A new study led by Dr. Pedro Rodríguez, from the National Centre for Genomic Analysis (CNAG), located at the Barcelona Science Park (PCB-UB), describes the first genetically confirmed cases in the African continent of the rare disease CAMRQ1. The genetic analysis, published in the journal Human Mutation, has identified a new variant in the VLDLR gene, contributing to a better understanding of this disease and providing new knowledge that could help improve its diagnosis and treatment in the future.
«Rare diseases» affect between 3.5% and 5.9% of the world's population, encompassing over 6,000 conditions. Cerebellar ataxia, mental retardation, and imbalance syndrome (CAMRQ) includes disorders like CAMRQ1, characterized by delayed walking acquisition, intellectual disability, speech delay, and cerebellar hypoplasia, with some cases presenting quadrupedal gait.
The study, a collaboration between CNAG, the United Arab Emirates University, and Cheikh Anta Diop University (Senegal), expands the understanding of these conditions. «With each rare disease we genetically analyze, we have the opportunity to find molecular answers that, ultimately, can help families obtain a diagnosis and improve their quality of life,» states Dr. Pedro Rodríguez, corresponding author and neurologist at CNAG. «In the case of CAMRQ1, the identification of the VLDLR variant provides us with new insights into the disease and its underlying mechanisms, potentially paving the way for future therapeutic approaches aimed at restoring VLDLR function.»
To date, cases of CAMRQ1 had been described in the Middle East, Europe, and East Asia. The lack of genetically confirmed cases in Africa, coupled with limited availability of population databases and the presence of additional features common in other neurodevelopmental disorders, made molecular diagnosis complex. The study coordinated by CNAG has improved the understanding of the disease's biology and expanded the available genetic and geographic information.
The research focused on four siblings from the same family affected by CAMRQ1. Through whole-exome sequencing, a novel homozygous missense variant in the VLDLR gene was identified. Subsequent analyses showed that the resulting p.(P565Q) protein is retained in the endoplasmic reticulum, preventing it from reaching the plasma membrane where it performs its function. This suggests the variant alters VLDLR-mediated signaling, including the reelin signaling pathway, crucial for neuronal orientation during brain development.
The results provide new knowledge on the molecular mechanisms underlying CAMRQ-related disorders, lay the groundwork for improving diagnosis in Africa, and contribute to clinical research on rare neurogenetic disorders in underrepresented populations. This research is part of CNAG's strategic area of rare diseases.
