Anaesthesia challenges of a parturient with paramyotonia congenita and terminal filum lipoma presenting for labour and caesarean section under epidural anaesthesia - a case report.

BACKGROUND: Paramyotonia congenita is a rare autosomal dominant myopathy which presents with periodic weakness due to cold and exercise. It is caused by mutations of the SCN4 gene which encodes the sodium channel in skeletal muscles. CASE PRESENTATION: We report a full term obstetric patient with both paramyotonia congenita and terminal filum lipoma who presents for induction of labour followed by an emergency caesarean section performed under epidural anesthesia. Her recovery is subsequently complicated by a 3-day history of postpartum paraparesis attributed to hypokalemic periodic paralysis. CONCLUSION: We describe the perioperative anesthesia considerations and challenges in this case with a review of the current literature. This case report highlights the importance of early proactive and collaborative multidisciplinary approach, maintaining normal temperature and electrolytes with a heightened vigilance for muscle-related perioperative complications.

A rare case of cephalexin-induced acute interstitial nephritis with hypokalemic periodic paralysis.

Drug-induced acute interstitial nephritis (AIN) is often encountered in clinical practice. Cephalexin is a first-generation cephalosporin with antimicrobial sensitivity ranging from Gram-positive to Gram-negative organisms. Cephalexin-induced AIN presenting with hypokalemic periodic paralysis (HPP) has been rarely reported. A 34-year-old female with recent history of oral cephalexin intake presented with acute onset paraplegia with deranged renal parameters and hypokalemia. She was treated conservatively with mechanical ventilator support. HPP could be a rare clinical presentation for cephalexin-induced AIN.

Skeletal Muscle Channelopathies.

Skeletal muscle channelopathies are rare genetic neuromuscular conditions that include the nondystrophic myotonias and periodic paralyses. They cause disabling muscle symptoms and can limit educational potential, work opportunities, socialization, and quality of life. Effective therapy is available, making it essential to recognize and treat this group of disorders. Here, the authors highlight important aspects regarding diagnosis and management using illustrative case reports.

33-year-old man • flaccid paralysis in limbs • 30-lb weight loss • thyromegaly without nodules • Dx?

Flaccid paralysis in arms and legs. 30-lb weight loss in previous month. Thyromegaly without nodules. Dx?

In vivo assessment of interictal sarcolemmal membrane properties in hypokalaemic and hyperkalaemic periodic paralysis.

OBJECTIVE: Hypokalaemic periodic paralysis (HypoPP) is caused by mutations of Cav1.1, and Nav1.4 which result in an aberrant gating pore current. Hyperkalaemic periodic paralysis (HyperPP) is due to a gain-of-function mutation of the main alpha pore of Nav1.4. This study used muscle velocity recovery cycles (MVRCs) to investigate changes in interictal muscle membrane properties in vivo. METHODS: MVRCs and responses to trains of stimuli were recorded in tibialis anterior and compared in patients with HyperPP(n = 7), HypoPP (n = 10), and normal controls (n = 26). RESULTS: Muscle relative refractory period was increased, and early supernormality reduced in HypoPP, consistent with depolarisation of the interictal resting membrane potential. In HyperPP the mean supernormality and residual supernormality to multiple conditioning stimuli were increased, consistent with increased inward sodium current and delayed repolarisation, predisposing to spontaneous myotonic discharges. CONCLUSIONS: The in vivo findings suggest the interictal resting membrane potential is depolarized in HypoPP, and mostly normal in HyperPP. The MVRC findings in HyperPP are consistent with presence of a window current, previously proposed on the basis of in vitro expression studies. Although clinically similar, HyperPP was electrophysiologically distinct from paramyotonia congenita. SIGNIFICANCE: MVRCs provide important in vivo data that complements expression studies of ion channel mutations.

Secondary hypokalemic paralysis with bulbar weakness and reversible electrophysiologic abnormalities: A case report and systematic review.

Hypokalemic periodic paralysis secondary to distal renal tubular acidosis presenting with prominent bulbar symptoms is extremely rare. The exact pathophysiology by which hypokalemia causes weakness is yet to be elucidated though muscle and nerve membrane hyperpolarization have been hypothesized. The pathophysiology of bulbar involvement in this condition is even more unclear. We report a case presenting as acute flaccid quadriplegia with prominent bulbar symptoms that reversed once potassium levels returned to normal. Serial nerve conduction studies were performed at various potassium levels revealing electrophysiologic abnormalities that corrected with potassium repletion. A systematic review of the literature was also conducted focusing on bulbar symptoms and electrophysiologic findings in hypokalemic periodic paralysis. Nerve conduction abnormalities in this condition are seldom documented, but reports have shown reduced amplitudes of compound motor action potentials and abnormal F-waves during acute attacks of hypokalemic paralysis.

Familial hypokalemic periodic paralysis in pregnancy: A case report.

Familial hypokalemic periodic paralysis (f-hypoPP) is a rare neuromuscular disorder causing intermittent muscle paralysis. Pregnancy can exacerbate f-hypoPP, yet obstetric management is not well documented. We present a case of a nulliparous woman with f-hypoPP, outlining a complete prenatal care plan generalizable to other women with known f-hypoPP. To our knowledge, this is the first obstetric f-hypoPP case to prioritize intrapartum oral potassium over intravenous potassium, as well as to outline the importance of multidisciplinary care. The patient had a spontaneous vaginal delivery at term with an uneventful postpartum period. Muscle weakness and episodes of relative hypokalemia in the second trimester and during labor were effectively treated with oral potassium supplementation. Care was provided by a multidisciplinary team, and caution was taken to avoid known triggers of paralytic episodes.

Recovery from acidosis is a robust trigger for loss of force in murine hypokalemic periodic paralysis.

Periodic paralysis is an ion channelopathy of skeletal muscle in which recurrent episodes of weakness or paralysis are caused by sustained depolarization of the resting potential and thus reduction of fiber excitability. Episodes are often triggered by environmental stresses, such as changes in extracellular K+, cooling, or exercise. Rest after vigorous exercise is the most common trigger for weakness in periodic paralysis, but the mechanism is unknown. Here, we use knock-in mutant mouse models of hypokalemic periodic paralysis (HypoKPP; NaV1.4-R669H or CaV1.1-R528H) and hyperkalemic periodic paralysis (HyperKPP; NaV1.4-M1592V) to investigate whether the coupling between pH and susceptibility to loss of muscle force is a possible contributor to exercise-induced weakness. In both mouse models, acidosis (pH 6.7 in 25% CO2) is mildly protective, but a return to pH 7.4 (5% CO2) unexpectedly elicits a robust loss of force in HypoKPP but not HyperKPP muscle. Prolonged exposure to low pH (tens of minutes) is required to cause susceptibility to post-acidosis loss of force, and the force decrement can be prevented by maneuvers that impede Cl- entry. Based on these data, we propose a mechanism for post-acidosis loss of force wherein the reduced Cl- conductance in acidosis leads to a slow accumulation of myoplasmic Cl- A rapid recovery of both pH and Cl- conductance, in the context of increased [Cl]in/[Cl]out, favors the anomalously depolarized state of the bistable resting potential in HypoKPP muscle, which reduces fiber excitability. This mechanism is consistent with the delayed onset of exercise-induced weakness that occurs with rest after vigorous activity.

Thyrotoxic hypokalemic periodic paralysis: a life-threatening disorder in Asian men.

Thyrotoxicosis can present as a sporadic form of hypokalaemic periodic paralysis. The condition is associated with massive intracellular shift of potassium, mainly in skeletal muscles. As the total body stores of potassium remain normal, overzealous potassium supplementation targeting serum potassium level results in a poor outcome. We present a fatal case of thyrotoxic hypokalaemic periodic paralysis.

A novel ATP1A2 mutation in a patient with hypokalaemic periodic paralysis and CNS symptoms.

Hypokalaemic periodic paralysis is a rare genetic neuromuscular disease characterized by episodes of skeletal muscle paralysis associated with low serum potassium. Muscle fibre inexcitability during attacks of paralysis is due to an aberrant depolarizing leak current through mutant voltage sensing domains of either the sarcolemmal voltage-gated calcium or sodium channel. We report a child with hypokalaemic periodic paralysis and CNS involvement, including seizures, but without mutations in the known periodic paralysis genes. We identified a novel heterozygous de novo missense mutation in the ATP1A2 gene encoding the α2 subunit of the Na+/K+-ATPase that is abundantly expressed in skeletal muscle and in brain astrocytes. Pump activity is crucial for Na+ and K+ homeostasis following sustained muscle or neuronal activity and its dysfunction is linked to the CNS disorders hemiplegic migraine and alternating hemiplegia of childhood, but muscle dysfunction has not been reported. Electrophysiological measurements of mutant pump activity in Xenopus oocytes revealed lower turnover rates in physiological extracellular K+ and an anomalous inward leak current in hypokalaemic conditions, predicted to lead to muscle depolarization. Our data provide important evidence supporting a leak current as the major pathomechanism underlying hypokalaemic periodic paralysis and indicate ATP1A2 as a new hypokalaemic periodic paralysis gene.

A Mixed Periodic Paralysis & Myotonia Mutant, P1158S, Imparts pH-Sensitivity in Skeletal Muscle Voltage-gated Sodium Channels.

Skeletal muscle channelopathies, many of which are inherited as autosomal dominant mutations, include myotonia and periodic paralysis. Myotonia is defined by a delayed relaxation after muscular contraction, whereas periodic paralysis is defined by episodic attacks of weakness. One sub-type of periodic paralysis, known as hypokalemic periodic paralysis (hypoPP), is associated with low potassium levels. Interestingly, the P1158S missense mutant, located in the third domain S4-S5 linker of the "skeletal muscle", Nav1.4, has been implicated in causing both myotonia and hypoPP. A common trigger for these conditions is physical activity. We previously reported that Nav1.4 is relatively insensitive to changes in extracellular pH compared to Nav1.2 and Nav1.5. Given that intense exercise is often accompanied by blood acidosis, we decided to test whether changes in pH would push gating in P1158S towards either phenotype. Our results suggest that, unlike in WT-Nav1.4, low pH depolarizes the voltage-dependence of activation and steady-state fast inactivation, decreases current density, and increases late currents in P1185S. Thus, P1185S turns the normally pH-insensitive Nav1.4 into a proton-sensitive channel. Using action potential modeling we predict a pH-to-phenotype correlation in patients with P1158S. We conclude that activities which alter blood pH may trigger the noted phenotypes in P1158S patients.

When muscle Ca2+ channels carry monovalent cations through gating pores: insights into the pathophysiology of type 1 hypokalaemic periodic paralysis.

Patients suffering from type 1 hypokalaemic periodic paralysis (HypoPP1) experience attacks of muscle paralysis associated with hypokalaemia. The disease arises from missense mutations in the gene encoding the α1 subunit of the dihydropyridine receptor (DHPR), a protein complex anchored in the tubular membrane of skeletal muscle fibres which controls the release of Ca2+ from sarcoplasmic reticulum and also functions as a Ca2+ channel. The vast majority of mutations consist of the replacement of one of the outer arginines in S4 segments of the α1 subunit by neutral residues. Early studies have shown that muscle fibres from HypoPP1 patients are abnormally depolarized at rest in low K+ to the point of inducing muscle inexcitability. The relationship between HypoPP1 mutations and depolarization has long remained unknown. More recent investigations conducted in the closely structurally related voltage-gated Na+ and K+ channels have shown that comparable S4 arginine substitutions gave rise to elevated inward currents at negative potentials called gating pore currents. Experiments performed in muscle fibres from different models revealed such an inward resting current through HypoPP1 mutated Ca2+ channels. In mouse fibres transfected with HypoPP1 mutated channels, the elevated resting current was found to carry H+ for the R1239H arginine-to-histidine mutation in a S4 segment and Na+ for the V876E HypoPP1 mutation, which has the peculiarity of not being located in S4 segments. Muscle paralysis probably results from the presence of a gating pore current associated with hypokalaemia for both mutations, possibly aggravated by external acidosis for the R1239H mutation.

Hypokalaemia periodic paralysis.

Hypokalaemic periodic paralysis is a rare skeletal muscle channelopathy causing flaccid paralysis, which predominantly presents in adolescents and young adults. I report a case of a 33-year-old Caucasian man who presented with sudden onset paralysis, following previous similar presentations without investigation. Blood tests revealed undetectable serum potassium levels in the context of paralysis. Other causes of hypokalaemia were excluded, and the patient was treated with planned lifelong prophylactic potassium replacement for a diagnosis of primary hypokalaemic periodic paralysis. This case demonstrates that, although rare, hypokalaemic periodic paralysis should be considered as a differential diagnosis in young patients who present with sudden flaccid paralysis and can easily be excluded by checking serum potassium levels at presentation.

Diverse phenotype of hypokalaemic periodic paralysis within a family.

Hypokalaemic periodic paralysis typically presents with intermittent mild-to-moderate weakness lasting hours to days. We report a case with an uncommon phenotype of late-onset myopathy without episodic paralytic attacks. Initial work-up including muscle biopsy was inconclusive. A subsequent review of the right deltoid biopsy, long exercise testing and repeated family history was helpful, followed by appropriate genetic testing. We identified a heterozygous pathogenic mutation in calcium ion channel (CACNA1S:c.1583G>A p.Arg528His) causing hypokalaemic periodic paralysis. Myopathy can present without episodic paralysis and the frequency of paralytic episodes does not correlate well with the development and progression of a fixed myopathy. Our report also highlights the intrafamilial phenotypic variation of hypokalaemic periodic paralysis secondary to a CACNA1S gene mutation.

Kir2.2 p.Thr140Met: a genetic susceptibility to sporadic periodic paralysis.

INTRODUCTION: Periodic paralyses (PP) are recurrent episodes of flaccid limb muscle weakness. Next to autosomal dominant forms, sporadic PP (SPP) cases are known but their genetics are unclear. METHODS: In a patient with hypokalemic SPP, we performed exome sequencing to identify a candidate gene. We sequenced this gene in 263 unrelated PP patients without any known causative mutations. Then we performed functional analysis of all variants found and molecular modelling for interpretation. RESULTS: Exome sequencing in the proband yielded three heterozygous variants predicted to be linked to disease. These encoded p.Thr140Met in the Kir2.2 potassium channel, p.Asp229Asn in protein kinase C theta, and p.Thr15943Ile in titin. Since all hitherto known causative PP genes code for ion channels, we studied the Kir2.2-encoding gene, KCNJ12, for involvement in PP pathogenesis. KCNJ12 screening in 263 PP patients revealed three further variants, each in a single individual and coding for p.Gly419Ser, p.Cys75Tyr, and p.Ile283Val. All four Kir2.2 variants were functionally expressed. Only p.Thr140Met displayed relevant functional alterations, i.e. homo-tetrameric channels produced almost no current, and hetero-tetrameric channels suppressed co-expressed wildtype Kir2.1 in a dominant-negative manner. Molecular modelling showed Kir2.2 p.Thr140Met to reduce movement of potassium ions towards binding sites in the hetero-tetramer pore compatible with a reduced maximal current. MD simulations revealed loss of hydrogen bonding with the p.Thr140Met substitution. DISCUSSION: The electrophysiological findings of p.Thr140Met are similar to those found in thyrotoxic PP caused by Kir2.6 mutations. Also, the homologous Thr140 residue is mutated in Kir2.6. This supports the idea that Kir2.2 p.Thr140Met conveys susceptibility to SPP and should be included in genetic screening.

Severe hypokalaemia as a cause of acute transient quadriparesis.

Hypokalaemic paralysis covers a heterogeneous group of disorders caused either by an enhanced shift of potassium into the cells or following a significant renal or gastrointestinal loss of potassium. We present the case of a 48-year-old Caucasian man with paralysis of both upper and lower extremities. ECG showed sinus rhythm and characteristic changes of hypokalaemia with depression of the ST segment, prolonged QTc interval of 581ms and U waves seen as a small positive deflection at the T wave in the middle precordial leads. We suspected the cause of hypokalaemia leading to paralysis to be due to administration of high doses of furosemide without oral potassium supplementation coupled with regular use of insulin. Initial therapy included both oral and intravenous potassium replacement and close monitoring of cardiac rhythm and serum potassium levels. Twenty-four hours after admission, the potassium level had normalised and the patient slowly recovered and gained strength. The patient was discharged after 1 week of careful follow-up and did not experience any serious degree of rebound hyperkalaemia. At the time of discharge, all laboratory tests were normal and ECG revealed a normal sinus rhythm and normal QTc intervals.

Thyrotoxic Channelopathies.

Thyrotoxic periodic paralysis (TPP), a disorder most commonly seen in Asian men, is characterized by abrupt onset of hypokalemia and paralysis. The condition primarily affects the lower extremities and is secondary to thyrotoxicosis. Early recognition of TPP is vital to initiating appropriate treatment and to avoiding the risk of rebound hyperkalemia that may occur if high-dose potassium replacement is given. Here we present a case of 31 year old male with thyrotoxic periodic paralysis with diagnostic and therapeutic approach.