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Cobalamin C disease(MAHCC)

MedGen UID:
341256
Concept ID:
C1848561
Disease or Syndrome
Synonyms: Cobalamin-C methylmalonic acidemia and homocystinuria; Methylmalonic acidemia and homocystinuria cblC type; methylmalonic aciduria and homocystinuria type cblC; Methylmalonic aciduria and homocystinuria, Vitamin B12-responsive; Vitamin B12 metabolic defect with combined deficiency of methylmalonyl-CoA mutase and homocysteine:methyltetrahydrofolate methyltransferase
SNOMED CT: CblC methylmalonic acidemia and homocystinuria (74653006); Cobalamin locus C variant (74653006); CblC - Cobalamin locus C (74653006); Cobalamin C disease (74653006)
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).
 
Genes (locations): MMACHC (1p34.1); PRDX1 (1p34.1)
 
Monarch Initiative: MONDO:0010184
OMIM®: 277400
Orphanet: ORPHA79282

Disease characteristics

Disorders of intracellular cobalamin metabolism have a variable phenotype and age of onset that are influenced by the severity and location within the pathway of the defect. The prototype and best understood phenotype is cblC; it is also the most common of these disorders. The age of initial presentation of cblC spans a wide range: In utero with fetal presentation of nonimmune hydrops, cardiomyopathy, and intrauterine growth restriction. Newborns, who can have microcephaly, poor feeding, and encephalopathy. Infants, who can have poor feeding and slow growth, neurologic abnormality, and, rarely, hemolytic uremic syndrome (HUS). Toddlers, who can have poor growth, progressive microcephaly, cytopenias (including megaloblastic anemia), global developmental delay, encephalopathy, and neurologic signs such as hypotonia and seizures. Adolescents and adults, who can have neuropsychiatric symptoms, progressive cognitive decline, thromboembolic complications, and/or subacute combined degeneration of the spinal cord. [from GeneReviews]
Authors:
Jennifer L Sloan  |  Nuria Carrillo  |  David Adams, et. al.   view full author information

Additional descriptions

From OMIM
Combined methylmalonic aciduria (MMA) and homocystinuria is a genetically heterogeneous disorder of cobalamin (cbl; vitamin B12) metabolism. The defect causes decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl), which results in decreased activity of the respective enzymes methylmalonyl-CoA mutase (MUT; 609058) and methyltetrahydrofolate:homocysteine methyltransferase, also known as methionine synthase (MTR; 156570). Different forms of the disorder have been classified according to complementation groups of cells in vitro: cblC, cblD (277410), cblF (277380), and cblJ (614857). Isolated methylmalonic acidurias have also been classified by complementation groups: MMA 'mut' (251000) is caused by mutation in the MUT gene on chromosome 6p21; MMA cblA (251100) is caused by mutation in the MMAA gene (607481) on 4q31; and MMA cblB (251110) is caused by mutation in the MMAB gene (607568) on 12q24. Methylmalonic aciduria and homocystinuria of cblC type is the most common inborn error of vitamin B12 (cobalamin) metabolism, with about 250 known cases (Lerner-Ellis et al., 2006). Affected individuals may have developmental, hematologic, neurologic, metabolic, ophthalmologic, and dermatologic clinical findings. Although considered a disease of infancy or childhood, some individuals develop symptoms in adulthood (Rosenblatt et al., 1997).  http://www.omim.org/entry/277400
From MedlinePlus Genetics
Some people with methylmalonic acidemia with homocystinuria develop a blood disorder called megaloblastic anemia. Megaloblastic anemia occurs when a person has a low number of red blood cells (anemia), and the remaining red blood cells are larger than normal (megaloblastic). The signs and symptoms of early-onset methylmalonic acidemia with homocystinuria worsen over time, and the condition can be life-threatening if it is not treated.

The signs and symptoms of methylmalonic acidemia with homocystinuria usually develop in infancy, although they can begin at any age. When the condition begins early in life, affected individuals typically grow more slowly than expected. This sign is sometimes iedentified before the baby is born. These infants can also have difficulty feeding and have an abnormally pale appearance (pallor). Eye abnormalities and neurological problems, including weak muscle tone (hypotonia) and seizures, are also common in people with methylmalonic acidemia with homocystinuria. Many infants and children with this condition have delayed development and intellectual disability, and some have an unusually small head size (microcephaly). 

When methylmalonic acidemia with homocystinuria begins in adolescence or adulthood, it may change an affected person's behavior and personality; the person may become less social and may experience hallucinations, delirium, and psychosis. In addition, these individuals can begin to lose previously acquired mental and physical abilities, resulting in a decline in school or work performance, difficulty controlling movements, memory problems, speech difficulties, a decline in intellectual function (dementia), or an extreme lack of energy (lethargy). Some people with methylmalonic acidemia with homocystinuria whose signs and symptoms begin later in life develop a condition called subacute combined degeneration of the spinal cord, which leads to numbness and weakness in the lower limbs, difficulty walking, and frequent falls.

Methylmalonic acidemia with homocystinuria is a disorder in which the body is unable to correctly process certain protein building blocks (amino acids), fat building blocks (fatty acids), and  cholesterol. The body is also unable to convert the amino acid homocysteine to another amino acid, methionine. Individuals with this disorder have a combination of features from two separate conditions, methylmalonic acidemia and homocystinuria. There are several forms of this combined condition, and the different forms have different genetic causes and signs and symptoms. The most common and best understood form, called cblC type (or cobalamin C disease), occurs in about 80 percent of affected individuals.   https://medlineplus.gov/genetics/condition/methylmalonic-acidemia-with-homocystinuria

Clinical features

From HPO
Hematuria
MedGen UID:
5488
Concept ID:
C0018965
Disease or Syndrome
The presence of blood in the urine. Hematuria may be gross hematuria (visible to the naked eye) or microscopic hematuria (detected by dipstick or microscopic examination of the urine).
Hemolytic-uremic syndrome
MedGen UID:
42403
Concept ID:
C0019061
Disease or Syndrome
A thrombotic microangiopathy with presence of non-immune, intravascular hemolytic anemia, thrombocytopenia and acute kidney injury. A vicious cycle of complement activation, endothelial cell damage, platelet activation, and thrombosis is the hallmark of the disease.
Homocystinuria
MedGen UID:
42485
Concept ID:
C0019880
Disease or Syndrome
Homocystinuria is an inherited disorder in which the body is unable to process certain building blocks of proteins (amino acids) properly. \n\nThe most common form of homocystinuria, called classic homocystinuria, is characterized by tall stature, nearsightedness (myopia), dislocation of the lens at the front of the eye, a higher risk of blood clotting disorders, and brittle bones that are prone to fracture (osteoporosis) or other skeletal abnormalities. Some affected individuals also have developmental delay and learning problems.\n\nLess common forms of homocystinuria can cause intellectual disability, slower growth and weight gain (failure to thrive), seizures, and problems with movement. They can also cause and a blood disorder called megaloblastic anemia, which occurs when a person has a low number of red blood cells (anemia), and the remaining red blood cells are larger than normal (megaloblastic).\n\nThe signs and symptoms of homocystinuria typically develop during childhood, although some mildly affected people may not show signs and symptoms until adulthood.
Kidney disorder
MedGen UID:
9635
Concept ID:
C0022658
Disease or Syndrome
A nonspecific term referring to disease or damage of the kidneys.
Proteinuria
MedGen UID:
10976
Concept ID:
C0033687
Finding
Increased levels of protein in the urine.
Cystathioninuria
MedGen UID:
66353
Concept ID:
C0220993
Disease or Syndrome
Cystathioninuria, an autosomal recessive phenotype with no striking pathologic features, is characterized by abnormal accumulation of plasma cystathionine, leading to increased urinary excretion. Because of the inconsistency and wide variety of disease associations, cystathioninuria is considered to be a benign biochemical anomaly (Mudd et al., 2001).
Renal insufficiency
MedGen UID:
332529
Concept ID:
C1565489
Disease or Syndrome
A reduction in the level of performance of the kidneys in areas of function comprising the concentration of urine, removal of wastes, the maintenance of electrolyte balance, homeostasis of blood pressure, and calcium metabolism.
Methylmalonic aciduria
MedGen UID:
343266
Concept ID:
C1855119
Disease or Syndrome
Increased concentration of methylmalonic acid in the urine.
Acute kidney injury
MedGen UID:
388570
Concept ID:
C2609414
Injury or Poisoning
Sudden loss of renal function, as manifested by decreased urine production, and a rise in serum creatinine or blood urea nitrogen concentration (azotemia).
Cardiac arrest
MedGen UID:
5456
Concept ID:
C0018790
Finding
An abrupt loss of heart function.
Hypotension
MedGen UID:
5715
Concept ID:
C0020649
Finding
Low Blood Pressure, vascular hypotension.
Tachycardia
MedGen UID:
21453
Concept ID:
C0039231
Finding
A rapid heartrate that exceeds the range of the normal resting heartrate for age.
Bradycardia
MedGen UID:
140901
Concept ID:
C0428977
Finding
A slower than normal heart rate (in adults, slower than 60 beats per minute).
Pulmonary arterial hypertension
MedGen UID:
425404
Concept ID:
C2973725
Disease or Syndrome
Pulmonary hypertension is defined mean pulmonary artery pressure of 25mmHg or more and pulmonary capillary wedge pressure of 15mmHg or less when measured by right heart catheterisation at rest and in a supine position.
Small for gestational age
MedGen UID:
65920
Concept ID:
C0235991
Finding
Smaller than normal size according to sex and gestational age related norms, defined as a weight below the 10th percentile for the gestational age.
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.
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.
Macrotia
MedGen UID:
488785
Concept ID:
C0152421
Congenital Abnormality
Median longitudinal ear length greater than two standard deviations above the mean and median ear width greater than two standard deviations above the mean (objective); or, apparent increase in length and width of the pinna (subjective).
Low-set ears
MedGen UID:
65980
Concept ID:
C0239234
Congenital Abnormality
Upper insertion of the ear to the scalp below an imaginary horizontal line drawn between the inner canthi of the eye and extending posteriorly to the ear.
Confusion
MedGen UID:
3587
Concept ID:
C0009676
Mental or Behavioral Dysfunction
Lack of clarity and coherence of thought, perception, understanding, or action.
Delirium
MedGen UID:
41445
Concept ID:
C0011206
Mental or Behavioral Dysfunction
A state of sudden and severe confusion.
Hydrocephalus
MedGen UID:
9335
Concept ID:
C0020255
Disease or Syndrome
Hydrocephalus is an active distension of the ventricular system of the brain resulting from inadequate passage of CSF from its point of production within the cerebral ventricles to its point of absorption into the systemic circulation.
Lethargy
MedGen UID:
7310
Concept ID:
C0023380
Sign or Symptom
A state of fatigue, either physical or mental slowness and sluggishness, with difficulties in initiating or performing simple tasks. Distinguished from apathy which implies indifference and a lack of desire or interest in the task. A person with lethargy may have the desire, but not the energy to engage in personal or socially relevant tasks.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Tremor
MedGen UID:
21635
Concept ID:
C0040822
Sign or Symptom
An unintentional, oscillating to-and-fro muscle movement about a joint axis.
Abnormality of extrapyramidal motor function
MedGen UID:
115941
Concept ID:
C0234133
Sign or Symptom
A neurological condition related to lesions of the basal ganglia leading to typical abnormalities including akinesia (inability to initiate changes in activity and perform volitional movements rapidly and easily), muscular rigidity (continuous contraction of muscles with constant resistance to passive movement), chorea (widespread arrhythmic movements of a forcible, rapid, jerky, and restless nature), athetosis (inability to sustain the muscles of the fingers, toes, or other group of muscles in a fixed position), and akathisia (inability to remain motionless).
Dementia
MedGen UID:
99229
Concept ID:
C0497327
Mental or Behavioral Dysfunction
A loss of global cognitive ability of sufficient amount to interfere with normal social or occupational function. Dementia represents a loss of previously present cognitive abilities, generally in adults, and can affect memory, thinking, language, judgment, and behavior.
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.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Cerebral cortical atrophy
MedGen UID:
1646740
Concept ID:
C4551583
Disease or Syndrome
Atrophy of the cortex of the cerebrum.
Megaloblastic anemia
MedGen UID:
1527
Concept ID:
C0002888
Disease or Syndrome
Anemia characterized by the presence of erythroblasts that are larger than normal (megaloblasts).
Thrombocytopenia
MedGen UID:
52737
Concept ID:
C0040034
Disease or Syndrome
A reduction in the number of circulating thrombocytes.
Thromboembolism
MedGen UID:
21532
Concept ID:
C0040038
Pathologic Function
The formation of a blood clot inside a blood vessel that subsequently travels through the blood stream from the site where it formed to another location in the body, generally leading to vascular occlusion at the distant site.
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.
Axial hypotonia
MedGen UID:
342959
Concept ID:
C1853743
Finding
Muscular hypotonia (abnormally low muscle tone) affecting the musculature of the trunk.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Neutropenia
MedGen UID:
163121
Concept ID:
C0853697
Finding
An abnormally low number of neutrophils in the peripheral blood.
Metabolic acidosis
MedGen UID:
65117
Concept ID:
C0220981
Pathologic Function
Metabolic acidosis (MA) is characterized by a fall in blood pH due to a reduction of serum bicarbonate concentration. This can occur as a result of either the accumulation of acids (high anion gap MA) or the loss of bicarbonate from the gastrointestinal tract or the kidney (hyperchloremic MA). By definition, MA is not due to a respirary cause.
Methylmalonic acidemia
MedGen UID:
120654
Concept ID:
C0268583
Disease or Syndrome
For this GeneReview, the term "isolated methylmalonic acidemia" refers to a group of inborn errors of metabolism associated with elevated methylmalonic acid (MMA) concentration in the blood and urine that result from the failure to isomerize (convert) methylmalonyl-coenzyme A (CoA) into succinyl-CoA during propionyl-CoA metabolism in the mitochondrial matrix, without hyperhomocysteinemia or homocystinuria, hypomethioninemia, or variations in other metabolites, such as malonic acid. Isolated MMA is caused by complete or partial deficiency of the enzyme methylmalonyl-CoA mutase (mut0 enzymatic subtype or mut– enzymatic subtype, respectively), a defect in the transport or synthesis of its cofactor, 5-deoxy-adenosyl-cobalamin (cblA, cblB, or cblD-MMA), or deficiency of the enzyme methylmalonyl-CoA epimerase. Prior to the advent of newborn screening, common phenotypes included: Infantile/non-B12-responsive form (mut0 enzymatic subtype, cblB), the most common phenotype, associated with infantile-onset lethargy, tachypnea, hypothermia, vomiting, and dehydration on initiation of protein-containing feeds. Without appropriate treatment, the infantile/non-B12-responsive phenotype could rapidly progress to coma due to hyperammonemic encephalopathy. Partially deficient or B12-responsive phenotypes (mut– enzymatic subtype, cblA, cblB [rare], cblD-MMA), in which symptoms occur in the first few months or years of life and are characterized by feeding problems, failure to thrive, hypotonia, and developmental delay marked by episodes of metabolic decompensation. Methylmalonyl-CoA epimerase deficiency, in which findings range from complete absence of symptoms to severe metabolic acidosis. Affected individuals can also develop ataxia, dysarthria, hypotonia, mild spastic paraparesis, and seizures. In those individuals diagnosed by newborn screening and treated from an early age, there appears to be decreased early mortality, less severe symptoms at diagnosis, favorable short-term neurodevelopmental outcome, and lower incidence of movement disorders and irreversible cerebral damage. However, secondary complications may still occur and can include intellectual disability, tubulointerstitial nephritis with progressive impairment of renal function, "metabolic stroke" (bilateral lacunar infarction of the basal ganglia during acute metabolic decompensation), pancreatitis, growth failure, functional immune impairment, bone marrow failure, optic nerve atrophy, arrhythmias and/or cardiomyopathy (dilated or hypertrophic), liver steatosis/fibrosis/cancer, and renal cancer.
Cystathioninemia
MedGen UID:
75699
Concept ID:
C0268618
Disease or Syndrome
An increased concentration of cystathionine in the blood.
Hypomethioninemia
MedGen UID:
336368
Concept ID:
C1848555
Finding
A decreased concentration of methionine in the blood.
Decreased circulating adenosylcobalamin concentration
MedGen UID:
336369
Concept ID:
C1848556
Finding
The concentration of adenosylcobalam in the blood circulation is below the lower limit of normal. Adenosylcobalamin is one of the active forms of vitamin B12.
Decreased methylmalonyl-CoA mutase activity
MedGen UID:
336374
Concept ID:
C1848579
Finding
An abnormality of Krebs cycle metabolism that is characterized by a decreased rate of methylmalonyl-CoA mutase activity.
Decreased methionine synthase activity
MedGen UID:
376395
Concept ID:
C1848580
Finding
A reduction in methionine synthase activity.
Hyperhomocystinemia
MedGen UID:
812677
Concept ID:
C3806347
Finding
An increased concentration of homocystine in the blood.
Abnormal circulating vitamin B12 concentration
MedGen UID:
866685
Concept ID:
C4021032
Finding
A deviation from the normal concentration of cobalamin (vitamin B12) in the blood. Vitamin B12 is one of the eight B vitamins.
Decreased circulating methylcobalamin concentration
MedGen UID:
867371
Concept ID:
C4021736
Finding
The concentration of methylcobalamin in the blood circulation is below the lower limit of normal. Methylcobalamin is a form of vitamin B12.
High forehead
MedGen UID:
65991
Concept ID:
C0239676
Finding
An abnormally increased height of the forehead.
Smooth philtrum
MedGen UID:
222980
Concept ID:
C1142533
Finding
Flat skin surface, with no ridge formation in the central region of the upper lip between the nasal base and upper vermilion border.
Long face
MedGen UID:
324419
Concept ID:
C1836047
Finding
Facial height (length) is more than 2 standard deviations above the mean (objective); or, an apparent increase in the height (length) of the face (subjective).
Pallor
MedGen UID:
69133
Concept ID:
C0241137
Finding
Abnormally pale skin.
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.
Reduced visual acuity
MedGen UID:
65889
Concept ID:
C0234632
Finding
Diminished clarity of vision.
Visual impairment
MedGen UID:
777085
Concept ID:
C3665347
Finding
Visual impairment (or vision impairment) is vision loss (of a person) to such a degree as to qualify as an additional support need through a significant limitation of visual capability resulting from either disease, trauma, or congenital or degenerative conditions that cannot be corrected by conventional means, such as refractive correction, medication, or surgery.
Pigmentary retinopathy
MedGen UID:
1643295
Concept ID:
C4551715
Disease or Syndrome
An abnormality of the retina characterized by pigment deposition. It is typically associated with migration and proliferation of macrophages or retinal pigment epithelial cells into the retina; melanin from these cells causes the pigmentary changes. Pigmentary retinopathy is a common final pathway of many retinal conditions and is often associated with visual loss.

Professional guidelines

PubMed

Huemer M, Diodato D, Martinelli D, Olivieri G, Blom H, Gleich F, Kölker S, Kožich V, Morris AA, Seifert B, Froese DS, Baumgartner MR, Dionisi-Vici C; EHOD consortium, Martin CA, Baethmann M, Ballhausen D, Blasco-Alonso J, Boy N, Bueno M, Burgos Peláez R, Cerone R, Chabrol B, Chapman KA, Couce ML, Crushell E, Dalmau Serra J, Diogo L, Ficicioglu C, García Jimenez MC, García Silva MT, Gaspar AM, Gautschi M, González-Lamuño D, Gouveia S, Grünewald S, Hendriksz C, Janssen MCH, Jesina P, Koch J, Konstantopoulou V, Lavigne C, Lund AM, Martins EG, Meavilla Olivas S, Mention K, Mochel F, Mundy H, Murphy E, Paquay S, Pedrón-Giner C, Ruiz Gómez MA, Santra S, Schiff M, Schwartz IV, Scholl-Bürgi S, Servais A, Skouma A, Tran C, Vives Piñera I, Walter J, Weisfeld-Adams J
J Inherit Metab Dis 2019 Mar;42(2):333-352. Epub 2019 Feb 17 doi: 10.1002/jimd.12041. PMID: 30773687
Almannai M, Marom R, Divin K, Scaglia F, Sutton VR, Craigen WJ, Lee B, Burrage LC, Graham BH
Mol Genet Metab 2017 Sep;122(1-2):60-66. Epub 2017 Jun 29 doi: 10.1016/j.ymgme.2017.06.011. PMID: 28693988Free PMC Article
Ahrens-Nicklas RC, Whitaker AM, Kaplan P, Cuddapah S, Burfield J, Blair J, Brochi L, Yudkoff M, Ficicioglu C
Genet Med 2017 Aug;19(8):926-935. Epub 2017 Feb 2 doi: 10.1038/gim.2016.214. PMID: 28151490Free PMC Article

Curated

American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Elevated C3 Acylcarnitine, Propionic Acidemia (PA) and Methylmalonic Acidemia (MMA), 2022

American College of Medical Genetics and Genomics, Algorithm, Propionic and Methylmalonic Acidemia: C3 Elevated, 2022

Recent clinical studies

Etiology

Demaret T, Bédard K, Soucy JF, Watkins D, Allard P, Levtova A, O'Brien A, Brunel-Guitton C, Rosenblatt DS, Mitchell GA
Mol Genet Metab 2024 May;142(1):108345. Epub 2024 Feb 10 doi: 10.1016/j.ymgme.2024.108345. PMID: 38387306
Huemer M, Diodato D, Martinelli D, Olivieri G, Blom H, Gleich F, Kölker S, Kožich V, Morris AA, Seifert B, Froese DS, Baumgartner MR, Dionisi-Vici C; EHOD consortium, Martin CA, Baethmann M, Ballhausen D, Blasco-Alonso J, Boy N, Bueno M, Burgos Peláez R, Cerone R, Chabrol B, Chapman KA, Couce ML, Crushell E, Dalmau Serra J, Diogo L, Ficicioglu C, García Jimenez MC, García Silva MT, Gaspar AM, Gautschi M, González-Lamuño D, Gouveia S, Grünewald S, Hendriksz C, Janssen MCH, Jesina P, Koch J, Konstantopoulou V, Lavigne C, Lund AM, Martins EG, Meavilla Olivas S, Mention K, Mochel F, Mundy H, Murphy E, Paquay S, Pedrón-Giner C, Ruiz Gómez MA, Santra S, Schiff M, Schwartz IV, Scholl-Bürgi S, Servais A, Skouma A, Tran C, Vives Piñera I, Walter J, Weisfeld-Adams J
J Inherit Metab Dis 2019 Mar;42(2):333-352. Epub 2019 Feb 17 doi: 10.1002/jimd.12041. PMID: 30773687
Almannai M, Marom R, Divin K, Scaglia F, Sutton VR, Craigen WJ, Lee B, Burrage LC, Graham BH
Mol Genet Metab 2017 Sep;122(1-2):60-66. Epub 2017 Jun 29 doi: 10.1016/j.ymgme.2017.06.011. PMID: 28693988Free PMC Article
Ku CA, Ng JK, Karr DJ, Reznick L, Harding CO, Weleber RG, Pennesi ME
Ophthalmic Genet 2016 Dec;37(4):404-414. Epub 2016 Mar 15 doi: 10.3109/13816810.2015.1121500. PMID: 26979128
McCully KS
Am J Clin Nutr 2007 Nov;86(5):1563S-8S. doi: 10.1093/ajcn/86.5.1563S. PMID: 17991676

Diagnosis

Yuan H, Deng S, Gao W, Li H, Yuan M
Metab Brain Dis 2021 Mar;36(3):447-452. Epub 2021 Jan 7 doi: 10.1007/s11011-020-00654-8. PMID: 33411215
Wei Y, Guan Y, Hao H
Muscle Nerve 2020 Jun;61(6):E37-E40. Epub 2020 Apr 9 doi: 10.1002/mus.26865. PMID: 32208535
Wang C, Li D, Cai F, Zhang X, Xu X, Liu X, Zhang C, Wang D, Liu X, Lin S, Zhang Y, Shu J
Eur J Med Genet 2019 Oct;62(10):103713. Epub 2019 Jul 4 doi: 10.1016/j.ejmg.2019.103713. PMID: 31279840
Huemer M, Diodato D, Martinelli D, Olivieri G, Blom H, Gleich F, Kölker S, Kožich V, Morris AA, Seifert B, Froese DS, Baumgartner MR, Dionisi-Vici C; EHOD consortium, Martin CA, Baethmann M, Ballhausen D, Blasco-Alonso J, Boy N, Bueno M, Burgos Peláez R, Cerone R, Chabrol B, Chapman KA, Couce ML, Crushell E, Dalmau Serra J, Diogo L, Ficicioglu C, García Jimenez MC, García Silva MT, Gaspar AM, Gautschi M, González-Lamuño D, Gouveia S, Grünewald S, Hendriksz C, Janssen MCH, Jesina P, Koch J, Konstantopoulou V, Lavigne C, Lund AM, Martins EG, Meavilla Olivas S, Mention K, Mochel F, Mundy H, Murphy E, Paquay S, Pedrón-Giner C, Ruiz Gómez MA, Santra S, Schiff M, Schwartz IV, Scholl-Bürgi S, Servais A, Skouma A, Tran C, Vives Piñera I, Walter J, Weisfeld-Adams J
J Inherit Metab Dis 2019 Mar;42(2):333-352. Epub 2019 Feb 17 doi: 10.1002/jimd.12041. PMID: 30773687
Aleman TS, Brodie F, Garvin C, Gewaily DY, Ficicioglu CH, Mills MD, Forbes BJ, Maguire AM, Davidson SL
Ophthalmic Genet 2015;36(4):339-48. Epub 2014 Feb 10 doi: 10.3109/13816810.2014.885059. PMID: 24512365

Therapy

Demaret T, Bédard K, Soucy JF, Watkins D, Allard P, Levtova A, O'Brien A, Brunel-Guitton C, Rosenblatt DS, Mitchell GA
Mol Genet Metab 2024 May;142(1):108345. Epub 2024 Feb 10 doi: 10.1016/j.ymgme.2024.108345. PMID: 38387306
Liu F, Wu Y, Li Z, Wan R
Clin Chim Acta 2022 Aug 1;533:31-39. Epub 2022 Jun 13 doi: 10.1016/j.cca.2022.06.004. PMID: 35709987
Nguyen MG, Tronick L, Modirian F, Mardach R, Besterman AD
Cold Spring Harb Mol Case Stud 2022 Feb;8(2) Epub 2022 Mar 24 doi: 10.1101/mcs.a006179. PMID: 35105663Free PMC Article
Almannai M, Marom R, Divin K, Scaglia F, Sutton VR, Craigen WJ, Lee B, Burrage LC, Graham BH
Mol Genet Metab 2017 Sep;122(1-2):60-66. Epub 2017 Jun 29 doi: 10.1016/j.ymgme.2017.06.011. PMID: 28693988Free PMC Article
McCully KS
Am J Clin Nutr 2007 Nov;86(5):1563S-8S. doi: 10.1093/ajcn/86.5.1563S. PMID: 17991676

Prognosis

Huemer M, Diodato D, Martinelli D, Olivieri G, Blom H, Gleich F, Kölker S, Kožich V, Morris AA, Seifert B, Froese DS, Baumgartner MR, Dionisi-Vici C; EHOD consortium, Martin CA, Baethmann M, Ballhausen D, Blasco-Alonso J, Boy N, Bueno M, Burgos Peláez R, Cerone R, Chabrol B, Chapman KA, Couce ML, Crushell E, Dalmau Serra J, Diogo L, Ficicioglu C, García Jimenez MC, García Silva MT, Gaspar AM, Gautschi M, González-Lamuño D, Gouveia S, Grünewald S, Hendriksz C, Janssen MCH, Jesina P, Koch J, Konstantopoulou V, Lavigne C, Lund AM, Martins EG, Meavilla Olivas S, Mention K, Mochel F, Mundy H, Murphy E, Paquay S, Pedrón-Giner C, Ruiz Gómez MA, Santra S, Schiff M, Schwartz IV, Scholl-Bürgi S, Servais A, Skouma A, Tran C, Vives Piñera I, Walter J, Weisfeld-Adams J
J Inherit Metab Dis 2019 Mar;42(2):333-352. Epub 2019 Feb 17 doi: 10.1002/jimd.12041. PMID: 30773687
Almannai M, Marom R, Divin K, Scaglia F, Sutton VR, Craigen WJ, Lee B, Burrage LC, Graham BH
Mol Genet Metab 2017 Sep;122(1-2):60-66. Epub 2017 Jun 29 doi: 10.1016/j.ymgme.2017.06.011. PMID: 28693988Free PMC Article
Ku CA, Ng JK, Karr DJ, Reznick L, Harding CO, Weleber RG, Pennesi ME
Ophthalmic Genet 2016 Dec;37(4):404-414. Epub 2016 Mar 15 doi: 10.3109/13816810.2015.1121500. PMID: 26979128
Ma X, Zhang Y, Yang Y, Liu X, Yang Z, Bao X, Qin J, Wu X
Brain Dev 2011 Oct;33(9):790-5. Epub 2011 Jul 20 doi: 10.1016/j.braindev.2011.06.001. PMID: 21764232
Thauvin-Robinet C, Roze E, Couvreur G, Horellou MH, Sedel F, Grabli D, Bruneteau G, Tonneti C, Masurel-Paulet A, Perennou D, Moreau T, Giroud M, de Baulny HO, Giraudier S, Faivre L
J Neurol Neurosurg Psychiatry 2008 Jun;79(6):725-8. Epub 2008 Feb 1 doi: 10.1136/jnnp.2007.133025. PMID: 18245139

Clinical prediction guides

Huemer M, Diodato D, Martinelli D, Olivieri G, Blom H, Gleich F, Kölker S, Kožich V, Morris AA, Seifert B, Froese DS, Baumgartner MR, Dionisi-Vici C; EHOD consortium, Martin CA, Baethmann M, Ballhausen D, Blasco-Alonso J, Boy N, Bueno M, Burgos Peláez R, Cerone R, Chabrol B, Chapman KA, Couce ML, Crushell E, Dalmau Serra J, Diogo L, Ficicioglu C, García Jimenez MC, García Silva MT, Gaspar AM, Gautschi M, González-Lamuño D, Gouveia S, Grünewald S, Hendriksz C, Janssen MCH, Jesina P, Koch J, Konstantopoulou V, Lavigne C, Lund AM, Martins EG, Meavilla Olivas S, Mention K, Mochel F, Mundy H, Murphy E, Paquay S, Pedrón-Giner C, Ruiz Gómez MA, Santra S, Schiff M, Schwartz IV, Scholl-Bürgi S, Servais A, Skouma A, Tran C, Vives Piñera I, Walter J, Weisfeld-Adams J
J Inherit Metab Dis 2019 Mar;42(2):333-352. Epub 2019 Feb 17 doi: 10.1002/jimd.12041. PMID: 30773687
Almannai M, Marom R, Divin K, Scaglia F, Sutton VR, Craigen WJ, Lee B, Burrage LC, Graham BH
Mol Genet Metab 2017 Sep;122(1-2):60-66. Epub 2017 Jun 29 doi: 10.1016/j.ymgme.2017.06.011. PMID: 28693988Free PMC Article
Ku CA, Ng JK, Karr DJ, Reznick L, Harding CO, Weleber RG, Pennesi ME
Ophthalmic Genet 2016 Dec;37(4):404-414. Epub 2016 Mar 15 doi: 10.3109/13816810.2015.1121500. PMID: 26979128
Beauchamp MH, Anderson V, Boneh A
J Inherit Metab Dis 2009 Dec;32 Suppl 1:S327-34. Epub 2009 Oct 15 doi: 10.1007/s10545-009-1284-8. PMID: 19830587
Thauvin-Robinet C, Roze E, Couvreur G, Horellou MH, Sedel F, Grabli D, Bruneteau G, Tonneti C, Masurel-Paulet A, Perennou D, Moreau T, Giroud M, de Baulny HO, Giraudier S, Faivre L
J Neurol Neurosurg Psychiatry 2008 Jun;79(6):725-8. Epub 2008 Feb 1 doi: 10.1136/jnnp.2007.133025. PMID: 18245139

Supplemental Content

Table of contents

    Clinical resources

    Practice guidelines

    • PubMed
      See practice and clinical guidelines in PubMed. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.

    Curated

    • ACMG ACT, 2022
      American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Elevated C3 Acylcarnitine, Propionic Acidemia (PA) and Methylmalonic Acidemia (MMA), 2022
    • ACMG Algorithm, 2022
      American College of Medical Genetics and Genomics, Algorithm, Propionic and Methylmalonic Acidemia: C3 Elevated, 2022

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