Israel Medical Association Journal

Severe combined immunodeficiencies represent a heterogeneous group of hereditary defects of the immune system that affect both T and B cells and whose etiology has only recently begun to be understood. A portion of these SCID patients bear a defect in either of the two recombination-activating genes, Rag-1 or Rag-2, while others have mutations in a newly identified gene, Artemis. Omenn syndrome is an unusual severe immunodeficiency with T cells but no B cells, and peculiar features also due to a defect in Rag-1 or Rag-2 genes. All these three forms are characterized by an impairment of the VDJ recombination, the process that insures the somatic diversification of immunoglobulin and T cell receptor-encoding genes. Recent findings have enabled us to better understand the pathophysiology of these three immunodeficiencies, which affect the V(D)J recombination process to a different extent and in different ways.

Background: The Bloom syndrome gene, BLM, was mapped to 15q26.1 and its product was found to encode a RecQ DNA helicase. The Fanconi anemia complementation group C gene was mapped to chromosome 9q22.3, but its product function is not sufficiently clear. Both are recessive disorders associated with an elevated predisposition to cancer due to genomic instability. A single predominant mutation of each disorder was reported in Ashkenazi Jews: 2281delATCTGAinsTAGATTC for Bloom syndrome (BLM-ASH) and IVS4+4A®T for Fanconi anemia complementation group C.

Objectives: To provide additional verification of the mutation rate of BLM and FACC[1] in unselected Ashkenazi and non-Ashkenazi populations analyzed at the Sheba Medical Center, and to trace the origin of each mutation.

Methods: We used polymerase chain reaction to identify mutations of the relevant genomic fragments, restriction analysis and gel electrophoresis. We then applied the Pronto^TM kit to verify the results in 244 samples and there was an excellent match.

Results: A heterozygote frequency of 1:111 for BLM-ASH and 1:92 for FACC was detected in more than 4,000 participants, none of whom reported a family history of the disorders. The Pronto^TM kit confirmed all heterozygotes. Neither of the mutations was detected in 950 anonymous non-Ashkenazi Jews. The distribution pattern of parental origin differed significantly between the two carrier groups, as well as between each one and the general population.

Conclusions: These findings as well as the absence of the mutations in non-Ashkenazi Jews suggest that: a) the mutations originated in the Israelite population that was exiled from Palestine by the Roman Empire in 70 AD and settled in Europe (Ashkenazi), in contrast to those who remained; and b) the difference in origin distribution of the BS[2] and FACC mutations can be explained by either a secondary migration of a subgroup with a subsequent genetic drift, or a separate geographic region of introduction for each mutation.

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[1] FACC = Fanconi anemia complementation group C

Fibromyalgia syndrome is a chronic, painful musculoske­letal disorder of unknown etiology and/or pathophysiology. During the last decade many studies have suggested autonomic nervous system involvement in this syndrome, although contradictory results have been reported. This review focuses on studies of the autonomic nervous system in fibromyalgia syndrome and related disorders, such as chronic fatigue syndrome and irritable bowel syndrome on the one hand and anxiety disorder on the other, and highlights techniques of dynamic assessment of heart rate variability, It raises the potentially important prognostic implications of protracted autonomic dysfunction in patient populations with fibromyalgia and related disorders, especially for cardiovas­cular morbidity and mortality.

Sjogren’s syndrome is a chronic inflammatory process invol­ving primarily the exocrine glands. Its association with lymphoma is well documented. A low grade marginal-zone lymphoma related to mucosa-associated lymphoid tissue is the commonest lymphoid neoplasia in Sjogren’s syndrome. We review the literature and comment on the molecular, clinical, histopathologic and therapeutic aspects of these tumors in Sjogrens syndrome.

Reactive arthritis is a disease affecting mostly young adults. Owing to a greater general awareness the diagnosis has become more common during recent years. It is well established that ReA is caused by an infection, mostly in genetically susceptible individuals. The pathogenetic mechan­isms are still poorly understood, and the treatment rests mainly on anti-inflammatory drugs or steroids. Vigorous and early treatment of the triggering infection may prevent the develop­ment of ReA but this is rarely possible in everyday clinical practice. Despite its name, the disease should be considered as a general disorder that affects not only the joints. The prognosis is not as good as earlier believed, and relapses or chronic development are not unusual.

Background: The association of carpal tunnel syndrome with occupational risk factors is well established. However, in clinical practice these factors are only rarely considered and evaluated. Managing these risk factors could prevent the occurrence of future cases and alleviate treatment of the afflicted individuals.

Objectives: To estimate the role of occupational risk factors in a large group of patients diagnosed by electro­physiological studies as suffering from CTS.

Methods: A group of 396 subjects (204 women, 165 men) who were tested in one laboratory by electrophysiological studies were further evaluated (by questionnaire) to determine the possible role of occupational and other risk factors in the etiology of their syndrome.

Results: Persons employed in high force — low repetitive or low force — high repetitive jobs, harbor an extra risk for developing CTS as compared with controls, OR=3.21 (95% C1 = 1.5-6.9) and OR=4.72 (95%C1 = 1.8-12.5), respectively. These jobs include typists/secretaries, nursing personnel, production workers and housewives.

Conclusion: Evaluation of a general group of examinees referred for electrophysiological studies on sympatology compatible with CTS may show that occupational risk factors play a substantial role in the development of symptoms. By increasing the awareness of clinicians and the public to these risk factors, appropriate preventive measures can be intro­duced and the burden of the disease reduced.

Anti-neutrophil cytoplasm antibodies are important markers of certain small vessel necrotizing vasculitides, but the optimal use of laboratory results in daily clinical practice necessitates collaboration between clinicians and laboratory specialists. Physicians must familiarize themselves with ANCA tests in ANCA-related vasculitides as well as in differential diagnostic patient populations in order to define cutoff values. Indirect immunofluorescence with a consensus-agreed technique combined with standardized enzyme immunoassays is the modality for detecting the main SSV-associated ANCA specificities using cutoff values that can sufficiently distinguish SVV from non-SVV patients. The combined use of IF and direct EIA to demonstrate proteinase 3-ANCA and myeloper­oxidase-ANCA at significant levels leads to a very high diagnostic specificity towards SVV conditions such as Wegen­er’s granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome, and limited forms of these such as renal-limited focal necrotizing glomerulonephritis. A strong reactivity of ANCA against several azurophil granule components indicates a drug-induced syndrome. ANCA-related SVV and drug­induced vasculitis or lupus syndromes have characteristic ANCA profiles that can help distinguish these conditions from other inflammatory diseases.

Paraneoplastic syndromes are disorders associated with cancer but without a direct effect of the tumor mass or its metastases on the nervous system. Small cell carcinoma of lung associated with paraneoplastic sensory neuronopathy and/or paraneoplastic encephalomyelitis with the presence of anti-Hu antibodies has been termed “anti-Hu syndrome. Anti-­Hu associated PSN-PEM is an immune disorder in which both cell-mediated and humoral mechanisms are involved. Patients are consiaered affected by Anti-Hu associated PSN-PEM when they develop clinical signs and symptoms of CNS dysfunction and/or sensory neuropathy not caused by metas­tases or other disorders, and serum or cerebrospinal fluid is positive for Hu abs. SCLC is found in more than 90% of patients with cancer and positive Hu abs. Individual patients with Hu abs associated to SCLC may suffer PSN-PEM, Iimbic encephalitis, brainstem encephalopathy, opsoclonus-myoclo­nus, paraneoplastic cerebellar degeneration or myelopathy. Hu abs have a specificity of 99% and sensitivity of 82% in detecting paraneoplastic neurological syndromes. There are two types of treatment: the first is to treat the cancer, the second is to suppress the immune reaction with the use of corticosteroids, cyclophosphamide, azathioprine, plasma ex­change, intravenous immunoglobulin and immunoadsorption however, treatment of paraneoplastic syndromes is generally unsatisfactory.

Knowledge on the pathophysiology of irritable bowel syndrome has evolved, beginning with disturbances in motility to visceral hypersensitivity, and ultimately to alterations in brain-gut bi­directional communication, where neurotransmitters such as serotonin play a key role. Recently, a multicomponent disease model that integrates all these alterations was proposed. This model is divided into physiological, cognitive, emotional and behavioral components that explain the gastrointestinal as well as the constitutional symptoms. In recent years there has been an explosion of research together with new developments in pharmacological treatments for lBS that support each compo­nent of this model. This review presents recent data in favor of these alterations in IBS.