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OPA3-Related 3-Methylglutaconic Aciduria

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

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

Author Information
, MD
National Human Genome Research Institute
Medical Genetics Branch
Section on Human Biochemical Genetics
National Institutes of Health
Bethesda, Maryland
Associate Professor of Pediatrics and Genetics, Institute of Genetic Medicine
Departments of Pediatrics and Genetics
Johns Hopkins University School of Medicine
Baltimore, Maryland
, PhD
National Human Genome Research Institute
Medical Genetics Branch
Section on Human Biochemical Genetics
National Institutes of Health
Bethesda, Maryland
, MD, PhD
Head of Metabolic Unit, Safra Children's Hospital
Sheba Medical Center
Tel Hashomer, Israel

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

Summary

Disease 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.

Diagnosis/testing. 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.

Management. 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.

Diagnosis

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 mutation analysis for the c.143-1G>C variant should be performed first in affected individuals of Iraqi Jewish origin.

Table 2. Summary of 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 mutation analysis 2See footnote 3See footnote 4
Sequence analysis 5Unknown
Deletion/duplication analysis 6Unknown 7

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

2. Mutation panels may vary by laboratory.

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

4. 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].

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

6. Testing that identifies exonic 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.

7. 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 Description

Natural History

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

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 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.

Prevalence

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

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
(3-MGCA-1)
Adult onset leukoencephalopathy, dementia, progressive spasticityAR
Secondary 3-MGA-uria
Defective phospholipid remodelingTAZ defect (Barth syndrome)3-MGCA type II (3-MGCA-2)(Cardio)myopathy, short stature, neutropenia, hypocholesterolemia, cognitive phenotype, mild dysmorphic features, OXPHOS dysfunctionXL
SERAC1 defect (MEGDEL syndrome)3-MGCA type IV
(3-MGCA-4)
Progressive spasticity, dystonia, deafness, Leigh syndrome-like MRI, severe psychomotor retardation, hypocholesterolemia, OXPHOS dysfunctionAR
Mitochondrial membrane disorderOPA3 defect (Costeff syndrome)3-MGCA type III
(3-MGCA-3)
Ataxia/extrapyramidal dysfunction, optic atrophyAR
TMEM70 defect3-MGCA type IV
(3-MGCA-4)
Broad phenotype, hypertrophic cardiomyopathy, myopathy, dysmorphic features, cataracts, psychomotor retardation, ATPase deficiency, lactic acidosis, hyperammonemiaAR
DNAJC19 defect (DCMA syndrome)3-MGCA type V (3-MGCA-5)Dilated cardiomyopathy, ECG abnormalities, non-progressive cerebellar ataxia, Small atrophic testes,
cryptorchidism, growth failure, anemia, steatosis hepatitis
AR
UnknownNOS 3-MGA-uria3-MGCA type IV
(3-MGCA-4)
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

1. 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-HIV)
3-methylglutaconyl-CoA hydratase deficiency500 to 1000 1Increased
TAZ defect (Barth syndrome)Mild to moderate 2Normal
OPA3 defect (Costeff syndrome) 3 9-187Normal
DNAJC19 defect (DCMA syndrome)Moderate 4Normal
NOS 3-MGA-uriaElevated to variable degreesNormal
Normal controls3.2-7NA

1. 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. Less than ten times the upper limit of normal

3. In 39 individuals [Elpeleg et al 1994]

4. 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.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

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
  • Medical genetics consultation

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.

Surveillance

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 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.

Other

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 mutant 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 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 mutation analysis for the c.143-1G>C mutation.

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

Molecular genetic testing. If the pathogenic variants have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

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

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the pathogenic variants have been identified.

Resources

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
    Israel
    Phone: +9723530 5017
    Fax: +9723530 2658
    Email: roma40@012.net.il
  • National Library of Medicine Genetics Home Reference
  • Save Babies Through Screening Foundation, Inc.
    P. O. Box 42197
    Cincinnati OH 45242
    Phone: 888-454-3383
    Email: email@savebabies.org
  • Children Living with Inherited Metabolic Diseases (CLIMB)
    Climb Building
    176 Nantwich Road
    Crewe CW2 6BG
    United Kingdom
    Phone: 0800-652-3181 (toll free); 0845-241-2172
    Fax: 0845-241-2174
    Email: info.svcs@climb.org.uk
  • Organic Acidemia Association
    PO Box 1008
    Pinole CA 94564
    Phone: 510-672-2476
    Fax: 866-539-4060 (toll-free)
    Email: carolbarton@oaanews.org

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

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
OPA319q13​.32Optic atrophy 3 proteinOPA3 @ LOVDOPA3

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

2585013-METHYLGLUTACONIC ACIDURIA, TYPE III; MGCA3
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 Symbol.

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

Pathogenic allelic variants (see Table 5)

  • c.143-1G>C. This homozygous acceptor splice site variant in OPA3 is the cause of OPA3-related 3-methylglutaconic aciduria 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 variant 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 pathogenic variants p.Gly93Ser and p.Gln105Glu result in a milder phenotype [Reynier et al 2004].

Table 5. Selected OPA3 Variants

Variant ClassificationDNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
Benignc.231T>Cp.(=) 2NM_025136​.2
NP_079412​.1
Pathogenicc.143-1G>C
(IVS1-1G>C)
--
c.277G>Ap.Gly93Ser 3
c.313C>Gp.Gln105Glu 3
c.320_337delp.Gln108_Glu113del
c.415C>Tp.Gln139Ter

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 (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

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

3. 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].

References

Literature Cited

  1. 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]
  2. Arn P, Funanage VL. 3-methylglutaconic aciduria disorders: the clinical spectrum increases. J Pediatr Hematol Oncol. 2006;28:62–3. [PubMed: 16462574]
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Suggested Reading

  1. Vockley J, Zschocke J, Knerr I, Vockley CW, Gibson KM. Branched chain organic acidurias. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 93. 2013. Available online. Accessed 4-17-14.

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 to live Web site
  • 27 April 2006 (mga) Original submission
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