兒童心臟科

時至今日，絕大多數的醫院都可藉由理學檢查和一般的檢驗來診斷心血管疾病。例如，以臨床症狀和血液生化得知高血脂症，利用心臟超音波檢查先天性心臟病、川崎病的冠狀動脈病變和心肌症，以及心電生理學診斷長 QT 症候群等。可是這些疾病在基因診斷學方面的研究並不普及，而且目前也只限於某些高危險家族。以下我們僅就目前兒童心血管疾病在基因學的進展方面簡要描述。

 

高脂蛋白血症

眾所周知，血漿中攜帶膽固醇的脂蛋白主要為低密度脂蛋白（LDL lipoprotein），而這種低密度脂蛋白是導致各種形式的冠心病的元兇。以下簡單描述低密度脂蛋白在循環中的機轉：肝臟所分泌 VLDL（低密度脂蛋白 LDL 的先驅物質）包含三酸甘油脂和膽固醇酯。經由肌肉和脂肪組織中的微血管將三酸甘油脂除去，其餘部分以膽固醇酯為核心，用脂蛋白元 B-100 (apolipoprotein B-100）包裝成低密度脂蛋白。血漿中的低密度脂蛋白以其脂蛋白元 B-100 部位與肝細胞表面的低密度脂蛋白接受器結合。經由接受器媒合之細胞吞噬作用，低密度脂蛋白進入肝細胞後在溶小體中崩解而釋出膽固醇於肝臟中。其中，低密度脂蛋白接受器的數目是以負回饋作用來調節的。假設肝細胞中的膽固醇含量增加，則會抑制低密度脂蛋白接受器基因的轉錄，於是減少低密度脂蛋白進入肝細胞中的數量，大多數的低密度脂蛋白便被留在血漿中。反之，當肝細胞中的膽固醇含量減少時，則增加低密度脂蛋白接受器基因的轉錄，從血漿中移走低密度脂蛋白。目前共發現四種單基因疾病會使得血漿中的低密度脂蛋白濃度上升，包括（一）Receptor

異常：同基因合子或異基因合子的家族性高膽固醇血症（LDLR，低密度脂蛋白接受器無作用），

（二）Transportation 異常：同基因合子或異基因合子的家族性 ligand-defective 脂蛋白元 B- 100（APOB-100，脂蛋白元 B-100 無法與低密度脂蛋白接受器結合），（三）體染色體隱性高膽固醇血症（ARH，低密度脂蛋白接受器活性異常），（四） Sitosterolemia （ABCG5 和 ABCG8基因突變所致的肝細胞內膽固醇的合成及清除失調，尤其是植物油方面的麥胚脂醇）。如下表所示：

 

Disease	Mutant Gene	Molecular Mechanism	Approximate Plasma Cholesterol Level (mg/dl)
Familial hypercholesterolemia	LDLR	Nonfunctional receptor fails to take up plasma cholesterol
Homozygous			300
Heterozygous			650

Familial ligand-defective apo B-100	APOB-100	Apolipoprotein B-100 fails to bind LDL receptor
Homozygous			275
Heterozygous			325
Autosomal recessive hypercholesterolemia	ARH	LDL-receptor activity is disrupted	450
Sitosterolemia	ABCG5 and ABCG8	Transcription factors (liver X receptor and sterol regulatory element binding protein) that regulate liver cholesterol synthesis and clearance are suppressed	150-650

 

心肌症

有些心肌症就目前所知，與基因變異的關係不大，下表列出非基因因素所導致的心肌症：

Cardiovascular conditions Atherosclerotic coronary artery disease Kawasaki disease

Hypertension Dysrhythmia Congenital heart defect

Chronic alteration of circulatory volume Cardiac transplantation

Major cardiac surgery or invasive cardiothoracic procedure within 1 month Obesity

Pulmonary parenchymal or vascular disease Pregnancy or the 3-month postpartum period Infection

Toxin or drug Radiation Immunologic disease

Connective tissue disease

Endocrine disease, including disease in an infant of a diabetic mother Nutritional deficiency

Granulomatous disease Malignancy

（表中有些疾病與基因可能有某種程度的關係，但主要還是非基因因素引起的）心肌症的病理發現如下表：

Glycogenosis

Free glycogen: types III, IX

Both free and intralysosomal glycogen: type II Pompe disease Amylopectin: type IV, polysaccharidosis

Glycoproteins Fucosidosis, type I Mannosidosis Sphingolipidosis Fabry disease

Mucopolysaccharidosis (type I, II, III, IV, VI) GM1 and GM2 gangliosidosis

Gaucher disease Oxalosis

Nemaline myopathy

Masses of intermediate filaments (desmin) Sarcoplasmic neutral fat

Systemic carnitine deficiency

Long-chain acyl-CoA dehydrogenase deficiency Very-long-chain acyl-CoA dehydrogenase deficiency Carnitine palmitoyl transferase type II deficiency

Multiple acyl-CoA dehydrogenase deficiency (glutaric acidemia type II) Barth syndrome

Sengers syndrome Refsum disease

Abnormal mitochondria (structural and/or numerical) Mitochondrial respiratory chain defects

Complex IV deficiency Leigh disease Friedreich ataxia Kearns-Sayre syndrome MELAS syndrome MERRF syndrome

Barth syndrome Sengers syndrome

Infantile histiocytoid "oncocytic" CM Left ventricular noncompaction Systemic carnitine deficiency

Nonspecific changes Endocardial fibroelastosis

Nuclear enlargement, hyperchromatism, and polymorphism Hypertrophy

Beckwith-Wiedemann syndrome Interstitial fibrosis

Mild mitochondrial changes in number and morphology

Alterations in sarcomere organization, myofilament loss, accumulation of residual bodies Iron deposition

Primary hemochromatosis Neonatal hemochromatosis Secondary hemochromatosis*

Inflammation with or without myocyte necrosis* Infective

Viral Rickettsial

Bacterial (Lyme disease)

Protozoal (Chagas disease, toxoplasmosis) Fungal

Parasitic

Granulomatous (sarcoid)

Giant cell myocarditis (idiopathic) Toxic

Allergic/immunologic Hypereosinophilic syndrome Systemic lupus erythematosus Dermatomyositis

Myocyte damage without inflammation* Ischemia (coagulable and coalescent)

Toxic

Single cytolysis Anthracycline Cyclophosphamide Radiation Catecholamines

Chloroquine (Zebra bodies by EM)

Nutritional deficiencies (beriberi, selenium deficiency) Adipose tissue replacement*

Obesity

Steroids

Parchment right ventricle and arrhythmogenic right ventricular CM

而與基因異常有關的心肌症主要分為四類：

1. 先天代謝異常

2. 症候群

3. 神經肌肉疾病

4. 家族遺傳性心肌症

其中佔最多數的第一類，還可分為浸潤性（佇積性）疾病，能量代謝疾病和產生可疑性心肌毒性代謝物等疾病。下表列出可能引起心肌症的各種先天代謝異常：

Disorders of glycogen metabolism

Glycogen storage disease type III (Cori disease: debranching enzyme deficiency)(H) Glycogen storage disease type IV (Andersen disease: branching enzyme deficiency)(D) Glycogen storage disease type IX (cardiac phosphorylase kinase deficiency) (H) Glycogen storage disease with normal acid maltase (H)

Disorders of mucopolysaccharide degradation Mucopolysaccharidosis type I (Hurler syndrome) (H, D) Mucopolysaccharidosis type II (Hunter syndrome) (H) Mucopolysaccharidosis type III (Sanfilippo syndrome) (H) Mucopolysaccharidosis type IV (Morquio syndrome) (H) Mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome) (D) Mucopolysaccharidosis type VII (Sly syndrome) (H)

Disorder of glycosphingolipid degradation (Fabry disease) (H) Disorder of glucosylceramide degradation (Gaucher disease) (H) Disorder of phytanic acid oxidation (Refsum disease) (D, H)

Disorders of combined ganglioside/mucopolysaccharide and oligosaccharide Degradation GM1 gangliosidosis (H, D)

GM2 gangliosidosis (Sandhoff disease) (H, D) Disorder of glycoprotein metabolism

Carbohydrate-deficient glycoprotein syndrome (neonatal olivopontocerebellar syndrome) Disorder of oxalic acid metabolism (oxalosis)

Diminished energy production Diminished energy production

Pyruvate dehydrogenase complex deficiency (Leigh disease) (H) Disorders of oxidative phosphorylation

Complex I deficiency (D) Complex II deficiency

Complex III deficiency (histiocytoid CM) (H)

Complex IV deficiency (muscle and Leigh disease forms) (H) Complex V deficiency (H)

Combined respiratory chain deficiencies Mitochondrial transfer RNA mutations MELAS syndrome (H)

MERRF syndrome (H, D)

Mitochondrial DNA deletions and duplications Kearns-Sayre syndrome (H)

Barth syndrome (3-methylglutaconic aciduria type II) (H, D) Sengers syndrome (H)

Disorders of fatty acid metabolism§

Primary or systemic carnitine deficiency (carnitine uptake deficiency) (H, D) Muscle carnitine deficiency (H, D)

Carnitine palmitoyl transferase type II deficiency Carnitine acylcarnitine translocase deficiency

Very-long-chain acyl-CoA dehydrogenase deficiency (H) Long-chain acyl-CoA dehydrogenase deficiency (H)

Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (D, H) Short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency

Multiple acyl-CoA dehydrogenase deficiency (glutaric acidemia type II) (H) Toxic intermediary metabolites

Disorders of amino acid or organic acid metabolism Propionic acidemia (D)

Methylmalonic acidemia Malonic acidemia

s-Ketothiolase deficiency (D) Mevalonic acidemia Tyrosinemia (H)

（H：肥厚性心肌症， D：擴張性心肌症，MELAS：Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes; MERRF, Myoclonic Epilepsy, Ragged Red Fibers）

至於和症候群有關的心肌症則如下表：

Single gene or gene pair defect (Mendelian disorder) Autosomal dominant inheritance

Noonan syndrome (H)

Cardio-facio-cutaneous syndrome (H)

LEOPARD syndrome/lentiginosis/multiple lentigines (H) Neurofibromatosis (H)

Beckwith-Wiedemann syndrome (H) Telecanthus, multiple congenital anomalies (H) Deaf-mutism (H)

Rubinstein-Taybi syndrome (H)

Autosomal recessive inheritance

Hypogonadism, multiple congenital anomalies, mental retardation (D) Microcephaly, mental retardation (D)

Palmoplantar keratosis (D)

Total lipodystrophy, insulin resistance, leprechaunism (H) Costello syndrome (H)

Macrosomia, postnatal growth and mental retardation, Costello-like features Mental retardation, unusual facies, arthritis, deafness

Facio-cardio-renal syndrome

Genitourinary anomalies, mental retardation Alstrom syndrome (D)

Marden-Walker syndrome Short-limbed dwarfism Leber congenital amaurosis

X-linked recessive inheritance

Cutis laxa, skeletal abnormalities (H) Microphthalmos, linear skin defects (H, D) Simpson-Golabi-Behmel-Rosen syndrome Mental retardation, precocious puberty, obesity Chromosome defect

Deletion 2q23 (A.E.L. and R.V.L., unpublished data, 1993) Deletion 10q25 mosaicism (A.E.L., unpublished data, 1988) Deletion 11p15 with aniridia, catalase deficiency Duplication 9p22 (A.E.L., unpublished data, 1993) Unknown genesis syndrome

Ectodermal dysplasia, hypothyroidism, agenesis corpus callosum, mental retardation Mental retardation, multiple congenital anomalies, neurological dysfunction, cataracts, arthropathy

Absent ulna and radius Hidrotic ectodermal dysplasia Hypogonadism, collagenomas

Mental retardation, craniosynostosis, multiple congenital anomalies Proteus syndrome

神經肌肉疾病主要是在 lower motor unit，侵犯周邊神經或骨骼肌，以肌肉無力來表現。這群疾病包括 muscular dystrophies ，先天性肌肉病症，代謝性肌肉病症和運動失調（ataxias）。與心肌症有關的神經肌肉疾病包括：

Muscular dystrophies DMD (D)

BMD (D)

Autosomal recessive muscular dystrophy (D) Myotonic dystrophy (H, D)

Emery-Dreifuss muscular dystrophy (D) Limb-girdle muscular dystrophy (D) Congenital muscular dystrophy Congenital myopathies

Centronuclear (myotubular) myopathy (D) Nemaline rod myopathy (D, H)

Minicore-multicore myopathy (D, H, R) Metabolic myopathies*

Ataxias

Friedreich ataxia (H) Refsum disease

 

家族遺傳性心肌症（單純的心肌症）包括所有的三種血循異常，亦即：肥厚性，擴張性和限制性，也可能和各種遺傳形式有關。列表如下：

Autosomal dominant inheritance Familial hypertrophic CM

Defect in cardiac myosin s heavy chain (linkage to chromosome 14q11-q12) Defect in cardiac troponin T (linkage to chromosome 1q3)

Defect in tropomyosin (linkage to chromosome 15q2)

Defect in cardiac myosin binding protein-C (linkage to chromosome 11p11.2) Linkage to chromosome 7q3 with Wolff-Parkinson-White syndrome

Familial CM with multiple mitochondrial DNA deletions (D) Familial dilated CM linked to chromosome 1p

Familial restrictive CM

Parchment right ventricle and arrhythmogenic right ventricle Noncompaction of the left ventricle

X-linked inheritance

Dilated CM (defect in dystrophin) Autosomal recessive inheritance*

Cardiac phosphorylase kinase deficiency (H)23,24 Familial dilated CM

Familial hypertrophic CM

Maternal (mitochondrial) inheritance C3303T tRNA Leu51

T9997C tRNA Gly52

Sporadic

Any of the above

除了少數疾病如 Pompe 氏病在心電圖上有短的 PR 和大的 QRS 等特徵外，心肌症在臨床心臟檢查上很少有特殊發現。因此，必須要做其他的理學檢查或檢驗才能獲得診斷。例如先天代謝異常可能合併有多重器官功能失調。症候群病人合併心肌症的並不多，Noonan 症候群是其中最為人熟知的一種。其他的情形以下表列出：

 

Organ System	Feature	Syndrome
Growth	Short stature	Noonan syndrome
		Multiple lentigines
		Mucopolysaccharidoses
	Macrosomia/overgrowth	Beckwith-Wiedemann syndrome
		Costello syndrome
Skeleton	Joint laxity	Cutis laxa, skeletal anomalies syndrome
	Pectus	Noonan syndrome
	Kyphoscoliosis	Mucopolysaccharidoses
Skin/hair	Wiry hair	Cardio-facio-cutaneous syndrome
	Palmar keratosis	Cardio-facio-cutaneous syndrome
		Palmoplantar keratosis
	Lentigines	Multiple lentigines
	Cafe au lait spots	Neurofibromatosis, type 1
		Noonan syndrome
	Neurofibromas	Neurofibromatosis, type 1
	Cutis laxa/loose skin	Costello syndrome
	Deep plantar furrows	Costello syndrome
	Linear skin defects	Microphthalmos with linear skin defects
	Lipodystrophy	Lipodystrophy, insulin resistance, leprechaunism
Facies	Distinctive	Noonan syndrome
		Cardio-facio-cutaneous

		syndrome
	Coarse	Mucopolysaccharidoses
		Pompe disease Inborn error of metabolism