Autosomal recessive hyper IgM syndrome: causes, symptoms, diagnosis, treatment

Autosomal recessive hyper IgM syndrome associated with a deficit of activation cytidine deaminase (HIGM2)

Following the discovery of the molecular basis of the X-linked hyper-IgM syndrome, descriptions of male and female patients with normal expression of CD40L appeared, increased sensitivity to bacterial, but not opportunistic infections, and in some families - with autosomal recessive inheritance. In 2000, Revy ssoavt. Published the results of a study of this group of patients with hyper-IgM syndrome, who found a mutation in the gene coding for the activation-inducible cytidine deaminase (AICDA).

The activation-inducible cytidine deaminase (AICDA) gene, localized on chromosome 12p13, consists of 5 exons and encodes a protein consisting of 198 amino acids. Mutations, most often homozygous, rarely heterozygous, are found predominantly in 3 ekeon.

AID belongs to the family of cytidine deaminases. AID is an RNA-editing enzyme that acts on one or more substrates of the template RNA. However, convincing evidence of the direct effect of cytidine deaminase on DNA has recently been obtained. Following this model, it was suggested that AID convert deoxycytidine (dC) to deoxyuridine (dU) in one DNA strand. At present, it is known that AID requires interaction with a specific coenzyme (enzymes) to induce class-switching recombination. It was also shown that the class switching recombination block occurs before double-strand breaks of the mu-switching domain DNA. Thus, the exact mechanism of functioning of AID is not completely understood, although the important role of this enzyme in the recombination of the switching of classes of immunoglobulins and somatic hypermutation is evident.

Symptoms

Patients with AID deficiency become ill in early childhood, the clinical picture is dominated by repeated bacterial infections of the respiratory tract and gastrointestinal tract, However, due to a milder clinical phenotype due to the absence of opportunistic infections in this group of patients, many of them diagnosed with immunodeficiency after 20 years. Similarly, patients with a mutation in CD40, patients with AID deficiency have significantly reduced levels of IgG and IgA, and normal or elevated IgM. Specific antibodies of IgG class to T-dependent protein antigens are absent, while IgM isogoagglutinins are present.

The number of CD19 ⁺ B-lymphocytes and CD27 ⁺ B-cell memory is normal, and T-cell immunity is usually preserved. A characteristic clinical finding in these patients is lymphoid hyperplasia, with giant germinal centers consisting of proliferating B-lymphocytes that simultaneously express IgM, IgD and CD38.

Diagnostics

The diagnosis of AID deficiency should be suspected in patients with impaired serum immunoglobulin levels corresponding to hyper-IgM syndrome, in combination with normal expression of CD40 ligand, and inability of peripheral blood lymphocytes, when stimulated in vitro with anti-CD40 and lymphokines, to produce other than IgM, classes of immunoglobulins. Confirm the molecular diagnosis, you can only find a mutation in the gene AID.

Treatment

Regular replacement therapy with intravenous immunoglobulin (400-600 mg / kg / month) can reduce the incidence of infectious manifestations, but does not affect lymphoid hyperplasia.

[1], [2], [3], [4]