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Mitochondrial complex I deficiency(MC1DN1)

MedGen UID:
374101
Concept ID:
C1838979
Disease or Syndrome
Synonyms: Complex 1 mitochondrial respiratory chain deficiency; Mitochondrial Respiratory Chain Complex I Deficiency; NADH coenzyme Q reductase deficiency
SNOMED CT: Nicotinamide adenine dinucleotide coenzyme Q reductase deficiency (237988006); Complex I deficiency (237988006); NADH - Nicotinamide adenine dinucleotide coenzyme Q reductase deficiency (237988006); Mitochondrial complex I deficiency (237988006)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Mitochondrial inheritance
MedGen UID:
165802
Concept ID:
C0887941
Genetic Function
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on the mitochondrial genome. Because the mitochondrial genome is essentially always maternally inherited, a mitochondrial condition can only be transmitted by females, although the condition can affect both sexes. The proportion of mutant mitochondria can vary (heteroplasmy).
X-linked dominant inheritance
MedGen UID:
376232
Concept ID:
C1847879
Finding
Source: Orphanet
A mode of inheritance that is observed for dominant traits related to a gene encoded on the X chromosome. In the context of medical genetics, X-linked dominant disorders tend to manifest very severely in affected males. The severity of manifestation in females may depend on the degree of skewed X inactivation.
 
Related gene: NDUFS4
 
Monarch Initiative: MONDO:0100133
OMIM®: 252010; 516001; 516003; 602694
Orphanet: ORPHA2609

Definition

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). [from ORDO]

Clinical features

From HPO
Exercise intolerance
MedGen UID:
603270
Concept ID:
C0424551
Finding
A functional motor deficit where individuals whose responses to the challenges of exercise fail to achieve levels considered normal for their age and gender.
Hypospadias
MedGen UID:
163083
Concept ID:
C0848558
Congenital Abnormality
Abnormal position of urethral meatus on the ventral penile shaft (underside) characterized by displacement of the urethral meatus from the tip of the glans penis to the ventral surface of the penis, scrotum, or perineum.
3-hydroxydicarboxylic aciduria
MedGen UID:
870283
Concept ID:
C4024725
Finding
The concentration of 2-hydroxydicarboxylic acid in the urine, normalized for urine concentration, is above the upper limit of normal.
Lacticaciduria
MedGen UID:
871116
Concept ID:
C4025585
Finding
An increased concentration of lactic acid in the urine.
Hypertrophic cardiomyopathy
MedGen UID:
2881
Concept ID:
C0007194
Disease or Syndrome
Hypertrophic cardiomyopathy (HCM) is defined by the presence of increased ventricular wall thickness or mass in the absence of loading conditions (hypertension, valve disease) sufficient to cause the observed abnormality.
Concentric hypertrophic cardiomyopathy
MedGen UID:
68651
Concept ID:
C0238044
Finding
Hypertrophic cardiomyopathy with an symmetrical and concentric pattern of hypertrophy.
Growth delay
MedGen UID:
99124
Concept ID:
C0456070
Pathologic Function
A deficiency or slowing down of growth pre- and postnatally.
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Vomiting
MedGen UID:
12124
Concept ID:
C0042963
Sign or Symptom
Forceful ejection of the contents of the stomach through the mouth by means of a series of involuntary spasmic contractions.
Liver failure
MedGen UID:
88444
Concept ID:
C0085605
Disease or Syndrome
A disorder characterized by the inability of the liver to metabolize chemicals in the body. Causes include cirrhosis and drug-induced hepatotoxicity. Signs and symptoms include jaundice and encephalopathy. Laboratory test results reveal abnormal plasma levels of ammonia, bilirubin, lactic dehydrogenase, and alkaline phosphatase.
Feeding difficulties in infancy
MedGen UID:
436211
Concept ID:
C2674608
Finding
Impaired feeding performance of an infant as manifested by difficulties such as weak and ineffective sucking, brief bursts of sucking, and falling asleep during sucking. There may be difficulties with chewing or maintaining attention.
Sensorineural hearing loss disorder
MedGen UID:
9164
Concept ID:
C0018784
Disease or Syndrome
A type of hearing impairment in one or both ears related to an abnormal functionality of the cochlear nerve.
Cerebral edema
MedGen UID:
2337
Concept ID:
C0006114
Pathologic Function
Abnormal accumulation of fluid in the brain.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Coma
MedGen UID:
1054
Concept ID:
C0009421
Disease or Syndrome
The complete absence of wakefulness and consciousness, which is evident through a lack of response to any form of external stimuli.
Dyskinesia
MedGen UID:
8514
Concept ID:
C0013384
Disease or Syndrome
A movement disorder which consists of effects including diminished voluntary movements and the presence of involuntary movements.
Lethargy
MedGen UID:
7310
Concept ID:
C0023380
Sign or Symptom
A state of disinterest, listlessness, and indifference, resulting in difficulty performing simple tasks or concentrating.
Leukodystrophy
MedGen UID:
6070
Concept ID:
C0023520
Disease or Syndrome
Leukodystrophy refers to deterioration of white matter of the brain resulting from degeneration of myelin sheaths in the CNS. Their basic defect is directly related to the synthesis and maintenance of myelin membranes. Symmetric white matter involvement at MRI is a typical finding in patients with leukodystrophies.
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
Babinski sign
MedGen UID:
19708
Concept ID:
C0034935
Finding
Upturning of the big toe (and sometimes fanning of the other toes) in response to stimulation of the sole of the foot. If the Babinski sign is present it can indicate damage to the corticospinal tract.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
Leukoencephalopathy
MedGen UID:
78722
Concept ID:
C0270612
Disease or Syndrome
This term describes abnormality of the white matter of the cerebrum resulting from damage to the myelin sheaths of nerve cells.
Bilateral tonic-clonic seizure
MedGen UID:
141670
Concept ID:
C0494475
Sign or Symptom
A bilateral tonic-clonic seizure is a seizure defined by a tonic (bilateral increased tone, lasting seconds to minutes) and then a clonic (bilateral sustained rhythmic jerking) phase.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Hyporeflexia
MedGen UID:
195967
Concept ID:
C0700078
Finding
Reduction of neurologic reflexes such as the knee-jerk reaction.
Cerebellar atrophy
MedGen UID:
196624
Concept ID:
C0740279
Disease or Syndrome
Cerebellar atrophy is defined as a cerebellum with initially normal structures, in a posterior fossa with normal size, which displays enlarged fissures (interfolial spaces) in comparison to the foliae secondary to loss of tissue. Cerebellar atrophy implies irreversible loss of tissue and result from an ongoing progressive disease until a final stage is reached or a single injury, e.g. an intoxication or infectious event.
Increased CSF lactate
MedGen UID:
257904
Concept ID:
C1167918
Finding
Increased concentration of lactate in the cerebrospinal fluid.
Reduced eye contact
MedGen UID:
303190
Concept ID:
C1445953
Finding
A reduced frequency or duration of eye contact.
Increased CSF protein concentration
MedGen UID:
329971
Concept ID:
C1806780
Finding
Increased concentration of protein in the cerebrospinal fluid.
Developmental regression
MedGen UID:
324613
Concept ID:
C1836830
Disease or Syndrome
Loss of developmental skills, as manifested by loss of developmental milestones.
Acute necrotizing encephalopathy
MedGen UID:
343241
Concept ID:
C1855020
Disease or Syndrome
Focal T2 hypointense basal ganglia lesion
MedGen UID:
868350
Concept ID:
C4022744
Finding
A darker than expected T2 signal on magnetic resonance imaging (MRI) of the basal ganglia. This term refers to a localized hypointensity affecting a particular region of the basal ganglia.
Focal T2 hyperintense basal ganglia lesion
MedGen UID:
892349
Concept ID:
C4024926
Finding
A lighter than expected T2 signal on magnetic resonance imaging (MRI) of the basal ganglia. This term refers to a localized hyperintensity affecting a particular region of the basal ganglia.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Muscle weakness
MedGen UID:
57735
Concept ID:
C0151786
Finding
Reduced strength of muscles.
Muscular atrophy
MedGen UID:
892680
Concept ID:
C0541794
Pathologic Function
The presence of skeletal muscular atrophy (which is also known as amyotrophy).
Poor head control
MedGen UID:
322809
Concept ID:
C1836038
Finding
Difficulty to maintain correct position of the head while standing or sitting.
Progressive macrocephaly
MedGen UID:
395368
Concept ID:
C1859896
Finding
The progressive development of an abnormally large skull.
Ragged-red muscle fibers
MedGen UID:
477048
Concept ID:
C3275417
Finding
An abnormal appearance of muscle fibers observed on muscle biopsy. Ragged red fibers can be visualized with Gomori trichrome staining as irregular and intensely red subsarcolemmal zones, whereas the normal myofibrils are green. The margins of affect fibers appear red and ragged. The ragged-red is due to the accumulation of abnormal mitochondria below the plasma membrane of the muscle fiber, leading to the appearance of a red rim and speckled sarcoplasm.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Apnea
MedGen UID:
2009
Concept ID:
C0003578
Sign or Symptom
Lack of breathing with no movement of the respiratory muscles and no exchange of air in the lungs. This term refers to a disposition to have recurrent episodes of apnea rather than to a single event.
Respiratory insufficiency
MedGen UID:
11197
Concept ID:
C0035229
Pathologic Function
Impairment of gas exchange within the lungs secondary to a disease process, neoplasm, or trauma, possibly resulting in hypoxia, hypercarbia, or both, but not requiring intubation or mechanical ventilation. Patients are normally managed with pharmaceutical therapy, supplemental oxygen, or both.
Respiratory failure
MedGen UID:
257837
Concept ID:
C1145670
Disease or Syndrome
A severe form of respiratory insufficiency characterized by inadequate gas exchange such that the levels of oxygen or carbon dioxide cannot be maintained within normal limits.
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Abnormal increased size of the spleen.
Lactic acidosis
MedGen UID:
1717
Concept ID:
C0001125
Disease or Syndrome
An abnormal buildup of lactic acid in the body, leading to acidification of the blood and other bodily fluids.
Hypoglycemia
MedGen UID:
6979
Concept ID:
C0020615
Disease or Syndrome
A decreased concentration of glucose in the blood.
Hyper-beta-alaninemia
MedGen UID:
75702
Concept ID:
C0268630
Disease or Syndrome
An increased concentration of alanine in the blood.
Severe lactic acidosis
MedGen UID:
374223
Concept ID:
C1839436
Finding
A severe form of lactic acidemia.
Increased intramyocellular lipid droplets
MedGen UID:
866481
Concept ID:
C4020730
Finding
An abnormal increase in intracellular lipid droplets In a muscle. The number and size of these drops can increase with somd disorders of lipid metabolism affecting muscle. See PMID 20691590 for histological images.
Elevated lactate:pyruvate ratio
MedGen UID:
1717835
Concept ID:
C5397670
Finding
An abnormal increase in the molar ratio of lactate to pyruvate in the blood circulation.
Tongue fasciculations
MedGen UID:
65987
Concept ID:
C0239548
Finding
Fasciculations or fibrillation affecting the tongue muscle.
Upslanted palpebral fissure
MedGen UID:
98390
Concept ID:
C0423109
Finding
The palpebral fissure inclination is more than two standard deviations above the mean for age (objective); or, the inclination of the palpebral fissure is greater than typical for age.
Short chin
MedGen UID:
784514
Concept ID:
C3697248
Finding
Decreased vertical distance from the vermilion border of the lower lip to the inferior-most point of the chin.
Cyanosis
MedGen UID:
1189
Concept ID:
C0010520
Sign or Symptom
Bluish discoloration of the skin and mucosa due to poor circulation or inadequate oxygenation of arterial or capillary blood.
Ptosis
MedGen UID:
2287
Concept ID:
C0005745
Disease or Syndrome
The upper eyelid margin is positioned 3 mm or more lower than usual and covers the superior portion of the iris (objective); or, the upper lid margin obscures at least part of the pupil (subjective).
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Rhythmic, involuntary oscillations of one or both eyes related to abnormality in fixation, conjugate gaze, or vestibular mechanisms.
Strabismus
MedGen UID:
21337
Concept ID:
C0038379
Disease or Syndrome
A misalignment of the eyes so that the visual axes deviate from bifoveal fixation. The classification of strabismus may be based on a number of features including the relative position of the eyes, whether the deviation is latent or manifest, intermittent or constant, concomitant or otherwise and according to the age of onset and the relevance of any associated refractive error.
Blindness
MedGen UID:
99138
Concept ID:
C0456909
Disease or Syndrome
Blindness is the condition of lacking visual perception defined as visual perception below 3/60 and/or a visual field of no greater than 10 degrees in radius around central fixation.
Optic disc pallor
MedGen UID:
108218
Concept ID:
C0554970
Finding
A pale yellow discoloration of the optic disk (the area of the optic nerve head in the retina). The optic disc normally has a pinkish hue with a central yellowish depression.
Undetectable visual evoked potentials
MedGen UID:
376697
Concept ID:
C1850069
Finding
Optic neuropathy
MedGen UID:
854546
Concept ID:
C3887709
Disease or Syndrome
Disorder of the optic nerve.
Decreased activity of mitochondrial complex I
MedGen UID:
393796
Concept ID:
C2677650
Finding
A reduction in the activity of the mitochondrial respiratory chain complex I, which is part of the electron transport chain in mitochondria.
Decreased activity of mitochondrial complex III
MedGen UID:
460434
Concept ID:
C3149083
Finding
A reduction in the activity of the mitochondrial respiratory chain complex III, which is part of the electron transport chain in mitochondria.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  

Professional guidelines

PubMed

Koopman WJ, Beyrath J, Fung CW, Koene S, Rodenburg RJ, Willems PH, Smeitink JA
EMBO Mol Med 2016 Apr 1;8(4):311-27. doi: 10.15252/emmm.201506131. PMID: 26951622Free PMC Article
Nouws J, Nijtmans LG, Smeitink JA, Vogel RO
Brain 2012 Jan;135(Pt 1):12-22. Epub 2011 Oct 27 doi: 10.1093/brain/awr261. PMID: 22036961

Recent clinical studies

Etiology

Choong CJ, Mochizuki H
Int J Mol Sci 2023 Dec 1;24(23) doi: 10.3390/ijms242317027. PMID: 38069350Free PMC Article
van de Wal MAE, Adjobo-Hermans MJW, Keijer J, Schirris TJJ, Homberg JR, Wieckowski MR, Grefte S, van Schothorst EM, van Karnebeek C, Quintana A, Koopman WJH
Brain 2022 Mar 29;145(1):45-63. doi: 10.1093/brain/awab426. PMID: 34849584Free PMC Article
Ehinger JK, Piel S, Ford R, Karlsson M, Sjövall F, Frostner EÅ, Morota S, Taylor RW, Turnbull DM, Cornell C, Moss SJ, Metzsch C, Hansson MJ, Fliri H, Elmér E
Nat Commun 2016 Aug 9;7:12317. doi: 10.1038/ncomms12317. PMID: 27502960Free PMC Article
Blanchet L, Buydens MC, Smeitink JA, Willems PH, Koopman WJ
Curr Pharm Des 2011 Dec 1;17(36):4023-33. doi: 10.2174/138161211798764870. PMID: 22188452
Koene S, Willems PH, Roestenberg P, Koopman WJ, Smeitink JA
J Inherit Metab Dis 2011 Apr;34(2):293-307. Epub 2010 Jan 27 doi: 10.1007/s10545-009-9005-x. PMID: 20107904

Diagnosis

Kimonis V, Al Dubaisi R, Maclean AE, Hall K, Weiss L, Stover AE, Schwartz PH, Berg B, Cheng C, Parikh S, Conner BR, Wu S, Hasso AN, Scott DA, Koenig MK, Karam R, Tang S, Smith M, Chao E, Balk J, Hatchwell E, Eis PS
J Med Genet 2021 May;58(5):314-325. Epub 2020 Jun 9 doi: 10.1136/jmedgenet-2020-106846. PMID: 32518176
Reinson K, Õunap K
EMBO Mol Med 2020 Nov 6;12(11):e13187. Epub 2020 Oct 30 doi: 10.15252/emmm.202013187. PMID: 33124751Free PMC Article
Alfadhel M, Nashabat M, Abu Ali Q, Hundallah K
Neurosciences (Riyadh) 2017 Jan;22(1):4-13. doi: 10.17712/nsj.2017.1.20160542. PMID: 28064324Free PMC Article
Koopman WJ, Beyrath J, Fung CW, Koene S, Rodenburg RJ, Willems PH, Smeitink JA
EMBO Mol Med 2016 Apr 1;8(4):311-27. doi: 10.15252/emmm.201506131. PMID: 26951622Free PMC Article
Fassone E, Rahman S
J Med Genet 2012 Sep;49(9):578-90. doi: 10.1136/jmedgenet-2012-101159. PMID: 22972949

Therapy

Hsieh VC, Niezgoda J, Sedensky MM, Hoppel CL, Morgan PG
Anesth Analg 2021 Oct 1;133(4):924-932. doi: 10.1213/ANE.0000000000005430. PMID: 33591116Free PMC Article
Schirris TJJ, Rossell S, de Haas R, Frambach SJCM, Hoogstraten CA, Renkema GH, Beyrath JD, Willems PHGM, Huynen MA, Smeitink JAM, Russel FGM, Notebaart RA
Biochim Biophys Acta Mol Basis Dis 2021 Apr 1;1867(4):166062. Epub 2021 Jan 13 doi: 10.1016/j.bbadis.2020.166062. PMID: 33385517
Mathieu L, Lopes Costa A, Le Bachelier C, Slama A, Lebre AS, Taylor RW, Bastin J, Djouadi F
Free Radic Biol Med 2016 Jul;96:190-8. Epub 2016 Apr 25 doi: 10.1016/j.freeradbiomed.2016.04.027. PMID: 27126960
Koopman WJ, Beyrath J, Fung CW, Koene S, Rodenburg RJ, Willems PH, Smeitink JA
EMBO Mol Med 2016 Apr 1;8(4):311-27. doi: 10.15252/emmm.201506131. PMID: 26951622Free PMC Article
Lin BY, Kao MC
Ann N Y Acad Sci 2015 Sep;1350:17-28. Epub 2015 Aug 14 doi: 10.1111/nyas.12858. PMID: 26273800

Prognosis

Tang X, Xu W, Song X, Ye H, Ren X, Yang Y, Zhang H, Wu S, Lan X
Genes Genomics 2022 Jun;44(6):691-698. Epub 2022 Apr 28 doi: 10.1007/s13258-022-01260-x. PMID: 35482246
Huttula S, Väyrynen H, Helisalmi S, Kytövuori L, Luukkainen L, Hiltunen M, Remes AM, Krüger J
Neurobiol Aging 2022 Jun;114:113-116. Epub 2022 Jan 21 doi: 10.1016/j.neurobiolaging.2021.09.026. PMID: 35131137
van de Wal MAE, Adjobo-Hermans MJW, Keijer J, Schirris TJJ, Homberg JR, Wieckowski MR, Grefte S, van Schothorst EM, van Karnebeek C, Quintana A, Koopman WJH
Brain 2022 Mar 29;145(1):45-63. doi: 10.1093/brain/awab426. PMID: 34849584Free PMC Article
Danhelovska T, Kolarova H, Zeman J, Hansikova H, Vaneckova M, Lambert L, Kucerova-Vidrova V, Berankova K, Honzik T, Tesarova M
BMC Pediatr 2020 Jan 29;20(1):41. doi: 10.1186/s12887-020-1912-x. PMID: 31996177Free PMC Article
Piekutowska-Abramczuk D, Assouline Z, Mataković L, Feichtinger RG, Koňařiková E, Jurkiewicz E, Stawiński P, Gusic M, Koller A, Pollak A, Gasperowicz P, Trubicka J, Ciara E, Iwanicka-Pronicka K, Rokicki D, Hanein S, Wortmann SB, Sperl W, Rötig A, Prokisch H, Pronicka E, Płoski R, Barcia G, Mayr JA
Am J Hum Genet 2018 Mar 1;102(3):460-467. Epub 2018 Feb 8 doi: 10.1016/j.ajhg.2018.01.008. PMID: 29429571Free PMC Article

Clinical prediction guides

Choong CJ, Mochizuki H
Int J Mol Sci 2023 Dec 1;24(23) doi: 10.3390/ijms242317027. PMID: 38069350Free PMC Article
Yoon JY, Daneshgar N, Chu Y, Chen B, Hefti M, Vikram A, Irani K, Song LS, Brenner C, Abel ED, London B, Dai DF
Clin Transl Med 2022 Jul;12(7):e954. doi: 10.1002/ctm2.954. PMID: 35872650Free PMC Article
Tang X, Xu W, Song X, Ye H, Ren X, Yang Y, Zhang H, Wu S, Lan X
Genes Genomics 2022 Jun;44(6):691-698. Epub 2022 Apr 28 doi: 10.1007/s13258-022-01260-x. PMID: 35482246
Frambach SJCM, de Haas R, Smeitink JAM, Russel FGM, Schirris TJJ
Life Sci 2022 Jul 1;300:120571. Epub 2022 Apr 22 doi: 10.1016/j.lfs.2022.120571. PMID: 35469913
Reinson K, Õunap K
EMBO Mol Med 2020 Nov 6;12(11):e13187. Epub 2020 Oct 30 doi: 10.15252/emmm.202013187. PMID: 33124751Free PMC Article

Recent systematic reviews

Fassone E, Rahman S
J Med Genet 2012 Sep;49(9):578-90. doi: 10.1136/jmedgenet-2012-101159. PMID: 22972949

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