DiagnosisClinical DiagnosisThe diagnosis of 3-methylglutaconic aciduria type 3 (3-MGCA 3) is suspected in a child with relatively normal early development and growth in combination with the following:Bilateral early-onset optic atrophyChoreoathetoid movement disorderNote: 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 excretions of 3-methylglutaconate (3-MGC) and 3-methylglutaric acid (3-MGA) in urine organic acids and by the identification of mutations in OPA3.TestingBiochemical testingUrinary excretion of 3-methylglutaconate (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 3-MGCA 3, urinary 3-MGC and 3-MGA are mildly increased (combined elevation <200 mmol/mol creatinine) (Table 1).Note: 3-MGA is derived from hydrogenation of 3-methylglutaconyl-CoA.Table 1. Combined Urinary Excretion of 3-MGC and 3-MGA in 3-MGCA 3View in own windowPhenotypeCombined Urinary Excretion: RangeIn mmol/mol CreatinineIn µmol/LIndividuals with 3-MGCA 39-187141-2245Normal controls3.2-720-98In a study of 39 individuals Individuals with 3-MGCA 3 have normal laboratory values for the following:Serum bicarbonate concentrationLiver and kidney function testsSerum and cerebrospinal fluid (CSF) lactic acid concentrationsSerum creatinine phosphokinase (CK) activityMolecular Genetic TestingGene. OPA3 is the only gene known to be associated with 3-MGCA 3.Clinical testingTargeted mutation analysisOne mutation, c.143-1G>C, accounts for 100% of disease-causing alleles in the Iraqi Jewish population [Anikster et al 2001].c.320_337del, found in an individual of Turkish-Kurdish origin with 3-MGCA 3, is the first mutation found to date in an individual of non-Iraqi Jewish origin [Kleta et al 2002].c. 415C>T (p. Q139X) nonsense mutation, found in the homozygous state in an individual of Indian origin with 3-MGCA 3, is the second mutation found to date in an individual of non-Iraqi Jewish origin [Ho et al 2008]. Sequence analysis of the OPA3 coding region to detect mutations not identified by targeted mutation analysisDeletion/duplication analysis. No deletions or duplications involving OPA3 have been reported to cause type 3-methylglutaconic aciduria type 3; however, a systematic analysis has yet to be performed.Table 2. Summary of Molecular Genetic Testing Used in 3-Methylglutaconic Aciduria Type 3View in own windowGene Symbol Test MethodMutations
DetectedMutation Detection Frequency by Test MethodTest AvailabilityIraqi JewishNon-Iraqi JewishOPA3Targeted mutation analysisc.143-1G>C ^{1100%0%ClinicalSequence analysisSequence variants 2UnknownDeletion / duplication analysis 3, 4Partial- or whole-gene deletions 4Unknown1. Mutation panels may vary by laboratory.2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.3. Testing that identifies deletions/duplications not detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, real-time PCR, multiplex ligation dependent probe amplification (MLPA), and array GH may be used.4. To date, no deletions or duplications involving OPA3 have been reported to cause 3-methylglutaconic aciduria type 3.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyConfirming the diagnosis in a proband If clinical findings point to 3-MGCA 3, 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 3-MGCA 3 (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 3-MGCA 3.To date, the c.143-1G>C mutation has been identified in all affected individuals of Iraqi Jewish descent. Thus, targeted mutation analysis for the c.143-1G>C mutation should be performed first in affected individuals of Iraqi Jewish origin.Carrier testing for:At-risk relatives requires prior identification of the disease-causing mutations in the family; Individuals of Iraqi Jewish origin relies on targeted mutation analysis for the c.143-1G>C mutation.Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersTwo heterozygous OPA3 point mutations, p.Gly93Ser and p.Gln105Glu, were reported in two families with autosomal dominant optic atrophy and cataract [Reynier et al 2004].}

Natural HistoryMost individuals with 3-methylglutaconic aciduria type 3 (3-MGCA 3) present within the first ten years of life with decreased visual acuity and/or choreoathetoid movement disorder. 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.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 3-MGCA 3, 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 3-MGCA 3, 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 yearsWere absent in four individuals ages 13 to 32 yearsUnstable spastic gait, increased tendon reflexes, and positive Babinski sign may be seen. In 36 individuals with 3-MGCA 3, 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 Other. 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 3-MGCA 3. Partial seizures were reported in one individual.Individuals with 3-MGCA 3 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 CorrelationsThe limited number of mutations found to date does not permit genotype-phenotype correlations.All individuals of Iraqi Jewish origin with 3-MGCA 3 have the same mutation; however, the phenotypic severity varies, even within the same family.

Differential DiagnosisElevated Excretion of 3-MGCIncreased urinary excretion of 3-methylglutaconate (3-MGC) is a relatively common finding in children investigated for suspected inborn errors of metabolism [Gunay-Aygun 2005]. The branched-chain organic acid 3-MGC is an intermediate of leucine degradation and the mevalonate shunt pathway that links sterol synthesis with mitochondrial acetyl-CoA metabolism (Figure 1).FigureFigure 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 Five forms of 3-methylglutaconic aciduria (3-MGCA) have been recognized (Table 3) [Sweetman & Williams 2001, Gunay-Aygun 2005]. The exact source of 3-MGC is known in only 3-MGCA 1, 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. Combined Urinary Excretion of 3-MGC and 3-MGA in 3-MGCA DisordersView in own windowDisorderUrinary Excretion
of 3-MGC and 3-MGA
in mmol/mol
Creatinine3-Hydroxyisovaleric Acid (3-HIV)
ExcretionGene SymbolProtein Name3-MGCA 1500 to 1000 ^{1IncreasedAUH3-methylglutaconyl-CoA hydratase (3-MGCH) 23-MGCA 2Mild to moderate 3NormalTAZTafazzin3-MGCA 3 4 9-187NormalOPA3Optic atrophy 3 protein3-MGCA 4Elevated to variable degreesNormal3-MGCA 5Moderate 5NormalDNAJC19DNAJC19Normal controls3.2-7NANANA1. 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].2. A mitochondrial leucine degradation enzyme3. Less than ten times the upper limit of normal4. In 39 individuals [Elpeleg et al 1994]5. Five to ten fold normal [Davey et al 2006]Clinical features 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.3-MGCA 1. The clinical features include nonspecific speech and language delay without metabolic derangement in some individuals and with hypoglycemia and metabolic acidosis in others. Failure to thrive and psychomotor retardation are common. Microcephaly and progressive neurologic impairment with spastic quadriplegia, seizures, and dystonia have been reported. Inheritance is autosomal recessive [Sweetman & Williams 2001, Ijlst et al 2002, Illsinger et al 2004].Individuals with 3-MGCA 1 excrete the highest levels of 3-MGC among all types of 3-MGCA (Table 3). 3-hydroxy-3-methylglutaric acid excretion is normal.3-MGCA 2 (Barth syndrome). The clinical features include dilated cardiomyopathy associated with skeletal myopathy, neutropenia, and growth retardation [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. Inheritance is X-linked.Moderately decreased plasma cholesterol (mostly of the LDL type) may be another clue for diagnosis of Barth syndrome.3-MGCA type 2 cannot always be distinguished from 3-MGCA type 3 or type 4 by urinary organic acid results alone.3-MGCA 4, the "unclassified" type, includes all other individuals with 3-MGCA with normal 3-MGCH enzyme activity [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.Several individuals have proven mitochondrial defects, including deficiency of respiratory chain complexes I, II, III, IV, and V [Scaglia et al 2001, Sweetman & Williams 2001].3-MGCA 5 (autosomal recessive Barth syndrome-like condition, or dilated cardiomyopathy with ataxia [DCMA]). DCMA, seen in the Dariusleut Hutterite population of Canada, is caused by mutations in DNAJC19 [Davey et al 2006]. The protein encoded by DNAJC19 shares sequence similarity with Tim14, an integral mitochondrial inner membrane protein that participates in mitochondrial protein import. The major clinical features are severe early-onset dilated cardiomyopathy, growth failure, and cerebellar ataxia. Many individuals excrete increased amounts of 3-MGC and 3-MGA; some may have optic atrophy. The mode of inheritance and the lack of skeletal myopathy and neutropenia distinguish DCMA syndrome from Barth syndrome.To explore whether mutations in OPA3 are present in individuals with nonspecific neurologic abnormalities and unexplained 3-MGCA, 11 individuals were screened; none were found to have mutations, suggesting that mutations in OPA3 are not a common cause of 3-MGCA in the absence of typical clinical features of 3-MGCA 3 [Neas et al 2005].Clinical Findings of 3-MGCA 3Optic 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 3-MGCA 3 [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 3-MGCA 3; conversely, most individuals with Behr syndrome do not manifest extrapyramidal dysfunction, one of the major features of 3-MGCA 3. Given that some individuals with 3-MGCA 3 do not have extrapyramidal dysfunction, it is not possible to distinguish Behr syndrome from 3-MGCA 3 based on clinical findings alone. At this time, 3-MGCA 3 is distinguished from Behr syndrome by the presence of elevated excretion of 3-MGC and 3-MGA in the urine. 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 mutations in OPA3. Cerebral palsy. As the neurologic symptoms of 3-MGCA 3 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.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).}

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with 3-methylglutaconic aciduria type 3 (3-MGCA 3), the following evaluations are recommended:Complete ophthalmologic examination Visual evoked potentialsComplete neurologic examinationDevelopmental/educational assessmentEchocardiogramTreatment of ManifestationsTreatment for 3-MGCA 3 is supportive.A multidisciplinary team including a neurologist, orthopedic surgeon, ophthalmologist, biochemical geneticist, and physical therapist is required for the care of individuals with 3-MGCA 3.Visual impairment, spasticity, and movement disorder should be treated as in the general population.SurveillanceOphthalmologic, neurologic, and orthopedic evaluations as needed based on individual findings are appropriate. Agents/Circumstances to AvoidThe following should be avoided:Tobacco and alcohol useMedications known to impair mitochondrial functionEvaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov 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.OtherA possible role for coenzyme Q₁₀ (CoQ₁₀) has been hypothesized in 3-MGCA 3 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 3-MGCA 3, in two individuals with Barth syndrome, and in four individuals with 3-MGCA 4 support this hypothesis.However, administration of CoQ₁₀ to six individuals with 3-MGCA 3 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.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. 3-Methylglutaconic Aciduria Type 3: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDOPA319q13​.32Optic atrophy 3 proteinOPA3 @ LOVDOPA3Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for 3-Methylglutaconic Aciduria Type 3 (View All in OMIM) View in own window 2585013-METHYLGLUTACONIC ACIDURIA, TYPE III; MGCA3 606580OPA3 GENE; OPA3Normal allelic variants. OPA3 consists of two exons and spans 32 kb of genomic DNA. A clinically non-significant sequence variation of OPA3, c.231T>C, was found in 60 of 98 control alleles [Neas et al 2005].Pathologic allelic variants (see Table 4)c.143-1G>C. This homozygous acceptor splice site mutation in OPA3 is the cause of 3-MGCA 3 in all individuals of Iraqi Jewish origin tested to date [Anikster et al 2001]. The resulting lack of mRNA expression manifests as the absence of an OPA3 band on a northern blotting of fibroblasts from affected individuals and as an inability to amplify OPA3 using the blood cDNA of affected individuals [Anikster et al 2001].p.Gly93Ser. A heterozygous c.277G>A point mutation in exon 2 of OPA3, resulting in a p.Gly93Ser substitution, is identified in the affected members of a French family with autosomal dominant optic atrophy and cataract [Reynier et al 2004]. p.Gln105Glu. A heterozygous c.313C>G transversion in exon 2 of OPA3, resulting in a p.Gln105Glu substitution, is identified in the affected members of a family with autosomal dominant optic atrophy and cataract [Reynier et al 2004].Heterozygous missense mutations p.Gly93Ser and p.Gln105Glu result in a milder phenotype [Reynier et al 2004].Table 4. Selected OPA3 Allelic VariantsView in own windowClass of Variant AlleleDNA Nucleotide Change
(Alias ¹)Protein Amino Acid ChangeReference SequencesNormalc.231T>Cp.(=) ^{2NM_025136​.2
NP_079412​.1Pathologicc.143-1G>C
(IVS1-1G>C)--c.277G>Ap.Gly93Ser 3c.313C>Gp.Gln105Glu 3c.320_337delp.Gln108_Glu113delc.415C>T p.Gln139XSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).1. Variant designation that does not conform to current naming conventions2. p.(=) designates that protein has not been analyzed, but no change is expected.3. Mutations 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 mutations on cell function is unknown. Homozygous acceptor splice site mutation c.143-1G>C in OPA3 with loss of function leads to typical 3-methylglutaconic aciduria type 3. Animal model. An ENU-induced mutant mouse carrying the missense mutation c.365T>C (p.Leu122Pro) of Opa3 showed a normal phenotype in the heterozygous state. However, mice homozygous for this mutation display severe multisystemic disease including cardiomyopathy, movement disorder, optic nerve involvement, and reduced life span [Davies et al 2008].}