| Knowledge-base field | Compact annotation | Evidence type | Key source(s) |
|---|---|---|---|
| Identity | **Reticular dysgenesis (RD)**; congenital aleukocytosis; AK2 deficiency; a particularly severe form of SCID. **MONDO:0009973; OMIM/MIM:267500.** Suggested ontology: MONDO:0009973; HPO term for severe combined immunodeficiency. | Aggregated disease resources; human cohort | Hoenig et al., *Blood*, May 2017; DOI: [10.1182/blood-2016-11-745638](https://doi.org/10.1182/blood-2016-11-745638). (pqac-00000002, pqac-00000018) |
| Genetics | Autosomal recessive disease caused by **biallelic germline loss-of-function variants in AK2** (adenylate kinase 2; MIM:103020), at chromosome 1p35.1. The 2017 cohort identified **22 variants among 30 patients from 27 families**; classes included missense, nonsense, splice-site, and 1–5,000-nucleotide deletions. Of 23 homozygous cases, **16 had a consanguineous background**. No reliable genotype–phenotype correlation has been established. | Human cohort | Discovery PMID: **19043416**; Hoenig et al., 2017. (pqac-00000000, pqac-00000001, pqac-00000018) |
| Hallmark phenotype and onset | Congenital persistent agranulocytosis or profound neutropenia, severe lymphopenia, early bacterial or fungal infection, promyelocyte-stage marrow arrest, and sensorineural hearing loss. In the international cohort, **27/29 (93%)** presented in the first month and 20/27 in the first week; bacterial sepsis occurred in **17/29 (59%)**, omphalitis in **5/29 (17%)**, anemia in **14/32 (44%)**, and thrombocytopenia in **14/31 (45%)**. Prematurity occurred in **11/29 (38%)** and small-for-gestational-age birth in **18/29 (62%)**. Suggested HPO concepts: agranulocytosis, neutropenia, lymphopenia, recurrent bacterial infection, omphalitis, anemia, thrombocytopenia, sensorineural hearing impairment, prematurity, and small for gestational age. | Human cohort | Hoenig et al., 2017. (pqac-00000005, pqac-00000018, pqac-00000020) |
| Immunology and marrow | All cohort patients had lymphopenia and persistent agranulocytosis; T-cell counts were universally low. Maternal T cells were detected in **13/23 (57%)**, with an allo-reactive rash in 4/13. Normal NK- and B-cell numbers occurred in only **2/24** and **4/25**, respectively. Marrow showed promyelocytic arrest in **22/26**, hypoplasia in 9/26, hyperplasia in 5/26, and dysmorphic lymphopoiesis in 9/26. Suggested HPO concepts: abnormal T-, B-, and NK-cell counts; maternal lymphocyte engraftment; myeloid maturation arrest. | Human cohort | Hoenig et al., 2017. (pqac-00000005, pqac-00000018, pqac-00000021) |
| Molecular mechanism | AK2 resides in the mitochondrial intermembrane space and catalyzes **ATP + AMP ⇌ 2 ADP**. AK2 loss disrupts adenine-nucleotide homeostasis, ADP supply to oxidative phosphorylation, ATP production, proliferation, survival, and lymphoid and granulocyte differentiation. Patient cells show reduced oxygen consumption and ATP production, with increased reactive oxygen species, mitochondrial mass, and membrane permeability. Suggested GO concepts: adenylate kinase activity, adenine-nucleotide homeostasis, oxidative phosphorylation, mitochondrial ATP synthesis, regulation of reactive oxygen species, granulocyte differentiation, and lymphocyte differentiation. Suggested GO cellular component: mitochondrial intermembrane space. | Human case; in vitro | Ghaloul-Gonzalez et al., *Scientific Reports*, October 2019; DOI: [10.1038/s41598-019-51922-2](https://doi.org/10.1038/s41598-019-51922-2). (pqac-00000002, pqac-00000004) |
| Purine-metabolic and single-cell findings | Single-cell RNA sequencing of marrow from two patients implicated altered RNA catabolism and ribonucleoprotein synthesis. CRISPR AK2-null human HSPCs showed increased AMP and IMP, depleted NAD+ and aspartate, reduced cellular RNA, ribosomal-subunit expression and protein synthesis, and profound hypoproliferation. AMP-deaminase inhibition normalized IMP but worsened the phenotype, suggesting that AMP catabolism may be compensatory. These findings were **preprint evidence as of 2021**. | Human marrow scRNA-seq; CRISPR HSPCs; preprint | Wang et al., bioRxiv, posted September 28, 2021; DOI: [10.1101/2021.07.05.450633](https://doi.org/10.1101/2021.07.05.450633). (pqac-00000017) |
| Diagnosis | Suspect RD in a neonate with profound leukopenia, combined lymphopenia and G-CSF-unresponsive agranulocytosis, marrow promyelocytic arrest, and failed hearing assessment. Evaluate CBC with differential, lymphocyte subsets and function, immunoglobulins, marrow morphology, maternal T-cell engraftment, auditory brainstem response, and **TREC newborn screening**. Confirm using AK2 sequencing plus deletion and duplication analysis. RNA sequencing can establish pathogenic splice effects, as demonstrated for **c.330+5G>A**, which causes exon 3 skipping. Suggested HPO concepts: low TREC, absent naïve T cells, reduced mitogen response, and bilateral sensorineural deafness. | Human case; human cohort | Ichikawa et al., *Cold Spring Harbor Molecular Case Studies*, June 2020; DOI: [10.1101/mcs.a005017](https://doi.org/10.1101/mcs.a005017). (pqac-00000007, pqac-00000008) |
| Treatment and outcomes | **Allogeneic HSCT is the only established curative therapy** for the hematopoietic and immunologic disease. Stable donor myeloid—not merely T-cell—engraftment is essential; conditioning with a myeloablative component is generally needed. In the cohort, 31 patients received 47 HSCTs at a median age of **2.4 months**; 13 required retransplantation. Overall survival was **21/31 (68%)**. T-cell-replete graft survival was **13/14 (93%)**, HLA-identical family graft survival was 6/6, unrelated-donor survival was **7/8 (88%)**, and haploidentical T-cell-depleted graft survival was **8/17 (47%)**. All five unconditioned haploidentical grafts failed. Suggested NCIT concepts: hematopoietic stem cell transplantation, allogeneic bone-marrow transplantation, cord-blood transplantation, and myeloablative conditioning. | Human cohort | Hoenig et al., 2017; subsequent EBMT/ESID guidance supports conditioning because unconditioned RD transplantation carries a high primary-graft-failure risk. (pqac-00000009, pqac-00000011, pqac-00000012, pqac-00000014) |
| Prognosis and disability | Untreated classical RD is usually fatal in infancy from overwhelming infection. Seven post-HSCT deaths occurred within six months, mainly from infection; later deaths reflected failure of durable donor myelopoiesis. Among 21 long-term survivors, **19 retained hearing impairment**, managed with hearing aids or cochlear implants; HSCT does not reliably correct the nonhematopoietic inner-ear defect. Quality-of-life burden includes hearing-related language and communication impairment and intensive transplant follow-up. | Human cohort | Hoenig et al., 2017. (pqac-00000011, pqac-00000012, pqac-00000018) |
| Models | **Zebrafish ak2 deficiency** recapitulates reduced HSPCs, impaired myeloid, lymphoid, and erythroid development, oxidative stress, apoptosis, and anemia. **Patient-derived iPSCs** reproduce promyelocyte arrest and an increased AMP/ADP ratio; antioxidant treatment restores granulocytic differentiation in vitro and rescues zebrafish hematopoietic phenotypes. Homozygous **Ak2-null mice are embryonic lethal before embryonic day 7**, limiting their utility for postnatal RD. Suggested organisms: *Danio rerio* (NCBI Taxon:7955), *Mus musculus* (NCBI Taxon:10090), and *Drosophila melanogaster* (NCBI Taxon:7227). | Zebrafish; patient iPSC; mouse | Rissone et al., *Journal of Experimental Medicine*, July 6, 2015; DOI: [10.1084/jem.20141286](https://doi.org/10.1084/jem.20141286). (pqac-00000003, pqac-00000019) |


*Table: Compact evidence table covering the identity, genetics, phenotype, mechanism, diagnosis, treatment, prognosis, and models of AK2-related reticular dysgenesis. It highlights quantitative findings from the 32-patient international cohort and labels each source by evidence type.*