Wilson's disease: a common liver disorder?

In two sibships 7 of 24 siblings were homozygous for Wilson''s disease. In family A, the largest kindred of this recessively inherited disease thus far reported, the proband presented with chronic active hepatitis, one sibling died of cirrhosis, a second had clinical evidence of chronic liver disease and two others had biochemical and histologic changes in liver biopsy specimens. In family B the proband had cirrhosis and portal hypertension and one sibling had biochemical and histologic evidence of liver disease. All six living patients had low serum concentrations of ceruloplasmin and copper and a high 24-hour urinary excretion of copper, which was greatly increased by administration of D-penicillamine. None showed neurologic abnormalities and only one had Kayser-Fleischer rings (detectable only by slit-lamp examination). Each patient had an erythrocyte sedimentation rate (ESR) of 8 mm/h or less. After 3 and 2 years, respectively, of D-penicillamine therapy the conditions of the two probands had improved. Liver function became normal in three siblings, and no abnormalities developed in the remaining one. Thus, since Wilson''s disease may present with chronic active hepatitis or cirrhosis with a normal ESR and without ocular or neurologic signs, it may be a more common cause of liver disease in young people than has been appreciated.     

Discrete subaortic stenosis as part of a short stature syndrome

Summary Observations in a family point to the existence of autosomal dominant inheritance for discrete subaortic stenosis (DSS), which made up part of a multisystem disorder. Both parents, offspring of two full siblings, had short stature, obstructive lung disease (OLD), hoarseness and upturned nose. The father alone had aortic stenosis and inguinal hernia.The six offspring, aged from 13 to 28 years, were followed up for up to 8 years. While one of them was virtually normal, and one had only minor abnormalities, four siblings displayed clinical signs of progressive aortic stenosis. Of the two eldest siblings who eventually died, necropsy in one showed a discrete subaortic stenosis, which was hemodynamically proven in one and surgically corrected in another sibling.Upturned nose was present in each examined member of the family, short stature and hoarseness in five of the siblings, DSS in four, OLD, inguinal hernia and congested episcleral veins in three, kyphoscoliosis in two, while epicanthus, strabismus, microphthalmos and widely spaced teeth were noted in the deceased female. The prevalence of some of these traits in roughly three-quarters of the sibship was consistent with an underlying single gene abnormality in affected heterozygous parents. We proposed that this constitutes a new syndrome.     

Community-based prevalence of rheumatic heart disease in rural Ethiopia: Five-year follow-up

BackgroundAs little is known about the prevalence and clinical progression of subclinical (latent) rheumatic heart disease (RHD) in sub-Saharan Africa, we report the results of a 5 year follow-up of a community based, echocardiographic study of the disease, originally carried out in a rural area around Jimma, Ethiopia.MethodsIndividuals with evidence of RHD detected during the baseline study as well as controls and their family members were screened with a short questionnaire together with transthoracic echocardiography.ResultsOf 56 individuals with RHD (37 definite and 19 borderline) in the original study, 36 (26 definite and 10 borderline) were successfully located 57.3 (range 44.9–70.7) months later. At follow-up two thirds of the definite cases still had definite disease; while a third had regressed. Approximately equal numbers of the borderline cases had progressed and regressed. Features of RHD had appeared in 5 of the 60 controls. There was an increased risk of RHD in the family relatives of borderline and definite cases (3.8 and 4.0 times respectively), notably among siblings. Compliance with penicillin prophylaxis was very poor.ConclusionsWe show the persistence of echocardiographically demonstrable RHD in a rural sub-Saharan population. Both progression and regression of the disease were found; however, the majority of the individuals who had definite features of RHD had evidence of continuing RHD lesions five years later. There was an increased risk of RHD in the family relatives of borderline and definite cases, notably among siblings. The findings highlight the problems faced in addressing the problem of RHD in the rural areas of sub-Saharan Africa. They add to the evidence that community-based interventions for RHD will be required, together with appropriate ways of identifying active disease, achieving adequate penicillin prophylaxis and developing vaccines for primary prevention.     

Pulmonary emphysema associated with the FZ alpha 1-antitrypsin phenotype.

In one family three brothers were found to have a moderate deficiency of alpha 1-antitrypsin associated with the unusual Pi (protease inhibitor) phenotype FZ. The Pi phenotypes of their six living siblings were found to be FM (in three), M (in two) and MZ (in one). The three FZ brothers all had moderate to severe obstructive airways disease, and two had at least moderately severe pulmonary emphysema. Additional risk factors included moderate cigarette smoking in two and prolonged exposure to grain dust in all three. The same risk factors applied to the six non-FZ siblings, but they had only mild symptoms and pulmonary dysfunction or no lung problems at all; one, a female smoker with the MZ phenotype, had probable early emphysema demonstrated radiologically. The three FZ men may have had reduced fertility, as they produced only 1 child among them, as compared with 39 among the other eight siblings. This family study thus suggests that individuals with the FZ phenotype are at risk for pulmonary emphysema and chronic obstructive airways disease, particularly in the presence of other risk factors, such as cigarette smoking and grain dust exposure.     

Increased plasma plant sterol levels in heterozygotes with sitosterolemia and xanthomatosis

Plasma sterol levels in a family of sitosterolemia and xanthomatosis were determined by a high performance liquid chromatography. Three affected siblings manifested marked xanthomatosis including subcutaneous soft tissues and generalized atherosclerosis. Two other siblings as well as children of the patients did not show such clinical symptoms and signs. Plasma levels of cholesterol, sitosterol, campesterol, and cholestanol in three affected subjects were 190 +/- 18.5, 25.9 +/- 11.6, 16.1 +/- 7.8, 1.84 +/- 0.92 mg/dl (mean +/- SD), respectively. Four daughters of the affected subjects, who should be considered as obligatory heterozygotes, showed moderately increased levels of these sterols (195 +/- 41.7, 1.33 +/- 0.44, 1.56 +/- 0.69, 0.80 +/- 0.28 mg/dl), which were significantly higher than those of normal subjects. Treatment with cholestyramine had little effect on the increased plasma plant sterol levels, but markedly decreased plasma cholestanol concentrations in two affected siblings. This report presents the clinical features of the patients with sitosterolemia and xanthomatosis and also demonstrates that heterozygotes with this disorder have increased plasma levels of plant sterols as well as cholestanol, and suggests that this rare disease might be inherited as an autosomal co-dominant trait in certain cases. The data also indicate that cholestyramine administration was not effective in this family for treatment of sitosterolemia.     

Segregation of lymphocyte low-molecular-weight DNA and antinuclear-antibodies in a family with systemic lupus erythematosus in first cousins

Summary All patients with systemic lupus erythematosus (SLE) demonstrated two classes of newly synthesized DNA in sucrose density gradients of PHA (phytohemagglutinin)-stimulated lymphocytes: a large-molecular-weight fraction that comigrates with control DNA and an excess low-molecularweight DNA (LMW-DNA) fraction not found in control lymphocytes. Excess LMW-DNA was independent of disease activity or drug therapy. LMW-DNA and serologic abnormalities were studied in a four-generation family in which two first cousins had SLE. Excess LMW-DNA was found in the cousins with SLE, sibling parents of the SLE patients, a common grandparent, four of nine siblings of one patient, and five of seven at risk children. Both males and females had excess LMW-DNA. Male-male transmission was observed. The expression of excess LMW-DNA in stimulated lymphocytes is inherited as an autosomal dominant genetic trait in this family. All unaffected adult family members with the marker had positive antinuclear antibodies (ANAs) except the grandmother. However, none of the five children with excess LMW-DNA showed positive ANAs. Excess LMW-DNA precedes the appearance of ANAs when found in children of adults with excess LMW-DNA, and may be a predisposing factor in the development of the immunologic responses of systemic lupus erythematosus.     

Regionalization in hereditary IgA nephropathy.

The genealogies of 80 patients with IgA nephropathy who were born in central or eastern Kentucky or whose parents were born in this region were researched. At a minimum, 48 of these patients were related to at least one other patient. On the basis of presence or absence of established kinships, the patients were divided into three groups. Twenty-nine patients in group 1 belonged to one large pedigree. Their birthplaces and those of their parents, grandparents, and great-grandparents clustered in the extreme eastern portion of the state. Seventeen other patients, group 2, were related to at least one other patient but not to a patient in group 1. Their birthplaces and those of their ancestors did not show significant clustering. With the exception of two siblings, the 34 patients of group 3 had no family members with IgA nephropathy. The birthplaces for these patients and ancestors were widely scattered. These data suggest that one or more genetically determined factors are important in the pathogenesis of IgA nephropathy in some patients. A founder effect, whereby a gene(s) conveying susceptibility to IgA nephropathy was carried into eastern Kentucky by one or more of the early settlers, would explain the geographic clustering of the birthplaces of the patients in group 1 and their ancestors. The characteristic immunopathology of IgA nephropathy may represent the histologic result of separate disease processes, one or more of which could be genetically influenced.     

Hereditary angioneurotic edema and Charcot-Marie-Tooth disease in the same family.

In one family two genetic diseases were transmitted as autosomal dominant traits; hereditary angioneurotic edema was inherited from the paternal side and Charcot-Marie Tooth disease from the maternal side of the family. The conditions occurred separately in 8 and 11 members respectively and together (an exceedingly rare occurrence) in 3. Of six siblings, two girls and four boys, all had Charcot-Marie-Tooth disease, and three, the two girls and one of the boys, also had hereditary angioneurotic edema.     

Phenotypical variation within 22 families with Pompe disease

Background

Pompe disease has a broad clinical spectrum, in which the phenotype is partially explained by the genotype. The aim of this study was to describe phenotypical variation among siblings with non-classic Pompe disease. We hypothesized that siblings and families with the same genotype share more similar phenotypes than the total population of non-classic Pompe patients, and that this might reveal genotype-phenotype correlations.

Methods

We identified all Dutch families in which two or three siblings were diagnosed with Pompe disease and described genotype, acid α-glucosidase activity, age at symptom onset, presenting symptoms, specific clinical features, mobility and ventilator dependency.

Results

We identified 22 families comprising two or three siblings. All carried the most common mutation c.-32-13 T?>?G in combination with another pathogenic mutation. The median age at symptom onset was 33 years (range 1–62 years). Within sibships symptom onset was either in childhood or in adulthood. The median variation in symptom onset between siblings was nine years (range 0–31 years). Presenting symptoms were similar across siblings in 14 out of 22 families. Limb girdle weakness was most frequently reported. In some families ptosis or bulbar weakness were present in all siblings. A large variation in disease severity (based on wheelchair/ventilator dependency) was observed in 11 families. This variation did not always result from a difference in duration of the disease since a third of the less affected siblings had a longer course of the disease. Enzyme activity could not explain this variation either. In most families male patients were more severely affected. Finally, symptom onset varied substantially in twelve families despite the same GAA genotype.

Conclusion

In most families with non-classic Pompe disease siblings share a similar phenotype regarding symptom onset, presenting symptoms and specific clinical features. However, in some families the course and severity of disease varied substantially. This phenotypical variation was also observed in families with identical GAA genotypes. The commonalities and differences indicate that besides genotype, other factors such as epigenetic and environmental effects influence the clinical presentation and disease course.

     

I can produce more offspring as you can imagine: first records on exceptionally large litters in roe deer in central/southern Europe

Most roe deer females produce twins and more rarely singletons and triplets. Some very rare reported cases of litters above three offspring refer to quadruplets which are, however, very much an exception in roe deer reproduction (only some tens of documented cases can be found in the scientific literature). In this paper, we present the first firm evidence that roe deer females are able to produce even five offspring. By examination of large sample set (n = 4690) of roe deer uteri and ovaries in two neighbouring countries in southern/central Europe (Italy and Slovenia), we found ten females that either carried or had potential to produce quadruplets, and in three does the (potential) litter size was even five. While one doe from Slovenia had five corpora lutea, two does from Tuscany, Italy, carried five foetuses. In both cases, all foetuses were normally and equally developed, indicating that none of them had predominant exposure to resorption/abortion. Six out of 13 females with exceptionally large potential litters (>3 offspring) had significantly higher body mass in comparison with mean body mass of all does harvested in the same hunting management district and in the same period, while five of them were significantly lighter. This indicates that some roe deer females can produce exceptionally large litters even when their phenotypic quality is not higher than the average in the population, and that such large litters are a stochastic episode rather than a reproductive performance of a very vital individual(s).     

Pancreatic Exocrine Function in Maturity Onset Diabetes Mellitus

Exocrine pancreatic function was studied in 14 inpatients with newly diagnosed maturity onset diabetes mellitus. Five patients had clinical and biochemical evidence of pancreatic disease (two carcinoma, three pancreatitis). The other nine patients had no clinical pancreatic disease but all except one had at least one abnormal result of pancreatic function tests. None of this group with idiopathic diabetes mellitus developed any clinical evidence of exocrine pancreatic disease over the next five years. Mild abnormalities of exocrine pancreatic function in newly diagnosed patients with diabetes but without clinical evidence of pancreatic disease do not usually develop into overt pancreatic disease, and are therefore probably clinically unimportant.     

Linkage and sequence analysis indicate that CCBE1 is mutated in recessively inherited generalised lymphatic dysplasia

Generalised lymphatic dysplasia (GLD) is characterised by extensive peripheral lymphoedema with visceral involvement. In some cases, it presents in utero with hydrops fetalis. Autosomal dominant and recessive inheritance has been reported. A large, non-consanguineous family with three affected siblings with generalised lymphatic dysplasia is presented. One child died aged 5 months, one spontaneously miscarried at 17 weeks gestation, and the third has survived with extensive lymphoedema. All three presented with hydrops fetalis. There are seven other siblings who are clinically unaffected. Linkage analysis produced two loci on chromosome 18, covering 22 Mb and containing 150 genes, one of which is CCBE1. A homozygous cysteine to serine change in CCBE1 has been identified in the proband, in a residue that is conserved across species. High density SNP analysis revealed homozygosity (a region of 900 kb) around the locus for CCBE1 in all three affected cases. This indicates a likely ancestral mutation that is common to both parents; an example of a homozygous mutation representing Identity by Descent (IBD) in this pedigree. Recent studies in zebrafish have shown this gene to be required for lymphangiogenesis and venous sprouting and are therefore supportive of our findings. In view of the conserved nature of the cysteine, the nature of the amino acid change, the occurrence of a homozygous region around the locus, the segregation within the family, and the evidence from zebrafish, we propose that this mutation is causative for the generalised lymphatic dysplasia in this family, and may be of relevance in cases of non-immune hydrops fetalis.     

Homozygotes for the autosomal dominant neoplasia syndrome (MEN1).

Families in which both parents are heterozygotes for the same autosomal dominant neoplasia syndrome are extremely unusual. Recently, we had the unique opportunity to evaluate three symptomatic siblings from the union between two unrelated individuals affected by multiple endocrine neoplasia type 1 (MEN1). When the three siblings and their parents and relatives were genotyped for 12 markers tightly linked to the MEN1 locus, at 11q13, two of the siblings were found to be homozygotes, and one a heterozygote, for MEN1. With regard to the MEN1 syndrome, no phenotypic differences were observed between the two homozygotes and the heterozygotes. However, the two homozygotes showed unexplained infertility, which was not the case for any of the heterozygotes. Thus, MEN1 appears to be a disease with complete dominance, and the presence of two MEN1 alleles with mutations of the type that occur constitutionally may be insufficient for tumor development.     

Genetic counselling for pulmonary arterial hypertension: a matter of variable variability

We report three cases which highlight the complex considerations surrounding genetic counselling for pulmonary arterial hypertension (PAH). The first counselee developed PAH symptoms shortly after his daughter’s death from PAH and was diagnosed with a delay of 1 year. An early diagnosis of familial PAH was established in the second counselee. Oral therapy was initiated immediately, and her functional status has since remained stable. The third counselee was a healthy woman who struggled to cope with her risk for familial PAH, having lost two siblings from the disease. These cases show that incomplete penetrance and variable expression need particular attention during clinical assessment and genetic counselling of heritable PAH patients and family members.     

Twin-singleton differences in intelligence?

The twin method has been criticised for its alleged non-generalisability. When population parameters of intellectual abilities are estimated from a twin sample, critics point to the twin-singleton differences in intrauterine and family environments. These differences are suggested to lead to suboptimal cognitive development in twins. Although previous studies have reported twin-singleton differences in intelligence, these studies had two major drawbacks: they tested young twins, and twins were compared with (genetically) unrelated singletons. To test accurately whether twin-singleton differences in intelligence exist, a group of adult twins and their non-twin siblings were administered the Dutch WAIS-III. The group was large enough to detect twin-singleton differences of magnitudes reported in earlier investigations. The data were analysed using maximum likelihood model fitting. No evidence of differences between adult twins and their non-twin siblings on cognitive performance was found. It is concluded that twin studies provide reliable estimates of heritabilities of intellectual abilities which can be generalised to the singleton population.     

CANCER OF THE LUNG IN WOMEN

Cancer of the lung in women has the same signs and symptoms as in men, but the disease seems to advance more rapidly. Of 35 female patients, half were under radiation therapy (for inoperable tumor) within four months after the first manifestation. In three of the five who had no symptoms, the cancer when diagnosed was inoperable.Scalene node biopsy confirmed metastasis in nine of the eleven cases in which it was used, and this procedure should be used after diagnosis whenever metastasis is not evident.Of the 35 women, two received only chemotherapy, 32 radiotherapy. Only four were alive at the time of report—one without evidence of disease at 20 months, one with symptoms of disease at 11 months, two under chemotherapy at two months, For 29 who received palliative or radical irradiation to the primary tumor site, the median survival time was 26 weeks.     

Germ-line mosaicism in tuberous sclerosis: how common?

Two-thirds of cases of tuberous sclerosis complex (TSC) are sporadic and usually are attributed to new mutations, but unaffected parents sometimes have more than one affected child. We sought to determine how many of these cases represent germ-line mosaicism, as has been reported for other genetic diseases. In our sample of 120 families with TSC, 7 families had two affected children and clinically unaffected parents. These families were tested for mutations in the TSC1 and TSC2 genes, by Southern blotting and by single-strand conformational analysis. Unique variants were detected in six families. Each variant was present and identical in both affected children of a family but was absent in both parents and the unaffected siblings. Sequencing of the variants yielded two frameshift mutations, one missense mutation, and two nonsense mutations in TSC2 and one nonsense mutation in TSC1. To determine which parent contributed the affected gametes, the families were analyzed for linkage to TSC1 and TSC2, by construction of haplotypes with markers flanking the two genes. Linkage analysis and loss-of-heterozygosity studies indicated maternal origin in three families, paternal origin in one family, and either being possible in two families. To evaluate the possibility of low-level somatic mosaicism for TSC, DNA from lymphocytes of members of the six families were tested by allele-specific PCR. In all the families, the mutant allele was detected only in the known affected individuals. We conclude that germ-line mosaicism was present in five families with mutations in the TSC2 gene and in one family with the causative mutation in the TSC1 gene. The results have implications for genetic counseling of families with seemingly sporadic TSC.     

City-wide screening for urinary abnormalities in schoolboys

Screening for urinary tract infection was carried out in 27,722 schoolboys aged 5 to 14 using Uricult to perform urine cultures and Hema-combistix to detect hematuria, proteinuria and glycosuria. Cultures of 10⁵ colonies per ml or more on two occasions were found in 40 cases (0.14%), but no case was confirmed by the family physician using standard culture techniques.Proteinuria was found in 136 cases (0.49%) and confirmed in 47 (37%) of the 126 children who were seen by their family physician. In this group 8.8% had evidence of pyelonephritic scarring on intravenous pyelograms without a positive urine culture.Hematuria was found in 19 children and confirmed in 10 (59%) of the 17 children who were seen by their family physician. No abnormalities were detected on intravenous pyelography in any case.Glycosuria was found in 12 cases and confirmed in five. Three of these children had renal glycosuria and two had previously undetected diabetes.     

R54C Mutation of NOTCH3 Gene in the First Rungus Family with CADASIL

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare hereditary stroke caused by mutations in NOTCH3 gene. We report the first case of CADASIL in an indigenous Rungus (Kadazan-Dusun) family in Kudat, Sabah, Malaysia confirmed by a R54C (c.160C>T, p.Arg54Cys) mutation in the NOTCH3. This mutation was previously reported in a Caucasian and two Korean cases of CADASIL. We recruited two generations of the affected Rungus family (n = 9) and found a missense mutation (c.160C>T) in exon 2 of NOTCH3 in three siblings. Two of the three siblings had severe white matter abnormalities in their brain MRI (Scheltens score 33 and 50 respectively), one of whom had a young stroke at the age of 38. The remaining sibling, however, did not show any clinical features of CADASIL and had only minimal changes in her brain MRI (Scheltens score 17). This further emphasized the phenotype variability among family members with the same mutation in CADASIL. This is the first reported family with CADASIL in Rungus subtribe of Kadazan-Dusun ethnicity with a known mutation at exon 2 of NOTCH3. The penetrance of this mutation was not complete during the course of this study.     

New chromosomal syndrome: Miller-Dieker syndrome and monosomy 17p13

Summary The Miller-Dieker Syndrome (MDS) consists of lissencephaly, characteristic facies, pre- and postnatal growth retardation, plus various other birth defects. Autosomal recessive inheritance has been presumed based on four reported families with two or more affected siblings. We present substantial evidence that monosomy 17p13.3 causes the MDS phenotype. This includes two patients with ring chromosome 17, one patient with a de novo 17p13 deletion, and one patient with monosomy 17p due to an unbalanced 7p; 17p translocation. We report the first prenatal diagnosis of MDS in a 20-week fetus from this latter family. Additionally, we report a balanced translocation between chromosome 17 and different autosomes (8, 12, and 15) in three of the four familial cases of lissencephaly. The finding of a chromosomal basis for this presumed autosomal recessive disorder significantly alters genetic counseling and makes prenatal diagnosis possible in some families.United States Air Force Medical Corps