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Reticular dysgenesis is a rare autosomal recessive immunodeficiency characterized by early differentiation arrest of the myeloid lineage, profound lymphopenia, and sensorineural hearing loss. The condition results from biallelic loss‐of‐function variants in AK2, which encodes mitochondrial adenylate kinase 2 critical for cellular energy homeostasis. Patients present in the neonatal period with agranulocytosis, T‐cell deficiency, and require early hematopoietic stem cell transplantation to survive (PMID:31673062). Functional studies across multiple models have established a direct link between AK2 deficiency and impaired mitochondrial respiration, confirming a primary bioenergetic mechanism.
Autosomal recessive inheritance is supported by two singleton case reports: an Old Order Amish patient homozygous for c.622T>C (p.Ser208Pro) and a boy with a noncanonical splice variant c.330+5G>A leading to exon 3 skipping (PMID:31673062; PMID:32532877). Both variants cosegregate with disease in homozygous state and are absent or extremely rare in population databases. RNA sequencing of patient and parental samples confirmed complete loss of normal splicing in c.330+5G>A, upgrading it from VUS to pathogenic (PMID:32532877).
A larger cohort study of 15 patients from nine kindreds identified two hypomorphic missense variants, p.Gly100Ser and p.Ala182Asp, which permit residual AK2 expression and enzymatic activity but still cause lymphopenia and hypogammaglobulinemia with intact hearing in most adults (PMID:31862378). This series expands the phenotypic spectrum beyond neonatal onset, highlighting B‐cell activation defects and recurrent sinopulmonary infections. The presence of these variants in multiple families underscores allelic heterogeneity and supports the autosomal recessive mode.
Functional characterization in patient‐derived cells revealed absent AK2 protein, dramatically reduced oxygen consumption rate, extracellular acidification rate, ATP production, and increased reactive oxygen species and mitochondrial mass in the p.Ser208Pro homozygote (PMID:31673062). In vitro assays of the hypomorphic variants showed impaired mitochondrial respiration and failure to regulate membrane potential in activated B cells, explaining the selective antibody deficiency (PMID:31862378).
CRISPR/Cas9 heterozygous AK2 knock‐out in HL-60 cells impaired neutrophil differentiation, recapitulating the myeloid arrest seen in patients and rescuable by fructose supplementation, suggesting potential adjunctive therapy (PMID:36555730). Artificial thymic organoid assays using CD34+ cells from AK2-deficient patients demonstrated an early block in T‐cell development, confirming a cell‐intrinsic requirement of AK2 for lymphopoiesis (PMID:32556283).
Expression studies in mouse embryonic and adult tissues show AK2 is uniquely up-regulated during neutrophil and macrophage differentiation, whereas other mitochondrial kinases cannot compensate, supporting a haploinsufficiency mechanism in heterozygous models and a complete loss in patient phenotypes (PMID:24587121).
No conflicting evidence has been reported to date, and all variants demonstrate concordant disease segregation and functional impact. The cumulative genetic and experimental data justify a ClinGen Strong gene‐disease association. Further longitudinal studies could refine genotype‐phenotype correlations and test metabolic rescue strategies.
Key Take-home: Biallelic AK2 variants cause autosomal recessive reticular dysgenesis via mitochondrial energy failure, supporting molecular diagnosis and informing therapeutic avenues.
Gene–Disease AssociationStrong17 probands (15 multipatient, 2 case reports) with biallelic AK2 variants; consistent AR inheritance and concordant functional data. Genetic EvidenceStrongBiallelic pathogenic variants in 17 unrelated probands across 11 families, including missense and splice mutations in AK2. Functional EvidenceModeratePatient cells, CRISPR models, and organoid assays demonstrate AK2 loss impairs mitochondrial function and hematopoietic differentiation. |