DeCure for Lissencephaly 7 with cerebellar hypoplasia
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for lissencephaly 7 with cerebellar hypoplasia — 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 moduleLissencephaly 7 with cerebellar hypoplasia 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 lissencephaly 7 with cerebellar hypoplasia 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
cyclin dependent kinase 5 (CDK5) — CDK5 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 4-chlorophenyldrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 3O0G · 1.95 Å · ligand {4-amino-2-[(4-chlorophenyl)amino]-1,3-thiazol-5-yl}(3-nitrophenyl)methanone (3O0). Experimental structure, not a prediction.
What the evidence adds up to
Lissencephaly 7 with cerebellar hypoplasia is caused by biallelic loss-of-function variants in CDK5. As of 2025, only two families have been reported. The second family, described in 2025, involved an infant with a homozygous novel missense variant c.149G>A (p.Arg50Gln) in CDK5. The infant had diffuse agyria, cerebellar hypoplasia, agenesis of the corpus callosum, refractory seizures, pyramidal signs, microcephaly, and growth failure. She achieved no developmental milestones and died at 4 months of age. In silico analysis predicted the variant caused instability of the CDK5 protein, and a yeast complementation assay showed a deleterious impact. The disease course and severity matched the first reported family, which had a splicing defect leading to loss-of-function.
RELN variants produce a graded series of neurodevelopmental disorders, not a single entity. Biallelic RELN variants cause a consistent severe phenotype that includes cerebellar hypoplasia, matching the reeler mouse. Only 11 individuals from six families had been reported before 2022. In 2022, seven additional individuals from four families with biallelic RELN variants were described. Monoallelic (heterozygous) RELN variants, found in 13 individuals from seven families, are associated with incomplete penetrance and variable expressivity. Some heterozygous individuals have moderate frontotemporal lissencephaly with normal cerebellar structure and intellectual disability with severe behavioural dysfunction; one adult had abnormal MRI but normal intelligence and neurological profile. Reduced RELN secretion in heterozygotes affects only cortical structure, leaving the cerebellum intact. The variant spectrum differs: biallelic cases carry a significantly higher proportion of loss-of-function variants, while monoallelic cases include missense and splice-site variants. Two canonical splice-site variants, observed in both biallelic and monoallelic individuals, caused exon skipping with in-frame loss of 46 or 52 amino acids. Previously reported functional studies showed that heterozygous missense variants p.Cys539Arg and p.Arg3207Cys severely reduced overall RELN secretion, suggesting a dominant-negative effect.
A 1999 report described a familial syndrome of lissencephaly, cleft palate, diffuse agyria, and severe cerebellar hypoplasia. Microscopy showed absence of cortical layering with preservation of the pia-glial barrier. Autosomal recessive inheritance was suggested by recurrence in siblings, though germ cell mosaicism for a dominant mutation was not excluded. A 2014 case report of cerebro-cerebellar lissencephaly described complete agenesis of the cerebellum and brainstem on CT, with multiple congenital abnormalities, noting that most previously reported cases showed hypoplasia or atrophy rather than complete agenesis.
What is still missing: no drug or treatment is mentioned in any of these abstracts. No clinical trial has been conducted for lissencephaly 7 or any RELN-related lissencephaly. The CDK5 form is vanishingly rare, with only two families known, making any trial design extremely difficult. For RELN-related disorders, the wide phenotypic range — from lethal malformation to normal adult intelligence — means that any future trial would need careful patient stratification by genotype and imaging phenotype. Funding for natural history studies and for developing any molecular therapy remains 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.
American Journal of Medical Genetics · 1999 · 30 citations
Familial lissencephaly with cleft palate and severe cerebellar hypoplasia
AbstractLissencephaly is a brain malformation characterized by absence of gyral formation, resulting in a smooth brain surface. Histologic study shows severe anomalies of cerebral cortical development. Several lissencephaly syndromes have been described. Here we report a familial syndrome of lissencephaly, cleft palate, diffuse agyria, and severe cerebellar hypoplasia. Microscopic examination of the abnormally thick cerebral cortex showed absence of cortical layering, with preservation of the pia-glial barrier. This is the first report of recurrent lissencephaly with cleft palate and severe cerebellar hypoplasia in which these unique neuropathology findings are described. Autosomal recessive inheritance is suggested by recurrence in sibs within the same family, but germ cell mosaicism for a dominant mutation is not excluded.
Monoallelic and biallelic mutations in<i>RELN</i>underlie a graded series of neurodevelopmental disorders
AbstractReelin, a large extracellular protein, plays several critical roles in brain development and function. It is encoded by RELN, first identified as the gene disrupted in the reeler mouse, a classic neurological mutant exhibiting ataxia, tremors and a 'reeling' gait. In humans, biallelic variants in RELN have been associated with a recessive lissencephaly variant with cerebellar hypoplasia, which matches well with the homozygous mouse mutant that has abnormal cortical structure, small hippocampi and severe cerebellar hypoplasia. Despite the large size of the gene, only 11 individuals with RELN-related lissencephaly with cerebellar hypoplasia from six families have previously been reported. Heterozygous carriers in these families were briefly reported as unaffected, although putative loss-of-function variants are practically absent in the population (probability of loss of function intolerance = 1). Here we present data on seven individuals from four families with biallelic and 13 individuals from seven families with monoallelic (heterozygous) variants of RELN and frontotemporal or temporal-predominant lissencephaly variant. Some individuals with monoallelic variants have moderate frontotemporal lissencephaly, but with normal cerebellar structure and intellectual disability with severe behavioural dysfunction. However, one adult had abnormal MRI with normal intelligence and neurological profile. Thorough literature analysis supports a causal role for monoallelic RELN variants in four seemingly distinct phenotypes including frontotemporal lissencephaly, epilepsy, autism and probably schizophrenia. Notably, we observed a significantly higher proportion of loss-of-function variants in the biallelic compared to the monoallelic cohort, where the variant spectrum included missense and splice-site variants. We assessed the impact of two canonical splice-site variants observed as biallelic or monoallelic variants in individuals with moderately affected or normal cerebellum and demonstrated exon skipping causing in-frame loss of 46 or 52 amino acids in the central RELN domain. Previously reported functional studies demonstrated severe reduction in overall RELN secretion caused by heterozygous missense variants p.Cys539Arg and p.Arg3207Cys associated with lissencephaly suggesting a dominant-negative effect. We conclude that biallelic variants resulting in complete absence of RELN expression are associated with a consistent and severe phenotype that includes cerebellar hypoplasia. However, reduced expression of RELN remains sufficient to maintain nearly normal cerebellar structure. Monoallelic variants are associated with incomplete penetrance and variable expressivity even within the same family and may have dominant-negative effects. Reduced RELN secretion in heterozygous individuals affects only cortical structure whereas the cerebellum remains intact. Our data expand the spectrum of RELN-related neurodevelopmental disorders ranging from lethal brain malformations to adult phenotypes with normal brain imaging.
A Novel Variant c. <scp>149G</scp> >A in <scp>CDK5</scp> Gene Causing Lissencephaly Type 7
AbstractLissencephaly is a genetically heterogeneous condition caused by aberrant neuronal migration. Cerebellar hypoplasia has been commonly associated in some subtypes of lissencephaly, notably the tubulinopathies. CDK5 is a microtubule-associated protein, and its defective function has been implicated in various neurodevelopmental and neurodegenerative disorders. Biallelic loss-of-function variant in CDK5 has been reported to cause lissencephaly type 7 in a single family to date. We describe an infant with diffuse agyria, cerebellar hypoplasia, and agenesis of the corpus callosum harboring a homozygous novel missense variant c.149G>A in CDK5. She had refractory seizures, pyramidal signs, microcephaly, and growth failure. She did not achieve any developmental milestones and succumbed at 4 months of age. The disease course and severity were similar to those observed in the patients in the first report, who had a splicing defect leading to loss-of-function. In silico functional analysis showed that the variant c.149G>A (p.Arg50Gln) caused instability of the CDK5 protein structure, potentially causing functional disruption. Functional analysis of the p.Arg50Gln variant, using a yeast complementation assay, showed a deleterious impact of the variant. In conclusion, this is the second family with CDK5-related lissencephaly type 7.
JOURNAL OF CLINICAL AND DIAGNOSTIC RESEARCH · 2014 · 0 citations · open access
Hind Brain Agenesis A Rare Imaging Findings In Cerebro Cerebellar Lissencephalic Syndrome
AbstractA case report of cerebro cerebellar lissencephaly shows complete agenesis of cerebellum and brainstem which is rare imaging finding of group lissencephaly (type I lissencephaly). Though agenesis of cerebellum and brainstem were included in literature, in most of the cases we saw a hypoplasia or atrophy of cerebellum in lissencephaly syndrome. The CT scan findings of this patient shows features of lissencephaly with complete agenesis of brain stem and cerebellum associated with multiple congenital abnormalities.
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.
