Corry Weemaes

Clinical spectrum of ataxia-telangiectasia in adulthood

Objective: To describe the phenotype of adult patients with variant and classic ataxia-telangiectasia (A-T), to raise the degree of clinical suspicion for the diagnosis variant A-T, and to assess a genotype–phenotype relationship for mutations in the ATM gene. Methods: Retrospective analysis of the clinical characteristics and course of disease in 13 adult patients with variant A-T of 9 families and 6 unrelated adults with classic A-T and mutation analysis of the ATM gene and measurements of ATM protein expression and kinase activity. Results: Patients with variant A-T were only correctly diagnosed in adulthood. They often presented with extrapyramidal symptoms in childhood, whereas cerebellar ataxia appeared later. Four patients with variant A-T developed a malignancy. Patients with classic and variant A-T had elevated serum α-fetoprotein levels and chromosome 7/14 rearrangements. The mildest variant A-T phenotype was associated with missense mutations in the ATM gene that resulted in expression of some residual ATM protein with kinase activity. Two splicing mutations, c.331 + 5G>A and c.496 + 5G>A, caused a more severe variant A-T phenotype. The splicing mutation c.331 + 5G>A resulted in less ATM protein and kinase activity than the missense mutations. Conclusions: Ataxia-telangiectasia (A-T) should be considered in patients with unexplained extrapyramidal symptoms. Early diagnosis is important given the increased risk of malignancies and the higher risk for side effects of subsequent cancer treatment. Measurement of serum α-fetoprotein and chromosomal instability precipitates the correct diagnosis. There is a clear genotype–phenotype relation for A-T, since the severity of the phenotype depends on the amount of residual kinase activity as determined by the genotype.

Immunodeficiency, centromeric region instability, facial anomalies syndrome (ICF)

The Immunodeficiency, Centromeric region instability, Facial anomalies syndrome (ICF) is a rare autosomal recessive disease described in about 50 patients worldwide and characterized by immunodeficiency, although B cells are present, and by characteristic rearrangements in the vicinity of the centromeres (the juxtacentromeric heterochromatin) of chromosomes 1 and 16 and sometimes 9. Other variable symptoms of this probably under-diagnosed syndrome include mild facial dysmorphism, growth retardation, failure to thrive, and psychomotor retardation. Serum levels of IgG, IgM, IgE, and/or IgA are low, although the type of immunoglobulin deficiency is variable. Recurrent infections are the presenting symptom, usually in early childhood. ICF always involves limited hypomethylation of DNA and often arises from mutations in one of the DNA methyltransferase genes (DNMT3B). Much of this DNA hypomethylation is in 1qh, 9qh, and 16qh, regions that are the site of whole-arm deletions, chromatid and chromosome breaks, stretching (decondensation), and multiradial chromosome junctions in mitogen-stimulated lymphocytes. By an unknown mechanism, the DNMT3B deficiency that causes ICF interferes with lymphogenesis (at a step after class switching) or lymphocyte activation. With the identification of DNMT3B as the affected gene in a majority of ICF patients, prenatal diagnosis of ICF is possible. However, given the variety of DNMT3B mutations, a first-degree affected relative should first have both alleles of this gene sequenced. Treatment almost always includes regular infusions of immunoglobulins, mostly intravenously. Recently, bone marrow transplantation has been tried.

Heterogeneous clinical presentation in ICF syndrome: correlation with underlying gene defects

Immunodeficiency with centromeric instability and facial anomalies (ICF) syndrome is a primary immunodeficiency, predominantly characterized by agammaglobulinemia or hypoimmunoglobulinemia, centromere instability and facial anomalies. Mutations in two genes have been discovered to cause ICF syndrome: DNMT3B and ZBTB24. To characterize the clinical features of this syndrome, as well as genotype–phenotype correlations, we compared clinical and genetic data of 44 ICF patients. Of them, 23 had mutations in DNMT3B (ICF1), 13 patients had mutations in ZBTB24 (ICF2), whereas for 8 patients, the gene defect has not yet been identified (ICFX). While at first sight these patients share the same immunological, morphological and epigenetic hallmarks of the disease, systematic evaluation of all reported informative cases shows that: (1) the humoral immunodeficiency is generally more pronounced in ICF1 patients, (2) B- and T-cell compartments are both involved in ICF1 and ICF2, (3) ICF2 patients have a significantly higher incidence of intellectual disability and (4) congenital malformations can be observed in some ICF1 and ICF2 cases. It is expected that these observations on prevalence and clinical presentation will facilitate mutation-screening strategies and help in diagnostic counseling.

Neuropathology in classical and variant ataxia-telangiectasia

Ataxia‐telangiectasia (A‐T) is classically characterized by progressive neurodegeneration, oculocutaneous telangiectasia, immunodeficiency and elevated α‐fetoprotein levels. Some patients, classified as variant A‐T, exhibit a milder clinical course. In the latter patients extrapyramidal symptoms, instead of cerebellar ataxia, tend to be the dominating feature and other classical disease hallmarks, like telangiectasia, appear later or even may be absent. Some patients with variant disease have clinically pronounced anterior horn cell degeneration. Neuropathological studies of genetically proven A‐T patients are lacking. The aims of our study were to describe the neuropathology of three A‐T patients; in two of them the diagnosis was genetically confirmed. The neuropathological findings were compared with those of all known published autopsy findings in A‐T patients up to now. Two classical A‐T patients aged 19 and 22 and a 33‐year‐old patient with variant disease were autopsied. In line with previous reports, our patients had severe cerebellar atrophy, less pronounced degeneration of the dentate nucleus and inferior olive, degeneration of the posterior columns and neurogenic muscular atrophy. In addition, all three had anterior horn cell degeneration, which was most prominent at the lumbar level. Compared to the literature, the degenerative changes in the brain stem of the variant A‐T patient were somewhat less than anticipated for his age. Degenerative changes in the cerebellum and spinal cord were comparable with those in the literature. Progeric changes were lacking. In conclusion, compared to classical A‐T, the variant A‐T patient showed essentially the same, only slightly milder neuropathological abnormalities, except for anterior horn degeneration.

Mutations in CDCA7 and HELLS cause immunodeficiency-centromeric instability-facial anomalies syndrome.

The life-threatening Immunodeficiency, Centromeric Instability and Facial Anomalies (ICF) syndrome is a genetically heterogeneous autosomal recessive disorder. Twenty percent of patients cannot be explained by mutations in the known ICF genes DNA methyltransferase 3B or zinc-finger and BTB domain containing 24. Here we report mutations in the cell division cycle associated 7 and the helicase, lymphoid-specific genes in 10 unexplained ICF cases. Our data highlight the genetic heterogeneity of ICF syndrome; however, they provide evidence that all genes act in common or converging pathways leading to the ICF phenotype.

Chromosome 7 in ataxia-telangiectasia

ATAXIA-TELANGIECTASIA, or the Louis-Bar syndrome, is a recessive autosomal disorder clinically characterized by progressive cerebel lar ataxia, oculocutaneous telangiectasia, immunodef ic iency, and a predisposi t ion to the deve lopment o f neoplasia. Most often pat ients die f rom pu lmona ry insufficiency or cancer in the first two decades of life. A T is one of the classical ch romosome breakage syndromes; the cells of the pat ients usually display an increased f requency of spontaneous chromosome breaks and rear rangements . C h r o m o s o m e 14 abnor malities are especially f requent and very often there is a t andem 14q/14q translocation, a so-called Dq + marker c h r o m o s o m e ; , Recent ly we have detected ano the r chromosomal abnormal i ty which might be especially associated with AT: in three subsequent ly studied patients we did not find D q + markers but typical ch romosome 7 abnormal i t ies .

Rituximab and intravenous immunoglobulins for relapsing postinfectious opsoclonus-myoclonus syndrome.

We describe 2 children with postinfectious opsoclonus-myoclonus syndrome. Although the patients initially responded to monotherapy with methylprednisolone, intravenous immunoglobulins, or rituximab, they manifested persistent neurologic deficits and relapsing signs. Treatment with rituximab in combination with intravenous immunoglobulin, however, resulted in significant longterm clinical improvement.

Primary Immunodeficiency Caused by an Exonized Retroposed Gene Copy Inserted in the CYBB Gene

Retrotransposon‐mediated insertion of a long interspersed nuclear element (LINE)‐1 or an Alu element into a human gene is a well‐known pathogenic mechanism. We report a novel LINE‐1‐mediated insertion of a transcript from the TMF1 gene on chromosome 3 into the CYBB gene on the X‐chromosome. In a Dutch male patient with chronic granulomatous disease, a 5.8‐kb, incomplete and partly exonized TMF1 transcript was identified in intron 1 of CYBB, in opposite orientation to the host gene. The sequence of the insertion showed the hallmarks of a retrotransposition event, with an antisense poly(A) tail, target site duplication, and a consensus LINE‐1 endonuclease cleavage site. This insertion induced aberrant CYBB mRNA splicing, with inclusion of an extra 117‐bp exon between exons 1 and 2 of CYBB. This extra exon contained a premature stop codon. The retrotransposition took place in an early stage of fetal development in the mother of the patient, because she showed a somatic mosaicism for the mutation that was not present in the DNA of her parents. However, the mutated allele was not expressed in the patients mother because the insertion was found only in the methylated fraction of her DNA.

Postmortem Findings in the Nijmegen Breakage Syndrome

Autopsy findings for two patients with the Nijmegen breakage syndrome (NBS) are presented. This syndrome has the same type of immunologic and cytogenetic abnormalities as ataxia telangiectasia (AT). In NBS, however, microcephaly is found and progressive cerebellar ataxia and oculocutaneous telangiectasia are lacking. We demonstrate a clear neuropathologic difference between these two syndromes, as the diffuse cortical cerebellar degeneration characteristic of AT was absent in NBS. In the thymus the histologic picture was suggestive of simple dysplasia. Lymphoid tissues were slightly atrophic but otherwise structurally normal. In one of the two presented cases an extranodal diffuse large cell malignant non-Hodgkin lymphoma of B cell immunoblastic type was found in Waldeyers ring, in the small and large intestines, and in the brain, whose sequelae had caused death. Six of the 19 patients known with certainty to have this syndrome have developed lymphoid malignancy, which indicates that these patients are prone to develop malignancies.

Chromosome studies in IgA‐deficient patients

Chromosome analysis was performed in 17 children ith IgA‐deficiency. In two patients a constitutional structural chromosome abnormality was found. A ring chromosome 22 was seen in one, while in the other a mosaicism of ring chromosome 18/18p+ was observed. Both patients wcre metanlly retarded and showed distinct congénital defects. From ten asymptomatic patients, spontaneous as well as X‐ray‐induced chromosome instability was investigated. There was no increased spontaneous instability, and also after irradiation the induced chromosome damage was within normal control levels. A relationship between IgA‐deficiency and X‐ray hypersensitivity, as might be suggested by the frequently occurring coïncidence of radiosensitivi‐ty and IgA‐deficiency in ataxia teleangiectasia patients, is not established.