Autosomal Dominant PRINCIPLES ‘= Environmental modifiers ‘© Founder effects + Gene dosage © Genetic modifiers MAJOR PHENOTYPIC FEATURES ‘+ Age at onset: Heterozygote—early to middle adulthood: homozygote—childhood Hypercholesterolemia Atherosclerosis Xanthomas ‘Arcus comneae HISTORY AND PHYSICAL FINDINGS Ls 8 previously healthy 45-year-old French Canaan post, mitted for a myocardial infarction. He had 9 mall xanthoma on his right Achilles tendon. His brother also had ‘coronary artery disease (CAD); his mother, mate ‘grandmother, and two maternal unclos hed family history, LL was belived to have an autosomal rm of hhypereholesterolemia. Molecular analysis raves that he was heterozygous fora deletion ofthe 5" end of the LDL. receptor ‘gene (LOLA, 8 mutation found in 59% of French Canadians ‘with familial hypercholesterolemia. Screening of his children Fevealed that two ofthe three children had elevated LDL ‘cholesterol levels, The cardiologist explained to LL. that in addition to drug therapy, effective treatment of his CAD required dietary and teste changes, euch as adit low in ‘Saturated fot and low in eholeterl, increased physical activity, ‘woight loss, and smoking cessation, LL, was not compliant ‘with treatment and died a year later of a myocarcal infarction. BACKGROUND Disease Etiology and Incidence Familial hypercholesterolemia (FH, MIM 143890) is an auto- somal dominant disorder of cholesterol and lipid metabolism caused by mutations in LDLR (see Chapter 12). FH occurs among al races and has a prevalence of 1 in 500 in most white populations. Ie accounts for somewhat less than 5% of patients with hypercholesterolemia. Pathogenesis ‘The LDL receptos, a transmembrane glycoprotein predomi- nanely expressed in the liver and adrenal cortex, plays a key role in cholesterol homeostasis. Ie binds apolipoprotein B-100, the sole protein of LDL, and apolipoprotein E, a protein found on very-low-density lipoproteins, intermediate-density lipoproteins, chylomicron remnants, and some high-density lipoproteins, Hepatic LDL receptors cleat approximately 50% Thompson &Thompson Sted. 206 FAMILIAL HYPERCHOLESTEROLEMIA (Low-Density Lipoprotein Receptor [LDLR] Mutation, MIM 143890) of intermediate-density lipoproteins and 66% to 80% of LDL from the circulation by endocytosis; poorly understood LDL receptorindependent pathways clear the remainder of the DL. Mutations associated with FH occur throughout LDLRs 2% to 10% are large insertions, deletions, or rearrangements mediated by recombination between Alu repeats within DLR. Some mutations appear t0 be dominant negative. Most mutations are private mutations, although some populations—such as Lebanese, French Canadians, South African Indians, South African Ashkenazi Jews, and Afrkaners—have common mutations and a high prevalence of disease because of founder effects. Homozygous or heterozygous mutations of LDLR decrease the effcieney of intermediate-density lipoprotein and LDL endocytosis and cause accumulation of plasma LDL. by increasing production of LDL from intermediate-density lipo- proteins and decreasing hepatic clearance of LDL. The ele- ‘ated plasma LDL levels cause atherosclerosis by increasing the clearance of LDL through LDL receptor-independent pathways, such as endocytosis of oxidized LDL: by: macro- phages and histiocytes. Monocytes, which infiltrate the are- Fal intima and endocytose oxidized LDL, form foam cells and release cytokines that cause proliferation of smooth muscle cells of the arcerial medi. Initially, the smooth muscle cells produce sufficient collagen and matrix proteins to form a fibrous cap over the foam cells because foam cells continue to endocytose oxidized LDL, howeves, they eventually rupcure theough the fibrous cap into the arterial lumen and trigger the formation of thrombi, a common cause of strokes and myo- cardial infarction. Environment, sex, and genetic background modify the effect of LDL receptor mutations on LDL plasma levels and thereby the occureence of atherosclerosis. Diet is the major environmental modifer of LDL plasma levels for example, most Tunisian FH heterozygotes have LDL levels in the ttormal North American range and rarely develop cardio- vascular disease and xanthomas. Similarly, Chinese FH het- trozygotes living in China rately have_xanthomas and cardiovascular disease, whereas. Chinese FH heterozygotes living in Western societies have clinical manifestations similar to those of white FH heterozygotes. Dietary cholesterol sup- Dresses the synthesis of LDL receptors, thereby raising plasma LDL levels: this effect of dietary cholesterol is potentiated by saturated fatty acids, such as palmitate from dairy products, and ameliorated by unsaturated fatty acids, such as oleate and linoleate. Because a similar diet does not elevate LDL levels ‘equally among. patients, other envieonmental and genetic factors must also influence LDL metabolism. A few families swith FH segregate a different dominant locus that reduces plasma LDL, providing evidence fora genetic modifier. Other forms of FH include type B hypercholesterolemia (MIM 144010), caused by ligand-defective apolipoprotein B-100, and autosomal dominant hypercholesterolemia (MIM 603776), due to PCSK9 mutations. In subjects withthe LDLR mutation IVS14#1G-A, the phenotype can be altered by a Single nucleotide polymoxphism (SNP) in APOA2, 2 SNP in EPHX2, or a SNP in GHR. A SNP in the promoter region of the G-substrate gene (GSBS) correlates with elevated plasma total cholesterol levels. A SNP in intron 17 of ITIH4 was(CASE 16 — FAMILIAL HYPERCHOLESTEROLEMIA 423 Figure C-16 An Ais ton xanthor fom a patant with fail hype clstrlea, Sh Souas& Aetnorbasmes associated with hypercholesterolemia susceptibility in a Japa- nese population. Phenotype and Natural History Hypercholesterolemia, dhe easiest fending in FH, usually man- iets at birth and is the onl clinical nding through the fst decade in heterozygous patients a all ages, the plasma cho- leserol concentration is greater than the 9Sth percentile in more than 95% of patents. Arcus corneae and tendon xan thomas begin to appear by the end of the second decade and by deach, 80% of FH heterozygotes have xanthomas (Fig C16). Neasly 40% of adule patents have recurrent nonpro- fresive polyarthritis and tenosynovitis. As tabulated, the development of CAD among FH heterozygotes depends on age and gender. In general, che untreated cholesterol level is steater than 300 mid Homozygous FH presents in the fist decade with tendon xanthomas and arcus comeae. Without aggressive treatment, homozygous FH is usually lethal by the age of 30 years. The tntreatedcholestevol_concentration is between 600 and 1000 mga. ‘Management Elevated plasma LDL cholesterol and a family history of hypercholesterolemia, xanthomas, or premature CAD strongly suggest a diagnosis of FH. Confirmation of the diagnosis requires quantification of LDL receptor function in the patient’ skin fibroblasts or identification of the LDLR muca- tion. In most populations, the plethora of LDLR mutations precludes direct DNA analysis unless a particular mutation is Strongly suspected. The absence of DNA confirmation does hot interfere with management of FH patients, however, because a definitive molecular diagnosis of FH does not provide prognostic or therapeutic information beyond that Slready derived from the family history and determination of plasma LDL cholesterol level ‘Regardless of whether they have FH, all patients with slevated LDL cholesterol levels require aggressive normaliza tion of the LDL cholesterol concentration 10 reduce their risk for CAD; rigorous normalization of the LDL cholesterol con- centration can prevent and reverse atherosclerosis, In FH het: ‘erozygotes, rigorous adherence toa low-fat, high-carbohydrate ‘Age- and Sex-Specific Rates (%) of CAD and Death in Familial Hypercholesterolemia Heteronygotes Females Age cD Dea 30 5 = 0 = 40 2024 7 03 ° 50 4551 25 12:20 2 oo 7585 30 4557 a5 30 Ed 100 80 7 EAD, Covey ary rom Rade Di, Hobbs HE: Disorders of lpoprotea metabo. tn Kasper DL, BesmwadF, Faes AS, eal, edocs Harsco’ principles of intra moicng 115, New York 2004, Mera Fi diet usually produces a 10% to 20% reduction in LDL cho- lesterol, but most patients also require treatment with one oF 4 combination of three classes of drags: bile acid sequestrants, 3-hydroxy-3-mechylglutaryl coenzyme A reductase inhibitors, and nicotinic acid (see Chapter 13). Current recommendations are initiation of drug therapy at 10 years of age for patients with an LDL cholesterol level of more then 190 mg/dL and a negative family history for premature CAD, and at 10 years of age for patients with an LDL cholesterol level of more than 160 mg/dl. and a positive family history for premature CAD. Among FH homozygotes, LDL apheresis can reduce plasma cholesterol levels by as much as 70%. The therapeutic effec- tiveness of apheresis is increased when it is combined with aggressive statin and nicotinic acid therapy. Liver transplanta- tion has also been used on rare occasions. INHERITANCE RISK Because FH is an autosomal dominant disorder, each child of ‘an affected parent has a 50% chance of inheriting the mutant LDLR allele. Untreated FH heterozygotes have a 100% isk for development of CAD by the age of 70 years if male and a 75% tsk if female (see Table). Current medical therapy mark- edly reduces this risk by normalizing plasma cholesterol QUESTIONS FOR SMALL GROUP DISCUSSION 1. What insights does FH provide into the more common poly= (genie causes of atherosclerosis and CAD? 2. Familial detective apolipoprotein B-100 Is 8 genocopy of FH, Wye 2. Vogotableolls are hydrogenated to make some margarines, What effect would eating margarine have on LDL receptor ‘expression compared with vegetable oil consumption? 4, Discuss genetic euecoptibility to infection and potential het- ferozygote advantage in the context of tho role of the LDL. receptor in hepatitis C infection. REFERENCES ager Ou, Habe Hi Diode of paren motto. n Longo D, Fauci AS. Kasper Dot al ets: Harsor's ines of itma eine, e618, New Yor 2013, Mes Srideman AD, Tsnias S, ati S: The sever hpacholsteoliapronoype: ‘nical egos, management, ard enarging tapas, J Am Coll Catt bss 147, 14 Varese MU Frill hypertosclania: vow, Ann Peis Ca: 10?— 117,204 Younghlom Koos JW: Faia yprcholestecemi,Avisble fom: pd ‘we cin grb NBKT 4884),Thoapson + Thompson FS4 20\p LONG QT SYNDROME (Cardiac Ion Channel Gene Mutations; MIM 192500) Autosomal Dominant or Recessive PRINCIPLES + Locus heterogeneity ‘+ Incomplete penetrance Generic susceptibility to medications MAJOR PHENOTYPIC FINDINGS + QTe prolongation (>470 msec in males, >480 msec in females) + Tachyarrhythmias (torsades de pointes) ‘+ Syncopal episodes Sudden deach HISTORY AND PHYSICAL FINDINGS ‘AB. isa S0,yearold woman with long QT /LOT) syndrome who presents tothe genatis clinic with her husband because they are contemplating a pregnancy. The couple wants to know the recurrence risk for this condition in their children and the genetic testing and be avaliable to thom. She ned about potential risks to her own hoath in carrying 9 pregnancy. The patient \was diagnosed withthe LOT syndrome inher early 20s when she was evaluated after the sudden death of her year-old brother. Overall, she is heslthy individual with normal hearing. no dysmorphic features, and an othernise negative review of systems. She has never had any fainting episodes, ‘Subsequently, sletrocardiographiefninge confirmed the diagnosis ofthe syndrome in AB., and a paternal aunt but not who had a normal GTe interval. Molecular testing revealed a missonse mutation in KCNH2, one that had been previously seen in ather families with Romane: Ward syndrome, type LOT2. A.B, was intelly prescribed p-blockade medication, which she is continuing, but hor eardologiets ‘decided thet the less than total efficacy of f-blockrs in LOT: 1nd the previous lethal event inher brother justified the use of ‘an implantable cardioverter defibrillators in AB, and her fected relatives. AB. is th first person in her femilyt0 pursue genetic counseling for the LOT syndrome. BACKGROUND Disease Etiology and Incidence ‘The LQT syndromes are a heterogeneous, panethnic group of disorders referred to as channclopathies. because they are caused by defects in cardiac ion channels. The overall preva- lence of LQT disorders is approximately 1 in 5000 to 7000 individeals. ‘The genetics underlying LQT syndromes is complex, First, there is locus heterogeneity. Mutations in atleast five known cardiac ion channel genes (KCNOL, KCNH2, SCNSA, KCNEI, and KCNE2) are responsible for most cases of LOT, ‘mutations in additional genes are known, but much rarer, Second, different mutant alleles in the same locus can result in two distinct LOT syndromes with two different inheritance patterns, the Romano-Ward syndrome and the autosomal recessive Jrvell and Lange-Nielsen syndrome (MIM 220400). Pathogenesis LOT syndrome is caused by repolarization defects in cardiac cell. Repolarization is a controlled process that requires a balance between inward currents of sodium and calcium and outward currents of potassium. Imbalances cause the action potential of cells to increase or decrease in duration, causing elongation or shortening, respectively, of the QT interval on clectrocardiographiy. Most cases of LQT syndrome are caused by loss-of-function mutations in genes that encode subunits or regulatory proteins for potassium channels (genes whose names begin with KCN), These mutations decrease the outward, repolarization current, thereby prolonging the action potential of the cell and lowering the threshold for another depolarization. In other LQT syndrome patients, gain-of-function mutations ina sodium channel gene, SCNSA, lead to an increased influx of sodium, resulting in similae shifting of action potential and repolarization effects. Phenotype and Natural History ‘The LQT syndromes are characterized by elongated QT inter- val and TFvvave abnormalities on electrocardiography (Fis, C28), including tachyarthythmia and torsades de. points, 4 ventricular tachycardia characterized by # change in ampli tude and twisting ofthe QRS complex. Torsades de pointes is, associated with a prolonged QT interval and typically stops A R os) t ‘oT eat Fetecorecton oma (Bante: reso) Figure C-28 A, Measurement of he OT itnal tam the elecrocagram ‘The aye dei the nol elecuocariogram wth he P wave representing aval aration, te ORS compl presenta venta aciaton a the tt Gf sortiur esto, a he T wave represen vn replat, (ving to heat rao sarstity af tho CT inane, is paramaterscoeted Inamaie) to hart ata eect th beat bat nel ld the (fe, GT en Oe can both be expessd in mlsoctnds or sande B rhythis ‘set in ong OT setae. Tre sm anon fd ett elercacoy apc ‘hao rcorings in @ patent with OT prngtian ard rans of conus ‘varying polymorphic verti tshyadi rsades de pits). Trsades do poste may sok spontaneously rogess overrule and cara est Soe Sources & Actnowtedyment.CASE 28 — LONG QTSYNDROME 447 spontancously but may persist and worsen to ventricular fibrillation. In the ‘most common LQT syndrome, Romano-Ward, syncope due to cardiac arrhythmia is the most frequent symptoms if undiagnosed or left untreated, it recurs and can, be fatal in 10% to 15% of cases. However, between 30% and ‘50% of individuals with che syndrome never show syncopal symptoms. Cardiac episodes are_most frequent from the ‘preteen years through the 20s, with the risk decreasing over time. Episodes may occur at any age when triggered by QT- prolonging medications (see lst at htxps/www.qrdrugs.org). Nonpharmacological triggers for cardiac events in the Romano-Ward syndrome differ on the basis of the gene responsible. LOTI triggers are typically adrenergic stimuli, including exercise and sudden emotion. Individuals with 1TQ2 are at risk with exercise and at rest and with auditory stimuli, such as alarm clocks and phones. LQT3 individuals hhave episodes with slower heart rates during rest periods and sleep. In addition, 40% of LT! cases are symptomatic before 10 years of age; in 10% of LTQ2 and rarely in LQT3 ddo symptoms occur before 10 years of age. There are at Teast 10 genes associated with LQT syndromes, of which ‘wo—KCNOI and KCNH2—account for aver 80% of cass. “The LOT syndrome exhibits reduced penetrance in tetms of both electrocardiographic abnormalities and syncopal epi Sodes, As many as 30% of affected individuals can have QT. intervals that overlap with the normal range. Variable expres: sion of the disorder can occur within and between familics. Due to reduced penetrance, exercise electrocardiography is, often used for diagnosis of at-risk family members but is not 100% sensitive, LQT syndromes may be accompanied by other findings on physical examination. For example, Jervell and Lange-Nielsen, Syndrome (MIM 220400) is characterized by congenital pro- found sensorineveal hearing loss together with LQT syn- drome. It is an autosomal recessive disorder caused by parsicular mucations within the same ewo genes (KCNOI and KCNEI) implicated in the autosomal dominant Romano- ‘Ward syndrome, Heterozygous relatives of Jervell and Lange Nielsen syndrome patients are not deaf but have a 25% risk for LQT syndrome. Treatment of the LQT syndrome is aimed at prevention of syncopal episodes and cardiac arrest. Optimal treatment is influenced by identification of the gene responsible in a given ‘ase, For instance, B-blocker therapy before the onset of symp- toms is most effective in LQT1 and, to 2 somewhat lesser extent in LQT2, but its efficacy in LQT3 is reduced. BeBlockade therapy must be monitored closely for age-related dose adjustment, and itis imperative that doses are not missed. Pacemakers may be necessary for individuals with bradyear diay access to external defibrillators may be appropriate. Implantable cardioverter defibrillators may be needed in indi viduals with LQT3 or in other individuals with the LOT syndrome in whom B-blocker therapy is problematic, such as in patients with asthma, depression, or diabetes and those with a history of family history of cardiac arrest. Medications such asthe antidepressant amitriptyline, overthe-counter cold ‘medications such as phenylephrine and diphenhydramine, or ‘antifungal drugs, including fluconazole and ketoconazole, should be avoided because of their effect on prolonging the QT interval or causing increased sympathetic tone. Activites ‘and spors likely to be associated with intense physical activity, ‘emotion, or stress should also be avoided. INHERITANCE RISK Individuals with the Romano-Ward syndrome have 2 50% cchance of having a child with the inherited gene mutations. Most individuals have an affected (although pethaps asymp- tomatic) parent, because the rate of de novo mutations is low. ‘A detailed family history and cateful cardiac evaluation of, family members are extremely important and could be lifes ing. The recurcence risk in siblings of patients with Jervell and Lange-Nielsen syndrome is 25%, as expeeted with an autoso- ‘mal recessive condition. The penetrance of LQT alone, without deafness, is 25% in heterozygous carriers in Jervell and Lange- ‘Nielsen syndcome families. QUESTIONS FOR SMALL GROUP DISCUSSION etic syndromes rely on clinical evaluation, lability of molecular testing, for diagnosis. n the ‘cso of LOT, how would you proceed with a patient thought to have LOT on family history? Why? 2, Discuss the ethics of testing minors inthis condition. 3. You have just diagnosed a child with Jervell and Lango- Jaen syndrome, What do you counsel the family in regard ‘orecutrence risk and management for other family members? 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