National Center for Advancing and Translational Sciences Genetic and Rare Diseases Information Center, a program of the National Center for Advancing and Translational Sciences

3-methylglutaconyl-CoA hydratase deficiency (AUH defect)


Other Names:
MGA type I; 3 alpha methylglutaconic aciduria type I; 3 methylglutaconyl CoA hydratase deficiency; MGA type I; 3 alpha methylglutaconic aciduria type I; 3 methylglutaconyl CoA hydratase deficiency; 3MG CoA hydratase deficiency; 3-MGCA type I (3-MGCA-1); 3 methylglutaconic aciduria type 1 See More
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The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.
orphanet

Orpha Number: 67046

Definition
3-methylglutaconic aciduria (3-MGA) type I is an inborn error of leucine metabolism with a variable clinical phenotype ranging from mildly delayed speech to psychomotor retardation, coma, failure to thrive, metabolic acidosis and dystonia.

Epidemiology
The disorder is very rare with less than 20 cases reported in the literature.

Clinical description
Clinical manifestations usually become apparent in the neonatal period or during infancy but the diagnosis may not be made until childhood. Some of the reported patients also displayed hypoglycaemia, spastic quadriparesis, microcephaly, progressive neurological deficit, seizures, vomiting, atrophy of the basal ganglia, severe hypotonia and hepatomegly.

Etiology
The syndrome is caused by mutations in the AUH gene (chromosome 9) encoding 3-methylglutaconyl-CoA hydratase, an enzyme involved in leucine degradation.

Diagnostic methods
As the clinical picture is variable and nonspecific, diagnosis can be made by assay of 3-methylglutaconyl-CoA hydratase activity in fibroblasts or leukocytes, quantitative analysis of urinary organic acid excretion or, more recently, analysis of bodily fluids by NMR spectroscopy.

Differential diagnosis
Patients with 3-MGA type I can be distinguished from those with other forms of 3-MGA (types II, III and IV; see these terms) by the distinctive pattern of metabolite excretion: 3-methylglutaconic acid levels are highly elevated (higher than those detected in other forms of 3-MGA) whereas methylglutaric acid levels are usually only slightly elevated, and there is a high level of 3-hydroxyisovaleric acid excretion (not present in other forms of 3-MGA).

Antenatal diagnosis
Prenatal diagnosis should be possible through detection of high levels of 3-hydroxyisovaleric acid in the amniotic fluid or through enzyme analysis of cultured amniocytes.

Genetic counseling
The syndrome is inherited as an autosomal recessive trait.

Management and treatment
Treatment is largely symptomatic but dietary management with a modest leucine restriction and supplementation with L-carnitine may be beneficial in some cases.

Visit the Orphanet disease page for more resources.
Last updated: 3/1/2007

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

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Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
3-Methylglutaconic aciduria 0003535
Failure to thrive
Faltering weight
Weight faltering
[ more ] 		0001508
30%-79% of people have these symptoms
Delayed speech and language development
Deficiency of speech development
Delayed language development
Delayed speech
Delayed speech acquisition
Delayed speech development
Impaired speech and language development
Impaired speech development
Language delay
Language delayed
Language development deficit
Late-onset speech development
Poor language development
Speech and language delay
Speech and language difficulties
Speech delay
[ more ] 		0000750
Global developmental delay 0001263
5%-29% of people have these symptoms
Abnormality of the basal ganglia 0002134
Coma 0001259
Dystonia 0001332
Hepatomegaly
Enlarged liver
0002240
Hypoglycemia
Low blood sugar
0001943
Microcephaly
Abnormally small skull
Decreased circumference of cranium
Decreased size of skull
Reduced head circumference
Small head circumference
[ more ] 		0000252
Progressive cerebellar ataxia 0002073
Seizure 0001250
Spastic tetraparesis 0001285
1%-4% of people have these symptoms
Psychomotor retardation 0025356
Percent of people who have these symptoms is not available through HPO
Ataxia 0001251
Athetosis
Involuntary writhing movements in fingers, hands, toes, and feet
0002305
Autosomal recessive inheritance 0000007
Cerebral atrophy
Degeneration of cerebrum
0002059
Cognitive impairment
Abnormality of cognition
Cognitive abnormality
Cognitive defects
Cognitive deficits
Intellectual impairment
Mental impairment
[ more ] 		0100543
Dysarthria
Difficulty articulating speech
0001260
Febrile seizure (within the age range of 3 months to 6 years)
Fever induced seizures
0002373
Hyperreflexia
Increased reflexes
0001347
Infantile onset
Onset in first year of life
Onset in infancy
[ more ] 		0003593
Leukoencephalopathy 0002352
Metabolic acidosis 0001942
Motor delay 0001270
Optic atrophy 0000648
Short attention span
Poor attention span
Problem paying attention
[ more ] 		0000736
Spastic tetraplegia 0002510
Urinary incontinence
Loss of bladder control
0000020
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Last updated: 7/1/2020

Making a diagnosis for a genetic or rare disease can often be challenging. Healthcare professionals typically look at a person’s medical history, symptoms, physical exam, and laboratory test results in order to make a diagnosis. The following resources provide information relating to diagnosis and testing for this condition. If you have questions about getting a diagnosis, you should contact a healthcare professional.

Newborn Screening

  • The Newborn Screening Coding and Terminology Guide has information on the standard codes used for newborn screening tests. Using these standards helps compare data across different laboratories. This resource was created by the National Library of Medicine.
  • An ACTion (ACT) sheet is available for this condition that describes the short-term actions a health professional should follow when an infant has a positive newborn screening result. ACT sheets were developed by experts in collaboration with the American College of Medical Genetics.
  • An Algorithm flowchart is available for this condition for determining the final diagnosis in an infant with a positive newborn screening result. Algorithms are developed by experts in collaboration with the American College of Medical Genetics.
  • Baby's First Test is the nation's newborn screening education center for families and providers. This site provides information and resources about screening at the local, state, and national levels and serves as the Clearinghouse for newborn screening information.
  • National Newborn Screening and Global Resource Center (NNSGRC) provides information and resources in the area of newborn screening and genetics to benefit health professionals, the public health community, consumers and government officials.

If you need medical advice, you can look for doctors or other healthcare professionals who have experience with this disease. You may find these specialists through advocacy organizations, clinical trials, or articles published in medical journals. You may also want to contact a university or tertiary medical center in your area, because these centers tend to see more complex cases and have the latest technology and treatments.

If you can’t find a specialist in your local area, try contacting national or international specialists. They may be able to refer you to someone they know through conferences or research efforts. Some specialists may be willing to consult with you or your local doctors over the phone or by email if you can't travel to them for care.

You can find more tips in our guide, How to Find a Disease Specialist. We also encourage you to explore the rest of this page to find resources that can help you find specialists.

Healthcare Resources

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Organizations Supporting this Disease

These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

Where to Start

  • Genetics Home Reference (GHR) contains information on 3-methylglutaconyl-CoA hydratase deficiency (AUH defect). This website is maintained by the National Library of Medicine.
  • The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.

In-Depth Information

  • GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.
  • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
  • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
  • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.

Questions sent to GARD may be posted here if the information could be helpful to others. We remove all identifying information when posting a question to protect your privacy. If you do not want your question posted, please let us know.