DeCure for Neuropathy, hereditary sensory and autonomic, type 1A
DeCure's autonomous Neuro AI scientist is researching a drug-repurposing hypothesis for neuropathy, hereditary sensory and autonomic, type 1A — 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 moduleNeuropathy, hereditary sensory and autonomic, type 1A 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
approvedL-SerineApproved drug
Structures already discussed alongside neuropathy, hereditary sensory and autonomic, type 1a in the retrieved literature, rendered from public PubChem SMILES. Which drugs appear here reflects the evidence found, not a ranked prediction.
Molecular view
Structure of human glutamate carboxypeptidase II (GCPII) — L-Serine has a real, experimentally solved structure in complex with this target (PDB 2PVV, 2.11 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 osedrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 2PVV · 2.11 Å · ligand L-Serine (OSE). Experimental structure, not a prediction.
What the evidence adds up to
Hereditary sensory and autonomic neuropathies are a clinically and genetically heterogeneous group of disorders, less common than Charcot-Marie-Tooth disease. Type 1A, which has minimal autonomic involvement and is more accurately termed hereditary sensory neuropathy type I, can present similarly to certain forms of Charcot-Marie-Tooth disease. The conditions are not caused by generalised metabolic defects but by discrete genetic origins affecting the formation of specific nerve proteins, with variable phenotypes due to dysfunction of peripheral nerve axons or their myelin. Proper identification of genetic defects provides the opportunity for better genetic counselling and, hopefully, therapies in the future.
Hereditary sensory autonomic neuropathy type IV is a rare autosomal recessive disorder beginning in infancy, characterised by anhidrosis, insensitivity to noxious stimuli leading to self-mutilating behaviour, and intellectual disability. It is caused by mutations in the NTRK1 gene encoding the high-affinity receptor of nerve growth factor; patients lack all NGF-dependent neurons, leading to lack of pain sensation and anhidrosis. A 2017 study reported nine patients from nine unrelated families with HSAN-IV due to various NTRK1 mutations, five of which were novel, and noted variable intellectual deficits and delayed diagnosis in some cases. A 2019 case report of a three-year-old boy with HSAN type 4 presenting with chronic trophic ulcers concluded that there is no definitive treatment available presently for this condition.
A 2001 report described a novel type of adult-onset HSAN in a Japanese family, with onset of anosmia at ages 20–50 years, followed by anhidrosis and sensory loss, but without skin ulceration. Both superficial and deep sensation were impaired in the most distal parts of all four limbs, and orthostatic hypotension was present in all three affected siblings. The authors considered this a unique subtype distinct from the HSAN I–V classification described by Dyck.
Painless injuries in children with HSAN carry a potential for misdiagnosis with other sensory neuropathies, especially leprosy. What remains missing are definitive treatments for any HSAN subtype, larger patient cohorts to clarify genotype-phenotype correlations, and clinical trials designed to test interventions in these rare, genetically defined populations.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Current Opinion in Neurology · 2004 · 73 citations
Hereditary sensory neuropathies
AbstractPURPOSE OF REVIEW: The hereditary sensory neuropathies, also known as the hereditary sensory and autonomic neuropathies, are a clinically and genetically heterogeneous group of disorders. As they are not as common as Charcot-Marie-Tooth disease, they do not receive the same level of attention, but there have been major advances in the identification of the causative genes in the past decade. Certain forms of hereditary sensory and autonomic neuropathy, especially hereditary sensory and autonomic neuropathy type I, which has minimal autonomic involvement and is more accurately termed hereditary sensory neuropathy type I, can present in a very similar fashion to certain forms of Charcot-Marie-Tooth disease (Charcot-Marie-Tooth type 2B, see below), and therefore it is important that clinicians who regularly manage patients with neuropathy are familiar with the latest developments in the hereditary sensory and autonomic neuropathies. This review will concentrate on the recent genetic advances in hereditary sensory and autonomic neuropathy, and especially on those forms that overlap clinically with Charcot-Marie-Tooth disease, hence the title of the review 'Hereditary sensory neuropathies' rather than hereditary sensory and autonomic neuropathies.
Acute sensory ataxic neuropathy associated with monospecific anti-GD1b IgG antibody
AbstractThe authors describe two patients with acute sensory ataxic neuropathy. Both had a profound loss of proprioception and generalized areflexia. High titers of monospecific anti-GD1b IgG antibody were detected in their sera during the acute phase. Sensory ataxia resolved within 2 weeks after the onset. Taken together with the induction of experimental sensory ataxic neuropathy sensitized with GD1b ganglioside, GD1b may be a target molecule for autoantibody in some patients with acute sensory ataxic neuropathy.
Charcot-Marie-Tooth Disease (Hereditary Motor Sensory Neuropathies) and Hereditary Sensory and Autonomic Neuropathies
AbstractBACKGROUND: Since the description of Charcot-Marie-Tooth disease over a century ago. it has now been recognized that these conditions are not caused by generalized metabolic defects but rather have various discrete genetic origins. These disorders can also have variable phenotypes due to dysfunction of peripheral nerve axons or their myelin due to the genetic defects that affect the formation of specific nerve proteins. REVIEW SUMMARY: This article summarizes the clinical presentation of various phenotypes of the hereditary motor sensory neuropathies and the hereditary sensory and autonomic neuropathies, genetic mutations, and their relevant protein products. Proper identification of the genetic defects provides the opportunity for better genetic counseling and hopefully therapies in the future.
American Journal of Medical Genetics Part A · 2017 · 28 citations
Exome sequencing identifies novel <i>NTRK1</i> mutations in patients with HSAN‐IV phenotype
AbstractHereditary sensory autonomic neuropathy type IV (HSAN-IV) is a rare autosomal recessive disorder that usually begins in infancy and is characterized by anhidrosis, insensitivity to noxious stimuli leading to self-mutilating behavior, and intellectual disability. HSAN-IV is caused by mutations in the neurotrophic tyrosine kinase receptor type 1 gene, NTRK1, encoding the high-affinity receptor of nerve growth factor (NGF) which maps to chromosome 1q21-q22. Patients with HSAN-IV lack all NGF-dependent neurons, the primary afferents and sympathetic postganglionic neurons leading to lack of pain sensation and the presence of anhidrosis, respectively. Herein, we report nine patients from nine unrelated families with HSAN-IV due to various mutations in NTRK1, five of which are novel. These are three missense and two nonsense mutations distributed in various domains of NTRK1 involved in binding of NGF. The affected patients had variable intellectual deficits, and some had delayed diagnosis of HSAN-IV. In addition to being the first report of HSAN-IV from the Arabian Peninsula, this report expands the mutational spectrum of patients with NTRK1 mutations and provides further insights for molecular and clinical diagnosis.
Annals of Indian Academy of Neurology · 2006 · 8 citations · open access
Painless injuries in a child: Hereditary sensory and autonomic neuropathy
AbstractHereditary sensory autonomic neuropathies (HSAN) are rare genetically determined neuropathies. They often manifest as painless injuries in children and there is a potential for misdiagnosis with other sensory neuropathies especially leprosy. We report two siblings who clinically, electrophysiologically and pathologically have HSAN. We also summarise the current classification and recent genetic advances.
Adult-onset hereditary sensory and autonomic neuropathy accompanied by anosmia but without skin ulceration
AbstractWe report a novel type of hereditary sensory and autonomic neuropathy (HSAN) with adult onset in a Japanese family. One male and 2 females of 6 siblings were affected. They developed anosmia initially at the ages of 20-50 years, followed by anhidrosis and sensory loss. Skin ulceration was absent. Both superficial and deep sensation were impaired in the most distal parts of all 4 limbs. Orthostatic hypotension was present in all patients. This is a unique subtype of HSAN distinct from the HSAN I-V described by Dyck.
International Journal of Research in Medical Sciences · 2019 · 3 citations · open access
A case of hereditary sensory and autonomic neuropathy type 4 presenting with chronic trophic ulcers
AbstractHereditary Sensory and Autonomic Neuropathy (HSAN) is a rare group of diseases involving varying degrees of peripheral nervous system. It is classified into five main types. HSAN type 4 is associated with insensitivity to pain and temperature and anihidrosis. The method of this study was to authors present a case report of a 3 year-old boy with Hereditary Sensory and Autonomic Neuropathy Type 4 presenting with chronic ulcers. Conclusions of this study was to HSAN type IV is a rare condition. There is no definitive treatment available presently for this condition.
Zurich Open Repository and Archive (University of Zurich) · 2017 · 0 citations · open access
Clinical and metabolic consequences of L-serine supplementation in hereditary sensory and autonomic neuropathy type 1C
AbstractHereditary sensory neuropathy type 1 (HSAN1) may be the first genetic neuropathy amenable to a specific mechanism-based treatment, as L-serine supplementation can be used to lower the neurotoxic levels of 1-deoxysphingolipids (1-deoxySL) that cause the neurodegeneration. The treatment is so far untested in HSAN1C caused by variants in the serine palmitoyl transferase subunit 2 (SPTLC2) gene. The aim of this study was to establish whether oral L-serine lowers 1-deoxySL in a patient with HSAN1C, to perform a dose escalation to find the minimal effective dose, and to assess the safety profile and global metabolic effects of the treatment. Our patient underwent a 52-wk treatment in which the L-serine dose was titrated up to 400 mg/kg/day. She was followed up by repeated clinical examination, nerve conduction testing, and skin biopsies to document effects on small nerve fibers. Serum was assayed for 1-deoxySL and metabolomics analysis of 111 metabolites. We found a robust lowering of 1-deoxySL, which correlated in a near-linear fashion with increased serum L-serine levels. Metabolomics analysis showed a modest elevation in glycine and a marked reduction in the level of cytosine, whereas most of the other assayed metabolites did not change. There were no direct side effects from the treatment, but the patient developed a transitory toe ulceration during the course of the study. The Charcot-Marie-Tooth neuropathy score increased by 1 point. We conclude that oral supplementation of L-serine decreases 1-deoxySL in HSAN1C without major global effects on metabolism. L-serine is therefore a potential treatment for HSAN1C.
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.
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