Adenosine Deaminase Deficiency with a Novel Gene Mutation.

Abstract

To the Editor: Adenosine deaminase (ADA) deficiency is a rare autosomal recessive form of severe combined immunodeficiency disorder (SCID) caused by mutations in the ADA gene [1]. ADA-SCID is associated with both Bearly^ and Blate onset^ of presentation due to wide variability in the genetic mutations. No data is available about its incidence in India, but it is expected to be high due to high consanguinity. We are presenting a case of ADA-SCID from India. Informed consent was obtained from the participants included in the study. A 6-mo boy, born of 2 degree consanguineous marriage presented with respiratory infections, failure to thrive, developmental delay and dysmorphic features like hairy forehead, frontal bossing, fused eyebrows and clinodactyly. Chest radiograph showed an absence of thymic shadow, the anterior end of ribs and costochondral junctions appeared normal. Complete blood count (CBC) revealed a low lymphocyte percentage (6 %) and absolute lymphocyte count (ALC – 771/ cumm) with normal blood indices (Hb 9.3 g/dl, platelet count 266 x10/L). Serum immunoglobulin and uric acid levels were normal. Patient was immunized as per schedule including BCG at birth. The infectious work up was negative. RBCADA levels were low (0.7 U/g Hb) [2]. The lymphocyte subset analysis (LSS) by flowcytometry showed marked reduction in absolute counts of T (655/cumm), B (23/cumm), NK (85/cumm) cells. Sanger sequencing revealed a novel homozygous missense mutation (c.42 T > C; p.Leu14Pro) in exon 2 ofADA gene and was predicted deleterious using SIFT, Polyphen and Panther software. Parents were carrier for the same mutation. This change was not detected in a statistically significant number of control samples. As reported, depletion of T, B and NK cells with severe infections and developmental delay was noted in our patient at an early age [3]. A low ALC and TBNK phenotype is associated with ADA deficiency, Purine Nucleoside Phosphorylase (PNP) deficiency and Reticular Dysgenesis. The present case showed low ADA levels with normal uric acid levels and normal ANC on CBC; hence, was evaluated for ADA gene studies. Developmental delay and neurological abnormalities are well described in ADA–SCID, however, the dysmorphic features with clinodactyly seen in this child is rare and not been reported in the literature. It is difficult to say if any other additional genetic abnormalities were responsible for the same, however we could not evaluate it by cytogenetic studies. Though, live vaccines are contraindicated in ADA–SCID, no immunization complication was observed in our patient. Murine ADA gene studies revealed that H15D mutation alters an ability of zinc to activate a water molecule postulated to play a role in the catalytic mechanism [4]. The L14P in our patient is located just before H15D mutation and may result in similar effects. Apart from hematopoietic stem cell transplantation (HSCT) or gene therapy or enzyme replacement therapy, supportive measures like immunoglobulin supplements, prophylactic antifungals, and antibiotic must be initiated immediately after diagnosis to reduce the morbidity [5]. Inspite of adequate supportive therapy our patient expired due to respiratory complications. Typical cl inical manifesta t ions, lymphopenia, immunophenotypic studies and RBC ADA levels provide a clue towards the underlying ADA deficiency that can be * Manisha Madkaikar madkaikarm@icmr.org.in