lipofuscin within and beneath the retinal pigment epithelium cells. In pursuit of the disease gene, we limited the minimum genetic region by recombination breakpoint analysis and mapped to this region a novel retina-specific gene (VMD2). Genetic mapping data, identification of five independent disease-specific mutations and expression studies provide evidence that mutations within the candidate gene are a cause of BMD. The 3′ UTR of the candidate gene contains a region of antisense complementarity to the 3′ UTR of the ferritin heavy-chain gene ( FTH1), indicating the possibility of antisense interaction between VMD2 and FTH1 transcripts.

The purpose of the present study was to evaluate the impact of liver transplantation on familial amyloidotic polyneuropathy (FAP met-30) patients' survival. Forty-five FAP patients were involved in the study; 15 non-transplanted FAP patients and 30 liver-transplanted patients. All patients' records were scrutinised for information on disease duration. Preoperative nutritional status was evaluated in all patients. No difference in survival was observed for transplanted patients overall compared to historical controls. However, for cases in good nutritional status, an increased survival can be expected as a significantly increased mortality rate for malnourished patients was observed (P < 0.05). Increased survival has so far not been found for transplanted FAP patients. However, none of the transplanted cases has yet reached the expected survival time for non-transplanted FAP control patients, which is 14 years. A high fatality rate of malnourished patients transplanted late in the course of the disease contributed significantly to the mortality among transplanted patients.

Spinocerebellar ataxia 7 (SCA7) is a neurodegenerative disorder characterized by degeneration of the cerebellum, brainstem and retina. The gene responsible for SCA7, located on chromosome 3p, recently was cloned and shown to contain a CAG repeat in the coding region of the gene, that is expanded in SCA7 patients of French origin. We examined the SCA7 repeat region in four Swedish SCA7 families as well as in 57 healthy controls. All Swedish SCA7 patients exhibited expanded CAG repeats with a strong negative correlation between repeat size and age of onset. The repeat length in SCA7 patients ranged from 40 to200 repeats. The largest expansion was observed in a juvenile case with an age of onset of 3 months, and represents the longest polyglutamine stretch ever reported. In patients with 59 repeats or more, visual impairment was the most common initial symptom observed, while ataxia predominates in patients with59 repeats. Two of the Swedish SCA7 families analysed in this study were shown to be related genealogically. The other two SCA7 families could not be traced back to a common ancestor. All four families shared the same allele on the disease chromosome at a locus closely linked to SCA7, suggesting the possibility of a founder effect in the Swedish population.

Flow cytometric DNA-index (DIFCM) and karyotype were analysed in 82 consecutive children with acute lymphoblastic leukemia (ALL) during a 10 year period. A statistically significant correlation existed between modal chromosome number and DIFCM(p= 0.009). DIFCMcould reliably identify leukemias with >51 chromosomes, whereas only three out of 12 cases with modal chromosome numbers between 47–51 were classified as aneuploid by DIFCM. In the pseudodiploid group only one out of 20 leukemias had a DIFCM>1.0. Five leukemias with a diploid karyotype showed an aneuploid DIFCMand in three patients the flow cytometric measurement revealed biclonality undetected by karyotyping. During treatment aneuploid clones could be detected by DIFCMin a substantial number of cases where the cytogenetic analysis was normal, and the opposite was also demonstrated in one case. DIFCMgave prognostic information, showing that cases with a DI >1.12 (corresponding to 51 chromosomes) had a superior outcome with treatment protocols today in use.

Amelogenesis imperfecta (AI) is a broad group of hereditary enamel defects that is characterized by a high degree of clinical diversity. Recently, the local hypoplastic form of autosomal dominant AI (AIH2) has been mapped to human chromosome 4q in a 17.6-cM region. This locus has been further refined to a 4-Mb interval between D4S2421 and Albumin. Recently, a cDNA clone for an enamel matrix protein, ameloblastin (AMBN), has been isolated. In this report, we have isolated a PAC human genomic clone containing the human AMBN gene. The AMBN was mapped by two color fluorescencein situhybridization using two P1 genomic clones for sequence-tagged site (STS) markers, D4S400 and D4S409, which flank the critical AIH2 region. Our results place AMBN at 4q21 between D4S409 (4q13) and D4S400 (4q21). Furthermore, the AMBN PAC genomic clone was shown to contain three STS markers, D4S2604, D4S2670, and D4S2609, which are contained within the critical region defined by six Swedish families with AIH2. AMBN is therefore a strong candidate gene for AIH2.

Amelogenesis imperfecta (AI) is a clinically and genetically heterogeneous group of inherited enamel defects. We recently mapped a locus for autosomal dominant local hypoplastic amelogenesis imperfecta (AIH2) to the long arm of chromosome 4. The disease gene was localized to a 17.6-cM region between the markers D4S392 and D4S395. The albumin gene (ALB), located in the same interval, was a candidate gene for autosomal dominant AI (ADAI) since albumin has a potential role in enamel maturation. Here we describe refined mapping of the AIH2 locus and the construction of marker maps by radiation hybrid mapping and yeast artificial chromosome (YAC)-based sequence tagged site-content mapping. A radiation hybrid map consisting of 11 microsatellite markers in the 5-cM interval between D4S409 and D4S1558 was constructed. Recombinant haplotypes in six Swedish ADAI families suggest that the disease gene is located in the interval between D4S2421 and ALB. ALB is therefore not likely to be the disease-causing gene. Affected members in all six families share the same allele haplotypes, indicating a common ancestral mutation in all families. The AIH2 critical region is less than 4 cM and spans a physical distance of approximately 4 Mb as judged from radiation hybrid maps. A YAC contig over the AIH2 critical region including several potential candidate genes was constructed.

To screen for transthyretin (TTR) related amyloidosis rapidly and reliably, we have developed a new method using a centrifugal concentrator device and electrospray ionization mass spectrometry (ESI-MS). Only 50 μl of serum is needed for the analysis. After preparation of the samples with anti-TTR antibody they were passed through a 1000 kDa cut off centrifugal concentrator which retained the antibody. By analyzing the obtained filtrate with ESI-MS, variant forms of TTR was detected. TTR (Met30), with a molecular weight 32.0 Da higher than the normal form of TTR, was found in all FAP patients examined. In 3 liver transplanted FAP patients, the abnormal peaks had disappeared. In conclusion, The TTR Met30 mutation was easily detected in serum samples by electrospray ionization mass spectrometry after centrifugal concentration. The proposed method is simple to perform, as no HPLC is required, and offers a possibility to screen populations for TTR related amyloidosis.

Amelogenesis imperfecta (AI) is a group of hereditary enamel defects, characterized by large clinical diversity. On the basis of differences in clinical manifestation and inheritance pattern, 14 different subtypes have been recognized. A locus for autosomal dominant AI (ADAI) of local hypoplastic type was recently mapped to the region between D4S392 and D4S395 on the long arm of chromosome 4. To test whether the chromosome 4 locus is responsible for other forms of AI as well, as linkage study was carried out with 17 families representing at least five clinical forms of ADAI. Admixture tests for heterogeneity performed with the marker D4S2456 gave statistical support for genetic heterogeneity of ADAI with the odds 78:1. Linkage to the ADAI locus on chromosome 4q ( AIH2 ) could only be demonstrated with families expressing the local hypoplastic type, and there was no support for heterogeneity within that group of families. Furthermore, linkage could be excluded for five families with other clinical forms of ADAI. The data therefore demonstrated that ADAI is genetically heterogeneous, and that at least two loci for it exist.

L-threo-DOPS is a synthetic precursor to norepinephrine (NE). In order to study its efficacy and dosage, we carried out an open pilot study in ten patients with orthostatic hypotension and a confirmed diagnosis of familial amyloidoticpolyneuropathy (FAP). The initial dosage was 200 mg of L-threo-DOPS daily, with a weekly increment of 100 mg, until a maintenance dose was reached. Ten patients were treated for 12 weeks and five of them for 24 weeks. The blood pressure (BP) and pulse rate were monitored weekly. Before treatment, after four and 12 weeks, the patients underwent clinical and laboratory examinations. Nine patients completed the study. There was a rise in mean BP values in all measurements. After 12 weeks of treatment the rise in mean systolic BP values were statistically significant (p < 0,01) in all measurements in upright position. When treatment was withdrawn BP fell to almost the same levels as before and when treatment was restarted (five patients), there was again a rise in mean BP values....

Familial amyloidotic polyneuropathy (FAP) is an inherited fatal form of amyloidosis caused by mutant transthyretin. The disease is characterized by progressive peripheral and autonomic neuropathy. Most of the transthyretin is produced by the liver, and we have shown previously that the metabolic deficiency can be corrected by liver transplantation. In the present study, the clinical results from the first 20 patients who underwent liver transplantation for FAP in Sweden are evaluated. Three of the patients suffered from renal failure and underwent a simultaneous kidney transplantation. Fourteen of the 20 patients (70%) are alive 10-52 months after transplantation. The patients' nutritional status at the time of transplantation had a significant impact on mortality and morbidity (P < 0.007). Long-standing disease was another negative prognostic factor (P < 0.02). One year after transplantation, the nutritional status had improved (P < 0.02). Improvements were also noted in walking capacity and for gastrointestinal and urogenital symptoms. The results show that liver transplantation offers an effective means to treat patients with FAP. The procedure should preferably be performed before the nutritional status is poor and advanced organ dysfunction has developed.

A gene (DYT1) for early onset idiopathic torsion dystonia was mapped to chromosome 9q34 in non-Jewish and Jewish families. The DYT1 gene region has been excluded in other families with adult onset and cervical or cranial onset idiopathic torsion dystonia from the United States, Great Britain, and France. The role of DYT1 in a Swedish family with adult onset idiopathic torsion dystonia in four generations was examined. The disease seems to be inherited in an autosomal dominant mode with reduced penetrance in this family. There were 10 affected family members, with a mean age of onset of 27 (range 18 to 50) years. The disease showed variable expression, with focal, multifocal, and generalised forms of dystonia in different family members. Genetic analysis excluded the chromosomal region containing the DYT1 locus as being responsible for dystonia in this family.

A hereditary myopathy with lactic acidosis during physical exercise, low physical work capacity, and paroxysmal myoglobinuria (HML), called "Myopathy with deficiency of succinate dehydrogenase and aconitase" (McKusick 255125) has been described in 19 members of nine families who lived in two geographically separate areas in northern Sweden. By using the unique Swedish historical archives, including Catechetical Meeting Records from a number of northern Swedish parishes, it has been possible to trace ancestors of the nine families including all known 19 cases back in time to some key couples, who lived up to 300 years ago (that is seven to ten generations). No common single couple or common links between families in the past was found in these registers as a support for a single or several mutations that had developed far back in time. The mode of inheritance in this family is most likely autosomal recessive. This material will be used for the chromosomal localisation of the gene.

Genetic factors are of major aetiological importance in Bipolar Affective Disorder (BPAD type I and II). The exact mode of inheritance of BPAD is unknown, but the recent demonstration of anticipation suggests that dynamic mutations could be involved in the clinical expression of the disease. We have used the repeat expansion detection (RED) method to test whether the anticipation in BPAD could be explained by the presence of expanded trinucleotide repeat sequences. Using a (CTG)10 oligonucleotide a significantly higher number of expanded CAG repeats were found in the genomic DNA of two independent samples of unrelated BPAD patients of Swedish and Belgian ancestry as compared with normal controls. The difference in repeat number was more consistent if data of the two samples of patients was pooled. In this study a CAG trinucleotide repeat expansion was associated for the first time with a major psychiatric disorder. It is possible that the CAG trinucleotide repeat expansion is involved in the clinical expression of BPAD and that it is the molecular basis explaining the phenomenon of anticipation observed in this disorder.

Familial amyloidotic polyneuropathy (FAP) is an autosomally inherited fatal disorder characterized by peripheral and autonomic polyneuropathy. The histories of two Swedish patients with FAP transthyretin Met 30 mutation (TTR Met 30) are presented. Patient I had no family history of FAR He suffered for more than 20 years from ill-defined non progressive neurological disturbances. His nutritional status remained unchanged. Biopsies and electromyography showed no amyloid deposits or axonal polyneuropathy, however, he was positive for TTR Met 30 gene. Patient 2 had a family history of late-onset, slowly progressive FAP and experienced a very slow progress of the disease. At the onset of symptoms, amyloid deposits were found in biopsy specimens, and axonal denervation was seen on electromyography. Twenty-five years later she could still walk without a walking cane. However, after onset of gastrointestinal disturbances, a rapid impairment of her nutritional status was observed.We conclude that the diagnosis of ...

Congenital dyserythropoietic anemia, type III (CDA III) is a rare autosomal dominant disorder characterized by macrocytic anemia, bone marrow erythroid hyperplasia and giant multinucleate erythroblasts. We have genetically characterized a large Swedish family in which the concurrence of CDA III and myeloma or benign monoclonal gammopathy is significantly higher than expected and have found that the causative genetic defect for CDA III maps to an 11 cM interval within 15q21-q25.

Amelogenesis imperfecta (AI), a disorder affecting the formation of enamel, is significantly more common in Northern Sweden than in other parts of the world. The disease is genetically and clinically heterogenous, and autosomal dominant, autosomal recessive and X-linked inheritance patterns have been recognized. Linkage analysis has identified two different loci for X-linked AI, one of which is identical to the gene encoding the enamel protein amelogenin. However, in families with an autosomal inheritance pattern for AI, the genetic basis of the disease still remains unknown. We report a linkage analysis study performed on three Swedish families where the affected members had an autosomal dominant variant of AI (ADAI) clinically characterized as local hypoplastic. Significant linkage to microsatellite markers on chromosome 4q were obtained, with a maximum lod score of 5.55 for the marker D4S428. Recombinations in the family localized the ADAI locus to the interval between D4S392 and D4S395. This chromosome region contains both a locus for the dental disorder dentinogenesis imperfecta and the albumin gene. Serum albumin has been suggested to play a role in enamel formation, and the albumin gene is therefore a candidate gene for this genetic disease.

The First International Workshop on liver transplantation in patients with familial amyloid polyneuropathy (FAP) was held at Huddinge Hospital in Stockholm, Sweden, September 10–11, 1993. Information was presented on 64 liver transplant recipients treated at 15 centers in 10 countries. Twenty-two patients had a follow-up time of more than 12 months, the longest follow-up was 41 months. Fifty-three patients had survived the procedure, while 11 had died within 8 months after the operation. The 1 and 2 year actuarial patient survival rate was 67 per cent. In most of the 22 patients surviving more than 1 year, the neurological symptoms had stabilized and the beneficial effect was most apparent as regards symptoms from the autonomic nervous system. There was consensus among the participants at the Workshop that liver transplantation for FAP is a worthwhile procedure and that such transplantation activities should continue. Transplantation should preferably be performed before the symptoms become severe and whi...

Co-existence of pseudo-Chediak–Higashi anomaly and double minutes containing C-MYC oncogene in three patients with AML M2

A female child is described with features of Silver's syndrome, including pre- and postnatal growth delay, triangular face, hypertelorism, clinodactyly and developmental delay. In all lymphocytes analyzed, a small deletion was found in chromosome 13. The karyotype was 46,XX,del(13)(q22-32).

Familial amyloid polyneuropathy (FAP) is a fatal autosomal dominant disorder. Progressive peripheral and autonomic neuropathy are associated with neural and visceral deposition of amyloid, derived most commonly from the Met-30 variant of the plasma protein transthyretin. We have reported previously that orthotopic liver transplantation causes prompt replacement of variant transthyretin by the donor wild-type in the plasma. We now report clinical outcome 1-2 years after transplantation. Three of the first four patients have improved general wellbeing, walking ability, and bowel function, and one of them has regained normal bladder and bowel function. There has been little objective improvement in peripheral neuropathy. The fourth patient, who had the most severe neurological deficits and a complicated postoperative course, has not improved but there has been no further deterioration in contrast to the inexorable progression before transplantation. Quantitative scintigraphy with radiolabelled serum amyloid P component showed visceral amyloid deposits in all three patients studied; in two who were followed serially the deposits regressed after transplantation in association with the clinical improvement. Another FAP patient who was also monitored prospectively for 2 years but who did not undergo transplantation, showed, as expected, progression of neuropathy and increased visceral amyloid deposition. Liver transplantation does therefore have important benefits in FAP during the first 2 years after surgery. Neurological decline is halted and amyloid deposits can be mobilised. The best timing and long-term results of the procedure must now be established.

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.

The finding of individuals homozygous for FAP I (familial amyloidotic polyneuropathy, transthyretin TTRMet30) with amyloid deposits in the vitreous body, gave us access to a unique material lacking wild type transthyretin and contaminating proteins. Amyloid TTR is modified in several ways. Besides the full-length protein and its dimer form, two smaller bands were identified by SDS-PAGE and protein sequencing. One corresponded to a peptide starting at amino acid Thr49, the other was a mixture of two peptides starting at positions 1 and 3 in a 3:1 ratio. Upon reduction the amount of the TTR dimer decreased, the monomer amount increased, and the resulting monomers became available for carboxymethylation. Moreover, the mobility of the small band, which includes Cys10, increased upon reduction. This cysteine seemed to be involved in an interchain disulfide bridge both between intact TTR molecules and between small fragments. The same pattern was found in heterozygous fibril material although smaller amounts of the truncated peptides were found. Fibrils were formed both from normal and mutated TTR in heterozygotes. The significance of our results for amyloid formation is discussed.

Chromosomes carrying the mutation causing the fragile X [fra(X)] syndrome have been shown to have an unstable DNA sequence close to or within the fragile site. The length variation is located within a DNA fragment containing a CGG trinucleotide repeat which is unstable in both mitosis and meiosis. We have used the probe StB12.3 from the region to analyze the mutations and the methylation patterns in 21 families segregating for the fra(X) syndrome. Among 40 fra(X) males all showed an abnormal pattern. The normal 2.8 kb band was absent in 36 individuals and replaced by a heterogeneous smear of larger size. The remaining four were shown to be "mosaics" with the presence of both mutated, unmethylated and mutated, methylated fragments. We found four normal transmitting males, one which was a great-grandson of another normal transmitting male indicating that the pre-mutation can remain stable through two meioses in the female. In nine fra(X) positive females the abnormal pattern consisted of a smear, usually seen in affected males, in addition to the normal bands. Five of these females were mentally normal. Of clinical importance is the prediction of mental impairment in females. We suggest that this is not made by the detection of the full mutation alone, but rather by the degree of methylation of the normal X chromosome. Our results suggest that difference of clinical expression in monozygotic twins may be correlated with difference in methylation pattern. Six out of 33 fra(X) negative females at risk were diagnosed as carriers. Our observations indicate that molecular heterogeneity is responsible for variable expression of the fra(X) syndrome in both males and females.