DeCure for Neuronal ceroid lipofuscinosis 8 northern epilepsy variant
DeCure's autonomous Neuro AI scientist is researching a drug-repurposing hypothesis for neuronal ceroid lipofuscinosis 8 northern epilepsy variant — 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 moduleNeuronal ceroid lipofuscinosis 8 northern epilepsy variant 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 neuronal ceroid lipofuscinosis 8 northern epilepsy variant 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
CLN8 transmembrane ER and ERGIC protein (CLN8) — CLN8 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 coadrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 9TKA · 2.7 Å · ligand COENZYME A (COA). Experimental structure, not a prediction.
What the evidence adds up to
Neuronal ceroid lipofuscinosis (NCL) is a group of autosomal recessive, inherited, lysosomal, and neurodegenerative diseases that cause progressive dementia, seizures, movement disorders, language delay or regression, progressive visual failure, and early death. Gene products for six of the eight forms of NCL have been discovered, and evidence points to functions for the CLN genes in the endosomal-lysosomal system, with neuron-specific roles. The development of mouse and large animal models has enabled comparative studies of the progressive effects of disease, including characterisation by morphological and biochemical means supplemented by metabonomic and microarray techniques.
Among the NCLs, only CLN2 disease, caused by biallelic pathogenic variants of the TPP1 gene, has an approved targeted therapy. In a study of 1,284 patients with epilepsy of unknown cause who had at least one symptom associated with CLN2, screening with a 160-gene epilepsy panel identified TPP1 variants in 25 individuals (1.9%), with 21 of those having two variants. The two most frequently reported variants were p.Arg208* and p.Asp276Val, and two novel variants were detected: p.Leu308Pro and c.89+3G>C Intron 2. The authors concluded that such genetic panels can be useful to confirm or exclude CLN2 diagnosis and, if confirmed, provide disease-specific treatment.
For other NCL subtypes, treatment remains symptomatic. A case report described a 22-year-old man with CLN3 variant (Juvenile NCL) who developed paroxysmal sympathetic hyperactivity after status epilepticus, which improved with propranolol. Another report described a 25-year-old man with a novel CLN6 mutation and variant late infantile-onset NCL who had drug-resistant seizures from age 10 and was put in an anaesthesia-induced coma until cannabis oil in combination with FDA-approved anti-seizure drugs proved lifesaving. The authors noted that cannabis oil use in drug-resistant epilepsy is anecdotal and remains highly controversial, and that treatment for NCL currently consists of symptomatic relief of seizures and supportive therapies for associated symptoms.
What is still missing are quantifiable endpoints for clinical trials, systematic characterisation of clinical progression across NCL subtypes, and prospective data on any intervention beyond CLN2. No controlled trial data exist for cannabis oil, propranolol, or any other repurposed drug in NCL. Patient stratification by genotype and disease stage, as well as funding for trials that measure survival or meaningful functional decline, remain 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.
Current Opinion in Neurology · 2003 · 98 citations
Progress towards understanding the neurobiology of Batten disease or neuronal ceroid lipofuscinosis
AbstractPURPOSE OF REVIEW: The identification of genes mutated in the neuronal ceroid lipofuscinoses has accelerated research into the mechanisms that underlie these fatal autosomal recessive storage disorders, which are often referred to as Batten disease. This review summarizes progress in this field since October 2001, describing advances in cell biology, the characterization of new animal models of neuronal ceroid lipofuscinosis, and the impact of novel methodology to reveal insights into its pathogenesis. RECENT FINDINGS: Gene products for six of the eight forms of neuronal ceroid lipofuscinosis have now been discovered, and concerted efforts are underway to understand the normal biology of each gene product and how this may be altered by mutation. Several lines of evidence point to functions for the CLN genes in the endosomal-lysosomal system, and suggest neuron-specific roles for these proteins. Indeed, a requirement for appropriate protein trafficking within neurons may explain the profound and selective effects of these disorders upon the central nervous system. The development of mouse and large animal models has enabled comparative studies of the progressive effects of disease, including characterization by morphological and biochemical means supplemented by metabonomic and microarray techniques. SUMMARY: Insights into disease mechanisms are building a detailed profile of the impact of neuronal ceroid lipofuscinosis upon the brain. With the eventual aim of developing successful therapeutic strategies, it will be equally important to characterize the clinical progression of the disorder, and to identify quantifiable endpoints that can ultimately be used in clinical trials.
Arquivos de Neuro-Psiquiatria · 2024 · 6 citations · open access
A needle in a haystack? The impact of a targeted epilepsy gene panel in the identification of a treatable but rapidly progressive metabolic epilepsy: CLN2 disease
AbstractAbstract Background Neuronal ceroid lipofuscinoses (NCL) are a group of autosomal recessive, inherited, lysosomal, and neurodegenerative diseases that causes progressive dementia, seizures, movement disorders, language delay/regression, progressive visual failure, and early death. Neuronal ceroid lipofuscinosis type 2 (CLN2), caused by biallelic pathogenic variants of the TPP1 gene, is the only NCL with an approved targeted therapy. The laboratory diagnosis of CLN2 is established through highly specific tests, leading to diagnostic delays and eventually hampering the provision of specific treatment for patients with CLN2. Epilepsy is a common and clinically-identifiable feature among NCLs, and seizure onset is the main driver for families to seek medical care. Objective To evaluate the results of the Latin America Epilepsy and Genetics Program, an epilepsy gene panel, as a comprehensive tool for the investigation of CLN2 among other genetic causes of epilepsy. Methods A total of 1,284 patients with epilepsy without a specific cause who had at least 1 symptom associated with CLN2 were screened for variants in 160 genes associated with epilepsy or metabolic disorders presenting with epilepsy through an epilepsy gene panel. Results Variants of the TPP1 gene were identified in 25 individuals (1.9%), 21 of them with 2 variants. The 2 most frequently reported variants were p.Arg208* and p.Asp276Val, and 2 novel variants were detected in the present study: p.Leu308Pro and c.89 + 3G > C Intron 2. Conclusion The results suggest that these genetic panels can be very useful tools to confirm or exclude CLN2 diagnosis and, if confirmed, provide disease-specific treatment for the patients.
Late-Infantile Neuronal Ceroid Lipofuscinosis (CLN2/Jansky-Bielschowsky Type) in Oman
AbstractThis study was conducted to see the pattern of neuronal ceroid lipofuscinosis in Oman. Eleven children (10 male) with late-infantile neuronal ceroid lipofuscinosis were seen in 5 families. Most of the patients, 9 of 11 (81.8%), were CLN2 type (late-infantile neuronal ceroid lipofuscinosis or Jansky-Bielschowsky), and 2 patients were the atypical type. Five children were seen in 1 extended family. All children had onset with seizures except in 1 family. The majority had onset between ages 1 to 4 years. Nine and of the 11 children had onset with myoclonic seizures. Neuroregression and microcephaly were noted in all. All children had brain volume reduction and typical cerebellar atrophy. Ophthalmological examination was abnormal in all. Clinical features, histological findings, and genetic study reveal that CLN2 type is the most common form of neuronal ceroid lipofuscinosis. There is male predominance of 90.1% in this part of the Arab world.
Paroxysmal sympathetic hyperactivity following status epilepticus in a 22-year-old with Juvenile Neuronal Ceroid Lipofuscinosis: A case report
AbstractThe Neuronal Ceroid Lipofuscinosis (NCL) refers to a group of rare neurolipidosis disorders characterized by progressive blindness, deterioration of speech and motor function, cognitive decline, behavior problems, seizures, and premature death. We report a case of a 22-year-old man with CLN3 variant, homozygous NCL (aka Juvenile Neuronal Ceroid Lipofuscinosis) complicated by epilepsy who presented with episodes of recurrent seizure-like activity following status epilepticus, but now without electrographic correlate. Episodes were accompanied by tachycardia, diaphoresis, hypertension, and a fearful facial expression likely representing paroxysmal sympathetic hyperactivity (PSH), and improved with administration of propranolol. It is possible that status epilepticus provoked these episodes of PSH.
American Journal of EEG Technology · 1984 · 2 citations
EEG Diagnosis of Late Infantile Neuronal Ceroid Lipofuscinosis
Abstract.Late infantile neuronal ceroid lipofuscinosis (LINCL) is a familial, neurodegenerative disease, and affects children at various ages. Epileptic seizures, encountered in LINCL, are often medically refractory, and EEG plays an important role in the diagnosis. In addition to deterioration of the background EEG and spontaneous epileptiform discharges, responses to intermmitent photic stimulation at slow rates are highly characteristic of the late infantile form, typically manifesting at ages 2–3 years. The diagnostic features were reviewed in affected siblings. EEG evaluations of an child exhibiting progressive neurological deterioration should always include intermmitent photic stimulation at slow rates.
Journal of Pediatric Epilepsy · 2015 · 1 citations
A Case of Neuronal Ceroid Lipofuscinosis Masquerading as Panayiotopoulos Syndrome
AbstractNeuronal ceroid lipofuscinosis (NCL) is probably the most common group of childhood progressive neurodegenerative disorders that typically present in childhood, and are uniformly fatal. We present here an unusual case of NCL based on clinical and electroencephalographic features as well as review the current literature on the early features of NCL. The purpose is to alert physicians about the atypical presentations of NCL encountered in clinical practice and to broaden their differential considerations so that earlier diagnoses can be made. In particular, patients presenting with epilepsy and behavioral problems who show developmental regression warrant further investigation.
Journal of Neurology Research · 2020 · 0 citations · open access
Successful Treatment of Super-Refractory Status Epilepticus With Cannabis Oil in a Patient With Neuronal Ceroid Lipofuscinosis
AbstractHerein we describe a case of a 25-year-old man diagnosed with the “variant late infantile-onset” neuronal ceroid lipofuscinosis (NCL) who has a novel mutation in the CLN6 gene located on chromosome 15. The patient developed seizures at the age of 10 years along with progressive symptoms of ataxia, spasticity, cognitive decline and visual difficulties. At the age of 25 years, the seizures were drug-resistant, and the patient was put in an anesthesia-induced coma until the use of cannabis oil in combination with Food and Drug Administration (FDA)-approved anti-seizure drugs proved to be lifesaving. Treatment for NCL currently consists of symptomatic relief of seizures, and supportive therapies for associated symptoms of behavior, language and visual difficulties. Although limited, recent data on the efficacy of cannabinoids for treatment-resistant epilepsy have been published. Since cannabis oil is not currently FDA approved for most formulations, its use in drug-resistant epilepsy is anecdotal and remains highly controversial. J Neurol Res. 2020;10(6):245-247 doi: https://doi.org/10.14740/jnr626
Journal of Neurology Research · 2020 · 0 citations · open access
Successful Treatment of Super-Refractory Status Epilepticus With Cannabis Oil in a Patient With Neuronal Ceroid Lipofuscinosis
AbstractHerein we describe a case of a 25-year-old man diagnosed with the “variant late infantile-onset” neuronal ceroid lipofuscinosis (NCL) who has a novel mutation in the CLN6 gene located on chromosome 15. The patient developed seizures at the age of 10 years along with progressive symptoms of ataxia, spasticity, cognitive decline and visual difficulties. At the age of 25 years, the seizures were drug-resistant, and the patient was put in an anesthesia-induced coma until the use of cannabis oil in combination with Food and Drug Administration (FDA)-approved anti-seizure drugs proved to be lifesaving. Treatment for NCL currently consists of symptomatic relief of seizures, and supportive therapies for associated symptoms of behavior, language and visual difficulties. Although limited, recent data on the efficacy of cannabinoids for treatment-resistant epilepsy have been published. Since cannabis oil is not currently FDA approved for most formulations, its use in drug-resistant epilepsy is anecdotal and remains highly controversial. J Neurol Res. 2020;10(6):245-247 doi: https://doi.org/10.14740/jnr626
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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