Lissencephaly 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.

Cobblestone lissencephaly (C-LIS) (TYPE II) is a rare and severe neuronal migration disorder characterized by a smooth brain surface with overmigrated neurons and abnormal formation of cerebral convolutions or gyri during fetal development, resulting in a cobblestone appearance. C-LIS is associated with eye anomalies and muscular dystrophy. This case report presents a detailed clinical and neuroimaging analysis of a patient diagnosed with cobblestone lissencephaly (Type II). It reviews pertinent literature to enhance our understanding of this complex condition. We report a case of a 6-year-old female child with cobblestone lissencephaly (C-LIS) (Type II) severe developmental delays, hypotonia, and recurrent intractable seizures. Magnetic resonance imaging (MRI) revealed a characteristic cobblestone appearance on the brain surface, indicative of abnormal neuronal migration. In addition to the classic findings of Type II Cobblestone lissencephaly, the patient displayed ventriculomegaly and cerebellar hypoplasia, contributing to the overall neurological impairment observed. The literature review highlights the genetic basis of cobblestone lissencephaly, emphasizing the involvement of genes associated with glycosylation processes and basement membrane integrity. Neuroimaging findings, including MRI and computed tomography scans, are crucial for accurate diagnosis and prognostication. Early identification of cobblestone lissencephaly allows for appropriate counseling and management strategies. However, the prognosis remains guarded, and interventions primarily focus on supportive care and seizure management. This case report contributes to the knowledge of cobblestone lissencephaly, shedding light on the clinical spectrum and neuroimaging features associated with this rare disorder. To clarify the underlying genetic mechanisms and possible therapeutic pathways for better patient outcomes, more investigation is necessary.

We discovered a hypomorphic reelin (Reln) mutant with abnormal cortical lamination and no cerebellar hypoplasia. This mutant, RelnCTRdel, carries a chemically induced splice-site mutation that truncates the C-terminal region (CTR) domain of RELN protein and displays remarkably distinct phenotypes from reeler The mutant does not have an inverted cortex, but cortical neurons overmigrate and invade the marginal zone, which are characteristics similar to a phenotype seen in the cerebral cortex of Vldlrnull mice. The dentate gyrus shows a novel phenotype: the infrapyramidal blade is absent, while the suprapyramidal blade is present and laminated. Genetic epistasis analysis showed that RelnCTRdel/Apoer2null double homozygotes have phenotypes akin to those of reeler mutants, while RelnCTRdel/Vldlrnull mice do not. Given that the receptor double knock-out mice resemble reeler mutants, we infer that RelnCTRdel/Apoer2null double homozygotes have both receptor pathways disrupted. This suggests that CTR-truncation disrupts an interaction with VLDLR (very low-density lipoprotein receptor), while the APOER2 signaling pathway remains active, which accounts for the hypomorphic phenotype in RelnCTRdel mice. A RELN-binding assay confirms that CTR truncation significantly decreases RELN binding to VLDLR, but not to APOER2. Together, the in vitro and in vivo results demonstrate that the CTR domain confers receptor-binding specificity of RELN. Reelin signaling is important for brain development and is associated with human type II lissencephaly. Reln mutations in mice and humans are usually associated with cerebellar hypoplasia. A new Reln mutant with a truncation of the C-terminal region (CTR) domain shows that Reln mutation can cause abnormal phenotypes in the cortex and hippocampus without cerebellar hypoplasia. Genetic analysis suggested that CTR truncation disrupts an interaction with the RELN receptor VLDLR (very low-density lipoprotein receptor); this was confirmed by a RELN-binding assay. This result provides a mechanistic explanation for the hypomorphic phenotype of the CTR-deletion mutant, and further suggests that Reln mutations may cause more subtle forms of human brain malformation than classic lissencephalies.