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The causes for neuropathic pain are manifold and remain unexplained in the majority of cases. In recent years a growing number of pain syndromes have been attributed to mutations in genes encoding voltage-gated sodium channels. Hence, this group of rare diseases should be considered in the differential diagnostics of neuropathic pain.Evaluation of topic-related literature and discussion of own experiences as well as consideration of current guidelines.Alterations in the electrical excitability of nociceptive neurons by pathogenic mutations in sodium channels lead to disease patterns, such as small fiber neuropathy and various pain syndromes. This article summarizes the knowledge on these genetic diseases and discusses the differential diagnosis of neuropathic pain. Current treatment concepts are presented and the predominantly experimental approaches to targeted modulation of sodium channels are discussed.The treatment of patients with chronic neuropathic pain requires interdisciplinary cooperation and is often difficult due to an unsatisfactory treatment response. Increasing knowledge on rare genetically determined channelopathies can contribute to the development of novel pharmaceuticals since ion channels are central players in the processing of pain.

Syncope can be the first manifestation of cardiac channelopathies, namely Brugada syndrome, long QT syndrome, short QT syndrome and catecholaminergic polymorphic ventricular tachycardia (CPVT). Patients affected by these rare diseases are at increased risk for sudden cardiac death due to ventricular tachyarrhythmias and require specific therapy and follow-up. As syncope is common in the general population, only few cases are caused by an underlying channelopathy. Nevertheless, the diagnosis should be considered in young patients with structurally normal hearts, especially if the history of syncope is typical for an arrhythmogenic cause, in the presence of characteristic echocardiogram (ECG) patterns, and if there is a family history of channelopathies or sudden cardiac death. On the other hand, syncope plays an important role in the management of patients with diagnosed channelopathies, as they may indicate an increased risk for sudden cardiac death. The predictive value and consequences for treatment vary between the different channelopathies. However, data on this issue are scarce due to the low prevalence of these diseases. This review highlights typical findings in the medical history and diagnostic tests that may point towards an underlying channelopathy in patients with syncope. It also discusses the prognostic and therapeutic implications of a history of syncope in patients with known channelopathies.

Implantable loop recorders (ILR) do not play a pivotal role in the current guidelines on ventricular arrhythmias except in identifying rhythm-symptom correlations if ventricular arrhythmias are assumed. Before a decision for a pure diagnostic implantable device is made, a thorough arrhythmic risk assessment is of major importance due to the potential lethal outcome of ventricular arrhythmias. Nevertheless, some clinical circumstances exist where long-term monitoring by an ILR may add significant information in electrical heart diseases, in patients with ventricular arrhythmias, or structural heart diseases and a potential risk of ventricular arrhythmias. As medical therapy (β-blocker therapy) plays an important role in long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardias (cpVT), the ILR can be used to control therapy in patients at risk. In electrical diseases without pharmacologic therapeutic options (e. g., Brugada syndrome), the ILR may be used in low-risk patients with atypical syncope as benign faints may occur without association to the underlying disease. Evidence on cardiomyopathies with preserved left ventricular function and nonsustained VT or premature ventricular complexes is scarce. The ILR may also add long-term information on the individual risk in these circumstances. In very rare diseases like infiltrative disease or muscular dystrophies, the ILR may also provide evidence on risk stratification. In summary, ILR in electrical heart diseases and in patients with ventricular tachycardia remains a very individual decision taking into account various clinical, electrocardiographic, and genetic parameters. The following review aims at highlighting possible indications and clinical scenarios for ILR in ventricular tachycardias and electrical heart diseases with-probably debatable-case presentations.

Loss of pain perception can result from neurodevelopmental defects, degeneration of nociceptive fibers, or altered excitability of sensory neurons. Hereditary neurodegeneration leading to pain loss is classified as sensory and autonomic neuropathy (HSAN). Mutations in approximately 15 genes have been identified in the group of HSAN disorders. Hallmark of the disease is a liability to injury because of impaired acute pain as a warning system to prevent harm. The clinically overlapping "congenital insensitivity to pain (CIP)" is caused by mutations in voltage-gated sodium channels, which control the excitability of nociceptors. However, mutations in the latter genes can also result in disorders with increased pain susceptibility. This review summarizes the clinical presentation of HSAN and pain-related channelopathies and discusses the underlying disease mechanisms.

Ion channel diseases are responsible for the occurrence of supraventricular bradycardia and tachycardia, ventricular tachycardia, syncope and sudden death. In the present paper the specific considerations for diagnostic pathways and therapeutic decision making will be focused on for the largest clinical entities, such as the long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia and Andersen-Tawil syndrome. All diseases are characterized by a specific pathognomic electrocardiographic (ECG) alteration. For most of the diseases a variety of mutations have been identified that code for different ion channel proteins. All have a high potential of arrhythmogenicity in common. It is important to know that the ECG alterations are often only transient, which makes repetitive recordings and sometimes provocation maneuvers necessary. The time of onset of disease varies so that the initiation of diagnostics starts at different ages. Therapy often remains an individual choice and is influenced by a number of factors, such as a family history of sudden death.

The myotonias and familial periodic paralyses are muscle channelopathies. They have in common an impaired muscle excitation that is caused by mutations in voltage-gated Na(+), K(+), Ca(2+), and Cl(-) channels. Membrane hyperexcitability usually results in myotonic stiffness; with increasing membrane depolarization hyperexcitability can be transiently turned into hypoexcitability causing transient weakness as in severe myotonia. Hypoexcitability due to long-lasting depolarization that inhibits action potential generation is the common mechanism for the periodic paralyses. Interictally, the ion channel malfunction may be compensated, so that specific exogenous or endogenous provocative factors are required to produce symptoms in the patients. An especially obvious triggering agent is the level of serum potassium, the ion decisive for resting membrane potential and degree of excitability. Periodic paralysis mutations for which the ion channel malfunction is not fully compensated interictally cause progressive myopathy.

Voltage-gated calcium channels are key components in a variety of physiological processes. Within the last decade an increasing number of voltage-gated Ca(2+) channelopathies in both humans and animal models has been described, most of which are related to the neurologic and muscular system. In humans, mutations were found in L-type Ca(v)1.2 and Ca(v)1.4 Ca(2+) channels as well as the non-L-type Ca(v)2.1 and T-type Ca(v)3.2 channels, resulting in altered electrophysiologic properties. Based on their widespread distribution within the CNS, voltage-gated calcium channels are of particular importance in the etiology and pathogenesis of various forms of epilepsy and neuropsychiatric disorders. In this review we characterise the different human Ca(2+) channelopathies known so far, further illuminating basic pathophysiologic mechanisms and clinical aspects.

Short QT syndrome is a new genetic disorder associated with familial atrial fibrillation and/or sudden death or syncope. To date, different mutations in genes encoding for cardiac ion channels (KCNH2, KCNQ1, and KCNJ2) have been identified to cause the short QT syndrome. The mutations lead to a gain of function of the affected current (IKr, IKs, and IK1). The phenotype is characterized by a shortened QT interval335 ms after correction for heart rate at rates80 beats/min. Furthermore, the QT interval poorly adapts to heart rate. Patients exhibit shortened atrial and ventricular effective refractory periods and, in the majority, inducibility of ventricular fibrillation. Death occurs already in newborns. Therapy of choice seems to be the implantable cardioverter defibrillator because of the high incidence of sudden death. Pharmacological treatment has been studied and it could be demonstrated, that some mutant currents may be insufficiently suppressed by drugs targeted to block the specific current such as, e.g., sotalol or ibutilide in patients with a mutation in the IKr-coding gene KCNH2 (HERG). Quinidine proved to be efficient in prolonging the QT interval and normalizing the effective refractory periods in some patients.

Identification of familial forms of different diseases has provided a unique opportunity to study how changes in the structure of a gene create a dysfunction in the physiology of the resulting protein. Changes in the genes encoding for ion channels produce modifications in the function of the channel. Changes in the sodium channel are responsible for long QT syndrome, Brugada syndrome and conduction defects. Changes in the potassium channels have been related to long QT syndrome, short QT syndrome and familial atrial fibrillation. Relating genetic modification and dysfunction allows to study the substrate for a disease, understand the physiopathologic mechanism and look for appropriate therapies.