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Bradycardia

MedGen UID:
140901
Concept ID:
C0428977
Finding
Synonyms: Bradyarrhythmia; Bradyarrhythmias; Bradycardias
SNOMED CT: Heart rate slow (48867003); Bradycardia (48867003); Slow heart beat (48867003); Decreased heart rate (48867003)
 
HPO: HP:0001662

Definition

A slower than normal heart rate (in adults, slower than 60 beats per minute). [from HPO]

Conditions with this feature

Glycogen storage disease, type IV
MedGen UID:
6642
Concept ID:
C0017923
Disease or Syndrome
The clinical manifestations of glycogen storage disease type IV (GSD IV) discussed in this entry span a continuum of different subtypes with variable ages of onset, severity, and clinical features. Clinical findings vary extensively both within and between families. The fatal perinatal neuromuscular subtype presents in utero with fetal akinesia deformation sequence, including decreased fetal movements, polyhydramnios, and fetal hydrops. Death usually occurs in the neonatal period. The congenital neuromuscular subtype presents in the newborn period with profound hypotonia, respiratory distress, and dilated cardiomyopathy. Death usually occurs in early infancy. Infants with the classic (progressive) hepatic subtype may appear normal at birth, but rapidly develop failure to thrive; hepatomegaly, liver dysfunction, and progressive liver cirrhosis; hypotonia; and cardiomyopathy. Without liver transplantation, death from liver failure usually occurs by age five years. Children with the non-progressive hepatic subtype tend to present with hepatomegaly, liver dysfunction, myopathy, and hypotonia; however, they are likely to survive without progression of the liver disease and may not show cardiac, skeletal muscle, or neurologic involvement. The childhood neuromuscular subtype is rare and the course is variable, ranging from onset in the second decade with a mild disease course to a more severe, progressive course resulting in death in the third decade.
D-Glyceric aciduria
MedGen UID:
452447
Concept ID:
C0342765
Disease or Syndrome
D-glyceric aciduria is a rare autosomal recessive metabolic disorder with a highly variable phenotype. Some patients have an encephalopathic presentation, with severe mental retardation, seizures, microcephaly, and sometimes early death, whereas others have a mild phenotype with only mild speech delay or even normal development (summary by Sass et al., 2010).
Carnitine acylcarnitine translocase deficiency
MedGen UID:
91000
Concept ID:
C0342791
Disease or Syndrome
Carnitine-acylcarnitine translocase (CACT) is a critical component of the carnitine shuttle, which facilitates the transfer of long-chain fatty acylcarnitines across the inner mitochondrial membrane. CACT deficiency causes a defect in mitochondrial long-chain fatty acid ß-oxidation, with variable clinical severity. Severe neonatal-onset disease is most common, with symptoms evident within two days after birth; attenuated cases may present in the first months of life. Hyperammonemia and cardiac arrhythmia are prominent in early-onset disease, with high rates of cardiac arrest. Other clinical features are typical for disorders of long-chain fatty acid oxidation: poor feeding, lethargy, hypoketotic hypoglycemia, hypotonia, transaminitis, liver dysfunction with hepatomegaly, and rhabdomyolysis. Univentricular or biventricular hypertrophic cardiomyopathy, ranging from mild to severe, may respond to appropriate dietary and medical therapies. Hyperammonemia is difficult to treat and is an important determinant of long-term neurocognitive outcome. Affected individuals with early-onset disease typically experience brain injury at presentation, and have recurrent hyperammonemia leading to developmental delay / intellectual disability. Affected individuals with later-onset disease have milder symptoms and are less likely to experience recurrent hyperammonemia, allowing a better developmental outcome. Prompt treatment of the presenting episode to prevent hypoglycemic, hypoxic, or hyperammonemic brain injury may allow normal growth and development.
Desmin-related myofibrillar myopathy
MedGen UID:
330449
Concept ID:
C1832370
Disease or Syndrome
Myofibrillar myopathy (MFM) is a noncommittal term that refers to a group of morphologically homogeneous, but genetically heterogeneous chronic neuromuscular disorders. The morphologic changes in skeletal muscle in MFM result from disintegration of the sarcomeric Z disc and the myofibrils, followed by abnormal ectopic accumulation of multiple proteins involved in the structure of the Z disc, including desmin, alpha-B-crystallin (CRYAB; 123590), dystrophin (300377), and myotilin (TTID; 604103). Genetic Heterogeneity of Myofibrillar Myopathy Other forms of MFM include MFM2 (608810), caused by mutation in the CRYAB gene (123590); MFM3 (609200), caused by mutation in the MYOT gene (604103); MFM4 (609452), caused by mutation in the ZASP gene (LDB3; 605906); MFM5 (609524), caused by mutation in the FLNC gene (102565); MFM6 (612954), caused by mutation in the BAG3 gene (603883); MFM7 (617114), caused by mutation in the KY gene (605739); MFM8 (617258), caused by mutation in the PYROXD1 gene (617220); MFM9 (603689), caused by mutation in the TTN gene (188840); MFM10 (619040), caused by mutation in the SVIL UNC45B gene (611220); MFM11 (619178), caused by mutation in the UNC45B gene (611220); and MFM12 (619424), caused by mutation in the MYL2 gene (160781). 'Desmin-related myopathy' is another term referring to MFM in which there are intrasarcoplasmic aggregates of desmin, usually in addition to other sarcomeric proteins. Rigid spine syndrome (602771), caused by mutation in the SEPN1 gene (606210), is another desmin-related myopathy. Goebel (1995) provided a review of desmin-related myopathy.
Timothy syndrome
MedGen UID:
331395
Concept ID:
C1832916
Disease or Syndrome
The first identified CACNA1C-related disorder, referred to as Timothy syndrome, consists of the combination of prolonged QT interval, autism, and cardiovascular malformation with syndactyly of the fingers and toes. Infrequent findings also include developmental and speech delay, seizures, and recurrent infections. With increased availability of molecular genetic testing, a wider spectrum of pathogenic variants and clinical findings associated with CACNA1C-related disorders has been recognized. Because CACNA1C is associated with calcium channel function, all individuals with a pathogenic variant in this gene are at risk for cardiac arrhythmia of a specific type. The clinical manifestations of a CACNA1C-related disorder include three phenotypes: Timothy syndrome with or without syndactyly. QT prolongation (QTc >480 ms) and arrhythmias in the absence of other syndromic features. Short QT syndrome (QTc <350 ms) or Brugada syndrome with short QT interval. These three phenotypes can be separated into two broad categories on the basis of the functional consequences of the pathogenic variants in CACNA1C: QT prolongation with or without a Timothy syndrome-associated phenotype associated with pathogenic variants inducing a gain of function at the cellular level (i.e., increased calcium current). Short QT interval with or without Brugada syndrome EKG pattern associated with pathogenic variants causing loss of function (i.e., reduced calcium current).
Paroxysmal extreme pain disorder
MedGen UID:
331565
Concept ID:
C1833661
Disease or Syndrome
SCN9A neuropathic pain syndromes (SCN9A-NPS) comprise SCN9A erythromelalgia (EM), SCN9A paroxysmal extreme pain disorder (PEPD), and SCN9A small fiber neuropathy (SFN). SCN9A-EM is characterized by recurrent episodes of bilateral intense, burning pain, and redness, warmth, and occasionally swelling. While the feet are more commonly affected than the hands, in severely affected individuals the legs, arms, face, and/or ears may be involved. SCN9A-PEPD is characterized by neonatal or infantile onset of autonomic manifestations that can include skin flushing, harlequin (patchy or asymmetric) color change, tonic non-epileptic attacks (stiffening), and syncope with bradycardia. Later manifestations are episodes of excruciating deep burning rectal, ocular, or submandibular pain accompanied by flushing (erythematous skin changes). SCN9A-SFN is characterized by adult-onset neuropathic pain in a stocking and glove distribution, often with a burning quality; autonomic manifestations such as dry eyes, mouth, orthostatic dizziness, palpitations, bowel or bladder disturbances; and preservation of large nerve fiber functions (normal strength, tendon reflexes, and vibration sense).
DK1-congenital disorder of glycosylation
MedGen UID:
332072
Concept ID:
C1835849
Disease or Syndrome
DOLK-congenital disorder of glycosylation (DOLK-CDG, formerly known as congenital disorder of glycosylation type Im) is an inherited condition that often affects the heart but can also involve other body systems. The pattern and severity of this disorder's signs and symptoms vary among affected individuals.\n\nIndividuals with DOLK-CDG typically develop signs and symptoms of the condition during infancy or early childhood. Nearly all individuals with DOLK-CDG develop a weakened and enlarged heart (dilated cardiomyopathy). Other frequent signs and symptoms include recurrent seizures; developmental delay; poor muscle tone (hypotonia); and dry, scaly skin (ichthyosis). Less commonly, affected individuals can have distinctive facial features, kidney disease, hormonal abnormalities, or eye problems.\n\nIndividuals with DOLK-CDG typically do not survive into adulthood, often because of complications related to dilated cardiomyopathy, and some do not survive past infancy.
Aminoacylase 1 deficiency
MedGen UID:
324393
Concept ID:
C1835922
Disease or Syndrome
Aminoacylase-1 deficiency (ACY1D) is a rare autosomal recessive inborn error of metabolism characterized by increased urinary excretion of specific N-actyl amino acids. Most patients show neurologic abnormalities such as intellectual disability, seizures, hypotonia, and motor delay (summary by Ferri et al., 2014).
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3
MedGen UID:
373087
Concept ID:
C1836439
Disease or Syndrome
Progressive external ophthalmoplegia is characterized by multiple mitochondrial DNA deletions in skeletal muscle. The most common clinical features include adult onset of weakness of the external eye muscles and exercise intolerance. Patients with C10ORF2-linked adPEO may have other clinical features including proximal muscle weakness, ataxia, peripheral neuropathy, cardiomyopathy, cataracts, depression, and endocrine abnormalities (summary by Fratter et al., 2010). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant progressive external ophthalmoplegia, see PEOA1 (157640). PEO caused by mutations in the POLG gene (174763) are associated with more complicated phenotypes than those forms caused by mutations in the SLC25A4 (103220) or C10ORF2 genes (Lamantea et al., 2002).
Sudden infant death-dysgenesis of the testes syndrome
MedGen UID:
332428
Concept ID:
C1837371
Disease or Syndrome
Sudden infant death with dysgenesis of the testes syndrome (SIDDT) is characterized by sudden cardiac or respiratory arrest, disordered testicular development, and neurologic dysfunction, and is uniformly fatal before 1 year of age (Slater et al., 2020).
Cobalamin C disease
MedGen UID:
341256
Concept ID:
C1848561
Disease or Syndrome
Disorders of intracellular cobalamin metabolism have a variable phenotype and age of onset that are influenced by the severity and location within the pathway of the defect. The prototype and best understood phenotype is cblC; it is also the most common of these disorders. The age of initial presentation of cblC spans a wide range: In utero with fetal presentation of nonimmune hydrops, cardiomyopathy, and intrauterine growth restriction. Newborns, who can have microcephaly, poor feeding, and encephalopathy. Infants, who can have poor feeding and slow growth, neurologic abnormality, and, rarely, hemolytic uremic syndrome (HUS). Toddlers, who can have poor growth, progressive microcephaly, cytopenias (including megaloblastic anemia), global developmental delay, encephalopathy, and neurologic signs such as hypotonia and seizures. Adolescents and adults, who can have neuropsychiatric symptoms, progressive cognitive decline, thromboembolic complications, and/or subacute combined degeneration of the spinal cord.
Lethal congenital glycogen storage disease of heart
MedGen UID:
337919
Concept ID:
C1849813
Disease or Syndrome
A rare glycogen storage disease with fetal or neonatal onset of severe cardiomyopathy with non-lysosomal glycogen accumulation and fatal outcome in infancy. Patients present with massive cardiomegaly, severe cardiac and respiratory complications and failure to thrive. Non-specific facial dysmorphism, bilateral cataracts, macroglossia, hydrocephalus, enlarged kidneys and skeletal muscle involvement have been reported in some cases.
Arthrogryposis multiplex congenita-whistling face syndrome
MedGen UID:
349231
Concept ID:
C1859711
Disease or Syndrome
An extremely rare type of arthrogryposis multiplex congenita with the combination of multiple joint contractures with movement limitation and microstomia with a whistling appearance of the mouth that may cause feeding, swallowing and speech difficulties, a distinctive expressionless facies, severe developmental delay, central and autonomous nervous system dysfunction, occasionally Pierre-Robin sequence and lethality generally occurring during the first months of life.
Congenital brain dysgenesis due to glutamine synthetase deficiency
MedGen UID:
400638
Concept ID:
C1864910
Disease or Syndrome
Congenital glutamine deficiency is a severe autosomal recessive disorder characterized by onset at birth of encephalopathy, lack of normal development, seizures, and hypotonia associated with variable brain abnormalities (summary by Haberle et al., 2011).
Short QT syndrome type 2
MedGen UID:
355890
Concept ID:
C1865019
Disease or Syndrome
Short QT syndrome is a cardiac channelopathy associated with a predisposition to atrial fibrillation and sudden cardiac death. Patients have a structurally normal heart, but electrocardiography (ECG) exhibits abbreviated QTc (Bazett's corrected QT) intervals of less than 360 ms (summary by Moreno et al., 2015). For a discussion of genetic heterogeneity of short QT syndrome, see SQT1 (609620).
Hypothyroidism, congenital, nongoitrous, 2
MedGen UID:
358389
Concept ID:
C1869118
Congenital Abnormality
Signs and symptoms of congenital hypothyroidism result from the shortage of thyroid hormones. Affected babies may show no features of the condition, although some babies with congenital hypothyroidism are less active and sleep more than normal. They may have difficulty feeding and experience constipation. If untreated, congenital hypothyroidism can lead to intellectual disability and slow growth. In the United States and many other countries, all hospitals test newborns for congenital hypothyroidism. If treatment begins in the first two weeks after birth, infants usually develop normally.\n\nCongenital hypothyroidism can also occur as part of syndromes that affect other organs and tissues in the body. These forms of the condition are described as syndromic. Some common forms of syndromic hypothyroidism include Pendred syndrome, Bamforth-Lazarus syndrome, and brain-lung-thyroid syndrome.\n\nCongenital hypothyroidism occurs when the thyroid gland fails to develop or function properly. In 80 to 85 percent of cases, the thyroid gland is absent, severely reduced in size (hypoplastic), or abnormally located. These cases are classified as thyroid dysgenesis. In the remainder of cases, a normal-sized or enlarged thyroid gland (goiter) is present, but production of thyroid hormones is decreased or absent. Most of these cases occur when one of several steps in the hormone synthesis process is impaired; these cases are classified as thyroid dyshormonogenesis. Less commonly, reduction or absence of thyroid hormone production is caused by impaired stimulation of the production process (which is normally done by a structure at the base of the brain called the pituitary gland), even though the process itself is unimpaired. These cases are classified as central (or pituitary) hypothyroidism.\n\nCongenital hypothyroidism is a partial or complete loss of function of the thyroid gland (hypothyroidism) that affects infants from birth (congenital). The thyroid gland is a butterfly-shaped tissue in the lower neck. It makes iodine-containing hormones that play an important role in regulating growth, brain development, and the rate of chemical reactions in the body (metabolism). People with congenital hypothyroidism have lower-than-normal levels of these important hormones.
Progressive familial heart block type IB
MedGen UID:
370220
Concept ID:
C1970298
Disease or Syndrome
Progressive familial heart block can be divided into type I and type II, with type I being further divided into types IA and IB. These types differ in where in the heart signaling is interrupted and the genetic cause. In types IA and IB, the heart block originates in the bundle branch, and in type II, the heart block originates in the atrioventricular node. The different types of progressive familial heart block have similar signs and symptoms.\n\nMost cases of heart block are not genetic and are not considered progressive familial heart block. The most common cause of heart block is fibrosis of the heart, which occurs as a normal process of aging. Other causes of heart block can include the use of certain medications or an infection of the heart tissue.\n\nHeart block occurs when the electrical signaling is obstructed anywhere from the atria to the ventricles. In people with progressive familial heart block, the condition worsens over time: early in the disorder, the electrical signals are partially blocked, but the block eventually becomes complete, preventing any signals from passing through the heart. Partial heart block causes a slow or irregular heartbeat (bradycardia or arrhythmia, respectively), and can lead to the buildup of scar tissue (fibrosis) in the cells that carry electrical impulses. Fibrosis contributes to the development of complete heart block, resulting in uncoordinated electrical signaling between the atria and the ventricles and inefficient pumping of blood in the heart. Complete heart block can cause a sensation of fluttering or pounding in the chest (palpitations), shortness of breath, fainting (syncope), or sudden cardiac arrest and death.\n\nProgressive familial heart block is a genetic condition that alters the normal beating of the heart. A normal heartbeat is controlled by electrical signals that move through the heart in a highly coordinated way. These signals begin in a specialized cluster of cells called the sinoatrial node (the heart's natural pacemaker) located in the heart's upper chambers (the atria). From there, a group of cells called the atrioventricular node carries the electrical signals to another cluster of cells called the bundle of His. This bundle separates into multiple thin spindles called bundle branches, which carry electrical signals into the heart's lower chambers (the ventricles). Electrical impulses move from the sinoatrial node down to the bundle branches, stimulating a normal heartbeat in which the ventricles contract slightly later than the atria.
Catecholaminergic polymorphic ventricular tachycardia 2
MedGen UID:
393837
Concept ID:
C2677794
Disease or Syndrome
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is characterized by episodic syncope occurring during exercise or acute emotion. The underlying cause of these episodes is the onset of fast ventricular tachycardia (bidirectional or polymorphic). Spontaneous recovery may occur when these arrhythmias self-terminate. In other instances, ventricular tachycardia may degenerate into ventricular fibrillation and cause sudden death if cardiopulmonary resuscitation is not readily available. The mean onset of symptoms (usually a syncopal episode) is between age seven and 12 years; onset as late as the fourth decade of life has been reported. If untreated, CPVT is highly lethal, as approximately 30% of affected individuals experience at least one cardiac arrest and up to 80% have one or more syncopal spells. Sudden death may be the first manifestation of the disease.
Congenital generalized lipodystrophy type 4
MedGen UID:
412871
Concept ID:
C2750069
Disease or Syndrome
Congenital generalized lipodystrophy type 4 (CGL4) combines the phenotype of classic Berardinelli-Seip lipodystrophy (608594) with muscular dystrophy and cardiac conduction anomalies (Hayashi et al., 2009). For a general description and a discussion of genetic heterogeneity of congenital generalized lipodystrophy, see CGL1 (608594).
Atrial septal defect 6
MedGen UID:
414348
Concept ID:
C2751315
Congenital Abnormality
Any atrial heart septal defect in which the cause of the disease is a mutation in the TLL1 gene.
Atrial fibrillation, familial, 10
MedGen UID:
462814
Concept ID:
C3151464
Disease or Syndrome
Atrial fibrillation is the most common sustained cardiac rhythm disturbance, affecting more than 2 million Americans, with an overall prevalence of 0.89%. The prevalence increases rapidly with age, to 2.3% between the ages of 40 and 60 years, and to 5.9% over the age of 65. The most dreaded complication is thromboembolic stroke (Brugada et al., 1997). For a discussion of genetic heterogeneity of atrial fibrillation, see 608583.
Microcephaly-cerebellar hypoplasia-cardiac conduction defect syndrome
MedGen UID:
482322
Concept ID:
C3280692
Disease or Syndrome
The Zaki-Gleeson syndrome is an autosomal recessive neurodevelopmental disorder characterized by profound mental retardation, severe microcephaly, poor growth, cerebellar hypoplasia, and second-degree cardiac conduction defects (Zaki et al., 2011).
Cutis laxa, autosomal recessive, type 1B
MedGen UID:
482428
Concept ID:
C3280798
Disease or Syndrome
EFEMP2-related cutis laxa, or autosomal recessive cutis laxa type 1B (ARCL1B), is characterized by cutis laxa and systemic involvement, most commonly arterial tortuosity, aneurysms, and stenosis; retrognathia; joint laxity; and arachnodactyly. Severity ranges from perinatal lethality as a result of cardiopulmonary failure to manifestations limited to the vascular and craniofacial systems.
Neonatal-onset encephalopathy with rigidity and seizures
MedGen UID:
482659
Concept ID:
C3281029
Disease or Syndrome
Lethal neonatal rigidity and multifocal seizure syndrome (RMFSL) is a severe autosomal recessive epileptic encephalopathy characterized by onset of rigidity and intractable seizures at or soon after birth. Affected infants achieve no developmental milestones and die within the first months or years of life (summary by Saitsu et al., 2014).
Hereditary sensory and autonomic neuropathy type 6
MedGen UID:
761278
Concept ID:
C3539003
Disease or Syndrome
Hereditary sensory and autonomic neuropathy type VI (HSAN6) is a severe autosomal recessive disorder characterized by neonatal hypotonia, respiratory and feeding difficulties, lack of psychomotor development, and autonomic abnormalities including labile cardiovascular function, lack of corneal reflexes leading to corneal scarring, areflexia, and absent axonal flare response after intradermal histamine injection (summary by Edvardson et al., 2012). For a discussion of genetic heterogeneity of hereditary sensory and autonomic neuropathy, see HSAN1 (162400).
Emery-Dreifuss muscular dystrophy 7, autosomal dominant
MedGen UID:
765974
Concept ID:
C3553060
Disease or Syndrome
Emery-Dreifuss muscular dystrophy is a genetically heterogeneous muscular disease that presents with muscular dystrophy, joint contractures, and cardiomyopathy with conduction defects (summary by Liang et al., 2011). For a discussion of genetic heterogeneity of EDMD, see 310300.
Encephalopathy-hypertrophic cardiomyopathy-renal tubular disease syndrome
MedGen UID:
766288
Concept ID:
C3553374
Disease or Syndrome
Primary coenzyme Q10 (CoQ10) deficiency is usually associated with multisystem involvement, including neurologic manifestations such as fatal neonatal encephalopathy with hypotonia; a late-onset slowly progressive multiple-system atrophy-like phenotype (neurodegeneration with autonomic failure and various combinations of parkinsonism and cerebellar ataxia, and pyramidal dysfunction); and dystonia, spasticity, seizures, and intellectual disability. Steroid-resistant nephrotic syndrome (SRNS), the hallmark renal manifestation, is often the initial manifestation either as isolated renal involvement that progresses to end-stage renal disease (ESRD), or associated with encephalopathy (seizures, stroke-like episodes, severe neurologic impairment) resulting in early death. Hypertrophic cardiomyopathy (HCM), retinopathy or optic atrophy, and sensorineural hearing loss can also be seen.
Sinoatrial node dysfunction and deafness
MedGen UID:
766932
Concept ID:
C3554018
Disease or Syndrome
Patients with sinoatrial node dysfunction and deafness have congenital severe to profound deafness without vestibular dysfunction, associated with episodic syncope due to intermittent pronounced bradycardia (Baig et al., 2011). See Jervell and Lange-Nielsen syndrome (220400) for discussion of another deafness syndrome with impaired cardiac conduction.
Atrial standstill 2
MedGen UID:
816731
Concept ID:
C3810401
Disease or Syndrome
Atrial standstill (AS) is a rare condition characterized by the absence of electrical and mechanical activity in the atria. On surface ECG, AS is distinguished by bradycardia, junctional (usually narrow complex) escape rhythm, and absence of the P wave. Nearly 50% of patients with AS experience syncope. AS can be persistent or transient, and diffuse or partial (summary by Fazelifar et al., 2005).
Chronic atrial and intestinal dysrhythmia
MedGen UID:
863911
Concept ID:
C4015474
Disease or Syndrome
Syndrome with characteristics of sick sinus syndrome and intestinal pseudo-obstruction. The heart and digestive issues develop at the same time, usually by age 20. The syndrome is caused by mutations in the SGO1 gene. This gene provides instructions for making part of a protein complex cohesin. This protein complex helps control the placement of chromosomes during cell division. Research suggests that SGO1 gene mutations may result in a cohesin complex that is less able to hold sister chromatids together, resulting in decreased chromosomal stability during cell division. This instability is thought to cause senescence of cells in the intestinal muscle and in the sinoatrial node, resulting in problems maintaining proper rhythmic movements of the heart and intestines.
Long QT syndrome 15
MedGen UID:
864132
Concept ID:
C4015695
Disease or Syndrome
Long QT syndrome (LQTS) is a cardiac electrophysiologic disorder, characterized by QT prolongation and T-wave abnormalities on the EKG that are associated with tachyarrhythmias, typically the ventricular tachycardia torsade de pointes (TdP). TdP is usually self-terminating, thus causing a syncopal event, the most common symptom in individuals with LQTS. Such cardiac events typically occur during exercise and emotional stress, less frequently during sleep, and usually without warning. In some instances, TdP degenerates to ventricular fibrillation and causes aborted cardiac arrest (if the individual is defibrillated) or sudden death. Approximately 50% of untreated individuals with a pathogenic variant in one of the genes associated with LQTS have symptoms, usually one to a few syncopal events. While cardiac events may occur from infancy through middle age, they are most common from the preteen years through the 20s. Some types of LQTS are associated with a phenotype extending beyond cardiac arrhythmia. In addition to the prolonged QT interval, associations include muscle weakness and facial dysmorphism in Andersen-Tawil syndrome (LQTS type 7); hand/foot, facial, and neurodevelopmental features in Timothy syndrome (LQTS type 8); and profound sensorineural hearing loss in Jervell and Lange-Nielson syndrome.
Lipoyl transferase 1 deficiency
MedGen UID:
904073
Concept ID:
C4225379
Disease or Syndrome
Lipoyl transferase 1 deficiency is a very rare inborn error of metabolism disorder, with a highly variable phenotype, typically characterized by neonatal to infancy-onset of seizures, psychomotor delay, and abnormal muscle tone that may include hypo- and/or hypertonia, resulting in generalized weakness, dystonic movements, and/or progressive respiratory distress, associated with severe lactic acidosis and elevated lactate, ketoglutarate and 2-oxoacids in urine. Additional manifestations may include dehydration, vomiting, signs of liver dysfunction, extrapyramidal signs, spastic tetraparesis, brisk deep tendon reflexes, speech impairment, swallowing difficulties, and pulmonary hypertension.
Mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency
MedGen UID:
902729
Concept ID:
C4225391
Disease or Syndrome
Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (ECHS1D) represents a clinical spectrum in which several phenotypes have been described: The most common phenotype presents in the neonatal period with severe encephalopathy and lactic acidosis and later manifests Leigh-like signs and symptoms. Those with presentation in the neonatal period typically have severe hypotonia, encephalopathy, or neonatal seizures within the first few days of life. Signs and symptoms typically progress quickly and the affected individual ultimately succumbs to central apnea or arrhythmia. A second group of affected individuals present in infancy with developmental regression resulting in severe developmental delay. A third group of affected individuals have normal development with isolated paroxysmal dystonia that may be exacerbated by illness or exertion. Across all three groups, T2 hyperintensity in the basal ganglia is very common, and may affect any part of the basal ganglia.
Atrial fibrillation, familial, 18
MedGen UID:
934603
Concept ID:
C4310636
Disease or Syndrome
Familial atrial fibrillation is an inherited abnormality of the heart's normal rhythm. Atrial fibrillation is characterized by episodes of uncoordinated electrical activity (fibrillation) in the heart's upper chambers (the atria), which cause a fast and irregular heartbeat. If untreated, this abnormal heart rhythm (arrhythmia) can lead to dizziness, chest pain, a sensation of fluttering or pounding in the chest (palpitations), shortness of breath, or fainting (syncope). Atrial fibrillation also increases the risk of stroke and sudden death. Complications of atrial fibrillation can occur at any age, although some people with this heart condition never experience any health problems associated with the disorder.
3-methylglutaconic aciduria type 8
MedGen UID:
934617
Concept ID:
C4310650
Disease or Syndrome
MGCA8 is an autosomal recessive metabolic disorder resulting in death in infancy. Features include hypotonia, abnormal movements, respiratory insufficiency with apneic episodes, and lack of developmental progress, often with seizures. Brain imaging is variable, but may show progressive cerebral atrophy. Laboratory studies show increased serum lactate and 3-methylglutaconic aciduria, suggesting a mitochondrial defect (summary by Mandel et al., 2016). For a phenotypic description and a discussion of genetic heterogeneity of 3-methylglutaconic aciduria, see MGCA type I (250950).
Sudden cardiac failure, infantile
MedGen UID:
934631
Concept ID:
C4310664
Disease or Syndrome
Language delay and attention deficit-hyperactivity disorder/cognitive impairment with or without cardiac arrhythmia
MedGen UID:
934645
Concept ID:
C4310678
Disease or Syndrome
GNB5-related neurodevelopmental disorder (GNB5-NDD) is characterized by a spectrum of neurodevelopmental phenotypes that range from severe-to-profound intellectual disability (ID; 31/41 reported individuals), to mild-to-moderate ID (5/41), to normal intellect with severe language disorder (5/41, one extended family). A unique and specific feature of GNB5-NDD – regardless of neurodevelopmental phenotype – is nearly universal bradycardia caused by sinoatrial node dysfunction (sick sinus syndrome). Most individuals with severe and profound ID have a developmental and epileptic encephalopathy with focal seizures or epileptic spasms, as well as visual impairment (central or retinal) with nystagmus, difficulty feeding, and gastroesophageal reflux disease. The risk of early mortality is increased.
Pseudo-TORCH syndrome 2
MedGen UID:
1373355
Concept ID:
C4479376
Disease or Syndrome
Pseudo-TORCH syndrome-2 (PTORCH2) is an autosomal recessive multisystem disorder characterized by antenatal onset of intracranial hemorrhage, calcification, brain malformations, liver dysfunction, and often thrombocytopenia. Affected individuals tend to have respiratory insufficiency and seizures, and die in infancy. The phenotype resembles the sequelae of intrauterine infection, but there is no evidence of an infectious agent. The disorder results from inappropriate activation of the interferon (IFN) immunologic pathway (summary by Meuwissen et al., 2016). For a discussion of genetic heterogeneity of PTORCH, see PTORCH1 (251290).
Mitochondrial complex 1 deficiency, nuclear type 13
MedGen UID:
1648370
Concept ID:
C4748770
Disease or Syndrome
Mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency
MedGen UID:
1664257
Concept ID:
C4749921
Disease or Syndrome
Combined oxidative phosphorylation deficiency-10 (COXPD10) is an autosomal recessive disorder resulting in variable defects of mitochondrial oxidative respiration. Affected individuals present in infancy with hypertrophic cardiomyopathy and lactic acidosis. The severity is variable, but can be fatal in the most severe cases (summary by Ghezzi et al., 2012). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
Mitochondrial complex 3 deficiency, nuclear type 10
MedGen UID:
1719382
Concept ID:
C5394051
Disease or Syndrome
Long QT syndrome 16
MedGen UID:
1713991
Concept ID:
C5394068
Disease or Syndrome
LQT16 Long QT syndrome-16 (LQT16) is characterized by a markedly prolonged corrected QT (QTc) interval and 2:1 atrioventricular (AV) block, with onset in the perinatal period. Patients experience bradycardia or ventricular tachyarrhythmias that may result in syncope, cardiac arrest, and/or sudden death (Reed et al., 2015; Wren et al., 2019). Patients with LQT14 (616247), LQT15 (616249), or LQT16, resulting from mutation in calmodulin genes CALM1 (114180), CALM2 (114182), or CALM3, respectively, typically have a more severe phenotype, with earlier onset, profound QT prolongation, and a high predilection for cardiac arrest and sudden death, than patients with mutations in other genes (Boczek et al., 2016). CPVT6 Catecholaminergic polymorphic ventricular tachycardia-6 (CPVT6) is characterized by childhood-onset syncopal episodes with exercise or stress. Electrocardiogram (ECG) shows a normal QT interval with a prominent U wave, and stress testing reveals premature ventricular contractions (PVCs) that may occur as bigeminy or couplets, and nonsustained ventricular tachycardia (Gomez-Hurtado et al., 2016).
Chromosome 1p36.33 duplication syndrome, atad3 gene cluster, autosomal dominant
MedGen UID:
1708515
Concept ID:
C5394150
Disease or Syndrome
Autosomal dominant chromosome 1p36.33 duplication syndrome is a severe multisystemic disorder characterized by neonatal respiratory insufficiency, hypotonia, and cardiomyopathy, resulting in death in the first weeks of life. Affected infants may also have seizures, contractures, and corneal opacities. Brain imaging shows variable anomalies, such as white matter changes, and laboratory studies suggest that the phenotype results from metabolic defects in mitochondrial and cholesterol homeostasis (summary by Gunning et al., 2020).
Mitochondrial complex 4 deficiency, nuclear type 4
MedGen UID:
1748100
Concept ID:
C5436683
Disease or Syndrome
Mitochondrial complex IV deficiency nuclear type 4 (MC4DN4) is an autosomal recessive multisystem metabolic disorder characterized by the onset of symptoms in infancy. Affected individuals show hypotonia, failure to thrive, and neurologic distress. Additional features include hepatomegaly, hepatic steatosis, increased serum lactate, and metabolic acidosis. Some patients may develop hypertrophic cardiomyopathy. Patient tissues show decreased levels and activity of mitochondrial respiratory complex IV. Death usually occurs in infancy (summary by Valnot et al., 2000 and Stiburek et al., 2009). For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see 220110.
Mitochondrial complex 1 deficiency, nuclear type 37
MedGen UID:
1783339
Concept ID:
C5543281
Disease or Syndrome
Epilepsy, idiopathic generalized, susceptibility to, 18
MedGen UID:
1794193
Concept ID:
C5561983
Finding
Idiopathic generalized epilepsy is characterized by various types of seizures, including childhood and juvenile absence epilepsy, juvenile myoclonic epilepsy, and epilepsy with generalized tonic-clonic seizures upon awakening (EGTCA). EEG often shows spike-wave discharges. EIG18 is an autosomal dominant disorder manifest as myoclonic seizures in infancy. Although the seizures remit, some patients may have later speech or cognitive impairment (summary by Becker et al., 2017 and Campostrini et al., 2018). For a general phenotypic description and a discussion of genetic heterogeneity of idiopathic generalized epilepsy (IGE), see 600669.
Neonatal encephalomyopathy-cardiomyopathy-respiratory distress syndrome
MedGen UID:
1799985
Concept ID:
C5568562
Disease or Syndrome
Primary coenzyme Q10 (CoQ10) deficiency is usually associated with multisystem involvement, including neurologic manifestations such as fatal neonatal encephalopathy with hypotonia; a late-onset slowly progressive multiple-system atrophy-like phenotype (neurodegeneration with autonomic failure and various combinations of parkinsonism and cerebellar ataxia, and pyramidal dysfunction); and dystonia, spasticity, seizures, and intellectual disability. Steroid-resistant nephrotic syndrome (SRNS), the hallmark renal manifestation, is often the initial manifestation either as isolated renal involvement that progresses to end-stage renal disease (ESRD), or associated with encephalopathy (seizures, stroke-like episodes, severe neurologic impairment) resulting in early death. Hypertrophic cardiomyopathy (HCM), retinopathy or optic atrophy, and sensorineural hearing loss can also be seen.
Gnb5-related intellectual disability-cardiac arrhythmia syndrome
MedGen UID:
1800300
Concept ID:
C5568877
Disease or Syndrome
GNB5-related neurodevelopmental disorder (GNB5-NDD) is characterized by a spectrum of neurodevelopmental phenotypes that range from severe-to-profound intellectual disability (ID; 31/41 reported individuals), to mild-to-moderate ID (5/41), to normal intellect with severe language disorder (5/41, one extended family). A unique and specific feature of GNB5-NDD – regardless of neurodevelopmental phenotype – is nearly universal bradycardia caused by sinoatrial node dysfunction (sick sinus syndrome). Most individuals with severe and profound ID have a developmental and epileptic encephalopathy with focal seizures or epileptic spasms, as well as visual impairment (central or retinal) with nystagmus, difficulty feeding, and gastroesophageal reflux disease. The risk of early mortality is increased.
Developmental and epileptic encephalopathy 101
MedGen UID:
1805172
Concept ID:
C5676955
Disease or Syndrome
Developmental and epileptic encephalopathy-101 (DEE101) is a severe autosomal recessive disorder characterized by early infantile epileptic encephalopathy and severe global developmental delay (summary by Blakes et al., 2022). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
Congenital myopathy 2b, severe infantile, autosomal recessive
MedGen UID:
1840936
Concept ID:
C5830300
Disease or Syndrome
Autosomal recessive congenital myopathy-2B (CMYP2B) is a disorder of the skeletal muscle characterized by severe hypotonia with lack of spontaneous movements and respiratory insufficiency, usually leading to death in infancy or early childhood (Agrawal et al., 2004). However, longer survival has also been reported, likely due to the type of mutation and extent of its impact (O'Grady et al., 2015). Mutations in the ACTA1 gene can cause a range of skeletal muscle diseases. About 90% of patients with ACTA1 mutations carry heterozygous mutations, usually de novo (CMYP2A; 161800), whereas 10% of patients carry biallelic ACTA1 mutations (CMYP2B) (Nowak et al., 2007). For a discussion of genetic heterogeneity of congenital myopathy, see CMYP1A (117000).
Congenital myopathy 22A, classic
MedGen UID:
1841089
Concept ID:
C5830453
Disease or Syndrome
Classic congenital myopathy-22A (CMYP22A) is an autosomal recessive muscle disorder characterized by onset of muscle weakness in utero or soon after birth. Early features may include fetal hypokinesia, breech presentation, and polyhydramnios. Affected individuals are born with severe hypotonia and require respiratory and feeding assistance. Those who survive the neonatal period show a 'classic' phenotype of congenital myopathy with delayed motor development, difficulty walking, proximal muscle weakness of the upper and lower limbs, facial and neck muscle weakness, easy fatigability, and mild limb contractures or foot deformities. Some have persistent respiratory insufficiency; dysmorphic facial features may be present (Zaharieva et al., 2016). For a discussion of genetic heterogeneity of congenital myopathy, see CMYP1A (117000).

Professional guidelines

PubMed

McGinley MP, Goldschmidt CH, Rae-Grant AD
JAMA 2021 Feb 23;325(8):765-779. doi: 10.1001/jama.2020.26858. PMID: 33620411
Wung SF
Crit Care Nurs Clin North Am 2016 Sep;28(3):297-308. Epub 2016 Jun 22 doi: 10.1016/j.cnc.2016.04.003. PMID: 27484658
Baruteau AE, Perry JC, Sanatani S, Horie M, Dubin AM
Eur J Pediatr 2016 Feb;175(2):151-61. Epub 2016 Jan 16 doi: 10.1007/s00431-015-2689-z. PMID: 26780751

Recent clinical studies

Etiology

Çinier G, Haseeb S, Bazoukis G, Yeung C, Gül EE
Curr Cardiol Rev 2021;17(1):60-67. doi: 10.2174/1573403X16666200721154143. PMID: 32693770Free PMC Article
Wung SF
Crit Care Nurs Clin North Am 2016 Sep;28(3):297-308. Epub 2016 Jun 22 doi: 10.1016/j.cnc.2016.04.003. PMID: 27484658
Baruteau AE, Perry JC, Sanatani S, Horie M, Dubin AM
Eur J Pediatr 2016 Feb;175(2):151-61. Epub 2016 Jan 16 doi: 10.1007/s00431-015-2689-z. PMID: 26780751
Agrawal A, Timothy J, Cincu R, Agarwal T, Waghmare LB
Clin Neurol Neurosurg 2008 Apr;110(4):321-7. Epub 2008 Mar 7 doi: 10.1016/j.clineuro.2008.01.013. PMID: 18329164
Poddar B, Basu S, Parmar VR
Indian J Pediatr 2006 Feb;73(2):131-4. doi: 10.1007/BF02820202. PMID: 16514221

Diagnosis

Sathnur N, Ebin E, Benditt DG
Cardiol Clin 2023 Aug;41(3):349-367. doi: 10.1016/j.ccl.2023.03.013. PMID: 37321686
Farkas JD, Long B, Koyfman A, Menson K
J Emerg Med 2020 Aug;59(2):216-223. Epub 2020 Jun 18 doi: 10.1016/j.jemermed.2020.05.001. PMID: 32565167
Kusumoto FM, Schoenfeld MH, Barrett C, Edgerton JR, Ellenbogen KA, Gold MR, Goldschlager NF, Hamilton RM, Joglar JA, Kim RJ, Lee R, Marine JE, McLeod CJ, Oken KR, Patton KK, Pellegrini CN, Selzman KA, Thompson A, Varosy PD
J Am Coll Cardiol 2019 Aug 20;74(7):e51-e156. Epub 2018 Nov 6 doi: 10.1016/j.jacc.2018.10.044. PMID: 30412709
Wung SF
Crit Care Nurs Clin North Am 2016 Sep;28(3):297-308. Epub 2016 Jun 22 doi: 10.1016/j.cnc.2016.04.003. PMID: 27484658
Baruteau AE, Perry JC, Sanatani S, Horie M, Dubin AM
Eur J Pediatr 2016 Feb;175(2):151-61. Epub 2016 Jan 16 doi: 10.1007/s00431-015-2689-z. PMID: 26780751

Therapy

Lewis K, Alshamsi F, Carayannopoulos KL, Granholm A, Piticaru J, Al Duhailib Z, Chaudhuri D, Spatafora L, Yuan Y, Centofanti J, Spence J, Rochwerg B, Perri D, Needham DM, Holbrook A, Devlin JW, Nishida O, Honarmand K, Ergan B, Khorochkov E, Pandharipande P, Alshahrani M, Karachi T, Soth M, Shehabi Y, Møller MH, Alhazzani W; GUIDE group
Intensive Care Med 2022 Jul;48(7):811-840. Epub 2022 Jun 1 doi: 10.1007/s00134-022-06712-2. PMID: 35648198
Sandborn WJ, Feagan BG, D'Haens G, Wolf DC, Jovanovic I, Hanauer SB, Ghosh S, Petersen A, Hua SY, Lee JH, Charles L, Chitkara D, Usiskin K, Colombel JF, Laine L, Danese S; True North Study Group
N Engl J Med 2021 Sep 30;385(14):1280-1291. doi: 10.1056/NEJMoa2033617. PMID: 34587385
Doiron KA, Hoffmann TC, Beller EM
Cochrane Database Syst Rev 2018 Mar 27;3(3):CD010754. doi: 10.1002/14651858.CD010754.pub2. PMID: 29582429Free PMC Article
Roqué i Figuls M, Giné-Garriga M, Granados Rugeles C, Perrotta C, Vilaró J
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Prescrire Int 2013 Nov;22(143):257-9. PMID: 24427831

Prognosis

Pérez-Iruela JA, Pastor-Fructuoso P, De Gracia-Rodríguez C, Soler-Vigil M, Gómez-Martínez MDV
Farm Hosp 2021 Mar 30;45(3):142-149. doi: 10.7399/fh.11669. PMID: 33941058
Neale J, Hudson LD
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Chen SY, Lu FL, Lee PI, Lu CY, Chen CY, Chou HC, Tsao PN, Hsieh WS
J Formos Med Assoc 2007 Feb;106(2):161-4. doi: 10.1016/S0929-6646(09)60233-3. PMID: 17339161

Clinical prediction guides

Chakraborty T, Kramer CL, Wijdicks EFM, Rabinstein AA
Neurocrit Care 2020 Feb;32(1):113-120. doi: 10.1007/s12028-019-00781-w. PMID: 31297663
Grape S, Kirkham KR, Frauenknecht J, Albrecht E
Anaesthesia 2019 Jun;74(6):793-800. Epub 2019 Apr 5 doi: 10.1111/anae.14657. PMID: 30950522
Doyen B, Matelot D, Carré F
Phys Sportsmed 2019 Sep;47(3):249-252. Epub 2019 Jan 21 doi: 10.1080/00913847.2019.1568769. PMID: 30640577
Baruteau AE, Perry JC, Sanatani S, Horie M, Dubin AM
Eur J Pediatr 2016 Feb;175(2):151-61. Epub 2016 Jan 16 doi: 10.1007/s00431-015-2689-z. PMID: 26780751
Sutton R
Prog Cardiovasc Dis 2013 Jan-Feb;55(4):339-44. doi: 10.1016/j.pcad.2012.11.005. PMID: 23472769

Recent systematic reviews

Feenstra ML, Jansen S, Eshuis WJ, van Berge Henegouwen MI, Hollmann MW, Hermanides J
J Clin Anesth 2023 Nov;90:111215. Epub 2023 Jul 27 doi: 10.1016/j.jclinane.2023.111215. PMID: 37515877
Ball NS, Knable BM, Relich TA, Smathers AN, Gionfriddo MR, Nemecek BD, Montepara CA, Guarascio AJ, Covvey JR, Zimmerman DE
Clin Toxicol (Phila) 2022 Aug;60(8):892-901. Epub 2022 Apr 20 doi: 10.1080/15563650.2022.2063135. PMID: 35442125
Rotella JA, Greene SL, Koutsogiannis Z, Graudins A, Hung Leang Y, Kuan K, Baxter H, Bourke E, Wong A
Clin Toxicol (Phila) 2020 Oct;58(10):943-983. Epub 2020 Apr 20 doi: 10.1080/15563650.2020.1752918. PMID: 32310006
Doiron KA, Hoffmann TC, Beller EM
Cochrane Database Syst Rev 2018 Mar 27;3(3):CD010754. doi: 10.1002/14651858.CD010754.pub2. PMID: 29582429Free PMC Article
Jacobs SE, Berg M, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG
Cochrane Database Syst Rev 2013 Jan 31;2013(1):CD003311. doi: 10.1002/14651858.CD003311.pub3. PMID: 23440789Free PMC Article

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