DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for Cold-induced sweating syndrome 1 — screening already-approved drugs against its 2-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleCold-induced sweating syndrome 1 maps to a 2-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 cold-induced sweating syndrome 1 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
kelch like family member 7 (KLHL7) — KLHL7 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 apo structuredrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 3II7 · 1.63 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
Cold-induced sweating syndrome type 1 (CISS1) is a rare autosomal recessive disorder caused by mutations in CRLF1. The hallmark symptom is profuse sweating, particularly on the upper body and hands, when the patient is exposed to cold. Its pathogenesis is not fully understood; in vitro evidence suggests CRLF1 may be involved in inducing a switch from a noradrenergic to a cholinergic transmitter phenotype, and the abnormal sweat response could also relate to altered temperature signals in the hypothalamus. A 2017 autonomic reflex screen in one CISS1 patient found normal Valsalva ratio and heart rate response to deep breathing, but a non-length-dependent decrease in sweat volume on quantitative sudomotor axon reflex testing, plus tilt-table evidence of reflex vasovagal syncope without loss of consciousness.
Longitudinal observation of a 30-year-old Japanese woman homozygous for a CRLF1 deletion showed that in infancy she had feeding difficulty, hyperthermia, and facial features resembling Crisponi syndrome, but no paroxysmal muscular contractions. Profuse sweating began at age 3, and cold-induced sweating was recognised in elementary school. By adolescence she had developed a Marfanoid habitus with progressive kyphoscoliosis. This supports the view that CISS and Crisponi syndrome may be a single clinical entity with age-dependent expression. An Italian boy with CISS1 was hypotonic at birth, had severe feeding difficulties, and showed facial dysmorphisms, short hands, and reduced tendon reflexes; EMG and nerve conduction studies excluded a peripheral neuropathy.
Treatment options are limited and often unsatisfactory. In a 2020 case of isolated non-syndromic cold-induced sweating in a 24-year-old Saudi male, clonidine 0.1 mg, amitriptyline, and fluoxetine were all discontinued due to side effects. Onabotulinum toxin A gave only a partial satisfactory result. A 2013 case of acquired idiopathic cold-induced hyperhidrosis in a 76-year-old man reported that clonidine and amitriptyline inhibited both the cold-induced sweating and the elevation of plasma noradrenaline, but this was not a CISS1 patient. No controlled trial of any drug for CISS1 has been reported.
What is still missing: any randomised or even systematic treatment trial for CISS1; a clear understanding of whether CRLF1 and CLCF1 mutations produce distinct or overlapping syndromes; and patient stratification by age, mutation type, or autonomic phenotype. Funding for natural history studies and for repurposing candidates such as clonidine or botulinum toxin in properly designed trials is absent.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Neurology · 2010 · 26 citations
Central and peripheral autonomic failure in cold-induced sweating syndrome type 1
AbstractCold-induced sweating syndrome type 1 (CISS1) is a rare disorder characterized by profuse sweating in a cold environment, determined by mutations in cytokine receptor–like factor 1 ( CRLF1 ).1 Its pathogenesis is not fully understood. It has been demonstrated in vitro that CRLF1 may be involved in inducing differentiation from a noradrenergic to a cholinergic transmitter phenotype. During development, catecholaminergic and cholinergic neurotransmission is required for the induction of secretory function, whereas cholinergic transmission becomes crucial for the maintenance of the secretory responsiveness.2 The abnormal sweat response in CISS1 could be also related to alterations in temperature signals acting on hypothalamus and preoptic areas.1
We report clinical, molecular, skin biopsy, and temperature monitoring data of an Italian boy with CISS1.
### Case report.
A 16-year-old boy had come to our observation at 1 year of age. His parents were healthy and unrelated. A brother, with facial dysmorphisms and hypotonia, had died at age 3 months from bronchopulmonary infection. Our patient was hypotonic at birth and experienced severe feeding difficulties. He had elongated face, high-arched palate, weak cry, large pinnae, short hands, tapering fingers, clinodactyly, and reduced tendon reflexes. Concentric needle EMG, nerve conduction velocity (NCV) studies (ulnar, median, peroneal, tibial, and sural nerves), and repetitive nerve stimulation testing excluded a …
American Journal of Medical Genetics Part A · 2010 · 15 citations
Cold‐induced sweating syndrome with neonatal features of Crisponi syndrome: Longitudinal observation of a patient homozygous for a <i>CRLF1</i> mutation
AbstractCold-induced sweating syndrome (CISS) is a rare autosomal recessive disorder caused by mutations in CRLF1 (cytokine receptor-like factor 1), characterized by profuse sweating in cold environmental temperature and craniofacial and skeletal features. Mutations in CRLF1 also cause Crisponi syndrome (CS), characterized by neonatal-onset paroxysmal muscular contractions as well as craniofacial and skeletal manifestations and abnormal functions of the autonomic nerve system. To date, it is an unresolved problem whether the two conditions are distinct clinical entities or a single clinical entity with variable expressions or with different presentations depending on the patients' age at diagnosis. We report on a 30-year-old Japanese woman with CISS and homozygous out-of-frame 23-base deletion of CRLF1. In infancy, she did not show paroxysmal muscular contractions, but showed feeding difficulty, hyperthermia, and facial characteristics including thick and arched eyebrows, a short nose with anteverted nostrils, full cheeks, an inverted upper lip, and a small mouth, resembling those observed in CS. Profuse sweating was noticed at 3 years of age. Cold-induced sweating was recognized in her elementary school days. In adolescence to adulthood, she showed a Marfanoid habitus with progressive kyphoscoliosis and craniofacial characteristics including dolichocephaly, a slender face with poor expression, a distinctive nose with hypoplastic nares, malar hypoplasia, prognathism, and a small mouth. This is the first report of detailed longitudinal observation of a patient with CRLF1 abnormalities, compatible with the notion that CISS and CS may be a single clinical entity.
Current problems in dermatology · 2016 · 7 citations
Genetic Disorders with Dyshidrosis: Ectodermal Dysplasia, Incontinentia Pigmenti, Fabry Disease, and Congenital Insensitivity to Pain with Anhidrosis
AbstractSweating is regulated by various neurohormonal mechanisms. A disorder in any part of the sweating regulatory pathways, such as the thermal center, neurotransmitters in the central to peripheral nerve, innervation of periglandular neurotransmission, and sweat secretion in the sweat gland itself, induces dyshidrosis. Therefore, hereditary disorders with dyshidrosis result from a variety of causes. These diseases have characteristic symptoms derived from each pathogenesis besides dyshidrosis. The information in this chapter is useful for the differential diagnosis of representative genetic disorders with dyshidrosis.
Neurology and Clinical Neuroscience · 2013 · 1 citations · open access
Case of acquired idiopathic cold‐induced hyperhidrosis
AbstractAbstract We report the case of a 76‐year‐old man with a 10‐year history of cold‐induced sweating. He noticed excessive sweating in winter starting at the age of 66 years. The sweat appeared shortly after exposure to a cold environment, and was limited to his neck, chest and arms. Piloerection was also noticed in the sweating areas. The results from a heat‐induced sweating test and axon reflex sweating test, as well as the histology of his sweat glands, were normal. The heart/mediastinum ratio of 123 I‐metaiodobenzylguanidine uptake was reduced, suggesting underlying pathomechanisms of incidental Lewy body disease. The cold‐induced sweating and elevation of plasma noradrenaline were inhibited by clonidine and amitriptyline. These results suggest the possibility of misconnection of afferent inputs under a cold environment to efferent pathways of heat‐induced sweating.
Journal of Dermatology & Dermatologic Surgery · 2020 · 1 citations · open access
Isolated cold-induced sweating in a young Saudi male: Case report
AbstractCold-induced sweating is a rare condition, which is reported in the literature as part of Crisponi syndrome in which patients have many neurological and skeletal abnormalities. We report a case of isolated nonsyndromic cold-induced sweating in a 24-year-old Saudi male. The patient was treated with many treatments, including clonidine 0.1 mg, amitriptyline, and fluoxetine, but these were discontinued due to side effects. The patient was treated with onabotulinum toxin A with partial satisfactory result. Treatment options for cold-induced sweating are limited, and in this case, inadequate.
Stem Cell Research · 2020 · 1 citations · open access
Crisponi syndrome/cold-induced sweating syndrome type 2: Reprogramming of CS/CISS2 individual derived fibroblasts into three clones of one iPSC line
AbstractCrisponi syndrome/cold-induced sweating syndrome type 2 (CS/CISS2) is a rare disease with severe dysfunctions of thermoregulatory processes. CS/CISS2 individuals suffer from recurrent episodes of hyperthermia in the neonatal period and paradoxical sweating at cold ambient temperatures in adolescence. Variants in CLCF1 (cardiotrophin-like-cytokine 1) cause CS/CISS2. Here, we summarize the generation of three clones of one stem cell line (iPSC) of a CS/CISS2 individual carrying the CLCF1 variant c.321C>G on both alleles. These patient derived iPSC clones show a normal karyotype, several pluripotency markers, and the ability to differentiate into the three germ layers.
Journal of Clinical Neuromuscular Disease · 2017 · 0 citations
Autonomic Reflex Screen Test Abnormalities in Cold-Induced Sweating Syndrome Type 1
AbstractCold-induced sweating syndrome (CISS) is a rare autosomal recessive disease due to mutation in the Cytokine receptor-like factor 1 (CRLF1). The characteristic symptom of CISS is the tendency to sweat profusely especially in the upper body and hands when the patient is exposed to cold temperature. We sought to first report the findings of autonomic reflex screen in a case of CISS type 1 with Cytokine receptor-like factor 1 mutation. Valsalva morphology, Valsalva ratio, and heart rate response to deep breathing were normal for the patient's age. Quantitative sudomotor axon reflex test showed nonlength dependent decrease in the sweat volume. Tilt table revealed evidence of reflex (vasovagal) "syncope," however, the patient was asymptomatic without loss of consciousness.
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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