NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

OPA3-Related 3-Methylglutaconic Aciduria

Synonyms: 3-Methylglutaconic Aciduria Type 3, Costeff Optic Atrophy Syndrome, Costeff Syndrome, Optic Atrophy Plus Syndrome

, MD, , PhD, and , MD, PhD.

Author Information

Initial Posting: ; Last Update: December 19, 2013.

Estimated reading time: 16 minutes


Clinical characteristics.

OPA3-related 3-methylglutaconic aciduria is characterized by optic atrophy and/or choreoathetoid movement disorder with onset before age ten years. Optic atrophy is associated with progressive, decreased visual acuity within the first years of life, sometimes associated with infantile-onset horizontal nystagmus. Most individuals have chorea, often severe enough to restrict ambulation. Some are confined to a wheelchair from an early age. Although most individuals develop spastic paraparesis, mild ataxia, and occasional mild cognitive deficit in their second decade, the course of the disease is relatively stable.


The diagnosis of OPA3-related 3-methylglutaconic aciduria is suggested by elevated urinary excretion of 3-methylglutaconate (3-MGC) and 3-methylglutaric acid (3-MGA) and confirmed by identification of biallelic OPA3 pathogenic variants.


Treatment of manifestations: Supportive and often provided by a multidisciplinary team; treatment of visual impairment, spasticity, and movement disorder as in the general population.

Agents/circumstances to avoid: Use of tobacco, alcohol, and medications known to impair mitochondrial function.

Genetic counseling.

OPA3-related 3-methylglutaconic aciduria is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal diagnosis for pregnancies at increased risk are possible if both pathogenic variants have been identified in an affected family member.


The diagnosis of OPA3-related 3-methylglutaconic aciduria is suspected in a child with relatively normal early development and growth in combination with the following:

  • Bilateral early-onset optic atrophy
  • Choreoathetoid movement disorder

Note: Progressive spasticity, cerebellar ataxia, and cognitive deterioration are variably seen in affected children and more commonly at later stages.

The diagnosis is confirmed by documentation of:

  • Increased urinary excretion of (3-MGC) and 3-methylglutaric acid (3-MGA). 3-MGC and 3-MGA are measured in the urine using gas chromatography-mass spectrometry (GC-MS). In OPA3-related 3-methylglutaconic aciduria, urinary 3-MGC and 3-MGA are mildly increased (combined elevation <200 mmol/mol creatinine) (Table 1).
    Note: (1) 3-MGA is derived from hydrogenation of 3-methylglutaconyl-CoA. (2) Individuals with OPA3-related 3-methylglutaconic aciduria have normal laboratory values for the following:
    • Serum bicarbonate concentration
    • Liver and kidney function tests
    • Serum and cerebrospinal fluid (CSF) lactic acid concentrations
    • Serum creatinine phosphokinase (CK) activity

Table 1.

Combined Urinary Excretion of 3-MGC and 3-MGA in OPA3-Related 3-Methylglutaconic Aciduria

PhenotypeCombined Urinary Excretion: Range
In mmol/mol CreatinineIn µmol/L
Individuals with OPA3-related 3-methylglutaconic aciduria9-187141-2245
Normal controls3.2-720-98

In a study of 39 individuals

  • Biallelic pathogenic variants in OPA3
    • If clinical findings point to OPA3-related 3-methylglutaconic aciduria and urinary excretion of 3-MGC and 3-MGA is elevated, the diagnosis can be confirmed by molecular genetic testing of OPA3.
    • Because the excretion of 3-MGC and 3-MGA is variable among individuals with OPA3-related 3-methylglutaconic aciduria (sometimes even overlapping that of normal controls) and is not always easy to detect on urine organic acid analysis, molecular genetic testing should be used in individuals whose findings otherwise strongly suggest OPA3-related 3-methylglutaconic aciduria.
    • To date, the c.143-1G>C pathogenic variant has been identified in all affected individuals of Iraqi Jewish descent. Thus, targeted analysis for the c.143-1G>C pathogenic variant should be performed first in affected individuals of Iraqi Jewish origin.

Table 2.

Molecular Genetic Testing Used in OPA3-Related 3-Methylglutaconic Aciduria

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by this Method
Iraqi JewishNon-Iraqi Jewish
OPA3Targeted analysis for pathogenic variants 2See footnote 3See footnote 4
Sequence analysis 5Unknown
Deletion/duplication analysis 6Unknown 7

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene.


Variant panels may vary by laboratory.


The variant c.143-1G>C accounts for 100% of pathogenic variants in the Iraqi Jewish population [Anikster et al 2001].


The variant c.320_337del, found in an individual of Turkish-Kurdish origin with OPA3-related 3-methylglutaconic aciduria, is the first pathogenic variant found to date in an individual of non-Iraqi Jewish origin [Kleta et al 2002]. The nonsense variant c. 415C>T (p.Gln139Ter), found in the homozygous state in an individual of Indian origin with OPA3-related 3-methylglutaconic aciduria, is the second pathogenic variant found to date in an individual of non-Iraqi Jewish origin [Ho et al 2008].


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.


To date, no deletions or duplications involving OPA3 have been reported to cause OPA3-related 3-methylglutaconic aciduria; however, a systematic analysis has yet to be performed.

Clinical Characeristics

Clinical Description

Most individuals with OPA3-related 3-methylglutaconic aciduria present within the first ten years of life with decreased visual acuity and/or choreoathetoid movement disorder. Although most develop spastic paraparesis, mild ataxia, and occasional mild cognitive deficit in their second decade, the course of the disease is relatively stable.

Optic atrophy manifests as decreased visual acuity within the first years of life, sometimes associated with infantile-onset horizontal nystagmus. The optic discs are pathologically pale, and the papillary vasculature is attenuated. Visual evoked potentials reveal bilateral prolonged latencies consistent with optic atrophy.

In 36 individuals with OPA3-related 3-methylglutaconic aciduria, visual acuity decreased with age:

  • In two children age two years, visual acuity appeared to be normal.
  • In 14 individuals age three to 21 years (14.2±5.5), visual acuity was 6/21 or less.
  • In 20 individuals age five to 37 years (18±9.5), visual acuity was 3/60 or less.

Some children have strabismus and gaze apraxia.

The electroretinogram (ERG) is normal.

Extrapyramidal dysfunction and spasticity cause most of the observed motor disability.

Most individuals have chorea, often severe enough to restrict ambulation. Some are confined to a wheelchair from an early age. In 36 individuals with OPA3-related 3-methylglutaconic aciduria, extrapyramidal signs:

  • Caused major disability in 17 individuals age two to 37 years (mean 16.1±17.8)
  • Caused minor disability in maintaining stable posture and fine motor activities in 12 individuals age two to 26 years (11.7±8.1)
  • Caused mild symptoms with no resulting disability in three individuals age 15 to 36 years
  • Were absent in four individuals ages 13 to 32 years

Unstable spastic gait, increased tendon reflexes, and positive Babinski sign may be seen. In 36 individuals with OPA3-related 3-methylglutaconic aciduria, spasticity was age-related:

  • Nine individuals age two to 12 years (5.9±3.5) did not have spasticity.
  • Four individuals age 11 to 26 years had mild spasticity but no related disability.
  • Eleven individuals age 13 to 37 years (21.4±9.3) had mild spasticity-related disability.
  • Twelve individuals age nine to 26 years (17.0±4.8) had severe spasticity-related disability.

Cerebellar dysfunction is usually mild. Ataxia and dysarthria causing mostly mild disability were detected in 18 of the 36 individuals reported by Elpeleg et al [1994].

Cognitive impairment is seen in some individuals. Of 36 individuals:

  • Nineteen individuals age two to 36 years (16.±18.7) had an IQ of ≥71.
  • Thirteen individuals age two to 37 years (14.7±9.2) had an IQ between 55 and 71.
  • Four individuals age nine to 26 years had an IQ between 40 and 54


  • Affected adults in the fourth decade of life have been reported; life expectancy beyond the fourth decade is unknown.
  • Cranial nerve functions, sensation, and muscle tone are normal.
  • Seizures are not typical in OPA3-related 3-methylglutaconic aciduria. Partial seizures were reported in one individual.
  • Individuals with OPA3-related 3-methylglutaconic aciduria have no cardiac or structural brain abnormalities.
  • The level of 3-methylglutaconate (3-MGC) or 3-methylglutaric acid (3-MGA) in urine does not correlate with the degree of neurologic damage.

Genotype-Phenotype Correlations

The limited number of pathogenic variants found to date does not permit genotype-phenotype correlations.

All individuals of Iraqi Jewish origin with OPA3-related 3-methylglutaconic aciduria have the same pathogenic variant; however, the phenotypic severity varies, even within the same family.


OPA3-related 3-methylglutaconic aciduria has been reported in approximately 40 individuals of Iraqi Jewish origin [Anikster et al 2001] and in one individual of Kurdish-Turkish descent [Kleta et al 2002].

The carrier rate in Iraqi Jews is estimated to be 1:10 [Anikster et al 2001].

Differential Diagnosis

Disorders in which excretion of 3-methylglutaconate (3-MGC) is increased

Increased urinary excretion of the branched-chain organic acid 3-methylglutaconate (3-MGC) is a relatively common finding in children investigated for suspected inborn errors of metabolism [Gunay-Aygun 2005]. 3-MGC is an intermediate of leucine degradation and the mevalonate shunt pathway that links sterol synthesis with mitochondrial acetyl-CoA metabolism (Figure 1).

Figure 1.

Figure 1.

Metabolic pathway diagram showing branched-chain organic acid 3-MGC as an intermediate of leucine degradation and the mevalonate shunt pathway that links sterol synthesis with mitochondrial acetyl-CoA

Classification of inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature has recently been updated by Wortmann et al [2013a] and Wortmann et al [2013b] (Table 3). Clinical features (Table 3) and biochemical findings (Table 4) of the 3-MGCA syndromes vary. Tissues with higher requirements for oxidative metabolism, such as the central nervous system and cardiac and skeletal muscle, are predominantly affected.

To explore whether pathogenic variants in OPA3 are present in individuals with nonspecific neurologic abnormalities and unexplained 3-MGCA, 11 individuals were screened; none were found to have pathogenic variants, suggesting that mutation of OPA3 is not a common cause of 3-MGCA in the absence of typical clinical features of OPA3-related 3-methylglutaconic aciduria [Neas et al 2005].

Five forms of 3-methylglutaconic aciduria (3-MGCA) have been recognized (Table 3) [Sweetman & Williams 2001, Gunay-Aygun 2005, Wortmann et al 2013a, Wortmann et al 2013b]. The exact source of 3-MGC is known in only 3-methylglutaconyl-CoA hydratase deficiency, the rarest of the five types, caused by primary deficiency of the mitochondrial enzyme 3-methylglutaconyl-CoA hydratase (3-MGCH), resulting in a block of leucine degradation.

Table 3.

New Classification for Inborn Errors of Metabolism with 3-Methylglutaconic Aciduria as Discriminative Feature

Patho-MechanismDisease NameFormer DesignationAdditional Hallmarks 1 of PhenotypeMode of Inheritance
Primary 3-MGA-uria
Organic aciduria3-methylglutaconyl-CoA hydratase deficiency (AUH defect)3-MGCA type I
Adult onset leukoencephalopathy, dementia, progressive spasticityAR
Secondary 3-MGA-uria
Defective phospholipid remodelingTAZ defect (Barth syndrome)3-MGCA type II
(Cardio)myopathy, short stature, neutropenia, hypocholesterolemia, cognitive phenotype, mild dysmorphic features, OXPHOS dysfunctionXL
SERAC1 defect (MEGDEL syndrome)3-MGCA type IV
Progressive spasticity, dystonia, deafness, Leigh syndrome-like MRI, severe psychomotor retardation, hypocholesterolemia, OXPHOS dysfunctionAR
Mitochondrial membrane disorderOPA3 defect (Costeff syndrome)3-MGCA type III
Ataxia/extrapyramidal dysfunction, optic atrophyAR
TMEM70 defect3-MGCA type IV
Broad phenotype, hypertrophic cardiomyopathy, myopathy, dysmorphic features, cataracts, psychomotor retardation, ATPase deficiency, lactic acidosis, hyperammonemiaAR
DNAJC19 defect (DCMA syndrome)3-MGCA type V
Dilated cardiomyopathy, ECG abnormalities, non-progressive cerebellar ataxia, Ssmall atrophic testes, cryptorchidism, growth failure, anemia, steatosis hepatitisAR
UnknownNOS 3-MGA-uria3-MGCA type IV
Variable, mostly progressive neurologic diseaseUnknown

From Wortmann et al [2013a]. Click here (pdf) for an expanded version of the table with information on protein subcellular localization and function.

DCMA = dilated cardiomyopathy with ataxia

NOS= not otherwise specified


In addition to 3-MGA-uria

Table 4.

Urinary Excretion of 3-MGC and 3-MGA in Inborn Errors of Metabolism with 3-Methylglutaconic Aciduria

DisorderUrinary Excretion
3-MGC and 3-MGA in mmol/mol Creatinine3-Hydroxyisovaleric Acid
3-methylglutaconyl-CoA hydratase deficiency500 to 1000 1Increased
TAZ defect (Barth syndrome)Mild to moderate 2Normal
OPA3 defect (Costeff syndrome) 39-187Normal
DNAJC19 defect (DCMA syndrome)Moderate 4Normal
NOS 3-MGA-uriaElevated to variable degreesNormal
Normal controls3.2-7NA

The urinary excretion of 3-methylglutaric acid (3-MGA) correlates with protein intake, whereas, in most individuals with other types of 3-MGCA the amount of 3-MGC in urine is not dependent on dietary leucine [Sweetman & Williams 2001].


Less than ten times the upper limit of normal


In 39 individuals [Elpeleg et al 1994]


Five- to tenfold normal [Davey et al 2006]

3-methylglutaconyl-CoA hydratase deficiency. The clinical features include nonspecific speech and language delay without metabolic derangement in some individuals and with hypoglycemia and metabolic acidosis in others (Table 3). Failure to thrive and psychomotor retardation are common. Microcephaly and progressive neurologic impairment with spastic quadriplegia, seizures, and dystonia have been reported. [Sweetman & Williams 2001, Ijlst et al 2002, Illsinger et al 2004].

TAZ defect (Barth syndrome). The clinical features include dilated cardiomyopathy associated with skeletal myopathy, neutropenia, and growth retardation (Table 3) [Walsh et al 1999, Ijlst et al 2002, Barth et al 2004]. Dilated cardiomyopathy presents within the first year of life or even prenatally [Barth et al 2004]. Cognitive development is normal, although an associated learning disorder has been described.

Moderately decreased plasma cholesterol (mostly of the LDL type) may be another clue for diagnosis of Barth syndrome.

TAZ defect cannot always be distinguished from OPA3 defect (Costeff syndrome) by urinary organic acid results alone (Table 4).

DNAJC19 defect (DCMA syndrome). DCMA, seen in the Dariusleut Hutterite population of Canada [Davey et al 2006] is characterized by severe early-onset dilated cardiomyopathy, growth failure, and cerebellar ataxia. Some may have optic atrophy. The mode of inheritance and the lack of skeletal myopathy and neutropenia distinguish DCMA syndrome from Barth syndrome.

Not otherwise specified 3-MGA-uria type (former 3-MGCA 4) includes all other individuals with 3-MGCA with normal 3-methylglutaconyl-CoA hydratase enzyme activity, and no defect in TAZ, SERAC1, OPA3, TMEM70, or DNAJC19 [Sweetman & Williams 2001, Gunay-Aygun 2005]. Most individuals in this group present early in life with nonspecific neurologic findings including psychomotor retardation and muscle tone abnormalities. Cardiomyopathy is common. Some have microcephaly, hearing loss, and retinitis pigmentosa, optic atrophy and/or cataracts. Some asymptomatic adults and pregnant women have been reported. Two brothers with a neurodegenerative disorder also had a myelodysplastic syndrome [Arn & Funanage 2006, Haimi et al 2006]. Persistent and episodic lactic acidosis are common. Some individuals have increased excretion of citric acid cycle intermediates.

Differential diagnosis of the clinical findings of OPA3-related methylglutaconic aciduria (Costeff syndrome)

Optic atrophy is seen in a number of syndromes as part of a complex phenotype. The combination of ataxia and optic atrophy is relatively nonspecific.

Pathologic pallor of optic atrophy may sometimes be difficult to differentiate from the physiologic optic disc pallor of infancy.

Behr syndrome. The clinical picture of Behr syndrome is most similar to OPA3-related methylglutaconic aciduria [Copeliovitch et al 2001]. Behr syndrome is an autosomal recessive disorder of childhood-onset optic atrophy and spinocerebellar degeneration characterized by ataxia, spasticity, intellectual disability, posterior column sensory loss, and peripheral neuropathy (OMIM 210000). Ataxia, an obligatory finding in Behr syndrome, is not seen in approximately half of individuals with OPA3-related methylglutaconic aciduria; conversely, most individuals with Behr syndrome do not manifest extrapyramidal dysfunction, one of the major features of OPA3-related methylglutaconic aciduria. Given that some individuals with OPA3-related methylglutaconic aciduria do not have extrapyramidal dysfunction, it is not possible to distinguish Behr syndrome from OPA3-related methylglutaconic aciduria based on clinical findings alone. At this time, OPA3-related methylglutaconic aciduria is distinguished from Behr syndrome by the presence of elevated excretion of 3-MGC and 3-MGA in urine (Table 4). It is possible that these two disorders are actually the same entity. It remains to be determined if individuals with Behr syndrome without elevated 3-MGA and 3-MGC excretion have mutation of OPA3.

Cerebral palsy. As the neurologic symptoms of OPA3-related methylglutaconic aciduria are relatively slow to progress, especially if the optic atrophy is not recognized, the disorder may be misdiagnosed as cerebral palsy [Straussberg et al 1998]. Therefore, cerebral palsy-like symptoms accompanied by optic atrophy and extrapyramidal signs in the absence of systemic acidosis should call for determination of urinary 3-MGC.


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with OPA3-related methylglutaconic aciduria (Costeff syndrome), the following evaluations are recommended:

  • Complete ophthalmologic examination
  • Visual evoked potentials
  • Complete neurologic examination
  • Developmental/educational assessment
  • Echocardiogram
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Treatment is supportive.

A multidisciplinary team including a neurologist, orthopedic surgeon, ophthalmologist, biochemical geneticist, and physical therapist is required for the care of affected individuals.

Visual impairment, spasticity, and movement disorder should be treated as in the general population.


Ophthalmologic, neurologic, and orthopedic evaluations as needed based on individual findings are appropriate.

Agents/Circumstances to Avoid

The following should be avoided:

  • Tobacco and alcohol use
  • Medications known to impair mitochondrial function

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search in the US and in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.


A possible role for coenzyme Q10 (CoQ10) has been hypothesized in the treatment of OPA3-related methylglutaconic aciduria because both 3-methylglutaconate (3-MGC) and CoQ10 can be produced from DMAPP, an intermediate metabolite in the synthesis of cholesterol [Costeff et al 1998]. Therefore, if CoQ10 production is impaired, more DMAPP would possibly be directed through the mevalonate shunt to 3-methyglutaconyl-CoA production. The findings of significantly lower-than-normal plasma concentrations of CoQ10 in six individuals with OPA3-related 3-methylglutaconic aciduria, in two individuals with Barth syndrome, and in four individuals with unclassified type 3-MGA-uria support this hypothesis.

However, administration of CoQ10 to six individuals with OPA3-related 3-methylglutaconic aciduria showed no clinical benefit or change in the excretion of 3-MGC [Costeff et al 1998]. The question of whether initiation of CoQ10 supplements early in the course of disease would prevent some neurologic damage remains to be answered.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

OPA3-related 3-methylglutaconic aciduria is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes and therefore carry one mutated allele.
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with OPA3-related 3-methylglutaconic aciduria are obligate heterozygotes (carriers) for a pathogenic variant in OPA3.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier (Heterozygote) Detection

Biochemical genetic testing. Because carriers have normal urinary excretion of 3-methylglutaric acid (3-MGA) and 3-methylglutaconate (3-MGC), carrier status cannot be determined using biochemical genetic testing.

Molecular genetic testing. Carrier testing for:

  • At-risk relatives requires prior identification of the pathogenic variants in the family;
  • Individuals of Iraqi Jewish origin relies on targeted analysis for the c.143-1G>C pathogenic variant.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Molecular genetic testing. Once the pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Biochemical genetic testing. Measurement of 3-MGC and 3-MGA in amniotic fluid is not reliable.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Costeff Support Group
    Sheba Medical Center
    Tel Hashomer 52621
    Phone: +9723530 5017
    Fax: +9723530 2658
  • National Library of Medicine Genetics Home Reference
  • Save Babies Through Screening Foundation, Inc.
    P. O. Box 42197
    Cincinnati OH 45242
    Phone: 888-454-3383
  • Metabolic Support UK
    5 Hilliards Court, Sandpiper Way
    Chester Business Park
    Chester CH4 9QP
    United Kingdom
    Phone: 0845 241 2173
  • Organic Acidemia Association
    Phone: 763-559-1797
    Fax: 866-539-4060 (toll-free)

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

OPA3-Related 3-Methylglutaconic Aciduria: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
OPA319q13​.32Optic atrophy 3 proteinOPA3 @ LOVDOPA3OPA3

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for OPA3-Related 3-Methylglutaconic Aciduria (View All in OMIM)

606580OPA3 GENE; OPA3

Gene structure. OPA3 comprises two exons and spans 32 kb of genomic DNA. For a detailed summary of gene and protein information, see Table A, Gene.

Benign variants. A clinically non-significant OPA3 sequence variant, c.231T>C, was found in 60 of 98 control alleles [Neas et al 2005].

Pathogenic variants (see Table 5)

Heterozygous missense pathogenic variants p.Gly93Ser and p.Gln105Glu result in a milder phenotype [Reynier et al 2004].

Table 5.

Selected OPA3 Variants

DNA Nucleotide Change
(Alias 1)
Predicted Protein ChangeReference Sequences
Benignc.231T>Cp.(=) 2NM_025136​.2
c.277G>Ap.Gly93Ser 3
c.313C>Gp.Gln105Glu 3

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​ See Quick Reference for an explanation of nomenclature.


Variant designation that does not conform to current naming conventions


p.(=) designates that protein has not been analyzed, but no change is expected.


Pathogenic variants associated with autosomal dominant optic atrophy and cataract

Normal gene product. OPA3 encodes a 179-amino acid (20-kd) protein that contains a mitochondrial targeting peptide, NRIKE, at amino acid residues 25-29 and is predicted to be exported to the mitochondrion [Anikster et al 2001]. It is ubiquitously expressed, with highest expression in skeletal muscle and kidney. In the brain, the cerebral cortex, medulla, cerebellum, and frontal lobe have slightly increased expression [Anikster et al 2001].

Abnormal gene product. The impact of the OPA3 pathogenic variants on cell function is unknown. Homozygous acceptor splice site variant c.143-1G>C in OPA3 with loss of function leads to typical OPA3-related methylglutaconic aciduria.

Animal model. An ENU-induced mutant mouse carrying the missense variant c.365T>C (p.Leu122Pro) of Opa3 showed a normal phenotype in the heterozygous state. However, mice homozygous for this variant display severe multisystem disease including cardiomyopathy, movement disorder, and optic nerve involvement; life span is reduced [Davies et al 2008].


Literature Cited

  • Anikster Y, Kleta R, Shaag A, Gahl WA, Elpeleg O. Type III 3-methylglutaconic aciduria (optic atrophy plus syndrome, or Costeff optic atrophy syndrome): identification of the OPA3 gene and its founder mutation in Iraqi Jews. Am J Hum Genet. 2001;69:1218–24. [PMC free article: PMC1235533] [PubMed: 11668429]
  • Arn P, Funanage VL. 3-methylglutaconic aciduria disorders: the clinical spectrum increases. J Pediatr Hematol Oncol. 2006;28:62–3. [PubMed: 16462574]
  • Barth PG, Valianpour F, Bowen VM, Lam J, Duran M, Vaz FM, Wanders RJ. X-linked cardioskeletal myopathy and neutropenia (Barth syndrome): an update. Am J Med Genet A. 2004;126A:349–54. [PubMed: 15098233]
  • Copeliovitch L, Katz K, Arbel N, Harries N, Bar-On E, Soudry M. Musculoskeletal deformities in Behr syndrome. J Pediatr Orthop. 2001;21:512–4. [PubMed: 11433166]
  • Costeff H, Apter N, Elpeleg ON, Prialnic M, Bohles HJ. Ineffectiveness of oral coenzyme Q10 supplementation in 3-methylglutaconic aciduria, type 3. Brain Dev. 1998;20:33–5. [PubMed: 9533558]
  • Davey KM, Parboosingh JS, McLeod DR, Chan A, Casey R, Ferreira P, Snyder FF, Bridge PJ, Bernier FP. Mutation of DNAJC19, a human homologue of yeast inner mitochondrial membrane co-chaperones, causes DCMA syndrome, a novel autosomal recessive Barth syndrome-like condition. J Med Genet. 2006;43:385–93. [PMC free article: PMC2564511] [PubMed: 16055927]
  • Davies VJ, Powell KA, White KE, Yip W, Hogan V, Hollins AJ, Davies JR, Piechota M, Brownstein DG, Moat SJ, Nichols PP, Wride MA, Boulton ME, Votruba M. A missense mutation in the murine Opa3 gene models human Costeff syndrome. Brain. 2008;131:368–80. [PubMed: 18222992]
  • Elpeleg ON, Costeff H, Joseph A, Shental Y, Weitz R, Gibson KM. 3-Methylglutaconic aciduria in the Iraqi-Jewish 'optic atrophy plus' (Costeff) syndrome. Dev Med Child Neurol. 1994;36:167–72. [PubMed: 7510656]
  • Gunay-Aygun M. 3-Methylglutaconic aciduria: a common biochemical marker in various syndromes with diverse clinical features. Mol Genet Metab. 2005;84:1–3. [PubMed: 15719488]
  • Haimi M, Elhasid R, Gershoni-Baruch R, Izraeli S, Wanders RJ, Mandel H. Myeloid dysplasia in familial 3-methylglutaconic aciduria. J Pediatr Hematol Oncol. 2006;28:69–72. [PubMed: 16462576]
  • Ho G, Walter JH, Christodoulou J. Costeff optic atrophy syndrome: New clinical case and novel molecular findings. J Inherit Metab Dis. 2008;31 Suppl 2:S419–23. [PubMed: 18985435]
  • Ijlst L, Loupatty FJ, Ruiter JP, Duran M, Lehnert W, Wanders RJ. 3-Methylglutaconic aciduria type I is caused by mutations in AUH. Am J Hum Genet. 2002;71:1463–6. [PMC free article: PMC378594] [PubMed: 12434311]
  • Illsinger S, Lucke T, Zschocke J, Gibson KM, Das AM. 3-methylglutaconic aciduria type I in a boy with fever-associated seizures. Pediatr Neurol. 2004;30:213–5. [PubMed: 15033206]
  • Kleta R, Skovby F, Christensen E, Rosenberg T, Gahl WA, Anikster Y. 3-Methylglutaconic aciduria type III in a non-Iraqi-Jewish kindred: clinical and molecular findings. Mol Genet Metab. 2002;76:201–6. [PubMed: 12126933]
  • Neas K, Bennetts B, Carpenter K, White R, Kirk EP, Wilson M, Kelley R, Baric I, Christodoulou J. OPA3 mutation screening in patients with unexplained 3-methylglutaconic aciduria. J Inherit Metab Dis. 2005;28:525–32. [PubMed: 15902555]
  • Reynier P, Amati-Bonneau P, Verny C, Olichon A, Simard G, Guichet A, Bonnemains C, Malecaze F, Malinge MC, Pelletier JB, Calvas P, Dollfus H, Belenguer P, Malthiery Y, Lenaers G, Bonneau D. OPA3 gene mutations responsible for autosomal dominant optic atrophy and cataract. J Med Genet. 2004;41:e110. [PMC free article: PMC1735897] [PubMed: 15342707]
  • Straussberg R, Brand N, Gadoth N. 3-Methyl glutaconic aciduria in Iraqi Jewish children may be misdiagnosed as cerebral palsy. Neuropediatrics. 1998;29:54–6. [PubMed: 9553953]
  • Sweetman L, Williams JC. Branched chain organic acidurias. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Basis of Inherited Disease. Vol 2. New York, NY: McGraw-Hill; 2001:2137-40.
  • Walsh R, Conway H, Roche G, Mayne PD. What is the origin of 3-methylglutaconic acid? J Inherit Metab Dis. 1999;22:251–5. [PubMed: 10384380]
  • Wortmann SB, Duran M, Anikster Y, Barth PG, Sperl W, Zschocke J, Morava E, Wevers RA. Inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature: proper classification and nomenclature. J Inherit Metab Dis. 2013a;36:923–8. [PubMed: 23296368]
  • Wortmann SB, Kluijtmans LA, Rodenburg RJ, Sass JO, Nouws J, van Kaauwen EP, Kleefstra T, Tranebjaerg L, de Vries MC, Isohanni P, Walter K, Alkuraya FS, Smuts I, Reinecke CJ, van der Westhuizen FH, Thorburn D, Smeitink JA, Morava E, Wevers RA. 3-Methylglutaconic aciduria-lessons from 50 genes and 977 patients. J Inherit Metab Dis. 2013b;36:913–21. [PubMed: 23355087]

Suggested Reading

  • Vockley J, Zschocke J, Knerr I, Vockley CW, Gibson KM. Branched chain organic acidurias. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 93.

Chapter Notes

Author History

Yair Anikster, MD, PhD (2006-present)
William A Gahl, MD, PhD; National Institutes of Health (2006-2013)
Meral Gunay-Aygun, MD (2006-present)
Marian Huizing, PhD (2013-present)

Revision History

  • 19 December 2013 (me) Comprehensive update posted live
  • 31 March 2009 (me) Comprehensive update posted live
  • 28 July 2006 (me) Review posted live
  • 27 April 2006 (mga) Original submission
Copyright © 1993-2019, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source ( and copyright (© 1993-2019 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

Bookshelf ID: NBK1473PMID: 20301646


  • PubReader
  • Print View
  • Cite this Page
  • Disable Glossary Links

Tests in GTR by Gene

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed
  • Gene
    Locus Links

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...