Autosomal-Recessive Mutations in SLC34A1 Encoding Sodium-Phosphate Cotransporter 2A Cause Idiopathic Infantile Hypercalcemia
Schlingmann KP, et al., (2016)
Journal of the American Society of Nephrology
High calcium in newborns – discovery of novel cause benefits children who may now be treated
A small number of newborns suffer from abnormally high calcium levels - a rare disease called idiopathic infantile hypercalcemia (IIH) - which can make them severely unwell . In recent years, hyperactivity of the enzyme activating Vitamin D has been identified as one cause of IIH. There is little specific treatment for this Vitamin D hyperactivity, except for omitting the recommended prophylactic Vitamin D and restricting calcium intake. Researchers from Münster, Germany, in collaboration with EURenOmics, have now identified disease mechanism causing IIH. Genetic studies on consanguineous families with IIH pinpointed the SLC34A1 gene as a promising candidate. SLC34A1 encodes a protein channel for sodium and phosphate that is needed in kidney to reclaim phosphate from the primary urine into the blood. Different animal models confirmed that phosphate wasting results in inappropriate activation of Vitamin D and is essential for the secondary development of high calcium levels. High phosphate diets, on the other hand, could restore normal phosphate, Vitamin D and calcium levels. Therefore, treatment of affected infants with phosphate supplementation is a novel, promising opportunity with few anticipated side effects and low cost. Newborns with IIH should therefore undergo investigation of their phosphate metabolism, while genetic analysis may help to identify children who will benefit from phosphate supplements.
Identification of mutations in the MYO9A gene in patients with congenital myasthenic syndrome
O'Connor E, et al., (2016)
Congenital myasthenic syndromes are a group of genetically diverse rare diseases caused by impaired structure and function of the neuromuscular junction. Typical symptoms include fatigable muscle weakness with a variety of accompanying features depending on the protein affected. In many patients diagnosed with congenital myasthenic syndrome, the causative gene is unknown. To identify genetic causation in a cohort of congenital myasthenic syndrome patients, the authors analysed their whole exome sequences. In a Kurdish and a German family, they found a mutation in the MYO9A gene, which encodes an unconventional myosin. Further experiments in cell cultures and in zebrafish suggest that MYO9A plays an important role in neuronal branching, axon guidance and formation of the neuromuscular junction during development, and is required for normal motor activity. The authors believe that MYO9A deficiency may affect the presynaptic motor axon and leads to congenital myasthenic syndrome.
The results highlight that not only the traditional neuromuscular junction-specific proteins, but also the so-called unconventional myosins, should be considered as candidate genes for congenital myasthenic syndrome. The study also is an example of how across-borders projects allow for identifying candidate genes for rare diseases. This work was conducted within RD-Connect and in collaboration with NeurOmics.
Improving the informed consent process in international collaborative rare disease research: effective consent for effective research
Gainotti S, el al., (2016)
European Journal of Human Genetics
Emerging genome sequencing technologies and increased international data sharing between scientists create new opportunities for rare disease research. However, they also challenge patient data protection. It is essential to find the best balance between facilitating research for development of new therapies and protecting patients' right to integrity. Obtaining patients’ consent needs to be coordinated between research centres worldwide and include the same core elements of consent. Therefore, the procedure needs to be planned carefully to address any potential ethical and legal hurdles that may arise in the future. Coordination of obtaining informed consent should to consider two situations:
• new research collections (biobanks and registries) for which information documents can be created according to current guidelines;
• established collections obtained without informed consent or with a consent not covering all core elements.
The article proposes a strategy to deal with consent in both situations. It demonstrates the example of RD-Connect consortia, where these principles are already applied. The established principles, lessons learned and implications for future research are directly relevant to other internationally collaborative rare-disease projects.