HSMR syndrome is caused by mutations in the CNNM2 gene, encoding for the CNNM2 protein. This protein is involved in renal Mg2+ homeostasis, although the mechanism is unknown. Different inheritance patterns have been observed, consisting of de novo mutations, autosomal dominant, and autosomal recessive. All patients have been reported to suffer from hypomagnesaemia (serum Mg2+ < 0.7mmol/L), intellectual disability, and refractory epilepsy. Those affected by bi-allelic loss of CNNM2 function have been reported with several neurological phenotypes, involving myelinization defects, opercularisation defects, and widened out cerebrospinal liquor spaces. In addition, motor skills defects, obesity, and communication/speech limitations, involving speech delay, expressive language disorder and limited vocabulary, have been observed. However, due to limited cases, phenotype-genotype correlations nor penetrance of symptoms have been found difficult to determine.
CNNM2