DeCure for Alpha-N-acetylgalactosaminidase deficiency
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for alpha-N-acetylgalactosaminidase deficiency — 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 moduleAlpha-N-acetylgalactosaminidase deficiency 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
No approved-drug candidate for alpha-n-acetylgalactosaminidase deficiency is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Molecular view
alpha-N-acetylgalactosaminidase (NAGA) — NAGA is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet 3s,4r,5s,6rdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 4DO4 · 1.4 Å · ligand N-[(3S,4R,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)piperidin-3-yl]acetamide (DJN). Experimental structure, not a prediction.
What the evidence adds up to
Alpha-N-acetylgalactosaminidase deficiency exists in two distinct clinical forms. A 1991 study of a 46-year-old Japanese woman with angiokeratoma corporis diffusum and glycoaminoaciduria found less than 2% of normal enzyme activity and no detectable immunoreactive enzyme protein. Her unaffected offspring had half-normal activity, consistent with autosomal recessive inheritance. Ultrastructural examination of her skin and blood cells showed prominent lysosomal inclusions containing diffuse amorphous and filamentous material. In contrast, patients with the infantile form of neuroaxonal dystrophy and the same enzyme deficiency had no angiokeratoma and no such visceral lysosomal inclusions. The adult-onset form is characterised by angiokeratoma, extensive lysosomal accumulation of sialoglycopeptides, and no detectable neurologic involvement; the infantile form is severe, with neuroaxonal dystrophy but without angiokeratoma.
A 2006 report described a new Spanish infant with Schindler disease who presented with hepatomegaly and cardiomyopathy, traits not previously associated with the disorder. The patient died at eight months of age. Alpha-N-acetylgalactosaminidase activity was reduced to 1.6% of controls in fibroblasts and 0.57% in liver. Other lysosomal enzyme activities linked to infantile cardiomyopathy were normal. The patient was a compound heterozygote for a novel mutation p.D217N and the previously reported mutation p.E325K. This case broadens the clinical spectrum of infantile forms and indicates that the disease should be considered in the diagnosis of metabolic cardiomyopathies. To date, only 12 patients from eight families were known.
A 1977 study of mutagen-treated human lymphoblastoid clones found one clone deficient in N-acetyl hexosaminidase A and B (resembling Sandhoff disease) and another deficient in alpha-galactosidase A (resembling Fabry disease). No storage of natural substrates was demonstrated in those clones. That work did not involve alpha-N-acetylgalactosaminidase deficiency.
What is still missing is any clinical trial of a treatment for either form of this ultra-rare lysosomal disorder. No enzyme replacement, gene therapy, or substrate reduction therapy has been tested in patients. The natural history remains poorly characterised, with fewer than two dozen reported cases across all phenotypes. Any future trial would need international collaboration to recruit even a handful of patients, and would require clear stratification by infantile versus adult-onset presentation, given the radically different organ involvement and disease course.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
British Journal of Dermatology · 2001 · 59 citations · open access
A new case of alpha-N-acetylgalactosaminidase deficiency with angiokeratoma corporis diffusum, with Meniere's syndrome and without mental retardation
Abstractalpha-N-acetylgalactosaminidase (alpha-NAGA) deficiency is a rare hereditary lysosomal storage disease, and only three alpha-NAGA-deficient patients with angiokeratoma corporis diffusum (Kanzaki) have been described. We report a further case in a 47-year-old Japanese woman, the product of a consanguineous marriage. The remarkable findings in this patient were her normal intelligence, Ménière's syndrome, disturbance of peripheral sensory nerves, hearing loss and cardiac hypertrophy. alpha-NAGA enzyme activity in her plasma was 0.77% of the normal value. Other enzyme activities, such as alpha-galactosidase, beta-galactosidase, alpha-L-fucosidase, beta-mannosidase and aspartylglucosaminidase, were within normal limits. A large quantity of amino acid O-glycans was detected in her urine. Gene analysis revealed a novel point mutation (G-->A transition) at nucleotide 11018 (986 in the cDNA) resulting in an Arg-329-Gln substitution. Kanzaki disease has the same enzyme defect as Schindler disease, but the manifestations are quite different.
Journal of Clinical Investigation · 1991 · 56 citations · open access
Lysosomal alpha-N-acetylgalactosaminidase deficiency, the enzymatic defect in angiokeratoma corporis diffusum with glycopeptiduria.
AbstractRecently a novel case of angiokeratoma corporis diffusum with glycoaminoaciduria was described in a 46-yr-old Japanese woman. Known causes of the cutaneous manifestation were eliminated by enzyme analyses, and further characterization of the accumulated urinary O-linked sialopeptides revealed identity to those excreted by patients with an infantile neuroaxonal dystrophy due to lysosomal alpha-N-acetylgalactosaminidase deficiency. Investigation of the alpha-N-acetylgalactosaminidase activity and protein in the proband revealed less than 2% of normal activity and the absence of detectable immunoreactive enzyme protein, findings comparable to those in the patients with infantile neuroaxonal dystrophy and alpha-N-acetylgalactosaminidase deficiency. In addition, the proband's unaffected offspring had half-normal levels of alpha-N-acetylgalactosaminidase activity, consistent with this enzymatic deficiency being the primary metabolic defect in this autosomal recessive trait. Ultrastructural examination of skin and blood cells from the adult proband revealed the presence of prominent lysosomal inclusions containing diffuse amorphous and filamentous material. In contrast, these morphologic findings were not observed in the nonneural tissues from patients with infantile neuroaxonal dystrophy and alpha-N-acetylgalactosaminidase deficiency. These studies document the occurrence of two forms of alpha-N-acetylgalactosaminidase deficiency and sialopeptiduria, a severe infantile-onset form of neuroaxonal dystrophy without angiokeratoma or visceral lysosomal inclusions and an adult-onset form characterized by angiokeratoma, extensive lysosomal accumulation of sialoglycopeptides and the absence of detectable neurologic involvement.
Journal of Inherited Metabolic Disease · 2006 · 20 citations
A new infantile case of α‐<i>N</i>‐acetylgalactosaminidase deficiency. Cardiomyopathy as a presenting symptom
Abstractalpha-N-Acetylgalactosaminidase deficiency is a lysosomal disorder with clinically very different infantile and adult forms. To date, 12 patients from eight families are known. Neuroaxonal dystrophy or moderate psychomotor retardation, without visceral involvement, have been reported in the infantile form. We describe a new Spanish patient with Schindler disease who presented with hepatomegaly and cardiomyopathy, traits not previously associated with this disease. There was no dysmorphism or neurological involvement in the patient, who died at the age of 8 months. alpha-N-Acetylgalactosaminidase activity was reduced in fibroblasts and liver to 1.6% and 0.57% of controls, respectively. Several lysosomal enzyme activities associated with infantile cardiomyopathy were found in the normal ranges. The patient was a compound heterozygote for the novel mutation p.D217N (c.649G>A) in exon 6 and the already reported mutation p.E325K (c.973G>A) in exon 8. The description of this new case broadens the clinical spectrum of the infantile forms and indicates that Schindler disease should be considered in the diagnosis of metabolic cardiomyopathies.
The deficiency of a lysosomal acid hydrolase in two clones derived from the human lymphoblastoid line F137 after mutagen treatment
AbstractTwo clones (out of a total of 181 clones tested) derived from the human lymphoblastoid (lymphoid) line F137 after mutagen treatment were found to be deficient in a lysosomal acid hydrolase. The clone N32 derived from EMS-treated F137 is deficient in N-acetyl hexosaminidase A and B but contains normal levels of N-acetyl hexosaminidase C and low levels of an enzyme resembling N-acetyl hexosaminidase S. Thus the enzyme deficiency in this clone appears to resemble the so-called Sandhoff variant of Tay-Sachs disease, a disease inherited as an autosomal recessive condition. The clone G3 derived from MNNG treated F137 is deficient in alpha-galactosidase A. This clone resembles the situation in X-linked Fabry's disease. Karyotype analysis of the clones failed to reveal any chromosome rearrangement or losses of chromosomal material that might have accounted for the mutations and it is suggested that a single point mutation might in each case account for the loss of enzyme activity. No storage of the natural substrates of the two enzymes could be demonstrated in the clones.
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.
