DeCure for Congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome
DeCure's autonomous Immuno AI scientist is researching a drug-repurposing hypothesis for congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome — screening already-approved drugs against its 1-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleCongenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome maps to a 1-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
approvedThalidomideApproved drug
Structures already discussed alongside congenital sideroblastic anemia-b-cell immunodeficiency-periodic fever-developmental delay syndrome in the retrieved literature, rendered from public PubChem SMILES. Which drugs appear here reflects the evidence found, not a ranked prediction.
Molecular view
Cereblon isoform 4 from Magnetospirillum gryphiswaldense — Thalidomide has a real, experimentally solved structure in complex with this target (PDB 5AMH, 1.2 Å). This is the drug's own deposited structure, not a prediction, and confirms it is a structurally characterised molecule rather than an untested guess.
Loading structure…
helix sheet ef2drag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 5AMH · 1.2 Å · ligand Thalidomide (EF2). Experimental structure, not a prediction.
What the evidence adds up to
Congenital sideroblastic anemia–B-cell immunodeficiency–periodic fever–developmental delay syndrome (SIFD) is an autosomal recessive disorder caused by biallelic mutations in TRNT1. In a 2013 collation of 12 cases from 10 families, median age at presentation was 2 months, median haemoglobin was 7.1 g/dL, and median mean corpuscular volume was 62.0 fL. B-cell lymphopenia (CD19⁺ range 0.016–0.22 × 10⁹/L) and panhypogammaglobulinaemia were present in most children. Median survival was 48 months; 7 of 12 died from cardiac or multiorgan failure. One child who received bone marrow transplantation at 9 months appeared cured of the haematologic and immunologic manifestations. A 2023 retrospective analysis of 71 reported patients found a mean age of onset of 3.0 months, a male:female ratio of 1:1, and a death rate of 28.2% (20/71), mainly from multi-organ failure. 15.5% (11/71) survived to adulthood, and symptoms resolved spontaneously in five patients. Biallelic mutations in exon 1–intron 5 were associated with more severe phenotypes and higher mortality.
Several treatments have been tried with limited success. Corticosteroids, immunosuppressants, and anakinra showed low efficacy in the 2023 review. Etanercept suppressed fever and improved anaemia in some reports. Adalimumab with intravenous immunoglobulin replacement controlled periodic fever for one month in a single patient, but fever recurred in the second month; thalidomide then controlled fever and normalised inflammatory markers. Infliximab and symptomatic treatments had no therapeutic effect in one patient, who died 17 days after umbilical cord blood stem cell transplantation from post-transplant infection and graft-versus-host disease. Bone marrow transplantation can treat severe SIFD but carries high risk. A 2024 case report described a 13-month-old boy with a milder phenotype who developed left ventricular dilated cardiomyopathy at age 2 years and, after COVID-19 infection at age 5, developed mitochondrial encephalomyopathy and respiratory failure.
The syndrome includes heterogeneous multisystem features beyond the classic tetralogy. A 2019 case report described a 40-year-old woman with genital and extragenital lichen sclerosus that became erythematous and painful during febrile episodes. A 2021 case report noted that mild phenotypes may be located in the N or C part of the TRNT1 protein, and that prominent skin involvement such as relapsing erythema nodosum is not common. A 2023 case series of three patients reported arthritis, low immunoglobulin A, and bilateral cataracts in two siblings, while a third patient had severe features and died after transplantation. The 2024 case report identified two novel heterozygous TRNT1 mutations (Thr49Fs and Ile122Thr) and emphasised the importance of genetic testing.
What is still missing is a prospective trial of thalidomide or other tumour necrosis factor inhibitors with standardised outcome measures, a clear understanding of which patients might benefit from early bone marrow transplantation versus medical management, and reliable biomarkers to stratify patients by disease severity and predict response to therapy.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Blood · 2013 · 116 citations · open access
A novel syndrome of congenital sideroblastic anemia, B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD)
AbstractCongenital sideroblastic anemias (CSAs) are a heterogeneous group of inherited disorders identified by pathological erythroid precursors with perinuclear mitochondrial iron deposition in bone marrow. An international collaborative group of physicians and laboratory scientists collated clinical information on cases of CSA lacking known causative mutations, identifying a clinical subgroup of CSA associated with B immunodeficiency, periodic fevers, and development delay. Twelve cases from 10 families were identified. Median age at presentation was 2 months. Anemia at diagnosis was sideroblastic, typically severe (median hemoglobin, 7.1 g/dL) and markedly microcytic (median mean corpuscular volume, 62.0 fL). Clinical course involved recurrent febrile illness and gastrointestinal disturbance, lacking an infective cause. Investigation revealed B-cell lymphopenia (CD19⁺ range, 0.016-0.22 × 10⁹/L) and panhypogammaglobulinemia in most cases. Children displayed developmental delay alongside variable neurodegeneration, seizures, cerebellar abnormalities, sensorineural deafness, and other multisystem features. Most required regular blood transfusion, iron chelation, and intravenous immunoglobulin replacement. Median survival was 48 months, with 7 deaths caused by cardiac or multiorgan failure. One child underwent bone marrow transplantation aged 9 months, with apparent cure of the hematologic and immunologic manifestations. We describe and define a novel CSA and B-cell immunodeficiency syndrome with additional features resembling a mitochondrial cytopathy. The molecular etiology is under investigation.
Frontiers in Immunology · 2021 · 14 citations · open access
Case Report: Expanding Clinical, Immunological and Genetic Findings in Sideroblastic Anemia With Immunodeficiency, Fevers and Development Delay (SIFD) Syndrome
AbstractSince the first description of the syndrome of sideroblastic anemia with immunodeficiency, fevers and development delay (SIFD), clinical pictures lacking both neurological and hematological manifestations have been reported. Moreover, prominent skin involvement, such as with relapsing erythema nodosum, is not a common finding. Up to this moment, no genotype and phenotype correlation could be done, but mild phenotypes seem to be located in the N or C part. B-cell deficiency is a hallmark of SIFD syndrome, and multiple others immunological defects have been reported, but not high levels of double negative T cells. Here we report a Brazilian patient with a novel phenotype of SFID syndrome, carrying multiple immune defects and harboring a novel mutation on TRNT1 gene.
SAGE Open Medical Case Reports · 2019 · 9 citations · open access
Congenital sideroblastic anemia associated with B cell immunodeficiency, periodic fevers, and developmental delay: A case report and review of mucocutaneous features
AbstractThis is a 40-year-old woman with sideroblastic anemia with B cell immunodeficiency, periodic fevers, and developmental delay syndrome, who has genital and extragenital lichen sclerosus on the abdomen and the upper back that have become erythematous and painful during febrile episodes. This report summarizes the published cases of sideroblastic anemia with B cell immunodeficiency, periodic fevers, and developmental delay and highlights associated mucocutaneous features.
Journal of Clinical Immunology · 2023 · 7 citations · open access
Thalidomide as an Effective Treatment in Sideroblastic Anemia, Immunodeficiency, Periodic Fevers, and Developmental Delay (SIFD)
AbstractPURPOSE: Sideroblastic anemia, immunodeficiency, periodic fevers, and developmental delay (SIFD) is an autosomal recessive syndrome caused by biallelic loss-of-function variant of tRNA nucleotidyl transferase 1 (TRNT1). Efficacious methods to treat SIFD are lacking. We identified two novel mutations in TRNT1 and an efficacious and novel therapy for SIFD. METHODS: We retrospectively summarized the clinical records of two patients with SIFD from different families and reviewed all published cases of SIFD. RESULTS: Both patients had periodic fever, developmental delay, rash, microcytic anemia, and B cell lymphopenia with infections. Whole-exome sequencing of patient 1 identified a previously unreported homozygous mutation of TRNT1 (c.706G > A/p.Glu236Lys). He received intravenous immunoglobulin (IVIG) replacement and antibiotics, but died at 1 year of age. Gene testing in patient 2 revealed compound heterozygous mutations (c.907C > G/p.Gln303Glu and c.88A > G/p.Met30Val) in TRNT1, the former of which is a novel mutation. Periodic fever was controlled in the first month after adalimumab therapy and IVIG replacement, but recurred in the second month. Adalimumab was discontinued and replaced with thalidomide, which controlled the periodic fever and normalized inflammatory markers effectively. A retrospective analysis of reported cases revealed 69 patients with SIFD carrying 46 mutations. The male: female ratio was 1: 1, and the mean age of onset was 3.0 months. The most common clinical manifestations in patients with SIFD were microcytic anemia (82.6%), hypogammaglobulinemia/B cell lymphopenia (75.4%), periodic fever (66.7%), and developmental delay (60.0%). In addition to the typical tetralogy, SIFD features several heterogeneous symptoms involving multiple systems. Corticosteroids, immunosuppressants, and anakinra have low efficacy, whereas etanercept suppressed fever and improved anemia in reports. Bone-marrow transplantation can be used to treat severe SIFD, but carries a high risk. In total, 28.2% (20/71) of reported patients died, mainly because of multi-organ failure. Biallelic mutations located in exon1-intron5 lead to more severe phenotypes and higher mortality. Furthermore, 15.5% (11/71) patients survived to adulthood. The symptoms could be resolved spontaneously in five patients. CONCLUSIONS: Thalidomide can control the inflammation of SIFD and represents a new treatment for SIFD.
Frontiers in Pediatrics · 2023 · 6 citations · open access
Case report: Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay: Three cases and a literature review
AbstractSideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD) is a serious autosomal recessive syndrome caused by biallelic mutations in cytosine–cytosine–adenosine tRNA nucleotidyltransferase 1 ( TRNT1 ). The main clinical features of SIFD are periodic fevers, developmental delay, sideroblastic or microcytic anemia, and immunodeficiency. Herein, we report three cases of SIFD with compound heterozygous variants of TRNT1 . Patients 1 and 2 were siblings; they presented with periodic fevers, arthritis, low immunoglobulin A, bilateral cataracts, anemia, and neurodevelopmental and developmental delay. Patient 3 had severed clinical features with recurrent fever and infections. She was treated with infliximab and symptomatic treatments but without therapeutic effect. She received a stem cell transplantation of umbilical cord blood but died of posttransplant infection and posttransplant graft-vs.-host disease 17 days after transplantation. Finally, a literature review revealed that TRNT1 variants differed among SIFD patients. Our cases and literature review further expand existing knowledge on the phenotype and TRNT1 variations of SIFD and suggest that the early genomic diagnosis of TRNT1 is valuable to promptly assess bone marrow transplantation and tumor necrosis factor inhibitor treatments, which might be effective for the immunodeficiency and inflammation caused by SIFD.
Case of Mitochondrial Encephalomyopathy secondary to COVID-19 in a Pediatric case of SIFD syndrome with a novel TRNT1 mutation
AbstractSyndrome of Congenital Sideroblastic Anemia, B-cell Immunodeficiency, Periodic Fevers, and Developmental Delay (SIFD) is caused by mutations in the tRNA nucleotidyltransferase 1 (TRNT1) gene. We present the case of a 13-month-old boy with developmental delay, microcytic anemia, and recurrent febrile illnesses. Immunological workup revealed B cell lymphopenia. Whole exome sequencing identified two novel heterozygous mutations in the TRNT1 gene (Thr49Fs and Ile122Thr). Our patient had a milder phenotype than previously reported cases of sideroblastic anemia. However, he developed left ventricular dilated cardiomyopathy at the age of 2 years. At the age of 5 years, COVID-19 infection resulted in mitochondrial encephalomyopathy and respiratory failure. Subsequent immunology evaluation revealed low IgG levels, prompting the initiation of immunoglobulin replacement therapy. This case highlights the importance of genetic testing in multisystem disorders and the variable clinical course in SIFD patients. Additionally, it emphasizes the unique susceptibility to COVID-19 due to immunodeficiency and mitochondrial defects.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
