Genotype and functional correlates of disease phenotype in deficiency of adenosine deaminase 2 (DADA2).

BACKGROUND: Deficiency of adenosine deaminase 2 (DADA2) is a syndrome with pleiotropic manifestations including vasculitis and hematologic compromise. A systematic definition of the relationship between adenosine deaminase 2 (ADA2) mutations and clinical phenotype remains unavailable. OBJECTIVE: We sought to test whether the impact of ADA2 mutations on enzyme function correlates with clinical presentation. METHODS: Patients with DADA2 with severe hematologic manifestations were compared with vasculitis-predominant patients. Enzymatic activity was assessed using expression constructs reflecting all 53 missense, nonsense, insertion, and deletion genotypes from 152 patients across the DADA2 spectrum. RESULTS: We identified patients with DADA2 presenting with pure red cell aplasia (n = 5) or bone marrow failure (BMF, n = 10) syndrome. Most patients did not exhibit features of vasculitis. Recurrent infection, hepatosplenomegaly, and gingivitis were common in patients with BMF, of whom half died from infection. Unlike patients with DADA2 with vasculitis, patients with pure red cell aplasia and BMF proved largely refractory to TNF inhibitors. ADA2 variants associated with vasculitis predominantly reflected missense mutations with at least 3% residual enzymatic activity. In contrast, pure red cell aplasia and BMF were associated with missense mutations with minimal residual enzyme activity, nonsense variants, and insertions/deletions resulting in complete loss of function. CONCLUSIONS: Functional interrogation of ADA2 mutations reveals an association of subtotal function loss with vasculitis, typically responsive to TNF blockade, whereas more extensive loss is observed in hematologic disease, which may be refractory to treatment. These findings establish a genotype-phenotype spectrum in DADA2.

Kearns Sayre Syndrome--case report with review of literature.

Kearns-Sayre Syndrome is form of rare mitochondrial cytopathy, first described by Thomas P. Kearns and George Pomeroy Sayre in 1958 and is characterized by progressive external opthalmoplegia, cardiac conduction block, pigmentary retinal degeneration, variable number of red ragged fibers on muscle biopsy. It presents before the child reaches the age of twenty. Kearns-Sayre syndrome may affect many organ systems and additional features may include myopathy, dystonia, bulbar symptoms in the form of dysarthria and nasal regurgitation and bilateral facial weakness. Endocrine abnormalities (e.g., diabetes, growth retardation/short stature, and hypoparathyroidism), bilateral sensorineural deafness, dementia, cataracts, and proximal renal tubular acidosis, skeletal muscle weakness (proximal more than distal) and exercise intolerance are additional features. Kearns Sayre Syndrome occurs as a result of large-scale single deletions (or rearrangements) of mitochondrial DNA (mtDNA), which is usually not inherited but occurs spontaneously, probably at the germ-cell level or very early in embryonic development. No disease-modifying therapy is available for Kearns-Sayre syndrome (KSS). Management is supportive vigilance for detection of associated problems. In the future, potential treatment in patients with Kearns-Sayre syndrome may attempt to inhibit mutant mtDNA replication or encourage replication of wild-type mtDNA.

Prevention of iron deficiency anemia (IDA): how far have we reached?

Anemia is a global problem of immense public health significance. Iron deficiency anemia is the most common nutritional disorder seen all over the world, more in the developing countries, particularly, affecting young children of 6-24 months of age, adolescents, women of reproductive age group and pregnant/ lactating women. Basic approach in prevention of IDA should include education and associated measures to increase the dietary intake of iron, dietary modification to enhance the iron absorption, fortification of food articles, in addition to control the infection and worm infestations. Supplemenldelim 1, of medicinal iron is key to success which can be achieved by daily or intermittent (biweekly/weekly) administration of oral iron to the target group. Reduction of nutritional anemia should receive top priority through proper planning by using better utilization of existing health infrastructure.

'NESTROFT'--an effective screening test for beta thalassemia trait.

OBJECTIVE: To evaluate the efficacy of NESTROFT (Naked Eye Single Tube Red Cell Osmotic Fragility Test) as a screening tool for detection of beta thalassemia trait. DESIGN: Prospective study. SETTING: Field camps in various parts of Gujarat and Maharashtra States. METHODS: A total of 2525 subjects were screened. NESTROFT, complete hemogram including red cell indices and calculation of Mentzer's Fraction (MF) and discriminant functions (DF1-4) were done in all subjects. HbA2 was performed in 830 initial subjects to compute sensitivity, specificity and predictive values for various parameters. RESULTS: NESTROFT (sensitivity 94.4%), as a single screening parameter was superior to any of the other evaluated parameters individually, besides being cost effective. Mean corpuscular volume (MCV) < 80 fl followed NESTROFT closely (sensitivity 93.7; p > 0.05). MCV < 75 fl had a significantly (p < 0.001) lower sensitivity (87.3%) in comparison to both of these parameters. In contrast, MF, DF1, DF2, DF3 and DF4 did not meet the requirements of a good screening test with sensitivity values of 66.2%, 54.9%, 47.2%, 64.1% and 55.6%, respectively. NESTROFT in combination with MCV < 80 fl proved 100% sensitive. However, the combination was not cost effective. CONCLUSION: NESTROFT is a sensitive, cost effective, rapid and reliable screening test for detection of beta thalassemia trait in a population.