I-12 Timothy Syndrome and Cardiomyopathy

potentials and twitch force were measured in muscle strips obtained from patients and controls. Of the 36 patients, 25 presented with chronic muscle weakness of varying degrees, up to wheelchair-dependence. The weakness was associated with intracellular Na overload and edema. Older patients revealed a vacuolar myopathy or a progressive muscular dystrophy. Weakness, intracellular Na overload and edema were increased and further raised by cooling and glucose/insulin, and almost completely normalized by 4 weeks of treatment with the carbonic anhydrase inhibitor acetazolamide (Jurkat-Rott et al., 2009). In vitro, the chronic weakness correlated to membrane depolarization, and acetazolamide repolarized the membrane and restored force. We conclude that membrane depolarization associated with intracellular Na overload and edema causes both episodic and permanent muscle weakness. The chronic weakness is reversible in muscles which show mild or only moderate fatty degeneration. Acetazolamide has direct and beneficial effects on weak muscle and can markedly improve both forms of weakness. In addition, we tested whether the edema in Duchenne muscular dystrophy (DMD) is caused by an osmotic effect due to increased myoplasmic Na content or by inflammation. The muscle edema was quantified on STIR images using background noise as reference. Na was quantified by a muscular tissue sodium concentration (TSC) sequence. A novel inversionrecovery (IR) sequence allowed us to determine mainly the myoplasmic Na by suppression of the extracellular 23Na signal, e.g. from vasogenic edema. Both intracellular TSC and water content were markedly increased in DMD compared to volunteers (p < 0.001). We conclude that the elevated myoplasmic Na concentration in DMD is osmotically relevant and causes a mainly intracellular muscle edema that contributes to the pathogenesis of DMD. We hypothesize that antiedematous treatment can reverse the edema and prevent the edema-induced muscle degeneration.