A novel frameshift variant in the ADA2 gene of a patient with a neurological phenotype: a case report.

BACKGROUND: Adenosine deaminase 2 (ADA2) deficiency is an inherited autoinflammatory syndrome caused by a defect in the ADA2 gene. Most common manifestations include peripheral vasculopathy, early-onset stroke, immunodeficiency, and haematological manifestations. Patients with pathogenic variants that are more detrimental to ADA2's enzymatic function (e.g. frameshift) have been reported to be prone to developing hematological phenotype. We report here the case of a 13-year-old Caucasian girl with a novel frameshift variant in the ADA2 gene and a clinical phenotype of early-onset stroke. CASE PRESENTATION: The patient was admitted to hospital with complaints of weakness in her right arm, unilateral facial weakness and speech problems. Her initial laboratory workup was normal; however, magnetic resonance imaging of her brain confirmed acute/subacute ischaemic changes in the posterior limb of the left-sided internal capsule and in the apical part of the thalamus. She also had manifestations of immunodeficiency - recurrent skin infections and otitis, chronic Molluscum contagiosum infection in anamnesis and B cell deficiency with a low level of serum IgA. The patient's DNA was analysed and two pathogenic variants were identified in the ADA2 gene, confirming a diagnosis of adenosine deaminase 2 (ADA2) deficiency. While one of the variants (c.506G > A (p.Arg169Gln)) has been reported previously, the other one is a novel frameshift variant, namely, c.464del (p.Pro155Hisfs*29). The patient received stroke rehabilitation, which significantly improved her functional state. Tumour necrosis factor inhibitor and methotrexate treatment was commenced, and the patient has remained stable with no further ischaemic events. CONCLUSIONS: Although rare, ADA2 deficiency should be considered in patients with early-onset stroke, especially with concomitant manifestations of inflammatory features or immunodeficiency. This case report extends the genotypic spectrum of ADA2 deficiency.

A nationwide epidemiological study of myasthenia gravis in Latvia.

BACKGROUND AND PURPOSE: Myasthenia gravis (MG) is an autoimmune disorder characterized by fatigable muscle weakness due to antibody-mediated impairment of neuromuscular transmission. The aim of this study was to investigate the incidence and prevalence of MG in Latvia, and to characterize this population by well-established clinical parameters such as age at onset, presence of associated antibodies and thymus pathology. METHODS: All prevalent cases on 1 January 2015 and cases of patients newly presenting with MG symptoms from 1 January 2010 to 31 December 2014 were selected from the database of the Neuromuscular Disease Clinic of Pauls Stradins Clinical University Hospital and Children's Clinical University Hospital. Crude rates were calculated based on population data. These were directly age-standardized to the European and World Health Organization world standard populations. The analysis of clinical characteristics was carried out in a cohort of patients who had undergone a complete set of electrophysiological, serological and radiological investigations (n = 153; 68%). RESULTS: During the study period 99 incident and 226 prevalent cases were identified. The total crude MG incidence was 9.7 per million person-years. The prevalence of MG on 1 January 2015 was 113.8 per million. 54.2% of patients tested positive for acetylcholine receptor antibodies, 7.8% for muscle specific kinase antibodies and 1.3% for lipoprotein related protein 4 antibodies. CONCLUSIONS: This is the first study of MG in Latvia and the second population-based study of MG in Eastern Europe. Our epidemiological results are similar to those in some other European and Northern American countries, and show high prevalence and increasing incidence of late-onset MG.

Clinical aspects of the health disturbances in Chernobyl Nuclear Power Plant accident clean-up workers (liquidators) from Latvia.

The health status of some 6,000 workers from Latvia who went to clean-up the Chernobyl Nuclear Power Plant (CNPP) site following the explosion on 26 April 1986 has been analyzed. The data on these workers have been recorded in the Latvian State Register of Occupational disease patients and people exposed to ionizing radiation due to Chernobyl NPP accident (Latvian State Register) that was established in 1994. From these data, estimates have been made of external ionizing radiation to which these workers were exposed together with observations on the impact of exposure to heavy metals (especially lead and zinc) and radioactive isotopes released during the reactor 'meltdown'. These factors along with psycho-emotional and social-economic stresses account for a marked excess of mortality and morbidity in the group of CNPP accident clean-up workers compared with that of the non-exposed normal Latvian population adjusted for age and sex. The number of diseases or conditions in the CNPP accident clean-up workers has progressively risen from an average of 1.3 in 1986 to 10.9 in 2007. This exceeds for the Latvian population when adjusted for age and sex. The most serious conditions affect the nervous, digestive, respiratory, cardiovascular, endocrine (especially thyroid) and immunological systems. While the morbidity associated with diseases of the respiratory and digestive systems has decreased in recent years that in the other systems is increasing. In recent years, there has been an increased occurrence of cancers affecting the thyroid, prostate and stomach. Clinical and laboratory investigations suggest that surviving CNPP accident clean-up workers exhibit signs of immuno-inflammatory reactions causing premature aging with evidence of autoimmune diseases and immunological deficiencies or abnormalities. It is suggested that the CNPP accident clean-up workers may have a specific syndrome, the 'Chernobyl post-radiation neurosomatic polypathy', due to sustained oxidant stress injury, as a result of exposure to radiation and lead.

Analysis of the immune status in Latvian Chernobyl clean-up workers with nononcological thyroid diseases.

The aim of the present work was to characterize the immune status of 385 individuals who participated in the 1986-90 clean-up work of the after effects of the Chernobyl nuclear power plant explosion. Fifty-nine Chernobyl clean-up workers developed the most common thyroid diseases; euthyroid nodular and diffuse goiter; 47 healthy blood donors were taken as controls. The levels of immunoglobulins (IgA, IgG and IgM), the numbers of peripheral blood leukocytes, lymphocytes, monocytes, T lymphocytes and their subpopulations (CD3+, CD4+, CD8+), B lymphocytes (CD19+), natural killer (NK) cells (CD16+), classical and alternative pathway activity of complement (CH50, APH50), the C3 split product C3d, and neutrophil phagocytosis were determined in the peripheral blood. We found a significantly decreased number of CD16+ cells (natural killer), of CD4+ and CD8+ T lymphocytes, a reduced neutrophil phagocytic activity as well as a significant complement activation in Chernobyl clean-up workers with and without thyroid diseases when compared with normal levels and those in the control group. In addition, the number of CD3+ and CD4+ cells was significantly higher in patients with nodular goiter when compared with that in patients with diffuse goiter. Levels of IgG and numbers of monocytes were significantly decreased in persons who worked in Chernobyl in 1986 during the first 2 months after the accident (with maximal radiation exposure) but were without correlation to thyroid disorders. Our results clearly reflect an impaired immune system in the Chernobyl clean-up workers even 10-14 years after the nuclear accident.