S-adenosylhomocysteine (SAH) hydrolase deficiency is a rare autosomal recessive disorder caused by pathogenic variants of the gene AHCY. Loss of SAH hydrolase causes SAH accumulation and impairs the methionine/S-adenosylmethionine (SAM) cycle that is integral to methylation reactions throughout the body. SAH hydrolase deficiency has been described in 16 patients with clinical features including intellectual disability, developmental delay, hypotonia, early mortality, and liver dysfunction. Although no immunologic sequelae have been previously noted, we report a 6-year-old boy with SAH hydrolase deficiency manifesting as combined immunodeficiency (CID).
Our patient had a longstanding diagnosis of SAH hydrolase deficiency with neurological manifestations including hypotonic quadriplegia, chronic static encephalopathy, and moyamoya vasculopathy complicated by a cerebral ischemic event. He initially presented to an outside hospital for Klebsiella pneumoniae sepsis and Pneumocystis jirovecii pneumonia (PJP). Infection history included recurrent upper respiratory infections. Following recovery, he was evaluated by our immunology department and was found to have persistent T cell lymphopenia (197; 700–4,200) with low numbers of CD4+ (97; 300–2,000) and CD8+ (90; 300–1,800) T cells, natural killer (NK) cells (45; 90–900), and B cells (70; 200–1,600). T cell receptor spectratyping demonstrated oligoclonal T cells and normal proliferative responses to anti-CD3. Humoral evaluation demonstrated hypogammaglobulinemia with normal IgA, IgM, and IgE, but absent vaccine responses. He was started on PJP prophylaxis and subcutaneous immunoglobulin. Hematopoietic cell transplantation (HCT) was considered but deferred due to the patient’s comorbidities.
We hypothesize that loss of SAH hydrolase in lymphocytes impairs DNA replication and gene expression changes that rely on nucleotide synthesis and DNA/histone methylation. Impairment of these processes in proliferating B and T cells could then lead to cell cycle arrest or apoptosis. This is analogous to adenosine deaminase (ADA)-severe combined immunodeficiency, where DNA synthesis is impaired in rapidly dividing T and B cells, leading to accumulation of toxic metabolites and cell death.
In summary, we report that SAH hydrolase deficiency can cause CID. This represents a novel cause of immunodeficiency and suggests that other defects in the SAM cycle might present with immunologic defects. Additional studies are needed to determine if HCT could be a treatment.
