Harpers

MUSCLE & THE CYTOSKELETON / 569Table 49–5. Some disorders (channelopathies)due to mutations in genes encoding polypeptideconstituents of ion channels. 1Ion Channel and MajorDisorder 2Organs InvolvedCentral core disease Ca 2+ release channel (RYR1)(MIM 117000)Skeletal muscleCystic fibrosisCFTR (Cl − channel)(MIM 219700)Lungs, pancreasHyperkalemic periodic Sodium channelparalysis (MIM 170500) Skeletal muscleHypokalemic periodic Slow Ca 2+ voltage channel (DHPR)paralysis (MIM 114208) Skeletal muscleMalignant hyperthermia Ca 2+ release channel (RYR1)(MIM 180901)Skeletal muscleMyotonia congenita Chloride channel(MIM 160800)Skeletal muscle1 Data in part from Ackerman NJ, Clapham DE: Ion channels—basic science and clinical disease. N Engl J Med 1997;336:1575.2 Other channelopathies include the long QT syndrome (MIM192500); pseudoaldosteronism (Liddle syndrome, MIM 177200);persistent hyperinsulinemic hypoglycemia of infancy (MIM601820); hereditary X-linked recessive type II nephrolithiasis of infancy(Dent syndrome, MIM 300009); and generalized myotonia,recessive (Becker disease, MIM 255700). The term “myotonia” signifiesany condition in which muscles do not relax after contraction.Inherited Cardiomyopathies Are Dueto Disorders of Cardiac EnergyMetabolism or to AbnormalMyocardial ProteinsAn inherited cardiomyopathy is any structural or functionalabnormality of the ventricular myocardium dueto an inherited cause. There are nonheritable types ofcardiomyopathy, but these will not be described here.As shown in Table 49–6, the causes of inherited cardiomyopathiesfall into two broad classes: (1) disordersof cardiac energy metabolism, mainly reflecting mutationsin genes encoding enzymes or proteins involved infatty acid oxidation (a major source of energy for themyocardium) and oxidative phosphorylation; and(2) mutations in genes encoding proteins involved in oraffecting myocardial contraction, such as myosin,tropomyosin, the troponins, and cardiac myosinbindingprotein C. Mutations in the genes encodingthese latter proteins cause familial hypertrophic cardiomyopathy,which will now be discussed.Table 49–6. Biochemical causes of inheritedcardiomyopathies. 1,2Proteins or ProcessCauseAffectedInborn errors of fatty acid Carnitine entry into cells andoxidationmitochondriaCertain enzymes of fatty acidoxidationDisorders of mitochondrial Proteins encoded by mitooxidativephosphorylation chondrial genesProteins encoded by nucleargenesAbnormalities of myocardial β-Myosin heavy chains, tropocontractileand structural nin, tropomyosin, dysproteinstrophin1 Based on Kelly DP, Strauss AW: Inherited cardiomyopathies.N Engl J Med 1994;330:913.2 Mutations (eg, point mutations, or in some cases deletions) inthe genes (nuclear or mitochondrial) encoding various proteins,enzymes, or tRNA molecules are the fundamental causes of theinherited cardiomyopathies. Some conditions are mild, whereasothers are severe and may be part of a syndrome affecting othertissues.Mutations in the Cardiac -Myosin HeavyChain Gene Are One Cause of FamilialHypertrophic CardiomyopathyFamilial hypertrophic cardiomyopathy is one of themost frequent hereditary cardiac diseases. Patients exhibithypertrophy—often massive—of one or both ventricles,starting early in life, and not related to any extrinsiccause such as hypertension. Most cases aretransmitted in an autosomal dominant manner; the restare sporadic. Until recently, its cause was obscure. However,this situation changed when studies of one affectedfamily showed that a missense mutation (ie, substitutionof one amino acid by another) in the β-myosinheavy chain gene was responsible for the condition.Subsequent studies have shown a number of missensemutations in this gene, all coding for highly conservedresidues. Some individuals have shown other mutations,such as formation of an α/β-myosin heavy chain hybridgene. Patients with familial hypertrophic cardiomyopathycan show great variation in clinical picture. This inpart reflects genetic heterogeneity; ie, mutation in anumber of other genes (eg, those encoding cardiacactin, tropomyosin, cardiac troponins I and T, essentialand regulatory myosin light chains, and cardiac myosinbindingprotein C) may also cause familial hypertrophic