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3-Methylglutaconic aciduria type 3(MGCA3)

MedGen UID:
108273
•Concept ID:
C0574084
•
Disease or Syndrome
Synonyms: 3-alpha methylglutaconic aciduria type III; 3-methylglutaconic aciduria type III; Costeff optic atrophy syndrome; Iraqi Jewish optic atrophy plus; MGA type III; MGCA3; OPA3, AUTOSOMAL RECESSIVE; OPA3-Related 3-Methylglutaconic Aciduria; OPTIC ATROPHY 3, AUTOSOMAL RECESSIVE; Optic atrophy infantile with chorea and spastic paraplegia
SNOMED CT: Costeff syndrome (297232009); 3-Methylglutaconic aciduria type 3 (297232009)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
•Concept ID:
C0441748
•
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal recessive inheritance (Orphanet)
 
Gene (location): OPA3 (19q13.32)
 
Monarch Initiative: MONDO:0009787
OMIM®: 258501
Orphanet: ORPHA67047

Disease characteristics

Excerpted from the GeneReview: Costeff Syndrome
Costeff syndrome is characterized by optic atrophy and/or choreoathetoid movement disorder with onset before age ten years. Optic atrophy is associated with progressive decrease in 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. [from GeneReviews]
Full text of GeneReview (by section):
Summary  |  Diagnosis  |  Clinical Characteristics  |  Genetically Related (Allelic) Disorders  |  Differential Diagnosis  |  Management  |  Genetic Counseling  |  Resources  |  Molecular Genetics  |  References  |  Chapter Notes
Authors:
Yair Anikster   view full author information

Additional descriptions

From OMIM
3-Methylglutaconic aciduria type III (MGCA3) is a neuroophthalmologic syndrome consisting of early-onset bilateral optic atrophy and later-onset spasticity, extrapyramidal dysfunction, and cognitive deficit. Urinary excretion of 3-methylglutaconic acid and of 3-methylglutaric acid is increased (Anikster et al., 2001). The phenotype is similar to Behr syndrome (210000) and may in some cases represent the same disorder (Sheffer et al., 1992; Lerman-Sagie, 1995). For a discussion of genetic heterogeneity of 3-methylglutaconic aciduria, see MGCA type I (250950).  http://www.omim.org/entry/258501
From MedlinePlus Genetics
Costeff syndrome is an inherited condition characterized by vision loss, delayed development, and movement problems. Vision loss is primarily caused by degeneration (atrophy) of the optic nerves, which carry information from the eyes to the brain. This optic nerve atrophy often begins in infancy or early childhood and results in vision impairment that worsens over time. Some affected individuals have rapid and involuntary eye movements (nystagmus) or eyes that do not look in the same direction (strabismus).

Development of motor skills, such as walking, is often delayed in people with Costeff syndrome. Affected individuals may also have speech difficulties (dysarthria). While some people with Costeff syndrome have mild to moderate intellectual disability, many have normal intelligence.

Movement problems in people with Costeff syndrome develop in late childhood and include muscle stiffness (spasticity), impaired muscle coordination (ataxia), and involuntary jerking movements (choreiform movements). As a result of these movement difficulties, individuals with Costeff syndrome may require wheelchair assistance.

Costeff syndrome is associated with increased levels of a substance called 3-methylglutaconic acid in the urine (3-methylglutaconic aciduria). The amount of this substance does not appear to influence the signs and symptoms of the condition. Costeff syndrome is one of a group of metabolic disorders that can be diagnosed by the presence of 3-methylglutaconic aciduria. People with Costeff syndrome also have high levels of another acid called 3-methylglutaric acid in their urine.  https://medlineplus.gov/genetics/condition/costeff-syndrome

Clinical features

From HPO
3-Methylglutaric aciduria
MedGen UID:
463302
•Concept ID:
C3151952
•
Finding
An abnormally increased level of 3-hydroxy-3-methylglutaric acid in the urine.
See: Feature record | Search on this feature
3-Methylglutaconic aciduria
MedGen UID:
777186
•Concept ID:
C3696376
•
Disease or Syndrome
An increased amount of 3-methylglutaconic acid in the urine.
See: Feature record | Search on this feature
Cerebellar ataxia
MedGen UID:
849
•Concept ID:
C0007758
•
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
See: Feature record | Search on this feature
Chorea
MedGen UID:
3420
•Concept ID:
C0008489
•
Disease or Syndrome
Chorea (Greek for 'dance') refers to widespread arrhythmic involuntary movements of a forcible, jerky and restless fashion. It is a random-appearing sequence of one or more discrete involuntary movements or movement fragments. Movements appear random because of variability in timing, duration or location. Each movement may have a distinct start and end. However, movements may be strung together and thus may appear to flow randomly from one muscle group to another. Chorea can involve the trunk, neck, face, tongue, and extremities.
See: Feature record | Search on this feature
Dysarthria
MedGen UID:
8510
•Concept ID:
C0013362
•
Mental or Behavioral Dysfunction
Dysarthric speech is a general description referring to a neurological speech disorder characterized by poor articulation. Depending on the involved neurological structures, dysarthria may be further classified as spastic, flaccid, ataxic, hyperkinetic and hypokinetic, or mixed.
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Spasticity
MedGen UID:
7753
•Concept ID:
C0026838
•
Sign or Symptom
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
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Babinski sign
MedGen UID:
19708
•Concept ID:
C0034935
•
Finding
Upturning of the big toe (and sometimes fanning of the other toes) in response to stimulation of the sole of the foot. If the Babinski sign is present it can indicate damage to the corticospinal tract.
See: Feature record | Search on this feature
Hyperreflexia
MedGen UID:
57738
•Concept ID:
C0151889
•
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
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Abnormality of extrapyramidal motor function
MedGen UID:
115941
•Concept ID:
C0234133
•
Sign or Symptom
A neurological condition related to lesions of the basal ganglia leading to typical abnormalities including akinesia (inability to initiate changes in activity and perform volitional movements rapidly and easily), muscular rigidity (continuous contraction of muscles with constant resistance to passive movement), chorea (widespread arrhythmic movements of a forcible, rapid, jerky, and restless nature), athetosis (inability to sustain the muscles of the fingers, toes, or other group of muscles in a fixed position), and akathisia (inability to remain motionless).
See: Feature record | Search on this feature
Cognitive impairment
MedGen UID:
90932
•Concept ID:
C0338656
•
Mental or Behavioral Dysfunction
Abnormal cognition is characterized by deficits in thinking, reasoning, or remembering.
See: Feature record | Search on this feature
Optic atrophy
MedGen UID:
18180
•Concept ID:
C0029124
•
Disease or Syndrome
Atrophy of the optic nerve. Optic atrophy results from the death of the retinal ganglion cell axons that comprise the optic nerve and manifesting as a pale optic nerve on fundoscopy.
See: Feature record | Search on this feature
Reduced visual acuity
MedGen UID:
65889
•Concept ID:
C0234632
•
Finding
Diminished clarity of vision.
See: Feature record | Search on this feature
Visual impairment
MedGen UID:
777085
•Concept ID:
C3665347
•
Finding
Visual impairment (or vision impairment) is vision loss (of a person) to such a degree as to qualify as an additional support need through a significant limitation of visual capability resulting from either disease, trauma, or congenital or degenerative conditions that cannot be corrected by conventional means, such as refractive correction, medication, or surgery.
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Recent clinical studies

Therapy

Ineffectiveness of oral coenzyme Q10 supplementation in 3-methylglutaconic aciduria, type 3.
Costeff H, Apter N, Elpeleg ON, Prialnic M, Böhles HJ
Brain Dev 1998 Jan;20(1):33-5. doi: 10.1016/s0387-7604(97)00096-x. PMID: 9533558

Clinical prediction guides

Ineffectiveness of oral coenzyme Q10 supplementation in 3-methylglutaconic aciduria, type 3.
Costeff H, Apter N, Elpeleg ON, Prialnic M, Böhles HJ
Brain Dev 1998 Jan;20(1):33-5. doi: 10.1016/s0387-7604(97)00096-x. PMID: 9533558
Iraqi-Jewish kindreds with optic atrophy plus (3-methylglutaconic aciduria type 3) demonstrate linkage disequilibrium with the CTG repeat in the 3' untranslated region of the myotonic dystrophy protein kinase gene.
Nystuen A, Costeff H, Elpeleg ON, Apter N, Bonné-Tamir B, Mohrenweiser H, Haider N, Stone EM, Sheffield VC
Hum Mol Genet 1997 Apr;6(4):563-9. doi: 10.1093/hmg/6.4.563. PMID: 9097959

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    • ACMG ACT, 2022
      American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Elevated C5-OH Acylcarnitine, Organic Acidemias, 2022
    • ACMG Algorithm, 2022
      American College of Medical Genetics and Genomics, Algorithm, Organic Acidemias: Elevated C5-OH, 2022

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