Permanent muscle weakness in hypokalemic periodic paralysis

Abstract

ObjectiveTo map the phenotypic spectrum in 55 individuals with mutations in CACNA1S known to cause hypokalemic periodic paralysis (HypoPP) using medical history, muscle strength testing, and muscle MRI.MethodsAdults with a mutation in CACNA1S known to cause HypoPP were included. Medical history was obtained. Muscle strength and MRI assessments were performed.ResultsFifty-five persons were included. Three patients presented with permanent muscle weakness and never attacks of paralysis. Seventeen patients presented with a mixed phenotype of periodic paralysis and permanent weakness. Thirty-one patients presented with the classical phenotype of periodic attacks of paralysis and no permanent weakness. Four participants were asymptomatic. Different phenotypes were present in 9 of 18 families. All patients with permanent weakness had abnormal replacement of muscle by fat on MRI. In addition, 20 of 35 participants with no permanent weakness had abnormal fat replacement of muscle on MRI. The most severely affected muscles were the paraspinal muscles, psoas, iliacus, the posterior muscles of the thigh and gastrocnemius, and soleus of the calf. Age was associated with permanent weakness and correlated with severity of weakness and fat replacement of muscle on MRI.ConclusionsOur results show that phenotype in individuals with HypoPP-causing mutations in CACNA1S varies from asymptomatic to periodic paralysis with or without permanent muscle weakness or permanent weakness as sole presenting picture. Variable phenotypes are found within families. Muscle MRI reveals fat replacement in patients with no permanent muscle weakness, suggesting a convergence of phenotype towards a fixed myopathy with aging.

Skeletal muscle channelopathies: a guide to diagnosis and management

“…MRI scanning of the muscles, usually lower limb muscles in SMC can demonstrate fatty infiltration of the muscles in keeping with the clinical development of fixed myopathy 25 or T1 STIR hyperintensity. In the case of periodic paralysis the STIR hyperintensity is thought to be reflective of disease activity i.e.…”

Autophagy is affected in patients with hypokalemic periodic paralysis: an involvement in vacuolar myopathy?

“…In addition, we found collapses of the sarcotubular system in some of the vacuoles, suggesting that less dense organelles become collateral damage, once vacuoles form and become filled with cellular debris, glycogen, autophagosomes expand outwards and crush anything less dense than sarcomers, as we have previously found in the mouse model of McArdle disease [ 13 ]. This may long-term affect muscle function and explain the permanent weakness in some of the hypoPP patients [ 1 ]. For this reason, we investigated the presence of endosomal, autophagosomal and lysosomal proteins in the vacuoles using selected markers for various stages of autophagic processing.…”

“…For this reason, we investigated the presence of endosomal, autophagosomal and lysosomal proteins in the vacuoles using selected markers for various stages of autophagic processing. The fact that the vacuoles did not appear to be fibre type specific suggests that a mechanism independent of fibre type cause the disturbances in autophagy and thus the vacuoles [ 1 ]. This immunohistochemical investigation led to a mapping of what appeared to be intermittent autophagic processing issues that is focused between early and late transition of endosomes and autophagosomes in a process that is calcium-dependent [ 14 ].…”

“…Patients with hypoPP experience episodes of paralysis typically either spontaneously or after exercise or a meal or drink rich in carbohydrates. Affection in patients with the common variation p.R528H in the CACNA1S gene range from permanent paralysis, to periodic paralysis with (mixed weakness) or without permanent weakness [ 1 ]. Subjects with the p.R528H variant in CACNA1S have also been found to be asymptomatic.…”

MRI in Neuromuscular Diseases: An Emerging Diagnostic Tool and Biomarker for Prognosis and Efficacy

“…Fat replacement of the psoas muscles are unusual for muscle diseases. Such a finding in a progressive myopathy should, therefore, lead to the suspicion of hypokalemic periodic paralysis 32 . Especially in combination with very focal “punch hole lesions” within muscles (see Fig 3).…”