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Organic aciduria

MedGen UID:
66037
Concept ID:
C0241775
Finding; Finding
HPO: HP:0001992

Definition

Excretion of non-amino organic acids in urine. [from HPO]

Conditions with this feature

Biotinidase deficiency
MedGen UID:
66323
Concept ID:
C0220754
Disease or Syndrome
If untreated, young children with profound biotinidase deficiency usually exhibit neurologic abnormalities including seizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss, and cutaneous abnormalities (e.g., alopecia, skin rash, candidiasis). Older children and adolescents with profound biotinidase deficiency often exhibit motor limb weakness, spastic paresis, and decreased visual acuity. Once vision problems, hearing loss, and developmental delay occur, they are usually irreversible, even with biotin therapy. Individuals with partial biotinidase deficiency may have hypotonia, skin rash, and hair loss, particularly during times of stress.
Holocarboxylase synthetase deficiency
MedGen UID:
120653
Concept ID:
C0268581
Disease or Syndrome
Holocarboxylase synthetase deficiency, a biotin-responsive multiple carboxylase deficiency (MCD), is characterized by metabolic acidosis, lethargy, hypotonia, convulsions, and dermatitis. Most patients present in the newborn or early infantile period, but some become symptomatic in the later infantile period (summary by Suzuki et al., 2005). Also see biotinidase deficiency (253260), another form of MCD with a later onset. Care must be taken to differentiate the inherited multiple carboxylase deficiencies from acquired biotin deficiencies, such as those that develop after excessive dietary intake of avidin, an egg-white glycoprotein that binds specifically and essentially irreversibly to biotin (Sweetman et al., 1981) or prolonged parenteral alimentation without supplemental biotin (Mock et al., 1981).
Deficiency of hydroxymethylglutaryl-CoA lyase
MedGen UID:
78692
Concept ID:
C0268601
Disease or Syndrome
3-Hydroxy-3-methylglutaryl-CoA lyase deficiency (HMGCLD) is a rare autosomal recessive disorder with the cardinal manifestations of metabolic acidosis without ketonuria, hypoglycemia, and a characteristic pattern of elevated urinary organic acid metabolites, including 3-hydroxy-3-methylglutaric, 3-methylglutaric, and 3-hydroxyisovaleric acids. Urinary levels of 3-methylcrotonylglycine may be increased. Dicarboxylic aciduria, hepatomegaly, and hyperammonemia may also be observed. Presenting clinical signs include irritability, lethargy, coma, and vomiting (summary by Gibson et al., 1988).
3-methylcrotonyl-CoA carboxylase 2 deficiency
MedGen UID:
347898
Concept ID:
C1859499
Disease or Syndrome
3-Methylcrotonylglycinuria is an autosomal recessive disorder of leucine catabolism. The clinical phenotype is highly variable, ranging from neonatal onset with severe neurologic involvement to asymptomatic adults. There is a characteristic organic aciduria with massive excretion of 3-hydroxyisovaleric acid and 3-methylcrotonylglycine, usually in combination with a severe secondary carnitine deficiency. MCC activity in extracts of cultured fibroblasts of patients is usually less than 2% of control (summary by Baumgartner et al., 2001). Also see 3-methylcrotonylglycinuria I (MCC1D; 210200), caused by mutation in the alpha subunit of 3-methylcrotonyl-CoA carboxylase (MCCC1; 609010).
Arginine:glycine amidinotransferase deficiency
MedGen UID:
436367
Concept ID:
C2675179
Disease or Syndrome
The creatine deficiency disorders (CDDs), inborn errors of creatine metabolism and transport, comprise three disorders: the creatine biosynthesis disorders guanidinoacetate methyltransferase (GAMT) deficiency and L-arginine:glycine amidinotransferase (AGAT) deficiency; and creatine transporter (CRTR) deficiency. Developmental delay and cognitive dysfunction or intellectual disability and speech-language disorder are common to all three CDDs. Onset of clinical manifestations of GAMT deficiency (reported in ~130 individuals) is between ages three months and two years; in addition to developmental delays, the majority of individuals have epilepsy and develop a behavior disorder (e.g., hyperactivity, autism, or self-injurious behavior), and about 30% have movement disorder. AGAT deficiency has been reported in 16 individuals; none have had epilepsy or movement disorders. Clinical findings of CRTR deficiency in affected males (reported in ~130 individuals) in addition to developmental delays include epilepsy (variable seizure types and may be intractable) and behavior disorders (e.g., attention deficit and/or hyperactivity, autistic features, impulsivity, social anxiety), hypotonia, and (less commonly) a movement disorder. Poor weight gain with constipation and prolonged QTc on EKG have been reported. While mild-to-moderate intellectual disability is commonly observed up to age four years, the majority of adult males with CRTR deficiency have been reported to have severe intellectual disability. Females heterozygous for CRTR deficiency are typically either asymptomatic or have mild intellectual disability, although a more severe phenotype resembling the male phenotype has been reported.
Brown-Vialetto-van Laere syndrome 2
MedGen UID:
766452
Concept ID:
C3553538
Disease or Syndrome
Brown-Vialetto-Van Laere syndrome-2 (BVVLS2) is an autosomal recessive progressive neurologic disorder characterized by early childhood onset of sensorineural deafness, bulbar dysfunction, and severe diffuse muscle weakness and wasting of the upper and lower limbs and axial muscles, resulting in respiratory insufficiency. Some patients may lose independent ambulation. Because it results from a defect in riboflavin metabolism, some patients may benefit from high-dose riboflavin supplementation (summary by Johnson et al., 2012; Foley et al., 2014). For discussion of genetic heterogeneity of Brown-Vialetto-Van Laere syndrome, see BVVLS1 (211530).
Mitochondrial pyruvate carrier deficiency
MedGen UID:
766521
Concept ID:
C3553607
Disease or Syndrome
Mitochondrial pyruvate carrier deficiency is an autosomal recessive metabolic disorder characterized by delayed psychomotor development and lactic acidosis with a normal lactate/pyruvate ratio resulting from impaired mitochondrial pyruvate oxidation (summary by Bricker et al., 2012).
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).
Myopathy with abnormal lipid metabolism
MedGen UID:
934789
Concept ID:
C4310822
Disease or Syndrome
Lipid storage myopathy due to FLAD1 deficiency is an autosomal recessive inborn error of metabolism that includes variable mitochondrial dysfunction. The phenotype is extremely heterogeneous: some patients have a severe disorder with onset in infancy and cardiac and respiratory insufficiency resulting in early death, whereas others have a milder course with onset of muscle weakness in adulthood. Some patients show significant improvement with riboflavin treatment (summary by Olsen et al., 2016).
Combined oxidative phosphorylation deficiency 55
MedGen UID:
1806598
Concept ID:
C5676915
Disease or Syndrome
Combined oxidative phosphorylation deficiency-55 (COXPD55) is characterized by global developmental delay, hypotonia, short stature, and impaired intellectual development with speech disabilities in childhood. Indolent progressive external ophthalmoplegia phenotype has been described in 1 patient (summary by Olahova et al., 2021). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).

Professional guidelines

PubMed

Division of Biochemistry and Metabolism, Medical Genetics Branch, Chinese Medical Association, Division of Genetics and Metabolism, Child Diseases and Health Care Branch, Chinese Association for Maternal and Child Health, Division of Genetics and Metabolism, Rare Diseases Committee of Beijing Medical Association
Zhejiang Da Xue Xue Bao Yi Xue Ban 2022 Feb 25;51(1):129-135. doi: 10.3724/zdxbyxb-2022-0164. PMID: 35576117Free PMC Article
Rips J, Almashanu S, Mandel H, Josephsberg S, Lerman-Sagie T, Zerem A, Podeh B, Anikster Y, Shaag A, Luder A, Staretz Chacham O, Spiegel R
J Inherit Metab Dis 2016 Mar;39(2):211-7. Epub 2015 Nov 13 doi: 10.1007/s10545-015-9899-4. PMID: 26566957
Kölker S, Christensen E, Leonard JV, Greenberg CR, Boneh A, Burlina AB, Burlina AP, Dixon M, Duran M, García Cazorla A, Goodman SI, Koeller DM, Kyllerman M, Mühlhausen C, Müller E, Okun JG, Wilcken B, Hoffmann GF, Burgard P
J Inherit Metab Dis 2011 Jun;34(3):677-94. Epub 2011 Mar 23 doi: 10.1007/s10545-011-9289-5. PMID: 21431622Free PMC Article

Recent clinical studies

Etiology

Dimitrov B, Molema F, Williams M, Schmiesing J, Mühlhausen C, Baumgartner MR, Schumann A, Kölker S
J Inherit Metab Dis 2021 Jan;44(1):9-21. Epub 2020 May 27 doi: 10.1002/jimd.12254. PMID: 32412122
Stockler S, Plecko B, Gospe SM Jr, Coulter-Mackie M, Connolly M, van Karnebeek C, Mercimek-Mahmutoglu S, Hartmann H, Scharer G, Struijs E, Tein I, Jakobs C, Clayton P, Van Hove JL
Mol Genet Metab 2011 Sep-Oct;104(1-2):48-60. Epub 2011 May 24 doi: 10.1016/j.ymgme.2011.05.014. PMID: 21704546
Zhang Y, Yang YL, Hasegawa Y, Yamaguchi S, Shi CY, Song JQ, Sayami S, Liu P, Yan R, Dong JH, Qin J
Chin Med J (Engl) 2008 Feb 5;121(3):216-9. PMID: 18298912
Kölker S, Koeller DM, Okun JG, Hoffmann GF
Ann Neurol 2004 Jan;55(1):7-12. doi: 10.1002/ana.10784. PMID: 14705106
Borum PR, Bennett SG
J Am Coll Nutr 1986;5(2):177-82. doi: 10.1080/07315724.1986.10720124. PMID: 3088084

Diagnosis

Dimitrov B, Molema F, Williams M, Schmiesing J, Mühlhausen C, Baumgartner MR, Schumann A, Kölker S
J Inherit Metab Dis 2021 Jan;44(1):9-21. Epub 2020 May 27 doi: 10.1002/jimd.12254. PMID: 32412122
Villani GR, Gallo G, Scolamiero E, Salvatore F, Ruoppolo M
Clin Exp Med 2017 Aug;17(3):305-323. Epub 2016 Sep 9 doi: 10.1007/s10238-016-0435-0. PMID: 27613073
Kölker S, Christensen E, Leonard JV, Greenberg CR, Boneh A, Burlina AB, Burlina AP, Dixon M, Duran M, García Cazorla A, Goodman SI, Koeller DM, Kyllerman M, Mühlhausen C, Müller E, Okun JG, Wilcken B, Hoffmann GF, Burgard P
J Inherit Metab Dis 2011 Jun;34(3):677-94. Epub 2011 Mar 23 doi: 10.1007/s10545-011-9289-5. PMID: 21431622Free PMC Article
Barić I
J Inherit Metab Dis 2008 Jun;31(3):293-4. doi: 10.1007/s10545-008-9977-y. PMID: 18563631
Zhang Y, Yang YL, Hasegawa Y, Yamaguchi S, Shi CY, Song JQ, Sayami S, Liu P, Yan R, Dong JH, Qin J
Chin Med J (Engl) 2008 Feb 5;121(3):216-9. PMID: 18298912

Therapy

Division of Biochemistry and Metabolism, Medical Genetics Branch, Chinese Medical Association, Division of Genetics and Metabolism, Child Diseases and Health Care Branch, Chinese Association for Maternal and Child Health, Division of Genetics and Metabolism, Rare Diseases Committee of Beijing Medical Association
Zhejiang Da Xue Xue Bao Yi Xue Ban 2022 Feb 25;51(1):129-135. doi: 10.3724/zdxbyxb-2022-0164. PMID: 35576117Free PMC Article
Ruzkova K, Weingarten TN, Larson KJ, Friedhoff RJ, Gavrilov DK, Sprung J
Paediatr Anaesth 2015 Aug;25(8):807-817. Epub 2015 May 5 doi: 10.1111/pan.12673. PMID: 25943188
Stockler S, Plecko B, Gospe SM Jr, Coulter-Mackie M, Connolly M, van Karnebeek C, Mercimek-Mahmutoglu S, Hartmann H, Scharer G, Struijs E, Tein I, Jakobs C, Clayton P, Van Hove JL
Mol Genet Metab 2011 Sep-Oct;104(1-2):48-60. Epub 2011 May 24 doi: 10.1016/j.ymgme.2011.05.014. PMID: 21704546
Borum PR, Bennett SG
J Am Coll Nutr 1986;5(2):177-82. doi: 10.1080/07315724.1986.10720124. PMID: 3088084
Similä S, von Wendt L, Linna SL, Saukkonen AL, Huhtaniemi I
Neuropadiatrie 1979 May;10(2):158-60. doi: 10.1055/s-0028-1085322. PMID: 386163

Prognosis

Villani GR, Gallo G, Scolamiero E, Salvatore F, Ruoppolo M
Clin Exp Med 2017 Aug;17(3):305-323. Epub 2016 Sep 9 doi: 10.1007/s10238-016-0435-0. PMID: 27613073
Ruzkova K, Weingarten TN, Larson KJ, Friedhoff RJ, Gavrilov DK, Sprung J
Paediatr Anaesth 2015 Aug;25(8):807-817. Epub 2015 May 5 doi: 10.1111/pan.12673. PMID: 25943188
Stockler S, Plecko B, Gospe SM Jr, Coulter-Mackie M, Connolly M, van Karnebeek C, Mercimek-Mahmutoglu S, Hartmann H, Scharer G, Struijs E, Tein I, Jakobs C, Clayton P, Van Hove JL
Mol Genet Metab 2011 Sep-Oct;104(1-2):48-60. Epub 2011 May 24 doi: 10.1016/j.ymgme.2011.05.014. PMID: 21704546
Kölker S, Christensen E, Leonard JV, Greenberg CR, Boneh A, Burlina AB, Burlina AP, Dixon M, Duran M, García Cazorla A, Goodman SI, Koeller DM, Kyllerman M, Mühlhausen C, Müller E, Okun JG, Wilcken B, Hoffmann GF, Burgard P
J Inherit Metab Dis 2011 Jun;34(3):677-94. Epub 2011 Mar 23 doi: 10.1007/s10545-011-9289-5. PMID: 21431622Free PMC Article
Baumgartner ER, Suormala T
Int J Vitam Nutr Res 1997;67(5):377-84. PMID: 9350481

Clinical prediction guides

Forny P, Hörster F, Baumgartner MR, Kölker S, Boy N
J Inherit Metab Dis 2023 May;46(3):520-535. Epub 2023 Jan 16 doi: 10.1002/jimd.12586. PMID: 36591944
Lichter-Konecki U, Nadkarni V, Moudgil A, Cook N, Poeschl J, Meyer MT, Dimmock D, Baumgart S
Mol Genet Metab 2013 Aug;109(4):354-9. Epub 2013 May 29 doi: 10.1016/j.ymgme.2013.05.014. PMID: 23791307
Kölker S, Christensen E, Leonard JV, Greenberg CR, Boneh A, Burlina AB, Burlina AP, Dixon M, Duran M, García Cazorla A, Goodman SI, Koeller DM, Kyllerman M, Mühlhausen C, Müller E, Okun JG, Wilcken B, Hoffmann GF, Burgard P
J Inherit Metab Dis 2011 Jun;34(3):677-94. Epub 2011 Mar 23 doi: 10.1007/s10545-011-9289-5. PMID: 21431622Free PMC Article
Yang Y, Sun F, Song J, Hasegawa Y, Yamaguchi S, Zhang Y, Jiang Y, Qin J, Wu X
J Child Neurol 2006 Dec;21(12):1020-4. doi: 10.1177/7010.2006.00231. PMID: 17156691
Baumgartner ER, Suormala T
Int J Vitam Nutr Res 1997;67(5):377-84. PMID: 9350481

Recent systematic reviews

Masnada S, Parazzini C, Bini P, Barbarini M, Alberti L, Valente M, Chiapparini L, De Silvestri A, Doneda C, Iascone M, Saielli LA, Cereda C, Veggiotti P, Corbetta C, Tonduti D
Eur J Paediatr Neurol 2020 Sep;28:151-158. Epub 2020 Jul 29 doi: 10.1016/j.ejpn.2020.07.007. PMID: 32800686

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