Neonatal diabetes with a rare LRBA mutation

Discussion

NDM is the commonly used term to describe monogenic forms of diabetes which typically present within the first 6 months of life.2 Index case presented at around 3 months of age. For infants with persistent hyperglycaemia including those with NDM, management is initially directed towards correction of fluid and electrolyte abnormalities and reduction of hyperglycaemia by the administration of a continuous infusion of intravenous insulin and fluids.3 The index infant presented with severe DKA to a local hospital and was managed appropriately. At admission to our hospital, there was no DKA (normal blood pH, ketones and bicarbonate); hence, infant was started on breast feeding and subcutaneous insulin therapy (basal-bolus regimen).

After stabilisation on insulin therapy and in absence of pancreatic hypoplasia/aplasia, consanguinity or syndromic features, empiric trial of oral sulfonylurea is recommended while awaiting genetic test results.4 Index infant was started on glibenclamide trial (while insulin was continued) on day 3 of hospital stay, discontinued after nearly 4 weeks, in view of no response. Infant was discharged on basal-bolus (glargine-regular) regimen of insulin with a plan to collect the report of genetic testing in follow-up.

Genetic testing of the index infant revealed homozygous single base deletion in exon 23 of the LRBA (lipopolysaccharide-responsive and beige-like anchor protein) gene. This mutation results in a frameshift and premature truncation of the protein 2 amino acids downstream to codon 1198 (p.Gln1198LysfsTer2). Both parents were found to be heterozygous for the same variant.

LRBA deficiency results in decreased frequency, aberrant phenotype and decreased suppressive function of regulatory-T cells (Treg). Treg cell depletion in patients with LRBA deficiency is compounded by impaired Treg cell phenotype and function, with decreased expression of key effector proteins involved in Treg cell suppression, such as CD25 and CTLA-4.5 LRBA localises to cytosol at lysosomes, the trans-Golgi network, the endoplasmic reticulum, the perinuclear endoplasmic reticulum and endocytic vacuoles.6 Mechanisms by which LRBA deficiency impairs mammalian target of rapamycin (mTOR) activation can involve defective autophagy.7 The lymphocyte subset, T lymphocyte subset and immunophenotyping of Treg cells done at the age of 9 months in the index infant were normal as of now, however, can evolve over time.

The clinical features observed in patients with LRBA deficiency are heterogeneous with age of presentation ranging from 2 months to 12 years. LRBA deficiency is characterised as early-onset hypogammaglobulinaemia, autoimmune manifestations, susceptibility to inflammatory bowel disease and recurrent infection.7 The disease phenotype can broadly be divided into an enteropathy phenotype, an autoimmunity phenotype and an immunodeficiency phenotype. The enteropathy phenotype includes autoimmune enteropathy, IBD/IBD (inflammatory bowel disease)-like disease and non-infectious diarrhoea; the autoimmunity phenotype includes mainly AIHA (autoimmune haemolytic anaemia) and/or ITP (immune thrombocytopenic purpura); and the immunodeficiency phenotype includes combined immunodeficiency, combined variable immune deficiency (CVID) and a CVID-like disease. There does not appear to be any genotype-phenotype correlation.8

LRBA deficiency also include patients without hypogammaglobulinaemia described as clinically variable syndrome with a wide spectrum of manifestations.9 A systematic review of 109 LRBA deficient patients found that 24% of them had insulin-dependent diabetes mellitus (IDDM). The authors reported most frequent autoimmune complications in patients with LRBA deficiency to be AIHA, ITP, IDDM and IBD.10 Other studies reported diabetes in 22%–44.4% of patients presenting before 6 months of age to childhood.11 12 The index infant presented with autoimmune diabetes (anti-GAD-65 positive) at an early age (4 months). He did not have symptoms suggestive of other associated complications of LRBA deficiency (enteropathy, recurrent infections, organomegaly) as of now. Screening done for coeliac disease, autoimmune hypothyroidism, associated congenital malformations was normal in the index infant. Immunoglobulin profile and Treg assay were normal. In the index infant we have planned to monitor his HbA1c every 3 months and screening for autoimmune and immunological dysfunction yearly.

Various pharmacological immunosuppressive treatment strategies used to attenuate autoimmune symptoms of LRBA deficiency have been reported (eg, steroids, azathioprine, infliximab, mycophenolate mofetil, rituximab and sirolimus). In addition, regular IgG substitutions can be used in patients with hypogammaglobulinaemia.13 A very promising therapeutic approach is the CTLA4 modulation by abatacept, with which a dramatic and sustained clinical improvement has been reported in LRBA-deficient patients with life-threatening chronic organ manifestations such as severe restrictive lung disease or enteropathy.14