Invasive fungal infections in patients treated with Bruton's tyrosine kinase inhibitors.

Bruton's tyrosine kinase (BTK) inhibitors are increasingly used in untreated and previously treated chronic lymphocytic leukaemia (CLL) patients. Invasive fungal infections (IFI) were rarely observed in patients treated for CLL in the pre-BTK era. In this article, we describe two patients with CLL who developed an IFI during treatment with the BTK inhibitor ibrutinib. The atypical presentation and the serious course of this complication are described.

IL-10 signaling in dendritic cells controls IL-1ß-mediated IFNγ secretion by human CD4+ T cells: relevance to inflammatory bowel disease.

Uncontrolled interferon γ (IFNγ)-mediated T-cell responses to commensal microbiota are a driver of inflammatory bowel disease (IBD). Interleukin-10 (IL-10) is crucial for controlling these T-cell responses, but the precise mechanism of inhibition remains unclear. A better understanding of how IL-10 exerts its suppressive function may allow identification of individuals with suboptimal IL-10 function among the heterogeneous population of IBD patients. Using cells from patients with an IL10RA deficiency or STAT3 mutations, we demonstrate that IL-10 signaling in monocyte-derived dendritic cells (moDCs), but not T cells, is essential for controlling IFNγ-secreting CD4+ T cells. Deficiency in IL-10 signaling dramatically increased IL-1ß release by moDCs. IL-1ß boosted IFNγ secretion by CD4+ T cells either directly or indirectly by stimulating moDCs to secrete IL-12. As predicted a signature of IL-10 dysfunction was observed in a subgroup of pediatric IBD patients having higher IL-1ß expression in activated immune cells and macroscopically affected intestinal tissue. In agreement, reduced IL10RA expression was detected in peripheral blood mononuclear cells and a subgroup of pediatric IBD patients exhibited diminished IL-10 responsiveness. Our data unveil an important mechanism by which IL-10 controls IFNγ-secreting CD4+ T cells in humans and identifies IL-1ß as a potential classifier for a subgroup of IBD patients.

Malignancy and mortality in paediatric-onset inflammatory bowel disease: a 3-year prospective, multinational study from the paediatric IBD Porto group of ESPGHAN.

BACKGROUND: Risk benefit strategies in managing inflammatory bowel diseases (IBD) are dependent upon understanding the risks of uncontrolled inflammation vs those of treatments. Malignancy and mortality in IBD have been associated with disease-related inflammation and immune suppression, but data are limited due to their rare occurrence. AIM: To identify and describe the most common causes of mortality, types of cancer and previous or current therapy among children and young adults with paediatric-onset IBD. METHODS: Information on paediatric-onset IBD patients diagnosed with malignancy or mortality was prospectively collected via a survey in 25 countries over a 42-month period. Patients were included if death or malignancy occurred after IBD diagnosis but before the age of 26 years. RESULTS: In total, 60 patients were identified including 43 malignancies and 26 fatal cases (9 due to cancer). Main causes of fatality were malignancies (n = 9), IBD or IBD-therapy related nonmalignant causes (n = 10; including 5 infections), and suicides (n = 3). Three cases, all fatal, of hepatosplenic T-cell lymphoma were identified, all were biologic-naïve but thiopurine-exposed. No other haematological malignancies were fatal. The 6 other fatal cancer cases included 3 colorectal adenocarcinomas and 3 cholangiocarcinomas (CCAs). Primary sclerosing cholangitis (PSC) was present in 5 (56%) fatal cancers (1 colorectal carcinoma, 3 CCAs and 1 hepatosplenic T-cell lymphoma). CONCLUSIONS: We report the largest number of paediatric-onset IBD patients with cancer and/or fatal outcomes to date. Malignancies followed by infections were the major causes of mortality. We identified PSC as a significant risk factor for cancer-associated mortality. Disease-related adenocarcinomas were a commoner cause of death than lymphomas.

A novel presenilin 1 mutation (L174 M) in a large Cuban family with early onset Alzheimer disease.

We studied a Cuban family with presenile dementia (autosomal dominant) consisting of 281 members within six generations, the proband descended from a Spanish founder. Mean age at onset was 59 years of age. Memory impairment was the main symptom in all patients, additionally, ischemic episodes were described in 4 (n = 18) patients. Neuropathological examination of brain material (1 patient) revealed neuronal loss, amyloid plaques, and neurofibrillary tangles. Thirty DNA samples were genotyped (regions on chromosome 1, 3, 10, 12, 14, 17, 19, 20, and 21). A maximum Lod score of 3.79 at theta = 0 was obtained for marker D14S43, located in a 9-cM interval in which all patients shared the same haplotype. Sequencing of the PSEN1 gene revealed a heterozygous base substitution, C520A (exon 6), which is predicted to cause an amino acid change from leucine to methionine in the TMIII of the presenilin 1 protein. The mutation was found to co-segregate with the disease phenotype and the associated disease haplotype. The C --> A change was not observed in 80 control chromosomes from the Cuban population. Leucine at position 174 is highly conserved among species and is identical in presenilin 1 and presenilin 2 proteins. We propose the L174 M mutation might lead to an abnormal N-terminal and probably C-terminal fragments and malfunction of the protein complex. In conclusion, we found a novel PSEN1 mutation in a large family with clinical and pathological diagnosis of early onset familial Alzheimer disease, which may be relevant for other Hispanic populations.

Hereditary vascular retinopathy, cerebroretinal vasculopathy, and hereditary endotheliopathy with retinopathy, nephropathy, and stroke map to a single locus on chromosome 3p21.1-p21.3.

We performed a genomewide search for linkage in an extended Dutch family with hereditary vascular retinopathy associated with migraine and Raynaud phenomenon. Patients with vascular retinopathy are characterized by microangiopathy of the retina, accompanied by microaneurysms and telangiectatic capillaries. The genome search, using a high throughput capillary sequencer, revealed significant evidence of linkage to chromosome 3p21.1-p21.3 (maximum pairwise LOD score 5.25, with D3S1578). Testing of two additional families that had a similar phenotype, cerebroretinal vasculopathy, and hereditary endotheliopathy with retinopathy, nephropathy, and stroke, revealed linkage to the same chromosomal region (combined maximum LOD score 6.30, with D3S1588). Haplotype analysis of all three families defined a 3-cM candidate region between D3S1578 and D3S3564. Our study shows that three autosomal dominant vasculopathy syndromes with prominent cerebroretinal manifestations map to the same 3-cM interval on 3p21, suggesting a common locus.

A mutation in SLC11A3 is associated with autosomal dominant hemochromatosis.

Hereditary hemochromatosis (HH) is a very common disorder characterized by iron overload and multi-organ damage. Several genes involved in iron metabolism have been implicated in the pathology of HH (refs. 1-4). We report that a mutation in the gene encoding Solute Carrier family 11, member A3 (SLC11A3), also known as ferroportin, is associated with autosomal dominant hemochromatosis.

Mutation-dependent aggregation of tau protein and its selective depletion from the soluble fraction in brain of P301L FTDP-17 patients.

Mutations in the gene for the microtubule-associated protein tau are associated with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). In this study we compared the presence of the P301L mutated tau protein from brain material of patients with that of the normal 4-repeat, using polyclonal antibodies specific for the P301L point mutation and its normal counterpart. We determined the relative ratio of mutated versus normal tau protein in the sarkosyl-soluble and -insoluble protein fractions from several brain regions. Although mutated and normal tau proteins are both present in the sarkosyl-insoluble deposits, quantitative analysis showed that the mutated protein is the major component. In the sarkosyl-soluble fraction of frontal and temporal cortex the overall ratio of 3-repeat versus 4-repeat tau isoforms is unchanged but there is a dramatic depletion of mutant tau protein. Furthermore, we observed an increase in tau-immunoreactive cleavage products with the P301L antibody, suggesting that the mutant protein is partly resistant to degradation and this is confirmed by pulse-chase experiments. This is the first direct evidence using patient material that shows a selective aggregation of mutant tau protein resulting in sarkosyl-insoluble deposits and the specific depletion of mutated tau protein in the soluble fraction.

The optimal stimulus to elicit suppression in small-angle convergent strabismus.

PURPOSE: To determine the optimal stimulus duration as well as the most appropriate luminance profile to elicit suppression in small-angle convergent strabismus. METHODS: In 10 subjects with small-angle convergent strabismus, using a device allowing binocular viewing and peripheral fusion, we determined what the optimal stimulus would be to elicit suppression. Three control subjects were also included in the study. Stimuli were shown randomly in the central 3 degrees of the visual field of either eye. Stimulus durations were varied in seven steps from 50 to 1000 ms and three luminance-time profiles were used: square wave, triangle and half-sinus, thus yielding 21 different stimuli. The peak light intensity was the same for all stimuli. RESULTS: Suppression, defined as the difference in the threshold sensitivities under monocular vs. binocular viewing, was found with our test device in five of the ten subjects, and ranged between 3 and 33 dB. Suppression was deepest with triangular or half-sinusoidal stimuli of 400 ms duration. Square wave stimuli elicited the smallest amount of suppression. CONCLUSION: Stimuli with a gradual increment and decrement, like triangular or half-sinusoidal stimuli, with a duration of 400 ms are the most effective to elicit suppression

A new gene, encoding an anion transporter, is mutated in sialic acid storage diseases.

Sialic acid storage diseases (SASD, MIM 269920) are autosomal recessive neurodegenerative disorders that may present as a severe infantile form (ISSD) or a slowly progressive adult form, which is prevalent in Finland (Salla disease). The main symptoms are hypotonia, cerebellar ataxia and mental retardation; visceromegaly and coarse features are also present in infantile cases. Progressive cerebellar atrophy and dysmyelination have been documented by magnetic resonance imaging (ref. 4). Enlarged lysosomes are seen on electron microscopic studies and patients excrete large amounts of free sialic acid in urine. A H+/anionic sugar symporter mechanism for sialic acid and glucuronic acid is impaired in lysosomal membranes from Salla and ISSD patients. The locus for Salla disease was assigned to a region of approximately 200 kb on chromosome 6q14-q15 in a linkage study using Finnish families. Salla disease and ISSD were further shown to be allelic disorders. A physical map with P1 and PAC clones was constructed to cover the 200-kb area flanked by the loci D6S280 and D6S1622, providing the basis for precise physical positioning of the gene. Here we describe a new gene, SLC17A5 (also known as AST), encoding a protein (sialin) with a predicted transport function that belongs to a family of anion/cation symporters (ACS). We found a homozygous SLC17A5 mutation (R39C) in five Finnish patients with Salla disease and six different SLC17A5 mutations in six ISSD patients of different ethnic origins. Our observations suggest that mutations in SLC17A5 are the primary cause of lysosomal sialic acid storage diseases.

FTDP-17: an early-onset phenotype with parkinsonism and epileptic seizures caused by a novel mutation.

Recently, mutations in the tau gene on chromosome 17 were found causative for autosomal dominantly inherited frontotemporal dementia and parkinsonism (FTDP-17). We describe a family carrying a missense mutation at nucleotide 1137 C --> T, resulting in the amino acid substitution P301S. Methods of investigations include clinical, electrophysiological, and imaging techniques. This kindred presents with a novel phenotype characterized by an early onset of rapidly progressive frontotemporal dementia and parkinsonism in combination with epileptic seizures. We define the dopaminergic deficits as being predominantly presynaptic by the use of single-photon emission computed tomography with a dopamine transporter ligand. The association of this early-onset phenotype with P301S mutation is not entirely consistent with current criteria for the diagnosis of frontotemporal dementias and may encourage the search for tau mutations in diseases similar but not identical to FTDP-17. Also, the change from proline to serine suggests that this mutation might contribute to tau hyperphosphorylation.

Phenotypic variation in hereditary frontotemporal dementia with tau mutations.

Several mutations in the tau gene have been found in families with hereditary frontotemporal dementia and parkinsonism linked to chromosome 17q21-22 (FTDP-17). This study is the first attempt to correlate genotype and phenotype in six families with FTDP-17 with mutations in the tau gene (deltaK280, G272V, P301L, and R406W). We have investigated tau pathology in 1 P301L and 1 R406W patient. The R406W family showed a significantly higher age at onset (59.2 +/- 5.5 years) and longer duration of illness (12.7 +/- 1.5 years) than the families with the other mutations. The six families showed considerable variation in clinical presentation, but none of them had early parkinsonism. Mutism developed significantly later in the R406W family than in the other families. Frontotemporal atrophy on neuroimaging in the R406W family was less severe than in the P301L and deltaK280 families. The P301L brain contained many pretangles in the frontal and temporal cortex, and the dentate gyrus of hippocampus, showing three tau bands (64, 68, and 72 kd) of extracted tau from the frontal cortex. The presence of many neurofibrillary tangles, many diffuse and classic neuritic plaques in the temporal and parietal cortex, and the hippocampus of the same P301L brain correlated with the presence of four sarkosyl-insoluble (60, 64, 68, and 72 kd) tau bands. The coexistence of characteristic P301L and Alzheimer pathology in the same brain needs further explanation. The R406W brain showed abundant neurofibrillary tangles in several brain regions, and four tau bands (60, 64, 68, and 72 kd) of extracted tau from these regions. The slower progression of the disease in the R406W family might be explained by the microtubule-binding properties of the mutant protein.

The tau gene in progressive supranuclear palsy: exclusion of mutations in coding exons and exon 10 splice sites, and identification of a new intronic variant of the disease-associated H1 haplotype in Italian cases.

Mutations in coding exons or exon 10 5'-splice-site of the gene for microtubule-associated protein tau can cause chromosome 17-linked frontotemporal dementia and parkinsonism (FTDP-17). We sequenced the 11 coding exons plus exon-intron boundaries of the tau gene in 15 cases of progressive supranuclear palsy (PSP), and found no mutations in coding exons or exon ten 5'-splice sites. These data indicate that typical PSP is not associated with tau gene mutations similar to those causing FTDP-17. We also observed a +39deltaG base change in the intron following exon 4 in three out of 69 PSP cases (all three Italians), whereas it was not found in 150 Dutch controls and once in 112 Italian controls. The +39deltaG variant arose in the context of the PSP-associated tau H1 haplotype. Although a pathogenic role cannot be entirely excluded, +39deltaG is likely to be a rare polymorphism that may be in linkage disequilibrium with a biologically relevant locus inside or near to the tau gene.

Quantitative visual fields under binocular viewing conditions in primary and consecutive divergent strabismus.

BACKGROUND: Although there have been a number of studies on the size of the suppression scotoma in divergent strabismus, there have been no reports on the full extent (i.e. size as well as depth) of this scotoma. METHODS: Binocular static perimetry was used to measure suppression scotomas in five patients with primary divergent strabismus and ten patients with consecutive divergent strabismus. Four control subjects were also included in the study. With two modified Friedmann visual field analysers, we measured the visual field of both eyes under monocular and binocular viewing conditions. The objective angle of squint ranged from 3 degrees to 25 degrees. Best corrected visual acuity was at least 0.4, but mostly 1.0 in both eyes. RESULTS: All subjects had normal visual fields for each eye under monocular viewing conditions. In 12 of the 15 subjects, we found a large area of suppression encompassing the projection of the fixation point as well as that of the fovea in the non-fixating eye under binocular viewing conditions. In 2 of these 12 patients, one with primary and one with consecutive divergent strabismus, the area of suppression was located nasally to the position of the fovea in the field of the non-fixating eye (nasal hemisuppression). In another two patients with divergent squint combined with vertical deviation, a small fixation-point suppression scotoma was found. The depth of suppression ranged from 3 dB to 16 dB. In one subject only, no suppression was found. CONCLUSIONS: Our findings indicate that the shape of the suppression scotoma is not related to the origin of divergent strabismus or to the angle of squint. Our results also indicate that the critical age for the development of suppression in divergent squint might be up to 14 years.

A physical and transcriptional map of the preaxial polydactyly locus on chromosome 7q36.

Preaxial polydactyly is a congenital hand malformation that includes duplicated thumbs, various forms of triphalangeal thumbs, and duplications of the index finger. A locus for preaxial polydactyly has been mapped to a region of 1.9 cM on chromosome 7q36 between polymorphic markers D7S550 and D7S2423. We constructed a detailed physical map of the preaxial polydactyly candidate region. With a combination of methods we identified and positioned 11 transcripts within this map. By recombination analysis on families with preaxial polydactyly, using newly developed polymorphic markers, we were able to reduce the candidate region to approximately 450 kb. The homeobox gene HLXB9, a putative receptor C7orf2, and two transcripts of unknown function, C7orf3 and C7orf4, map in the refined candidate region and have been subjected to mutation analysis in individuals with preaxial polydactyly.

High prevalence of mutations in the microtubule-associated protein tau in a population study of frontotemporal dementia in the Netherlands.

Mutations in microtubule-associated protein tau recently have been identified in familial cases of frontotemporal dementia (FTD). We report the frequency of tau mutations in a large population-based study of FTD carried out in the Netherlands from January 1994 to June 1998. Thirty-seven patients had >/=1 first-degree relative with dementia. A mutation in the tau gene was found in 17.8% of the group of patients with FTD and in 43% of patients with FTD who also had a positive family history of FTD. Three distinct missense mutations (G272V, P301L, R406W) accounted for 15.6% of the mutations. These three missense mutations, and a single amino acid deletion (DeltaK280) that was detected in one patient, strongly reduce the ability of tau to promote microtubule assembly. We also found an intronic mutation at position +33 after exon 9, which is likely to affect the alternative splicing of tau. Tau mutations are responsible for a large proportion of familial FTD cases; however, there are also families with FTD in which no mutations in tau have been found, which indicates locus and/or allelic heterogeneity. The different tau mutations may result in disturbances in the interactions of the protein tau with microtubules, resulting in hyperphosphorylation of tau protein, assembly into filaments, and subsequent cell death.

Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17.

Thirteen families have been described with an autosomal dominantly inherited dementia named frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), historically termed Pick's disease. Most FTDP-17 cases show neuronal and/or glial inclusions that stain positively with antibodies raised against the microtubule-associated protein Tau, although the Tau pathology varies considerably in both its quantity (or severity) and characteristics. Previous studies have mapped the FTDP-17 locus to a 2-centimorgan region on chromosome 17q21.11; the tau gene also lies within this region. We have now sequenced tau in FTDP-17 families and identified three missense mutations (G272V, P301L and R406W) and three mutations in the 5' splice site of exon 10. The splice-site mutations all destabilize a potential stem-loop structure which is probably involved in regulating the alternative splicing of exon10. This causes more frequent usage of the 5' splice site and an increased proportion of tau transcripts that include exon 10. The increase in exon 10+ messenger RNA will increase the proportion of Tau containing four microtubule-binding repeats, which is consistent with the neuropathology described in several families with FTDP-17.

Quantitative perimetry under binocular viewing conditions in microstrabismus.

In order to elucidate the type, size and depth of suppression scotomata in microstrabismus and small angle convergent strabismus, we performed binocular static perimetry in 14 subjects with strabismus and four normal observers. The strabismic cases had an objective angle of convergent squint between 1 and 8 deg, visual acuity between 0.1 and 1.25, and limited stereopsis. During testing the subjects fused pictures on two Friedmann visual field analyzers. Right and left eyes were studied separately under both monocular and binocular viewing conditions. In five strabismics a suppression scotoma was found in the squinting eye, with a diameter of 5-30 deg and a depth ranging from 4 to 14 dB. No suppression scotomata could be detected in the nine other subjects nor in the four normal observers. In conclusion, only 36% of subjects with strabismus were found to have a suppression scotoma. These scotomata were centered around the fixation point of the squinting eye, in some cases also encompassing the foveal area, and varying in depth and size.

A novel acid alpha-glucosidase mutation identified in a Pakistani family with glycogen storage disease type II.

A novel mutation, C118T, in exon 2 of the acid alpha-glucosidase gene has been found in an infant with glycogen storage disease type II. This mutation is predicted to result in protein truncation. The phenotype was that of the severe infantile form of the disorder with lack of motor development, but with eye regard, social smile and vocalization. The parents were heterozygous for C118T and belong to an Islamic community opposed to termination of pregnancy. As the C118T mutation results in the loss of one of two AvaI sites present in an informative PCR product, reliable premarriage carrier detection became possible and was acceptable to the members of this extended family.