Lissencephaly

Muscle-eye-brain disease (MEB) and Walker Warburg Syndrome (WWS) belong to a spectrum of autosomal recessive diseases characterized by ocular dysgenesis, neuronal migration defects, and congenital muscular dystrophy. Until now, the pathophysiology of MEB/WWS has been attributed to alteration in dystroglycan post-translational modification. Here, we provide evidence that mutations in a gene coding for a major basement membrane protein, collagen IV alpha 1 (COL4A1), are a novel cause of MEB/WWS. Using a combination of histological, molecular, and biochemical approaches, we show that heterozygous Col4a1 mutant mice have ocular dysgenesis, neuronal localization defects, and myopathy characteristic of MEB/WWS. Importantly, we identified putative heterozygous mutations in COL4A1 in two MEB/WWS patients. Both mutations occur within conserved amino acids of the triple-helix-forming domain of the protein, and at least one mutation interferes with secretion of the mutant proteins, resulting instead in intracellular accumulation. Expression and posttranslational modification of dystroglycan is unaltered in Col4a1 mutant mice indicating that COL4A1 mutations represent a distinct pathogenic mechanism underlying MEB/WWS. These findings implicate a novel gene and a novel mechanism in the etiology of MEB/WWS and expand the clinical spectrum of COL4A1-associated disorders.

Metabolic adaptation is increasingly recognized as a key factor in tumor progression, yet its involvement in metastatic bone disease is not understood. Bone is as an adipocyte-rich organ, and a major site of metastasis from prostate cancer. Bone marrow adipocytes are metabolically active cells capable of shaping tumor metabolism via lipolysis and lipid transfer. In this study, using in vitro and in vivo models of marrow adiposity, we demonstrate that marrow fat cells promote Warburg phenotype in metastatic prostate cancer cells. We show increased expression of glycolytic enzymes, increased lactate production, and decreased mitochondrial oxidative phosphorylation in tumor cells exposed to adipocytes that require paracrine signaling between the two cell types. We also reveal that prostate cancer cells are capable of inducing adipocyte lipolysis as a postulated mechanism of sustenance. We provide evidence that adipocytes drive metabolic reprogramming of tumor cells via oxygen-independent mechanism of HIF-1α activation that can be reversed by HIF-1α downregulation. Importantly, we also demonstrate that the observed metabolic signature in tumor cells exposed to adipocytes mimics the expression patterns seen in patients with metastatic disease. Together, our data provide evidence for a functional relationship between marrow adipocytes and tumor cells in bone that has likely implications for tumor growth and survival within the metastatic niche.

Lissencephaly ('smooth brain') is a severe brain disease associated with numerous symptoms, including cognitive impairment, and shortened lifespan. The main causative gene of this disease - lissencephaly-1 (LIS1) - has been a focus of intense scrutiny since its first identification almost 30 years ago. LIS1 is a critical regulator of the microtubule motor cytoplasmic dynein, which transports numerous cargoes throughout the cell, and is a key effector of nuclear and neuronal transport during brain development. Here, we review the role of LIS1 in cellular dynein function and discuss recent key findings that have revealed a new mechanism by which this molecule influences dynein-mediated transport. In addition to reconciling prior observations with this new model for LIS1 function, we also discuss phylogenetic data that suggest that LIS1 may have coevolved with an autoinhibitory mode of cytoplasmic dynein regulation.

BackgroundClassic lissencephaly is a malformation of cortical development that includes agyria and pachygyria. The major clinical symptoms are developmental impairment, muscular hypotonia, and drug-resistant epilepsy. The severity of the clinical phenotype depends on the associated gene and mutation. This study aimed to systematically investigate the genotype-specific course of the disease including neurodevelopmental outcome, medical complications, use of non-pharmacological supportive therapies, and its impact on the quality of life of the affected families.Methods47 patients with genetically and radiologically confirmed lissencephaly were included with mutation in LIS1/PAFAH1B1 (n = 38), DCX (n = 5 males), DYNC1H1 (n = 2), TUBA1A (n = 1) and TUBG1 (n = 1) genes. Standardized questionnaires were completed by families and treating pediatricians. Quality of life was assessed with the PedsQL™ Family Impact Module.ResultsPrenatal abnormalities, most commonly microcephaly, were observed in 14/37 (38%) of LIS1/PAFAH1B1 patients and 2/5 (40%) of DCX patients. Early symptoms included microcephaly, developmental delay, muscular hypotonia, and epileptic seizures. The median age at suspected diagnosis was 5 months for LIS1/PAFAH1B1 patients and 9 months for DCX patients. Compared to LIS1/PAFAH1B1, DCX-related lissencephaly patients showed significantly better neurodevelopmental outcome in reaching more advanced milestones such as walking unassisted (z=-2.23, p = 0.026) and speaking sentences (z=-2.53, p = 0.011). Frequent medical complications included recurrent respiratory infections (14/38 (37%) of LIS1/PAFAH1B1 patients; 1/4 (25%) of DCX patients) and dysphagia/ vomiting (23/37 (62%); 2/4 (50%)), which may require tube feeding (15/38 (40%); 1/5 (20%)). A median of eight different supportive therapies was used per patient (range 1-17), with physiotherapy and respiratory therapy considered the most effective. The scores obtained for health-related quality of life (HRQL) were low (parental HRQL mean 61.23; SD 16.79).ConclusionsOur study confirms the severely impaired developmental potential and frequent neurological and medical complications in lissencephaly patients from an early age. The psychomotor prognosis in LIS1/PAFAH1B1-related lissencephaly is significantly worse compared to DCX-related lissencephaly. Supportive therapies are used intensively and are considered to be very effective. The disease puts a high burden on caregivers and the entire family. This emphasizes the need for appropriate epilepsy treatment, personalized care for patients and professional support for their families.