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Disease Profile

Not otherwise specified 3-MGA-uria type

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.

Unknown

Age of onset

Infancy

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ICD-10

E71.1

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

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Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

3 alpha methylglutaconic aciduria type IV; 3 methylglutaconic aciduria type IV

Categories

Congenital and Genetic Diseases; Metabolic disorders; Newborn Screening

Summary

The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.
orphanet

Orpha Number: 67048

Definition
3-methylglutaconic aciduria (3-MGA) type IV, or unclassified 3-MGA, is a clinically heterogeneous disorder characterised by increased 3-methylglutaconic acid excretion in individuals that cannot be classified as having one of the other forms of 3-MGA (3-MGA I, II or III).

Epidemiology
The prevalence of this disorder is unknown.

Clinical description
Patients usually present during the first year of life with neurological findings including psychomotor retardation, hypotonia, developmental delay, seizures and progressive spasticity, together with severe failure to thrive. Cardiomyopathy, hepatic dysfunction, eye anomalies, microcephaly, deafness, dysmorphism, neonatal hypoglycaemia, thrombocytopaenia and lactic acidosis have also been reported. Cerebellar dysgenesis may be revealed by magnetic resonance imaging. In contrast, a small number of asymptomatic patients have been diagnosed as having 3-MGA type IV.

Etiology
The aetiology remains unknown: unlike patients with 3-MGA type I, individuals with 3MGA type IV display normal 3-methylglutaconyl-CoA hydratase activity in cultured fibroblasts. Mitochondrial respiratory chain abnormalities have been detected in some 3MGA type IV patients but the clinical heterogeneity associated with this disorder suggests that the 3-methylglutaconic aciduria seen in 3-MGA type IV patients may result from a variety of causes and genetic factors.

Diagnostic methods
3-methylglutaconic aciduria can be diagnosed by analysis of urinary organic acid excretion but specific diagnosis of 3-MGA type IV requires exclusion of all other forms of 3-MGA. As the genetic factors responsible for the other forms of 3-MGA have now been determined, molecular analysis provides a valuable tool for accurate diagnosis.

Differential diagnosis
3-MGA type IV can be distinguished from the type I disorder by normal excretion of 3-hydroxyisovaleric acid. 3-MGA type II may be excluded by the mode of inheritance (transmission is X-linked recessive in 3-MGA type II) and on the basis of the clinical phenotype (the type II disorder is characterised by neutropaenia, skeletal myopathy, dilated cardiomyopathy and growth delay). Depending on the manifestations present, clinical differentiation of types III and IV may be more problematic, but the occurrence of 3-MGA type III is largely restricted to the Iraqi-Jewish population. In addition to other forms of 3-MGA, the differential diagnosis should also include cerebral palsy, dilated cardiomyopathy with ataxia (see this term) and other organic acidurias.

Genetic counseling
The disorder has been reported to be inherited as an autosomal recessive trait.

Management and treatment
At present there is no effective treatment for 3-MGA type IV and a leucine-restricted diet appears to be of no benefit.

Prognosis
The prognosis depends on the clinical phenotype but the neurological complications can be severe with a potentially fatal disease course.

Visit the Orphanet disease page for more resources.

Symptoms

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.

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
Global developmental delay
0001263
Intellectual disability
Mental deficiency
Mental retardation
Mental retardation, nonspecific
Mental-retardation

[ more ]

0001249
Muscular hypotonia
Low or weak muscle tone
0001252
Seizure
0001250
Spasticity
Involuntary muscle stiffness, contraction, or spasm
0001257
30%-79% of people have these symptoms
Dysgenesis of the cerebellar vermis
0002195
5%-29% of people have these symptoms
Cardiomyopathy
Disease of the heart muscle
0001638
Cataract
Clouding of the lens of the eye
Cloudy lens

[ more ]

0000518
Decreased liver function
Liver dysfunction
0001410
Hearing impairment
Deafness
Hearing defect

[ more ]

0000365
Hypoglycemia
Low blood sugar
0001943
Iris hypopigmentation
Light eye color
0007730
Lactic acidosis
Increased lactate in body
0003128
Microcephaly
Abnormally small skull
Decreased circumference of cranium
Decreased size of skull
Reduced head circumference
Small head circumference

[ more ]

0000252
Thrombocytopenia
Low platelet count
0001873
Percent of people who have these symptoms is not available through HPO
3-Methylglutaric aciduria
0003344
Areflexia
Absent tendon reflexes
0001284
Autosomal recessive inheritance
0000007
Biventricular hypertrophy
0200128
Cerebellar dysplasia
0007033
Cryptorchidism
Undescended testes
Undescended testis

[ more ]

0000028
Inguinal hernia
0000023
Neonatal hypotonia
Low muscle tone, in neonatal onset
0001319
Neonatal respiratory distress
Infantile respiratory distress
Newborn respiratory distress
Respiratory distress, neonatal

[ more ]

0002643
Severe global developmental delay
0011344
Single transverse palmar crease
0000954
Subvalvular aortic stenosis
Narrowing of blood vessel below aortic heart valve
0001682

Diagnosis

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

  • 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.

    Organizations

    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

      Learn more

      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

      • MedlinePlus Genetics contains information on Not otherwise specified 3-MGA-uria type. This website is maintained by the National Library of Medicine.

        In-Depth Information

        • 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.