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Hypertrophic cardiomyopathy

MedGen UID:
2881
Concept ID:
C0007194
Disease or Syndrome
Synonyms: Cardiomyopathies, Hypertrophic; Cardiomyopathy, Hypertrophic; Hypertrophic Cardiomyopathies; Hypertrophic Cardiomyopathy
SNOMED CT: Hypertrophic cardiomyopathy (233873004); HCM - Hypertrophic cardiomyopathy (233873004)
 
HPO: HP:0001639
Monarch Initiative: MONDO:0005045
Orphanet: ORPHA217569

Definition

A condition in which the myocardium is hypertrophied without an obvious cause. The hypertrophy is generally asymmetric and may be associated with obstruction of the ventricular outflow tract. [from NCI]

Conditions with this feature

Pallister-Killian syndrome
MedGen UID:
120540
Concept ID:
C0265449
Disease or Syndrome
Pallister-Killian syndrome (PKS) is a dysmorphic condition involving most organ systems, but is also characterized by a tissue-limited mosaicism; most fibroblasts have 47 chromosomes with an extra small metacentric chromosome, whereas the karyotype of lymphocytes is normal. The extra metacentric chromosome is an isochromosome for part of the short arm of chromosome 12: i(12)(p10) (Peltomaki et al., 1987; Warburton et al., 1987).
Infantile GM1 gangliosidosis
MedGen UID:
75665
Concept ID:
C0268271
Disease or Syndrome
GLB1-related disorders comprise two phenotypically distinct lysosomal storage disorders: GM1 gangliosidosis and mucopolysaccharidosis type IVB (MPS IVB). The phenotype of GM1 gangliosidosis constitutes a spectrum ranging from severe (infantile) to intermediate (late-infantile and juvenile) to mild (chronic/adult). Type I (infantile) GM1 gangliosidosis begins before age 12 months. Prenatal manifestations may include nonimmune hydrops fetalis, intrauterine growth restriction, and placental vacuolization; congenital dermal melanocytosis (Mongolian spots) may be observed. Macular cherry-red spot is detected on eye exam. Progressive central nervous system dysfunction leads to spasticity and rapid regression; blindness, deafness, decerebrate rigidity, seizures, feeding difficulties, and oral secretions are observed. Life expectancy is two to three years. Type II can be subdivided into the late-infantile (onset age 1-3 years) and juvenile (onset age 3-10 years) phenotypes. Central nervous system dysfunction manifests as progressive cognitive, motor, and speech decline as measured by psychometric testing. There may be mild corneal clouding, hepatosplenomegaly, and/or cardiomyopathy; the typical course is characterized by progressive neurologic decline, progressive skeletal disease in some individuals (including kyphosis and avascular necrosis of the femoral heads), and progressive feeding difficulties leading to aspiration risk. Type III begins in late childhood to the third decade with generalized dystonia leading to unsteady gait and speech disturbance followed by extrapyramidal signs including akinetic-rigid parkinsonism. Cardiomyopathy develops in some and skeletal involvement occurs in most. Intellectual impairment is common late in the disease with prognosis directly related to the degree of neurologic impairment. MPS IVB is characterized by skeletal dysplasia with specific findings of axial and appendicular dysostosis multiplex, short stature (below 15th centile in adults), kyphoscoliosis, coxa/genu valga, joint laxity, platyspondyly, and odontoid hypoplasia. First signs and symptoms may be apparent at birth. Bony involvement is progressive, with more than 84% of adults requiring ambulation aids; life span does not appear to be limited. Corneal clouding is detected in some individuals and cardiac valvular disease may develop.
Tyrosinemia type I
MedGen UID:
75688
Concept ID:
C0268490
Disease or Syndrome
Untreated tyrosinemia type I usually presents either in young infants with severe liver involvement or later in the first year with liver dysfunction and renal tubular dysfunction associated with growth failure and rickets. Untreated children may have repeated, often unrecognized, neurologic crises lasting one to seven days that can include change in mental status, abdominal pain, peripheral neuropathy, and/or respiratory failure requiring mechanical ventilation. Death in the untreated child usually occurs before age ten years, typically from liver failure, neurologic crisis, or hepatocellular carcinoma. Combined treatment with nitisinone and a low-tyrosine diet has resulted in a greater than 90% survival rate, normal growth, improved liver function, prevention of cirrhosis, correction of renal tubular acidosis, and improvement in secondary rickets.
Renal carnitine transport defect
MedGen UID:
90999
Concept ID:
C0342788
Disease or Syndrome
Systemic primary carnitine deficiency (CDSP) is a disorder of the carnitine cycle that results in defective fatty acid oxidation. It encompasses a broad clinical spectrum including the following: Metabolic decompensation in infancy typically presenting between age three months and two years with episodes of hypoketotic hypoglycemia, poor feeding, irritability, lethargy, hepatomegaly, elevated liver transaminases, and hyperammonemia triggered by fasting or common illnesses such as upper respiratory tract infection or gastroenteritis. Childhood myopathy involving heart and skeletal muscle with onset between age two and four years. Pregnancy-related decreased stamina or exacerbation of cardiac arrhythmia. Fatigability in adulthood. Absence of symptoms. The latter two categories often include mothers diagnosed with CDSP after newborn screening has identified low carnitine levels in their infants.
3-Methylglutaconic aciduria type 2
MedGen UID:
107893
Concept ID:
C0574083
Disease or Syndrome
Barth syndrome is characterized in affected males by cardiomyopathy, neutropenia, skeletal myopathy, prepubertal growth delay, and distinctive facial gestalt (most evident in infancy); not all features may be present in a given affected male. Cardiomyopathy, which is almost always present before age five years, is typically dilated cardiomyopathy with or without endocardial fibroelastosis or left ventricular noncompaction; hypertrophic cardiomyopathy can also occur. Heart failure is a significant cause of morbidity and mortality; risk of arrhythmia and sudden death is increased. Neutropenia is most often associated with mouth ulcers, pneumonia, and sepsis. The nonprogressive myopathy predominantly affects the proximal muscles, and results in early motor delays. Prepubertal growth delay is followed by a postpubertal growth spurt with remarkable "catch-up" growth. Heterozygous females who have a normal karyotype are asymptomatic and have normal biochemical studies.
Costello syndrome
MedGen UID:
108454
Concept ID:
C0587248
Disease or Syndrome
While the majority of individuals with Costello syndrome share characteristic findings affecting multiple organ systems, the phenotypic spectrum is wide, ranging from a milder or attenuated phenotype to a severe phenotype with early lethal complications. Costello syndrome is typically characterized by failure to thrive in infancy as a result of severe postnatal feeding difficulties; short stature; developmental delay or intellectual disability; coarse facial features (full lips, large mouth, full nasal tip); curly or sparse, fine hair; loose, soft skin with deep palmar and plantar creases; papillomata of the face and perianal region; diffuse hypotonia and joint laxity with ulnar deviation of the wrists and fingers; tight Achilles tendons; and cardiac involvement including: cardiac hypertrophy (usually typical hypertrophic cardiomyopathy), congenital heart defect (usually valvar pulmonic stenosis), and arrhythmia (usually supraventricular tachycardia, especially chaotic atrial rhythm/multifocal atrial tachycardia or ectopic atrial tachycardia). Relative or absolute macrocephaly is typical, and postnatal cerebellar overgrowth can result in the development of a Chiari I malformation with associated anomalies including hydrocephalus or syringomyelia. Individuals with Costello syndrome have an approximately 15% lifetime risk for malignant tumors including rhabdomyosarcoma and neuroblastoma in young children and transitional cell carcinoma of the bladder in adolescents and young adults.
Danon disease
MedGen UID:
209235
Concept ID:
C0878677
Disease or Syndrome
Danon disease is a multisystem condition with predominant involvement of the heart, skeletal muscles, and retina, with overlying cognitive dysfunction. Males are typically more severely affected than females. Males usually present with childhood onset concentric hypertrophic cardiomyopathy that is progressive and often requires heart transplantation. Rarely, hypertrophic cardiomyopathy can evolve to resemble dilated cardiomyopathy. Most affected males also have cardiac conduction abnormalities. Skeletal muscle weakness may lead to delayed acquisition of motor milestones. Learning disability and intellectual disability, most often in the mild range, are common. Additionally, affected males can develop retinopathy with subsequent visual impairment. The clinical features in females are broader and more variable. Females are more likely to have dilated cardiomyopathy, with a smaller proportion requiring heart transplantation compared to affected males. Cardiac conduction abnormalities, skeletal muscle weakness, mild cognitive impairment, and pigmentary retinopathy are variably seen in affected females.
Cardio-facio-cutaneous syndrome
MedGen UID:
266149
Concept ID:
C1275081
Congenital Abnormality
Cardiofaciocutaneous (CFC) syndrome is characterized by cardiac abnormalities (pulmonic stenosis and other valve dysplasias, septal defects, hypertrophic cardiomyopathy, rhythm disturbances), distinctive craniofacial appearance, and cutaneous abnormalities (including xerosis, hyperkeratosis, ichthyosis, keratosis pilaris, ulerythema ophryogenes, eczema, pigmented moles, hemangiomas, and palmoplantar hyperkeratosis). The hair is typically sparse, curly, fine or thick, woolly or brittle; eyelashes and eyebrows may be absent or sparse. Nails may be dystrophic or fast growing. Some form of neurologic and/or cognitive delay (ranging from mild to severe) is seen in all affected individuals. Neoplasia, mostly acute lymphoblastic leukemia, has been reported in some individuals.
Deficiency of 3-hydroxyacyl-CoA dehydrogenase
MedGen UID:
266222
Concept ID:
C1291230
Disease or Syndrome
3-hydroxyacyl-CoA dehydrogenase deficiency is an inherited condition that prevents the body from converting certain fats to energy, particularly during prolonged periods without food (fasting).\n\nInitial signs and symptoms of this disorder typically occur during infancy or early childhood and can include poor appetite, vomiting, diarrhea, and lack of energy (lethargy). Affected individuals can also have muscle weakness (hypotonia), liver problems, low blood sugar (hypoglycemia), and abnormally high levels of insulin (hyperinsulinism). Insulin controls the amount of sugar that moves from the blood into cells for conversion to energy. Individuals with 3-hydroxyacyl-CoA dehydrogenase deficiency are also at risk for complications such as seizures, life-threatening heart and breathing problems, coma, and sudden death. This condition may explain some cases of sudden infant death syndrome (SIDS), which is defined as unexplained death in babies younger than 1 year.\n\nProblems related to 3-hydroxyacyl-CoA dehydrogenase deficiency can be triggered by periods of fasting or by illnesses such as viral infections. This disorder is sometimes mistaken for Reye syndrome, a severe disorder that may develop in children while they appear to be recovering from viral infections such as chicken pox or flu. Most cases of Reye syndrome are associated with the use of aspirin during these viral infections.
Congenital generalized lipodystrophy type 2
MedGen UID:
318593
Concept ID:
C1720863
Congenital Abnormality
Berardinelli-Seip congenital lipodystrophy (BSCL) is usually diagnosed at birth or soon thereafter. Because of the absence of functional adipocytes, lipid is stored in other tissues, including muscle and liver. Affected individuals develop insulin resistance and approximately 25%-35% develop diabetes mellitus between ages 15 and 20 years. Hepatomegaly secondary to hepatic steatosis and skeletal muscle hypertrophy occur in all affected individuals. Hypertrophic cardiomyopathy is reported in 20%-25% of affected individuals and is a significant cause of morbidity from cardiac failure and early mortality.
Congenital muscular hypertrophy-cerebral syndrome
MedGen UID:
315658
Concept ID:
C1802395
Disease or Syndrome
Cornelia de Lange syndrome (CdLS) encompasses a spectrum of findings from mild to severe. Severe (classic) CdLS is characterized by distinctive facial features, growth restriction (prenatal onset; <5th centile throughout life), hypertrichosis, and upper-limb reduction defects that range from subtle phalangeal abnormalities to oligodactyly (missing digits). Craniofacial features include synophrys, highly arched and/or thick eyebrows, long eyelashes, short nasal bridge with anteverted nares, small widely spaced teeth, and microcephaly. Individuals with a milder phenotype have less severe growth, cognitive, and limb involvement, but often have facial features consistent with CdLS. Across the CdLS spectrum IQ ranges from below 30 to 102 (mean: 53). Many individuals demonstrate autistic and self-destructive tendencies. Other frequent findings include cardiac septal defects, gastrointestinal dysfunction, hearing loss, myopia, and cryptorchidism or hypoplastic genitalia.
Myofibrillar myopathy 1
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) (182920), 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.
Familial hypertrophic cardiomyopathy 6
MedGen UID:
331466
Concept ID:
C1833236
Disease or Syndrome
Mutations in the PRKAG2 gene (602743) give rise to a moderate, essentially heart-specific, nonlysosomal glycogenosis with clinical onset typically in late adolescence or in the third decade of life, ventricular pre-excitation predisposing to supraventricular arrhythmias, mild to severe cardiac hypertrophy, enhanced risk of sudden cardiac death in midlife, and autosomal dominant inheritance with full penetrance (summary by Burwinkel et al., 2005).
Familial hypertrophic cardiomyopathy 10
MedGen UID:
331754
Concept ID:
C1834460
Disease or Syndrome
Any hypertrophic cardiomyopathy in which the cause of the disease is a mutation in the MYL2 gene.
Mitochondrial phosphate carrier deficiency
MedGen UID:
324373
Concept ID:
C1835845
Disease or Syndrome
Mitochondrial phosphate carrier deficiency (MPCD) is an autosomal recessive disorder characterized by onset of cardiorespiratory insufficiency soon after birth. Patients usually require intervention in the neonatal period. The disorder may result in death in infancy, although those that survive have stabilization or amelioration of symptoms with age. Most affected individuals have hypotonia, delayed motor development, and exercise intolerance, but cognitive development is normal. Laboratory studies typically show increased serum lactate, although this may not be present. Muscle biopsy shows abnormal mitochondria and lipid accumulation. There is phenotypic variability likely depending on the location of the mutation (summary by Bhoj et al., 2015).
Alpha-B crystallinopathy
MedGen UID:
324735
Concept ID:
C1837317
Disease or Syndrome
Alpha-B crystallin-related myofibrillar myopathy is an autosomal dominant muscular disorder characterized by adult onset of progressive muscle weakness affecting both the proximal and distal muscles and associated with respiratory insufficiency, cardiomyopathy, and cataracts. There is phenotypic variability both within and between families (Fardeau et al., 1978; Selcen and Engel, 2003). A homozygous founder mutation in the CRYAB gene has been identified in Canadian aboriginal infants of Cree origin who have a severe fatal infantile hypertonic form of myofibrillar myopathy; see 613869. For a phenotypic description and a discussion of genetic heterogeneity of myofibrillar myopathy, see MFM1 (601419).
Familial hypertrophic cardiomyopathy 8
MedGen UID:
324806
Concept ID:
C1837471
Disease or Syndrome
Any hypertrophic cardiomyopathy in which the cause of the disease is a mutation in the MYL3 gene.
Toriello-Lacassie-Droste syndrome
MedGen UID:
333068
Concept ID:
C1838329
Disease or Syndrome
Oculoectodermal syndrome (OES) is characterized by the association of epibulbar dermoids and aplasia cutis congenita. Affected individuals exhibit congenital scalp lesions which are atrophic, nonscarring, hairless regions that are often multiple and asymmetric in distribution, and may have associated hamartomas. Ectodermal changes include linear hyperpigmentation that may follow the lines of Blaschko and, rarely, epidermal nevus-like lesions. Epibulbar dermoids may be uni- or bilateral. Additional ocular anomalies such as skin tags of the upper eyelid and rarely optic nerve or retinal changes or microphthalmia can be present. Phenotypic expression is highly variable, and various other abnormalities have occasionally been reported, including growth failure, lymphedema, and cardiovascular defects, as well as neurodevelopmental symptoms such as developmental delay, epilepsy, learning difficulties, and behavioral abnormalities. Benign tumor-like lesions such as nonossifying fibromas of the long bones and giant cell granulomas of the jaws have repeatedly been observed and appear to be age-dependent, becoming a common manifestation in individuals aged 5 years or older (summary by Boppudi et al., 2016).
Mitochondrial complex I deficiency
MedGen UID:
374101
Concept ID:
C1838979
Disease or Syndrome
Isolated complex I deficiency is a rare inborn error of metabolism due to mutations in nuclear or mitochondrial genes encoding subunits or assembly factors of the human mitochondrial complex I (NADH: ubiquinone oxidoreductase) and is characterized by a wide range of manifestations including marked and often fatal lactic acidosis, cardiomyopathy, leukoencephalopathy, pure myopathy and hepatopathy with tubulopathy. Among the numerous clinical phenotypes observed are Leigh syndrome, Leber hereditary optic neuropathy and MELAS syndrome (see these terms).
Noonan syndrome-like disorder with loose anagen hair
MedGen UID:
334697
Concept ID:
C1843181
Disease or Syndrome
Noonan syndrome-like disorder with loose anagen hair is characterized by facial features similar to those observed in Noonan syndrome (163950), including hypertelorism, ptosis, downslanting palpebral fissures, low-set posteriorly angulated ears, and overfolded pinnae. In addition, patients display short stature, frequently with growth hormone (GH; see 139250) deficiency; cognitive deficits; relative macrocephaly; small posterior fossa resulting in Chiari I malformation; hypernasal voice; cardiac defects, especially dysplasia of the mitral valve and septal defects; and ectodermal abnormalities, in which the most characteristic feature is the hair anomaly, including easily pluckable, sparse, thin, slow-growing hair (summary by Bertola et al., 2017). Reviews Komatsuzaki et al. (2010) reviewed the clinical manifestations of patients with Noonan syndrome, Costello syndrome (218040), and cardiofaciocutaneous syndrome (CFC; see 115150) compared to patients with mutations in the SHOC2 gene. They noted that although there is phenotypic overlap among the disorders, loose anagen/easily pluckable hair had not been reported in mutation-positive patients with Noonan, CFC, or Costello syndrome, and appeared to be a distinctive feature of SHOC2 mutation-positive patients. Genetic Heterogeneity of Noonan Syndrome-Like Disorder with Loose Anagen Hair NSLH2 (617506) is caused by mutation in the PPP1CB gene (600590) on chromosome 2p23.
Myopathy, myosin storage, autosomal recessive
MedGen UID:
340603
Concept ID:
C1850709
Disease or Syndrome
Noonan syndrome 4
MedGen UID:
339908
Concept ID:
C1853120
Disease or Syndrome
Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population.
Mitochondrial complex II deficiency, nuclear type 1
MedGen UID:
344401
Concept ID:
C1855008
Disease or Syndrome
Mitochondrial complex II deficiency is an autosomal recessive multisystemic metabolic disorder with a highly variable phenotype. Some patients have multisystem involvement of the brain, heart, and muscle with onset in infancy, whereas others have only isolated cardiac or muscle involvement. Measurement of complex II activity in muscle is the most reliable means of diagnosis; however, there is no clear correlation between residual complex II activity and severity or clinical outcome. In some cases, treatment with riboflavin may have clinical benefit (summary by Jain-Ghai et al., 2013). Complex II, also known as succinate dehydrogenase, is part of the mitochondrial respiratory chain. Genetic Heterogeneity of Mitochondrial Complex II Deficiency See MC2DN2 (619166), caused by mutation in the SDHAF1 gene (612848) on chromosome 19q13; MC2DN3 (619167), caused by mutation in the SDHD gene (602690) on chromosome 11q23; and MC2DN4 (619224), caused by mutation in the SDHB gene (185470) on chromosome 1p36. Fullerton et al. (2020) reviewed the genetic basis of isolated mitochondrial complex II deficiency.
Friedreich ataxia and congenital glaucoma
MedGen UID:
344787
Concept ID:
C1856688
Disease or Syndrome
Friedreich ataxia 1
MedGen UID:
383962
Concept ID:
C1856689
Disease or Syndrome
Friedreich ataxia (FRDA) is characterized by slowly progressive ataxia with onset usually before age 25 years (mean age at onset: 10-15 yrs). FRDA is typically associated with dysarthria, muscle weakness, spasticity particularly in the lower limbs, scoliosis, bladder dysfunction, absent lower-limb reflexes, and loss of position and vibration sense. Approximately two thirds of individuals with FRDA have cardiomyopathy, up to 30% have diabetes mellitus, and approximately 25% have an "atypical" presentation with later onset or retained tendon reflexes.
Sengers syndrome
MedGen UID:
395228
Concept ID:
C1859317
Disease or Syndrome
Sengers syndrome is an autosomal recessive mitochondrial disorder characterized by congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy, exercise intolerance, and lactic acidosis. Mental development is normal, but affected individuals may die early from cardiomyopathy (summary by Mayr et al., 2012). Skeletal muscle biopsies of 2 affected individuals showed severe mtDNA depletion (Calvo et al., 2012).
Noonan syndrome 3
MedGen UID:
349931
Concept ID:
C1860991
Disease or Syndrome
Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population.
Familial hypertrophic cardiomyopathy 9
MedGen UID:
348780
Concept ID:
C1861065
Disease or Syndrome
Any hypertrophic cardiomyopathy in which the cause of the disease is a mutation in the TTN gene.
Familial hypertrophic cardiomyopathy 4
MedGen UID:
350526
Concept ID:
C1861862
Disease or Syndrome
An autosomal dominant condition caused by mutation(s) in the MYBPC3 gene, encoding MYBPC3 protein. It is characterized by severe neonatal hypertrophic cardiomyopathy.
Familial hypertrophic cardiomyopathy 3
MedGen UID:
349382
Concept ID:
C1861863
Disease or Syndrome
Any hypertrophic cardiomyopathy in which the cause of the disease is a mutation in the TPM1 gene.
Familial hypertrophic cardiomyopathy 2
MedGen UID:
349383
Concept ID:
C1861864
Disease or Syndrome
An autosomal dominant subtype of familial hypertrophic cardiomyopathy caused by mutation(s) in the TNNT2 gene, encoding troponin T, cardiac muscle.
LEOPARD syndrome 2
MedGen UID:
370588
Concept ID:
C1969056
Disease or Syndrome
Noonan syndrome with multiple lentigines (NSML) is a condition in which the cardinal features consist of lentigines, hypertrophic cardiomyopathy, short stature, pectus deformity, and dysmorphic facial features, including widely spaced eyes and ptosis. Multiple lentigines present as dispersed flat, black-brown macules, mostly on the face, neck and upper part of the trunk with sparing of the mucosa. In general, lentigines do not appear until age four to five years but then increase to the thousands by puberty. Some individuals with NSML do not exhibit lentigines. Approximately 85% of affected individuals have heart defects, including hypertrophic cardiomyopathy (HCM) (typically appearing during infancy and sometimes progressive) and pulmonary valve stenosis. Postnatal growth retardation resulting in short stature occurs in fewer than 50% of affected persons, although most affected individuals have a height that is less than the 25th percentile for age. Sensorineural hearing deficits, present in approximately 20%, are poorly characterized. Intellectual disability, typically mild, is observed in approximately 30% of persons with NSML.
Noonan syndrome 5
MedGen UID:
370589
Concept ID:
C1969057
Disease or Syndrome
Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population.
Mucolipidosis type II
MedGen UID:
435914
Concept ID:
C2673377
Disease or Syndrome
GNPTAB-related disorders comprise the phenotypes mucolipidosis II (ML II) and mucolipidosis IIIa/ß (ML IIIa/ß), and phenotypes intermediate between ML II and ML IIIa/ß. ML II is evident at birth and slowly progressive; death most often occurs in early childhood. Orthopedic abnormalities present at birth may include thoracic deformity, kyphosis, clubfeet, deformed long bones, and/or dislocation of the hip(s). Growth often ceases in the second year of life; contractures develop in all large joints. The skin is thickened, facial features are coarse, and gingiva are hypertrophic. All children have cardiac involvement, most commonly thickening and insufficiency of the mitral valve and, less frequently, the aortic valve. Progressive mucosal thickening narrows the airways, and gradual stiffening of the thoracic cage contributes to respiratory insufficiency, the most common cause of death. ML IIIa/ß becomes evident at about age three years with slow growth rate and short stature; joint stiffness and pain initially in the shoulders, hips, and fingers; gradual mild coarsening of facial features; and normal to mildly impaired cognitive development. Pain from osteoporosis becomes more severe during adolescence. Cardiorespiratory complications (restrictive lung disease, thickening and insufficiency of the mitral and aortic valves, left and/or right ventricular hypertrophy) are common causes of death, typically in early to middle adulthood. Phenotypes intermediate between ML II and ML IIIa/ß are characterized by physical growth in infancy that resembles that of ML II and neuromotor and speech development that resemble that of ML IIIa/ß.
Combined oxidative phosphorylation deficiency 5
MedGen UID:
435972
Concept ID:
C2673642
Disease or Syndrome
This syndrome is characterised by severe hypotonia, lactic academia and congenital hyperammonaemia.
Familial hypertrophic cardiomyopathy 11
MedGen UID:
436962
Concept ID:
C2677506
Disease or Syndrome
Any hypertrophic cardiomyopathy in which the cause of the disease is a mutation in the ACTC1 gene.
Myopathy with postural muscle atrophy, X-linked
MedGen UID:
395525
Concept ID:
C2678055
Disease or Syndrome
Emery-Dreifuss muscular dystrophy (EDMD) is characterized by the clinical triad of: joint contractures that begin in early childhood; slowly progressive muscle weakness and wasting initially in a humero-peroneal distribution that later extends to the scapular and pelvic girdle muscles; and cardiac involvement that may manifest as palpitations, presyncope and syncope, poor exercise tolerance, and congestive heart failure along with variable cardiac rhythm disturbances. Age of onset, severity, and progression of muscle and cardiac involvement demonstrate both inter- and intrafamilial variability. Clinical variability ranges from early onset with severe presentation in childhood to late onset with slow progression in adulthood. In general, joint contractures appear during the first two decades, followed by muscle weakness and wasting. Cardiac involvement usually occurs after the second decade and respiratory function may be impaired in some individuals.
Familial hypertrophic cardiomyopathy 15
MedGen UID:
413312
Concept ID:
C2750459
Disease or Syndrome
Any hypertrophic cardiomyopathy in which the cause of the disease is a mutation in the VCL gene.
Familial hypertrophic cardiomyopathy 14
MedGen UID:
442484
Concept ID:
C2750467
Disease or Syndrome
Any hypertrophic cardiomyopathy in which the cause of the disease is a mutation in the MYH6 gene.
Familial hypertrophic cardiomyopathy 13
MedGen UID:
442487
Concept ID:
C2750472
Disease or Syndrome
Any hypertrophic cardiomyopathy in which the cause of the disease is a mutation in the TNNC1 gene.
Noonan syndrome 6
MedGen UID:
413028
Concept ID:
C2750732
Disease or Syndrome
Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population.
Optic atrophy 7
MedGen UID:
414112
Concept ID:
C2751812
Disease or Syndrome
A rare, syndromic, hereditary optic neuropathy disorder characterized by early-onset, severe, progressive visual impairment, optic disc pallor and central scotoma, variably associated with dyschromatopsia, auditory neuropathy (e.g. mild progressive sensorineural hearing loss), sensorimotor axonal neuropathy and, occasionally, moderate hypertrophic cardiomyopathy.
Myofibrillar myopathy, BAG3-related
MedGen UID:
414119
Concept ID:
C2751831
Disease or Syndrome
Myofibrillar myopathy-6 is an autosomal dominant severe neuromuscular disorder characterized by onset in the first decade of rapidly progressive generalized and proximal muscle weakness, respiratory insufficiency, cardiomyopathy, and skeletal deformities related to muscle weakness. Muscle biopsy shows fiber-type grouping, disruption of the Z lines, and filamentous inclusions, and sural nerve biopsy shows a neuropathy, often with giant axonal neurons. Most patients are severely affected by the second decade and need cardiac transplant, ventilation, and/or a wheelchair (summary by Jaffer et al., 2012). For a phenotypic description and a discussion of genetic heterogeneity of myofibrillar myopathy (MFM), see MFM1 (601419).
Growth retardation, developmental delay, coarse facies, and early death
MedGen UID:
414158
Concept ID:
C2752001
Congenital Abnormality
Growth retardation, developmental delay, and facial dysmorphism (GDFD) is an autosomal recessive multiple congenital anomaly syndrome characterized by severe psychomotor retardation, poor overall growth, and dysmorphic facial features. Additional features may include cardiac malformations and deafness (summary by Daoud et al., 2016).
Myopathy, autophagic vacuolar, infantile-onset
MedGen UID:
419364
Concept ID:
C2931230
Disease or Syndrome
Infantile-onset autophagic vacuolar myopathy is characterized by increased cardiac and skeletal muscle glycogen with normal acid maltase (GAA; 606800). Skeletal muscle biopsy shows characteristic intracytoplasmic vacuoles that stain for sarcolemmal proteins and complement proteins. Similar pathologic findings are seen in Danon disease (300257), caused by mutation in the LAMP2 gene (309060) on chromosome Xq24, and X-linked myopathy with excessive autophagy (XMEA; 310440), which has been mapped to Xq28.
Myopathy, lactic acidosis, and sideroblastic anemia 2
MedGen UID:
462152
Concept ID:
C3150802
Disease or Syndrome
Myopathy, lactic acidosis, and sideroblastic anemia-2 is an autosomal recessive disorder of the mitochondrial respiratory chain. The disorder shows marked phenotypic variability: some patients have a severe multisystem disorder from infancy, including cardiomyopathy and respiratory insufficiency resulting in early death, whereas others present in the second or third decade of life with sideroblastic anemia and mild muscle weakness (summary by Riley et al., 2013). For a discussion of genetic heterogeneity of MLASA, see MLASA1 (600462).
Congenital dyserythropoietic anemia, type IV
MedGen UID:
462276
Concept ID:
C3150926
Disease or Syndrome
Congenital dyserythropoietic anemia type IV is an autosomal dominant inherited red blood cell disorder characterized by ineffective erythropoiesis and hemolysis resulting in anemia. Circulating erythroblasts and erythroblasts in the bone marrow show various morphologic abnormalities. Affected individuals with CDAN4 also have increased levels of fetal hemoglobin (summary by Arnaud et al., 2010). For a discussion of genetic heterogeneity of congenital dyserythropoietic anemia, see CDAN1 (224120).
Noonan syndrome 7
MedGen UID:
462320
Concept ID:
C3150970
Disease or Syndrome
Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population.
HSD10 disease
MedGen UID:
781653
Concept ID:
C3266731
Disease or Syndrome
HSD10 mitochondrial disease (HSD10MD) most commonly presents as an X-linked neurodegenerative disorder with highly variable severity and age at onset ranging from the neonatal period to early childhood. The features are usually multisystemic, consistent with mitochondrial dysfunction. Some affected males have a severe infantile form associated with cardiomyopathy that may result in death in early childhood, whereas other rare patients may have juvenile onset or even atypical presentations with normal neurologic development. More severely affected males show developmental regression in infancy or early childhood, often associated with early-onset intractable seizures, progressive choreoathetosis and spastic tetraplegia, optic atrophy or retinal degeneration resulting in visual loss, and mental retardation. Heterozygous females may show non-progressive developmental delay and intellectual disability, but may also be clinically normal. Although the diagnosis can be aided by the observation of increased urinary levels of metabolites of isoleucine breakdown (2-methyl-3 hydroxybutyrate and tiglylglycine), there is not a correlation between these laboratory features and the phenotype. In addition, patients do not develop severe metabolic crises in the neonatal period as observed in other organic acidurias, but may show persistent lactic acidosis, most likely reflecting mitochondrial dysfunction (summary by Rauschenberger et al., 2010; Zschocke, 2012). In a review of this disorder, Zschocke (2012) noted that although it was originally thought to be an inborn error of branched-chain fatty acid and isoleucine metabolism resulting from decreased HSD17B10 dehydrogenase activity (HSD17B10 'deficiency'), subsequent studies have shown that the HSD17B10 gene product has additional functions and also acts as a component of the mitochondrial RNase P holoenzyme, which is involved in mitochondrial tRNA processing and maturation and ultimately mitochondrial protein synthesis. The multisystemic features of HSD10MD most likely result from the adverse effect of HSD17B10 mutations on mitochondrial function, rather than from the effects on the dehydrogenase activity (see PATHOGENESIS).
Nuclearly-encoded mitochondrial complex V (ATP synthase) deficiency 1
MedGen UID:
477906
Concept ID:
C3276276
Disease or Syndrome
A distinct group of inborn defects of complex V (ATP synthase) is represented by the enzyme deficiency due to nuclear genome mutations characterized by a selective inhibition of ATP synthase biogenesis. Biochemically, the patients show a generalized decrease in the content of ATP synthase complex which is less than 30% of normal. Most cases present with neonatal-onset hypotonia, lactic acidosis, hyperammonemia, hypertrophic cardiomyopathy, and 3-methylglutaconic aciduria. Many patients die within a few months or years (summary by Mayr et al., 2010). Genetic Heterogeneity of Mitochondrial Complex V Deficiency Other nuclear types of mitochondrial complex V deficiency include MC5DN2 (614052), caused by mutation in the TMEM70 gene (612418) on chromosome 8q21; MC5DN3 (614053), caused by mutation in the ATP5E gene (ATP5F1E; 606153) on chromosome 20q13; MC5DN4 (615228), caused by mutation in the ATP5A1 gene (ATP5FA1; 164360) on chromosome 18q; MC5DN5 (618120), caused by mutation in the ATP5D gene (ATP5F1D; 603150) on chromosome 19p13; and MC5DN6 (618683), caused by mutation in the USMG5 gene (ATP5MD; 615204) on chromosome 10q24. Mutations in the mitochondrial-encoded MTATP6 (516060) and MTATP8 (516070) genes can also cause mitochondrial complex V deficiency (see, e.g., 500015).
Nuclearly-encoded mitochondrial complex V (ATP synthase) deficiency 2
MedGen UID:
481329
Concept ID:
C3279699
Disease or Syndrome
mutation is characterized by early neonatal onset of hypotonia, hypetrophic cardiomyopathy and apneic spells within hours after birth accompanied by lactic acidosis, hyperammonemia and 3-methylglutaconic aciduria.
Nuclearly-encoded mitochondrial complex V (ATP synthase) deficiency 3
MedGen UID:
481338
Concept ID:
C3279708
Disease or Syndrome
Any mitochondrial proton-transporting ATP synthase complex deficiency in which the cause of the disease is a mutation in the ATP5F1E gene.
Multiple mitochondrial dysfunctions syndrome 2
MedGen UID:
482008
Concept ID:
C3280378
Disease or Syndrome
Multiple mitochondrial dysfunctions syndrome-2 (MMDS2) with hyperglycinemia is a severe autosomal recessive disorder characterized by developmental regression in infancy. Affected children have an encephalopathic disease course with seizures, spasticity, loss of head control, and abnormal movement. Additional more variable features include optic atrophy, cardiomyopathy, and leukodystrophy. Laboratory studies show increased serum glycine and lactate. Most patients die in childhood. The disorder represents a form of 'variant' nonketotic hyperglycinemia and is distinct from classic nonketotic hyperglycinemia (NKH, or GCE; 605899), which is characterized by significantly increased CSF glycine. Several forms of 'variant' NKH, including MMDS2, appear to result from defects of mitochondrial lipoate biosynthesis (summary by Baker et al., 2014). For a general description and a discussion of genetic heterogeneity of multiple mitochondrial dysfunctions syndrome, see MMDS1 (605711).
Pyruvate dehydrogenase lipoic acid synthetase deficiency
MedGen UID:
482517
Concept ID:
C3280887
Disease or Syndrome
Hyperglycinemia, lactic acidosis, and seizures is a severe autosomal recessive disorder characterized by onset of hypotonia and seizures associated with increased serum glycine and lactate in the first days of life. Affected individuals develop an encephalopathy or severely delayed psychomotor development, which may result in death in childhood. The disorder represents a form of 'variant' nonketotic hyperglycinemia and is distinct from classic nonketotic hyperglycinemia (NKH, or GCE; 605899), which is characterized by significantly increased CSF glycine. Several forms of 'variant' NKH, including HGCLAS, appear to result from defects of mitochondrial lipoate biosynthesis (summary by Baker et al., 2014).
Combined oxidative phosphorylation deficiency 9
MedGen UID:
482864
Concept ID:
C3281234
Disease or Syndrome
Combined oxidative phosphorylation defect type 9 is a rare mitochondrial disease due to a defect in mitochondrial protein synthesis characterized by initially normal growth and development followed by the infantile-onset of failure to thrive, psychomotor delay, poor feeding, dyspnea, severe hypertrophic cardiomyopathy and hepatomegaly. Laboratory studies report increased plasma lactate and alanine, abnormal liver enzymes and decreased activity of mitochondrial respiratory chain complexes I, III, IV, and V.
Mitochondrial complex III deficiency, nuclear type 1
MedGen UID:
762097
Concept ID:
C3541471
Disease or Syndrome
Autosomal recessive mitochondrial complex III deficiency is a severe multisystem disorder with onset at birth of lactic acidosis, hypotonia, hypoglycemia, failure to thrive, encephalopathy, and delayed psychomotor development. Visceral involvement, including hepatopathy and renal tubulopathy, may also occur. Many patients die in early childhood, but some may show longer survival (de Lonlay et al., 2001; De Meirleir et al., 2003). Genetic Heterogeneity of Mitochondrial Complex III Deficiency Mitochondrial complex III deficiency can be caused by mutation in several different nuclear-encoded genes. See MC3DN2 (615157), caused by mutation in the TTC19 gene (613814) on chromosome 17p12; MC3DN3 (615158), caused by mutation in the UQCRB gene (191330) on chromosome 8q; MC3DN4 (615159), caused by mutation in the UQCRQ gene (612080) on chromosome 5q31; MC3DN5 (615160), caused by mutation in the UQCRC2 gene (191329) on chromosome 16p12; MC3DN6 (615453), caused by mutation in the CYC1 gene (123980) on chromosome 8q24; MC3DN7 (615824), caused by mutation in the UQCC2 gene (614461) on chromosome 6p21; MC3DN8 (615838), caused by mutation in the LYRM7 gene (615831) on chromosome 5q23; MC3DN9 (616111), caused by mutation in the UQCC3 gene (616097) on chromosome 11q12; and MC3DN10 (618775), caused by mutation in the UQCRFS1 gene (191327) on chromosome 19q12. See also MTYCB (516020) for a discussion of a milder phenotype associated with isolated mitochondrial complex III deficiency and mutations in a mitochondrial-encoded gene.
Coenzyme Q10 deficiency, primary 1
MedGen UID:
764868
Concept ID:
C3551954
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.
Combined oxidative phosphorylation deficiency 10
MedGen UID:
766443
Concept ID:
C3553529
Disease or Syndrome
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).
Dilated cardiomyopathy 1KK
MedGen UID:
811544
Concept ID:
C3714995
Disease or Syndrome
Any dilated cardiomyopathy in which the cause of the disease is a mutation in the MYPN gene.
Cardiofaciocutaneous syndrome 3
MedGen UID:
815336
Concept ID:
C3809006
Disease or Syndrome
Cardiofaciocutaneous (CFC) syndrome is characterized by cardiac abnormalities (pulmonic stenosis and other valve dysplasias, septal defects, hypertrophic cardiomyopathy, rhythm disturbances), distinctive craniofacial appearance, and cutaneous abnormalities (including xerosis, hyperkeratosis, ichthyosis, keratosis pilaris, ulerythema ophryogenes, eczema, pigmented moles, hemangiomas, and palmoplantar hyperkeratosis). The hair is typically sparse, curly, fine or thick, woolly or brittle; eyelashes and eyebrows may be absent or sparse. Nails may be dystrophic or fast growing. Some form of neurologic and/or cognitive delay (ranging from mild to severe) is seen in all affected individuals. Neoplasia, mostly acute lymphoblastic leukemia, has been reported in some individuals.
Noonan syndrome 8
MedGen UID:
815563
Concept ID:
C3809233
Disease or Syndrome
Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population.
Nephronophthisis 16
MedGen UID:
815650
Concept ID:
C3809320
Disease or Syndrome
The nephronophthisis (NPH) phenotype is characterized by reduced renal concentrating ability, chronic tubulointerstitial nephritis, cystic renal disease, and progression to end-stage renal disease (ESRD) before age 30 years. Three age-based clinical subtypes are recognized: infantile, juvenile, and adolescent/adult. Infantile NPH can present in utero with oligohydramnios sequence (limb contractures, pulmonary hypoplasia, and facial dysmorphisms) or postnatally with renal manifestations that progress to ESRD before age 3 years. Juvenile NPH, the most prevalent subtype, typically presents with polydipsia and polyuria, growth retardation, chronic iron-resistant anemia, or other findings related to chronic kidney disease (CKD). Hypertension is typically absent due to salt wasting. ESRD develops at a median age of 13 years. Ultrasound findings are increased echogenicity, reduced corticomedullary differentiation, and renal cysts (in 50% of affected individuals). Histologic findings include tubulointerstitial fibrosis, thickened and disrupted tubular basement membrane, sporadic corticomedullary cysts, and normal or reduced kidney size. Adolescent/adult NPH is clinically similar to juvenile NPH, but ESRD develops at a median age of 19 years. Within a subtype, inter- and intrafamilial variability in rate of progression to ESRD is considerable. Approximately 80%-90% of individuals with the NPH phenotype have no extrarenal features (i.e., they have isolated NPH); ~10%-20% have extrarenal manifestations that constitute a recognizable syndrome (e.g., Joubert syndrome, Bardet-Biedl syndrome, Jeune syndrome and related skeletal disorders, Meckel-Gruber syndrome, Senior-Løken syndrome, Leber congenital amaurosis, COACH syndrome, and oculomotor apraxia, Cogan type).
Combined oxidative phosphorylation deficiency 16
MedGen UID:
815669
Concept ID:
C3809339
Disease or Syndrome
A rare mitochondrial oxidative phosphorylation disorder with complex I and IV deficiency characterized by hypertrophic cardiomyopathy, hepatic steatosis with elevated liver transaminases, exercise intolerance and muscle weakness. Neuro-opthalmological features (hemiplegic migraine, Leigh-like lesions on brain MRI, pigmentary retinopathy) have been reported later in life.
Renal-hepatic-pancreatic dysplasia 2
MedGen UID:
815764
Concept ID:
C3809434
Disease or Syndrome
RHPD2 is an autosomal recessive multisystemic disorder with severe abnormalities apparent in utero and often resulting in fetal death or death in infancy. The main organs affected include the kidney, liver, and pancreas, although other abnormalities, including cardiac, skeletal, and lung defects, may also be present. Affected individuals often have situs inversus. The disorder results from a defect in ciliogenesis and ciliary function, as well as in cell proliferation and epithelial morphogenesis; thus, the clinical manifestations are highly variable (summary by Grampa et al., 2016). For a discussion of genetic heterogeneity of renal-hepatic-pancreatic dysplasia, see RHPD1 (208540).
Mitochondrial DNA depletion syndrome 12b (cardiomyopathic type), autosomal recessive
MedGen UID:
815773
Concept ID:
C3809443
Disease or Syndrome
Mitochondrial DNA depletion syndrome-12B is an autosomal recessive mitochondrial disorder characterized by childhood onset of slowly progressive hypertrophic cardiomyopathy and generalized skeletal myopathy resulting in exercise intolerance, and, in some patients, muscle weakness and atrophy. Skeletal muscle biopsy shows ragged-red fibers, mtDNA depletion, and accumulation of abnormal mitochondria (summary by Echaniz-Laguna et al., 2012). For a discussion of genetic heterogeneity of mtDNA depletion syndromes, see MTDPS1 (603041).
Combined oxidative phosphorylation deficiency 17
MedGen UID:
815856
Concept ID:
C3809526
Disease or Syndrome
Combined oxidative phosphorylation deficiency-17 is an autosomal recessive disorder of mitochondrial dysfunction characterized by onset of severe hypertrophic cardiomyopathy in the first year of life. Other features include hypotonia, poor growth, lactic acidosis, and failure to thrive. The disorder may be fatal in early childhood (summary by Haack et al., 2013).
Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type)
MedGen UID:
815922
Concept ID:
C3809592
Disease or Syndrome
FBXL4-related encephalomyopathic mitochondrial DNA (mtDNA) depletion syndrome is a multi-system disorder characterized primarily by congenital or early-onset lactic acidosis and growth failure, feeding difficulty, hypotonia, and developmental delay. Other neurologic manifestations can include seizures, movement disorders, ataxia, autonomic dysfunction, and stroke-like episodes. All affected individuals alive at the time they were reported (median age: 3.5 years) demonstrated significant developmental delay. Other findings can involve the heart (hypertrophic cardiomyopathy, congenital heart malformations, arrhythmias), liver (mildly elevated transaminases), eyes (cataract, strabismus, nystagmus, optic atrophy), hearing (sensorineural hearing loss), and bone marrow (neutropenia, lymphopenia). Survival varies; the median age of reported deaths was two years (range 2 days – 75 months), although surviving individuals as old as 36 years have been reported. To date FBXL4-related mtDNA depletion syndrome has been reported in 50 individuals.
Very long chain acyl-CoA dehydrogenase deficiency
MedGen UID:
854382
Concept ID:
C3887523
Disease or Syndrome
Deficiency of very long-chain acyl-CoA dehydrogenase (VLCAD), which catalyzes the initial step of mitochondrial ß-oxidation of long-chain fatty acids with a chain length of 14 to 20 carbons, is associated with three phenotypes. The severe early-onset cardiac and multiorgan failure form typically presents in the first months of life with hypertrophic or dilated cardiomyopathy, pericardial effusion, and arrhythmias, as well as hypotonia, hepatomegaly, and intermittent hypoglycemia. The hepatic or hypoketotic hypoglycemic form typically presents during early childhood with hypoketotic hypoglycemia and hepatomegaly, but without cardiomyopathy. The later-onset episodic myopathic form presents with intermittent rhabdomyolysis provoked by exercise, muscle cramps and/or pain, and/or exercise intolerance. Hypoglycemia typically is not present at the time of symptoms.
Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 3
MedGen UID:
903495
Concept ID:
C4225154
Disease or Syndrome
Mitochondrial complex IV deficiency nuclear type 9 (MC4DN9) is an autosomal recessive multisystem metabolic disorder characterized by neonatal hypertrophic cardiomyopathy resulting in death in early infancy. Patient tissues show decreased levels and activity of mitochondrial respiratory complex IV (summary by Huigsloot et al., 2011). For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see 220110.
Osteochondrodysplasia, complex lethal, symoens-barnes-gistelinck type
MedGen UID:
900688
Concept ID:
C4225162
Disease or Syndrome
Complex lethal osteochondrodysplasia of the Symoens-Barnes-Gistelinck type is characterized by severe skeletal osteopenia, microcephaly, multiple fractures, and congenital anomalies including ascites, pleural effusion, and intracranial ventriculomegaly (Symoens et al., 2015).
Mitochondrial DNA depletion syndrome 14 (cardioencephalomyopathic type)
MedGen UID:
903789
Concept ID:
C4225163
Disease or Syndrome
Any mitochondrial DNA depletion syndrome in which the cause of the disease is a mutation in the OPA1 gene.
Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome
MedGen UID:
894196
Concept ID:
C4225171
Disease or Syndrome
Individuals with TANGO2-related metabolic encephalopathy and arrhythmias can present in acute metabolic crisis (hypoglycemia, elevated lactate, mild hyperammonemia) or with developmental delay, regression, and/or seizures. The acute presentation varies from profound muscle weakness, ataxia, and/or disorientation to a comatose state. Individuals can present with intermittent acute episodes of rhabdomyolysis. The first episode of myoglobinuria has been known to occur as early as age five months. Acute renal tubular damage due to myoglobinuria can result in acute kidney injury and renal failure. During acute illness, transient electrocardiogram changes can be seen; the most common is QT prolongation. Life-threatening recurrent ventricular tachycardia or torsade de pointes occurs primarily during times of acute illness. Individuals who do not present in metabolic crises may present with gait incoordination, progressively unsteady gait, difficulty with speech, or clumsiness. Intellectual disability of variable severity is observed in almost all individuals. Seizures are observed outside the periods of crises in more than 75% of individuals. Hypothyroidism has been reported in more than one third of individuals.
Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 4
MedGen UID:
905398
Concept ID:
C4225304
Disease or Syndrome
Mitochondrial complex IV deficiency nuclear type 13 (MC4DN13) is an autosomal recessive metabolic disorder characterized by the onset of hypertrophic cardiomyopathy soon after birth. Affected individuals have hypotonia, weakness, and failure to thrive, resulting in death in infancy. Laboratory studies show increased serum lactate and decreased levels and activity of mitochondrial respiratory complex IV (summary by Baertling et al., 2015). For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see 220110.
Coenzyme Q10 deficiency, primary, 7
MedGen UID:
908175
Concept ID:
C4225392
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.
Mucopolysaccharidosis-plus syndrome
MedGen UID:
934594
Concept ID:
C4310627
Disease or Syndrome
MPSPS is an autosomal recessive inborn error of metabolism resulting in a multisystem disorder with features of the mucopolysaccharidosis lysosomal storage diseases (see, e.g., 607016). Patients present in infancy or early childhood with respiratory difficulties, cardiac problems, anemia, dysostosis multiplex, renal involvement, coarse facies, and delayed psychomotor development. Most patients die of cardiorespiratory failure in the first years of life (summary by Kondo et al., 2017).
Combined oxidative phosphorylation deficiency 31
MedGen UID:
934628
Concept ID:
C4310661
Disease or Syndrome
Combined oxidative phosphorylation deficiency-31 is an autosomal recessive multisystem disorder characterized by left ventricular noncompaction (LVNC), global developmental delay, and severe hypotonia. More variable features include seizures, cataract, and abnormal movements. The disorder becomes apparent soon after birth or in early infancy, and patients may die in early childhood. Biochemical studies are consistent with a defect in mitochondrial function (summary by Eldomery et al., 2016). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
Sudden cardiac failure, infantile
MedGen UID:
934631
Concept ID:
C4310664
Disease or Syndrome
Mitochondrial DNA depletion syndrome 12a (cardiomyopathic type), autosomal dominant
MedGen UID:
934643
Concept ID:
C4310676
Disease or Syndrome
MTDPS12A is characterized by severe hypotonia due to mitochondrial dysfunction apparent at birth. Affected infants have respiratory insufficiency requiring mechanical ventilation and have poor or no motor development. Many die in infancy, and those that survive have profound hypotonia with significant muscle weakness and inability to walk independently. Some patients develop hypertrophic cardiomyopathy. Muscle samples show mtDNA depletion and severe combined mitochondrial respiratory chain deficiencies (summary by Thompson et al., 2016). For a discussion of genetic heterogeneity of mtDNA depletion syndromes, see MTDPS1 (603041).
Harel-Yoon syndrome
MedGen UID:
934644
Concept ID:
C4310677
Disease or Syndrome
Harel-Yoon syndrome is a syndromic neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability, truncal hypotonia, spasticity, and peripheral neuropathy. Other more variable features such as optic atrophy may also occur. Laboratory studies in some patients show evidence of mitochondrial dysfunction (summary by Harel et al., 2016).
Noonan syndrome-like disorder with loose anagen hair 1
MedGen UID:
1379805
Concept ID:
C4478716
Disease or Syndrome
Autosomal recessive cutis laxa type 2D
MedGen UID:
1376619
Concept ID:
C4479409
Disease or Syndrome
Autosomal recessive cutis laxa type IID (ARCL2D) is characterized by generalized skin wrinkling with sparse subcutaneous fat and dysmorphic progeroid facial features. Most patients also exhibit severe hypotonia as well as cardiovascular and neurologic involvement (summary by Van Damme et al., 2017). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive cutis laxa, see ARCL1A (219100).
Combined oxidative phosphorylation deficiency 8
MedGen UID:
1377817
Concept ID:
C4518839
Disease or Syndrome
COXPD8 is an autosomal recessive disorder due to dysfunction of the mitochondrial respiratory chain. The main clinical manifestation is a lethal infantile hypertrophic cardiomyopathy, but there may also be subtle skeletal muscle and brain involvement. Biochemical studies show combined respiratory chain complex deficiencies in complexes I, III, and IV in cardiac muscle, skeletal muscle, and brain. The liver is not affected (summary by Gotz et al., 2011). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
Joubert syndrome 32
MedGen UID:
1626697
Concept ID:
C4540342
Disease or Syndrome
JBTS32 is an autosomal recessive developmental disorder characterized by delayed psychomotor development, intellectual disability, dysmorphic facial features, and postaxial polydactyly. Brain imaging shows cerebellar abnormalities consistent with the molar tooth sign (MTS) (summary by De Mori et al., 2017). For discussion of genetic heterogeneity of Joubert syndrome, see JBTS1 (213300).
LEOPARD syndrome 1
MedGen UID:
1631694
Concept ID:
C4551484
Disease or Syndrome
Noonan syndrome with multiple lentigines (NSML) is a condition in which the cardinal features consist of lentigines, hypertrophic cardiomyopathy, short stature, pectus deformity, and dysmorphic facial features, including widely spaced eyes and ptosis. Multiple lentigines present as dispersed flat, black-brown macules, mostly on the face, neck and upper part of the trunk with sparing of the mucosa. In general, lentigines do not appear until age four to five years but then increase to the thousands by puberty. Some individuals with NSML do not exhibit lentigines. Approximately 85% of affected individuals have heart defects, including hypertrophic cardiomyopathy (HCM) (typically appearing during infancy and sometimes progressive) and pulmonary valve stenosis. Postnatal growth retardation resulting in short stature occurs in fewer than 50% of affected persons, although most affected individuals have a height that is less than the 25th percentile for age. Sensorineural hearing deficits, present in approximately 20%, are poorly characterized. Intellectual disability, typically mild, is observed in approximately 30% of persons with NSML.
Noonan syndrome 1
MedGen UID:
1638960
Concept ID:
C4551602
Disease or Syndrome
Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population.
Acyl-CoA dehydrogenase family, member 9, deficiency of
MedGen UID:
1648400
Concept ID:
C4747517
Disease or Syndrome
MC1DN20 is an autosomal recessive multisystem disorder characterized by infantile onset of acute metabolic acidosis, hypertrophic cardiomyopathy, and muscle weakness associated with a deficiency of mitochondrial complex I activity in muscle, liver, and fibroblasts (summary by Haack et al., 2010). For a discussion of genetic heterogeneity of mitochondrial complex I deficiency, see 252010.
Mitochondrial complex 1 deficiency, nuclear type 2
MedGen UID:
1648466
Concept ID:
C4748737
Disease or Syndrome
Mitochondrial complex 1 deficiency, nuclear type 6
MedGen UID:
1648496
Concept ID:
C4748759
Disease or Syndrome
Mitochondrial complex 1 deficiency, nuclear type 7
MedGen UID:
1648484
Concept ID:
C4748760
Disease or Syndrome
Mitochondrial complex 1 deficiency, nuclear type 11
MedGen UID:
1648356
Concept ID:
C4748769
Disease or Syndrome
Mitochondrial complex 1 deficiency, nuclear type 13
MedGen UID:
1648370
Concept ID:
C4748770
Disease or Syndrome
Mitochondrial complex 1 deficiency, nuclear type 14
MedGen UID:
1648440
Concept ID:
C4748777
Disease or Syndrome
Mitochondrial complex 1 deficiency, nuclear type 15
MedGen UID:
1648320
Concept ID:
C4748778
Disease or Syndrome
Mitochondrial complex 1 deficiency, nuclear type 19
MedGen UID:
1648450
Concept ID:
C4748791
Disease or Syndrome
Mitochondrial complex 1 deficiency, nuclear type 22
MedGen UID:
1648347
Concept ID:
C4748796
Disease or Syndrome
Mitochondrial complex 1 deficiency, nuclear type 29
MedGen UID:
1648451
Concept ID:
C4748830
Disease or Syndrome
Combined oxidative phosphorylation deficiency 37
MedGen UID:
1675208
Concept ID:
C5193031
Disease or Syndrome
Combined oxidative phosphorylation deficiency-37 is an autosomal recessive multisystem disorder apparent at birth or in the first months of life. Affected individuals have hypotonia, failure to thrive, and neurodegeneration with loss of developmental milestones, as well as liver dysfunction. Some patients may have hypertrophic cardiomyopathy, loss of vision and hearing, and/or seizures. Mitochondrial respiratory dysfunction is apparent in liver and skeletal muscle tissue. Most patients die in childhood (summary by Zeharia et al., 2016). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
Combined oxidative phosphorylation deficiency 38
MedGen UID:
1682102
Concept ID:
C5193064
Disease or Syndrome
Mitochondrial complex 5 (ATP synthase) deficiency, nuclear type 6
MedGen UID:
1684729
Concept ID:
C5231461
Disease or Syndrome
Mitochondrial complex V (ATP synthase) deficiency nuclear type 6 (MC5DN6) is an autosomal recessive progressive and degenerative disorder characterized by episodic regression of gross motor skills beginning in early childhood. The episodes are associated with metabolic stress, including fever, illness, and general anesthesia. Patients develop gait difficulties or loss of ambulation, as well as other variable abnormalities, including abnormal movements, hemiplegia, and persistent lethargy. Brain imaging shows degenerative features in the basal ganglia and brainstem consistent with a diagnosis of Leigh syndrome (see 256000) (summary by Barca et al., 2018). For a discussion of genetic heterogeneity of mitochondrial complex V deficiency, see MC5DN1 (604273).
Mitochondrial complex 3 deficiency, nuclear type 10
MedGen UID:
1719382
Concept ID:
C5394051
Disease or Syndrome
Pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal
MedGen UID:
1716458
Concept ID:
C5394137
Disease or Syndrome
Neonatal lethal pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome (PHRINL) is an autosomal recessive multisystem disorder with onset in utero and death in the neonatal period. Rare patients may survive a few months. Affected infants show respiratory insufficiency and almost no spontaneous movement at birth, usually requiring mechanical ventilation and admission to the neonatal intensive care unit. Additional features include corneal clouding, seizures, dysmorphic facies, contractures, and progressive pontocerebellar hypoplasia with simplified gyral pattern and white matter abnormalities. Some patients may have cardiac anomalies or cardiac hypertrophy. Laboratory studies show evidence consistent with mitochondrial defects and/or abnormal cholesterol or lipid metabolism. Depending on the type of mutation or deletion, some patients may have a less severe disorder (see GENOTYPE/PHENOTYPE CORRELATIONS) (summary by Desai et al., 2017).
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).
Combined oxidative phosphorylation deficiency 40
MedGen UID:
1714731
Concept ID:
C5394232
Disease or Syndrome
Combined oxidative phosphorylation deficiency-40 (COXPD40) is an autosomal recessive mitochondrial disorder with onset in utero or soon after birth. Affected individuals have severe hypertrophic cardiomyopathy, poor growth, and sensorineural hearing loss. Laboratory studies show evidence of mitochondrial dysfunction, such as lactic acidosis. Patient-derived tissues and cells show variably decreased activities of mitochondrial respiratory complexes I, III, IV, and V. The disorder is lethal, with no reported patients surviving past infancy (summary by Friederich et al., 2018). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
Combined oxidative phosphorylation deficiency 44
MedGen UID:
1718899
Concept ID:
C5394293
Disease or Syndrome
Combined oxidative phosphorylation deficiency-44 (COXPD44) is an autosomal recessive mitochondrial disorder with multisystemic manifestations. Most affected individuals present in infancy or early childhood with global developmental delay, hypotonia, and abnormal movements. Most patients develop seizures, often associated with status epilepticus, and some patients may have optic atrophy. One patient with hypertrophic cardiomyopathy has been reported. Serum lactate may be increased, although that finding is inconsistent. Detailed biochemical analysis shows variable combined deficiencies of mitochondrial oxidative complexes that appear to be tissue-specific (summary by Wei et al., 2020). For discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).
Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency
MedGen UID:
1748867
Concept ID:
C5399977
Disease or Syndrome
Mitochondrial complex IV deficiency nuclear type 2 (MC4DN2) is an autosomal recessive multisystem metabolic disorder characterized by the onset of symptoms at birth or in the first weeks or months of life. Affected individuals have severe hypotonia, often associated with feeding difficulties and respiratory insufficiency necessitating tube feeding and mechanical ventilation. The vast majority of patients develop hypertrophic cardiomyopathy in the first days or weeks of life, which usually leads to death in infancy or early childhood. Patients also show neurologic abnormalities, including developmental delay, nystagmus, fasciculations, dystonia, EEG changes, and brain imaging abnormalities compatible with a diagnosis of Leigh syndrome (see 256000). There may also be evidence of systemic involvement with hepatomegaly and myopathy, although neurogenic muscle atrophy is more common and may resemble spinal muscular atrophy type I (SMA1; 253300). Serum lactate is increased, and laboratory studies show decreased mitochondrial complex IV protein and activity levels in various tissues, including heart and skeletal muscle. Most patients die in infancy of cardiorespiratory failure (summary by Papadopoulou et al., 1999). For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see 220110.
Mitochondrial complex IV deficiency
MedGen UID:
1750917
Concept ID:
C5435656
Disease or Syndrome
Mitochondrial complex IV deficiency nuclear type 1 (MC4DN1) is an autosomal recessive metabolic disorder characterized by rapidly progressive neurodegeneration and encephalopathy with loss of motor and cognitive skills between about 5 and 18 months of age after normal early development. Affected individuals show hypotonia, failure to thrive, loss of the ability to sit or walk, poor communication, and poor eye contact. Other features may include oculomotor abnormalities, including slow saccades, strabismus, ophthalmoplegia, and nystagmus, as well as deafness, apneic episodes, ataxia, tremor, and brisk tendon reflexes. Brain imaging shows bilateral symmetric lesions in the basal ganglia, consistent with a clinical diagnosis of Leigh syndrome (see 256000). Some patients may also have abnormalities in the brainstem and cerebellum. Laboratory studies usually show increased serum and CSF lactate and decreased levels and activity of mitochondrial respiratory complex IV in patient tissues. There is phenotypic variability, but death in childhood, often due to central respiratory failure, is common (summary by Tiranti et al., 1998; Tiranti et al., 1999; Teraoka et al., 1999; Poyau et al., 2000) Genetic Heterogeneity of Mitochondrial Complex IV Deficiency Most isolated COX deficiencies are inherited as autosomal recessive disorders caused by mutations in nuclear-encoded genes; mutations in the mtDNA-encoded COX subunit genes are relatively rare (Shoubridge, 2001; Sacconi et al., 2003). Mitochondrial complex IV deficiency caused by mutation in nuclear-encoded genes, in addition to MC4DN1, include MC4DN2 (604377), caused by mutation in the SCO2 gene (604272); MC4DN3 (619046), caused by mutation in the COX10 gene (602125); MC4DN4 (619048), caused by mutation in the SCO1 gene (603664); MC4DN5 (220111), caused by mutation in the LRPPRC gene (607544); MC4DN6 (615119), caused by mutation in the COX15 gene (603646); MC4DN7 (619051), caused by mutation in the COX6B1 gene (124089); MC4DN8 (619052), caused by mutation in the TACO1 gene (612958); MC4DN9 (616500), caused by mutation in the COA5 gene (613920); MC4DN10 (619053), caused by mutation in the COX14 gene (614478); MC4DN11 (619054), caused by mutation in the COX20 gene (614698); MC4DN12 (619055), caused by mutation in the PET100 gene (614770); MC4DN13 (616501), caused by mutation in the COA6 gene (614772); MC4DN14 (619058), caused by mutation in the COA3 gene (614775); MC4DN15 (619059), caused by mutation in the COX8A gene (123870); MC4DN16 (619060), caused by mutation in the COX4I1 gene (123864); MC4DN17 (619061), caused by mutation in the APOPT1 gene (616003); MC4DN18 (619062), caused by mutation in the COX6A2 gene (602009); MC4DN19 (619063), caused by mutation in the PET117 gene (614771); MC4DN20 (619064), caused by mutation in the COX5A gene (603773); and MC4DN21 (619065), caused by mutation in the COXFA4 gene (603883). Mitochondrial complex IV deficiency has been associated with mutations in several mitochondrial genes, including MTCO1 (516030), MTCO2 (516040), MTCO3 (516050), MTTS1 (590080), MTTL1 (590050), and MTTN (590010).
Mitochondrial complex 4 deficiency, nuclear type 7
MedGen UID:
1754683
Concept ID:
C5436685
Disease or Syndrome
Mitochondrial complex IV deficiency nuclear type 7 (MC4DN7) is an autosomal recessive metabolic encephalomyopathic disorder with highly variable manifestations. Only a few patients have been reported. Some patients have normal early development then show rapid neurodegeneration with progressive muscle weakness, gait disturbances, and cognitive decline in mid to late childhood. Other features may include seizures and visual impairment. Brain imaging shows progressive leukodystrophy with cystic lesions. In contrast, at least 1 patient has been reported who presented in the neonatal period with metabolic acidosis, hydrocephalus, hypotonia, and cortical blindness. This patient developed hypertrophic cardiomyopathy resulting in early death. All patients had increased serum lactate and decreased levels and activity of mitochondrial respiratory complex IV (summary by Massa et al., 2008 and Abdulhag et al., 2015). For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see 220110.
Mitochondrial complex 4 deficiency, nuclear type 10
MedGen UID:
1746545
Concept ID:
C5436692
Disease or Syndrome
Mitochondrial complex IV deficiency nuclear type 10 (MC4DN10) is an autosomal recessive multisystem metabolic disorder characterized by the onset of severe symptoms soon after birth. Affected infants have respiratory and neurologic distress, metabolic lactic acidosis, and dysmorphic features, including microphthalmia. Death occurs in early infancy. Postmortem examination has demonstrated systemic involvement with hepatomegaly, hypertrophic cardiomyopathy, renal hypoplasia, and adrenal hyperplasia. There is also abnormal brain myelination and cavitating brain lesions. Patient tissues show decreased levels and activity of mitochondrial respiratory complex IV (summary by Weraarpachai et al., 2012). For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see 220110.
Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities
MedGen UID:
1750805
Concept ID:
C5436848
Disease or Syndrome
Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities (NEDCASB) is an autosomal recessive multisystemic disorder characterized by global neurodevelopmental delay, severely impaired intellectual development, poor overall growth, and spasticity of the lower limbs resulting in gait difficulties. Most affected individuals also develop progressive hypertrophic cardiomyopathy in childhood or have cardiac developmental anomalies. Additional more variable features include dysmorphic facies and axonal sensory peripheral neuropathy. Brain imaging tends to show thin corpus callosum and polymicrogyria (summary by Garcia-Cazorla et al., 2020).
Maple syrup urine disease, type 3
MedGen UID:
449386
Concept ID:
CN043137
Disease or Syndrome
The phenotypes of dihydrolipoamide dehydrogenase (DLD) deficiency are an overlapping continuum that ranges from early-onset neurologic manifestations to adult-onset liver involvement and, rarely, a myopathic presentation. Early-onset DLD deficiency typically manifests in infancy as hypotonia with lactic acidosis. Affected infants frequently do not survive their initial metabolic decompensation, or die within the first few years of life during a recurrent metabolic decompensation. Children who live beyond the first two to three years frequently exhibit growth deficiencies and residual neurologic deficits (intellectual disability, spasticity, ataxia, and seizures). In contrast, isolated liver involvement can present as early as the neonatal period and as late as the third decade. Evidence of liver injury/failure is preceded by nausea and emesis and frequently associated with encephalopathy and/or coagulopathy. Acute metabolic episodes are frequently associated with lactate elevations, hyperammonemia, and hepatomegaly. With resolution of the acute episodes affected individuals frequently return to baseline with no residual neurologic deficit or intellectual disability. Liver failure can result in death, even in those with late-onset disease. Individuals with the myopathic presentation may experience muscle cramps, weakness, and an elevated creatine kinase.
Myosin storage myopathy
MedGen UID:
374868
Concept ID:
C1842160
Disease or Syndrome
Myosin storage myopathy, also known as hyaline body myopathy, is a congenital myopathy characterized by the accumulation of ATPase and antibody positive myosin in hyaline subsarcolemmal bodies in type I muscle fibers. The clinical features are variable, with different patients displaying proximal, scapuloperoneal, or generalized weakness and progressive or nonprogressive courses (summary by Dye et al., 2006).

Recent clinical studies

Etiology

Butters A, Semsarian CR, Bagnall RD, Yeates L, Stafford F, Burns C, Semsarian C, Ingles J
Circ Heart Fail 2021 Mar;14(3):e007537. Epub 2021 Mar 16 doi: 10.1161/CIRCHEARTFAILURE.120.007537. PMID: 33724884
Alis D, Asmakutlu O, Topel C, Karaarslan E
Pediatr Radiol 2021 Apr;51(4):594-604. Epub 2021 Jan 20 doi: 10.1007/s00247-020-04884-x. PMID: 33474633
Cui H, Schaff HV, Dearani JA, Lahr BD, Viehman JK, Geske JB, Nishimura RA, Ommen SR
J Thorac Cardiovasc Surg 2021 Mar;161(3):997-1006.e3. Epub 2020 Aug 25 doi: 10.1016/j.jtcvs.2020.08.066. PMID: 32977972
Darwish RK, Haghighi A, Seliem ZS, El-Saiedi SA, Radwan NH, El-Gayar DF, Elfeel NS, Abouelhoda M, Mehaney DA
Cardiol Young 2020 Dec;30(12):1910-1916. Epub 2020 Oct 5 doi: 10.1017/S1047951120003157. PMID: 33012304
Montenegro Sá F, Oliveira M, Belo A, Correia J, Azevedo O, Morais J; Portuguese Registry of Hypertrophic Cardiomyopathy investigators.
Rev Esp Cardiol (Engl Ed) 2020 Dec;73(12):1018-1025. Epub 2020 Feb 28 doi: 10.1016/j.rec.2020.01.007. PMID: 32115394

Diagnosis

Alis D, Asmakutlu O, Topel C, Karaarslan E
Pediatr Radiol 2021 Apr;51(4):594-604. Epub 2021 Jan 20 doi: 10.1007/s00247-020-04884-x. PMID: 33474633
Cui H, Schaff HV, Dearani JA, Lahr BD, Viehman JK, Geske JB, Nishimura RA, Ommen SR
J Thorac Cardiovasc Surg 2021 Mar;161(3):997-1006.e3. Epub 2020 Aug 25 doi: 10.1016/j.jtcvs.2020.08.066. PMID: 32977972
Darwish RK, Haghighi A, Seliem ZS, El-Saiedi SA, Radwan NH, El-Gayar DF, Elfeel NS, Abouelhoda M, Mehaney DA
Cardiol Young 2020 Dec;30(12):1910-1916. Epub 2020 Oct 5 doi: 10.1017/S1047951120003157. PMID: 33012304
Chung H, Park CH, Kim Y, Kim JY, Min PK, Yoon YW, Lee KA, Lee BK, Hong BK, Kim TH, Rim SJ, Kwon HM, Choi EY
Clin Cardiol 2020 Nov;43(11):1317-1325. Epub 2020 Aug 20 doi: 10.1002/clc.23445. PMID: 32815161Free PMC Article
Montenegro Sá F, Oliveira M, Belo A, Correia J, Azevedo O, Morais J; Portuguese Registry of Hypertrophic Cardiomyopathy investigators.
Rev Esp Cardiol (Engl Ed) 2020 Dec;73(12):1018-1025. Epub 2020 Feb 28 doi: 10.1016/j.rec.2020.01.007. PMID: 32115394

Therapy

Khan N, Chitturi KR, Hatcher C, Clewing M, Nagueh SF
Methodist Debakey Cardiovasc J 2021 Apr 5;17(1):65-67. Epub 2021 Mar 25 doi: 10.14797/VRZW9460. PMID: 34104323Free PMC Article
Cui H, Schaff HV, Dearani JA, Lahr BD, Viehman JK, Geske JB, Nishimura RA, Ommen SR
J Thorac Cardiovasc Surg 2021 Mar;161(3):997-1006.e3. Epub 2020 Aug 25 doi: 10.1016/j.jtcvs.2020.08.066. PMID: 32977972
Ho CY, Mealiffe ME, Bach RG, Bhattacharya M, Choudhury L, Edelberg JM, Hegde SM, Jacoby D, Lakdawala NK, Lester SJ, Ma Y, Marian AJ, Nagueh SF, Owens A, Rader F, Saberi S, Sehnert AJ, Sherrid MV, Solomon SD, Wang A, Wever-Pinzon O, Wong TC, Heitner SB
J Am Coll Cardiol 2020 Jun 2;75(21):2649-2660. doi: 10.1016/j.jacc.2020.03.064. PMID: 32466879
Wang S, Cui H, Ji K, Song C, Ren C, Guo H, Zhu C, Wang S, Lai Y
Cardiovasc Diabetol 2020 May 13;19(1):64. doi: 10.1186/s12933-020-01036-1. PMID: 32404127Free PMC Article
Kimmelstiel C, Zisa DC, Kuttab JS, Wells S, Udelson JE, Wessler BS, Rastegar H, Kapur NK, Weintraub AR, Maron BJ, Maron MS, Rowin EJ
Circ Cardiovasc Interv 2019 Jul;12(7):e007673. Epub 2019 Jul 12 doi: 10.1161/CIRCINTERVENTIONS.118.007673. PMID: 31296080Free PMC Article

Prognosis

Gonçalves AV, Rosa SA, Branco L, Galrinho A, Fiarresga A, Lopes LR, Thomas B, Baquero L, Carmo MM, Ferreira RC
Int J Cardiovasc Imaging 2021 Jul;37(7):2237-2244. Epub 2021 Feb 17 doi: 10.1007/s10554-021-02186-3. PMID: 33598850
Chung H, Park CH, Kim Y, Kim JY, Min PK, Yoon YW, Lee KA, Lee BK, Hong BK, Kim TH, Rim SJ, Kwon HM, Choi EY
Clin Cardiol 2020 Nov;43(11):1317-1325. Epub 2020 Aug 20 doi: 10.1002/clc.23445. PMID: 32815161Free PMC Article
Montenegro Sá F, Oliveira M, Belo A, Correia J, Azevedo O, Morais J; Portuguese Registry of Hypertrophic Cardiomyopathy investigators.
Rev Esp Cardiol (Engl Ed) 2020 Dec;73(12):1018-1025. Epub 2020 Feb 28 doi: 10.1016/j.rec.2020.01.007. PMID: 32115394
Yang J, Wang L, Sun T, Guo Q, Liu F, Zhou Y
Perfusion 2020 Jul;35(5):384-392. Epub 2019 Nov 1 doi: 10.1177/0267659119883996. PMID: 31674878
Kimmelstiel C, Zisa DC, Kuttab JS, Wells S, Udelson JE, Wessler BS, Rastegar H, Kapur NK, Weintraub AR, Maron BJ, Maron MS, Rowin EJ
Circ Cardiovasc Interv 2019 Jul;12(7):e007673. Epub 2019 Jul 12 doi: 10.1161/CIRCINTERVENTIONS.118.007673. PMID: 31296080Free PMC Article

Clinical prediction guides

Gonçalves AV, Rosa SA, Branco L, Galrinho A, Fiarresga A, Lopes LR, Thomas B, Baquero L, Carmo MM, Ferreira RC
Int J Cardiovasc Imaging 2021 Jul;37(7):2237-2244. Epub 2021 Feb 17 doi: 10.1007/s10554-021-02186-3. PMID: 33598850
Alis D, Asmakutlu O, Topel C, Karaarslan E
Pediatr Radiol 2021 Apr;51(4):594-604. Epub 2021 Jan 20 doi: 10.1007/s00247-020-04884-x. PMID: 33474633
Montenegro Sá F, Oliveira M, Belo A, Correia J, Azevedo O, Morais J; Portuguese Registry of Hypertrophic Cardiomyopathy investigators.
Rev Esp Cardiol (Engl Ed) 2020 Dec;73(12):1018-1025. Epub 2020 Feb 28 doi: 10.1016/j.rec.2020.01.007. PMID: 32115394
Yang J, Wang L, Sun T, Guo Q, Liu F, Zhou Y
Perfusion 2020 Jul;35(5):384-392. Epub 2019 Nov 1 doi: 10.1177/0267659119883996. PMID: 31674878
Kimmelstiel C, Zisa DC, Kuttab JS, Wells S, Udelson JE, Wessler BS, Rastegar H, Kapur NK, Weintraub AR, Maron BJ, Maron MS, Rowin EJ
Circ Cardiovasc Interv 2019 Jul;12(7):e007673. Epub 2019 Jul 12 doi: 10.1161/CIRCINTERVENTIONS.118.007673. PMID: 31296080Free PMC Article

Recent systematic reviews

Papanastasiou CA, Zegkos T, Karamitsos TD, Rowin EJ, Maron MS, Parcharidou D, Kokkinidis DG, Karvounis H, Rimoldi O, Maron BJ, Efthimiadis GK
Int J Cardiol 2021 Jun 1;332:127-132. Epub 2021 Mar 29 doi: 10.1016/j.ijcard.2021.03.056. PMID: 33794232
Kamp NJ, Chery G, Kosinski AS, Desai MY, Wazni O, Schmidler GS, Patel M, Lopes RD, Morin DP, Al-Khatib SM
Prog Cardiovasc Dis 2021 May-Jun;66:10-16. Epub 2020 Nov 7 doi: 10.1016/j.pcad.2020.11.001. PMID: 33171204
Zhou Y, He W, Zhou Y, Zhu W
J Thromb Thrombolysis 2020 Aug;50(2):311-317. doi: 10.1007/s11239-019-02008-3. PMID: 31792707
Tower-Rader A, Mohananey D, To A, Lever HM, Popovic ZB, Desai MY
JACC Cardiovasc Imaging 2019 Oct;12(10):1930-1942. Epub 2018 Sep 12 doi: 10.1016/j.jcmg.2018.07.016. PMID: 30219395
Norrish G, Cantarutti N, Pissaridou E, Ridout DA, Limongelli G, Elliott PM, Kaski JP
Eur J Prev Cardiol 2017 Jul;24(11):1220-1230. Epub 2017 May 9 doi: 10.1177/2047487317702519. PMID: 28482693

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