Progressive muscle atrophy with hypokalaemic periodic paralysis and calcium channel mutation

Background: Motor neuron degeneration in conjunction with hypokalaemic periodic paralysis (HypoPP) has been recognized as distinct from HypoPP-related myopathy. Several studies have described familial cases of HypoPP that had developed a disabling motor neuron disorder resembling spinal muscle atrophy or progressive muscle atrophy (PMA). At the time of these reports, the molecular basis of HypoPP was unknown.

Patients and methods: We report a patient with familial HypoPP and a fatal course of PMA. In the studied familiy HypoPP arose from a mutation in the calcium channel gene CACNA1S encoding p.R528H which has been related to HypoPP before. The index patient demonstrated a clinical syndrome of HypoPP in conjunction with PMA. Postmortem studies showed cystatin-C- positive neuronal inclusions which are common morphological features of PMA and the classic form of ALS.

Discussion: Given the rarity of HypoPP and PMA, a chance association of the CACNA1S mutation and this phenotype was unlikely. A single case of HypoPP with PMA within the genetic trait of CACNA1S-linked HypoPP does not permit the conclusion that the PMA phenotype is caused by the calcium channel mutation. Nevertheless, the CACNA1S gene may represent a previously unknown genetic risk factor of PMA. It is well conceivable though that genetic variants of the CACNA1S gene may contribute to a common pathway in HypoPP, vacuolar myopathy and motor neuron disease.