Clinical Diagnosis

The 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 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 excretions of 3-methylglutaconate (3-MGC) and 3-methylglutaric acid (3-MGA) in urine organic acids and by the identification of mutations in the OPA3 gene.

Testing

Biochemical testing

Urinary 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.

For laboratories offering biochemical testing, see .

Individuals with 3-MGCA 3 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

Molecular Genetic Testing

Gene. OPA3 is the only gene known to be associated with 3-MGCA 3.

Clinical testing

• Targeted mutation analysis
  • One 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. Sequence analysis of the OPA3 coding region is available on a clinical basis for individuals in whom mutations are not identified by targeted mutation analysis.
• Deletion/duplication analysis. No deletions or duplications involving OPA3 as causative of type 3-methylglutacenic aciduria type 3 have been reported to date; however, a systematic analysis has yet to be performed.

Table 2. Summary of Molecular Genetic Testing Used in 3-Methylglutaconic Aciduria Type 3

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method		Test Availability
			Iraqi Jewish	Non-Iraqi Jewish
OPA3	Targeted mutation analysis	c.143-1G>C 1	100%	0%	Clinical
	Sequence analysis	Sequence variants 2	Unknown
	Deletion/duplication analysis 3, 4	Partial- or whole-gene deletions 4	Unknown

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. 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. No deletions or duplications involving OPA3 as causative of type 3 3-methylglutacenic aciduria have been reported to date.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

Confirming 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.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

Two 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 History

Most 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 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 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 Correlations

The 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.

Prevalence

3-MGCA 3 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].

Elevated Excretion of 3-MGC

Increased 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).

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

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.

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 the DNAJC19 gene [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 3

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 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).

Evaluations Following Initial Diagnosis

To 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 potentials
• Complete neurologic examination
• Developmental/educational assessment
• Echocardiogram

Treatment of Manifestations

Treatment 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.

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

Testing 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 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.

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Mode of Inheritance

3-methylglutaconic aciduria type 3 (3-MGCA 3) 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 3-MGCA 3 are obligate heterozygotes (carriers) for a disease-causing mutation in the OPA3 gene.

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 using molecular genetic testing for at-risk family members is possible once the mutations have been identified in the family.

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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. Both disease-causing alleles of an affected family member must be identified in the family before prenatal testing can be performed.

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 available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

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]
3. 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]
4. 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]
5. 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]
6. 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]
7. 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(Pt 2):368–80. [PubMed: 18222992]
8. 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]
9. 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]
10. 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]
11. Ho G, Walter JH, Christodoulou J (2008) Costeff optic atrophy syndrome: New clinical case and novel molecular findings. J Inherit Metab Dis [Epub ahead of print] [PubMed: 18985435]
12. 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]
13. 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]
14. 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]
15. 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]
16. 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]
17. Scaglia F, Sutton VR, Bodamer OA, Vogel H, Shapira SK, Naviaux RK, Vladutiu GD. Mitochondrial DNA depletion associated with partial complex II and IV deficiencies and 3-methylglutaconic aciduria. J Child Neurol. 2001;16:136–8. [PubMed: 11292221]
18. 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]
19. Sweetman L, Williams JC (2001) Branched chain organic acidurias. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The Metabolic and Molecular Basis of Inherited Disease, Vol 2. McGraw-Hill, New York, pp 2137-40.
20. 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]

Suggested Reading

1. Sweetman L, Williams JC. Branched chain organic acidurias. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B (eds) The Metabolic and Molecular Bases of Inherited Disease (OMMBID), McGraw-Hill, New York, Chap 93. Available at www​.ommbid.com. Accessed 09-02-08.

Revision History

• 31 March 2009 (me) Comprehensive update posted live
• 28 July 2006 (me) Review posted to live Web site
• 27 April 2006 (mga) Original submission