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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; Costeff syndrome; Iraqi Jewish optic atrophy plus; MGA type III; MGCA3; OPA3, AUTOSOMAL RECESSIVE; OPA3-Related 3-Methylglutaconic Aciduria; Optic atrophy 3; OPTIC ATROPHY 3, AUTOSOMAL RECESSIVE; Optic atrophy infantile with chorea and spastic paraplegia
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM, 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 homozygotes. In the context of medical genetics, autosomal recessive disorders manifest in homozygotes (with two copies of the mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele). [HPO:curators]
Autosomal recessive inheritance (HPO, OMIM, Orphanet)
SNOMED CT: Costeff syndrome (297232009); 3-Methylglutaconic aciduria type 3 (297232009)
 
Gene (location): OPA3 (19q13.32)
OMIM®: 258501
Orphanet: ORPHA67047

Disease characteristics

Excerpted from the GeneReview: OPA3-Related 3-Methylglutaconic Aciduria
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. [from GeneReviews]
Authors:
Meral Gunay-Aygun  |  Marjan Huizing  |  Yair Anikster   view full author information

Additional descriptions

From OMIM
Type III 3-methylglutaconic aciduria 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).  http://www.omim.org/entry/258501
From GHR
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://ghr.nlm.nih.gov/condition/costeff-syndrome

Clinical features

3-Methylglutaconic aciduria
MedGen UID:
777186
Concept ID:
C3696376
Disease or Syndrome
A group of five inherited disorders caused by mutations in the AUH, DNAJC19, OPA3, and TAZ genes. The disorders are characterized by impairment in the function of mitochondria, resulting in the accumulation and excretion of 3-methylglutaconic acid, and the presence of 3-methylglutaric acid in the urine.
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- oder overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Chorea
MedGen UID:
3420
Concept ID:
C0008489
Disease or Syndrome
A neurological condition affecting the involuntary movements. It is characterized by brief, non-repetitive irregular muscle contractions. It is seen in patients with Huntington's disease.
Dysarthria
MedGen UID:
8510
Concept ID:
C0013362
Mental or Behavioral Dysfunction
Disorders of speech articulation caused by imperfect coordination of pharynx, larynx, tongue, or face muscles. This may result from CRANIAL NERVE DISEASES; NEUROMUSCULAR DISEASES; CEREBELLAR DISEASES; BASAL GANGLIA DISEASES; BRAIN STEM diseases; or diseases of the corticobulbar tracts (see PYRAMIDAL TRACTS). The cortical language centers are intact in this condition. (From Adams et al., Principles of Neurology, 6th ed, p489)
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A form of muscle hypertonia associated with upper MOTOR NEURON DISEASE. Resistance to passive stretch of a spastic muscle results in minimal initial resistance (a "free interval") followed by an incremental increase in muscle tone. Tone increases in proportion to the velocity of stretch. Spasticity is usually accompanied by HYPERREFLEXIA and variable degrees of MUSCLE WEAKNESS. (From Adams et al., Principles of Neurology, 6th ed, p54)
Babinski sign
MedGen UID:
19708
Concept ID:
C0034935
Finding
A reflex characterized by upward movement of the great toe and an outward movement of the rest of the toes, when the sole of the foot is stroked. It is a normal reflex up to the age of two. Its presence beyond that age indicates neurological damage.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Autonomic nervous system overreaction to stimuli, most commonly after spinal cord injury at a T-5 level and above.
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).
Cognitive impairment
MedGen UID:
90932
Concept ID:
C0338656
Mental or Behavioral Dysfunction
A notable change in cognitive function.
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A form of muscle hypertonia associated with upper MOTOR NEURON DISEASE. Resistance to passive stretch of a spastic muscle results in minimal initial resistance (a "free interval") followed by an incremental increase in muscle tone. Tone increases in proportion to the velocity of stretch. Spasticity is usually accompanied by HYPERREFLEXIA and variable degrees of MUSCLE WEAKNESS. (From Adams et al., Principles of Neurology, 6th ed, p54)
3-Methylglutaconic aciduria
MedGen UID:
777186
Concept ID:
C3696376
Disease or Syndrome
A group of five inherited disorders caused by mutations in the AUH, DNAJC19, OPA3, and TAZ genes. The disorders are characterized by impairment in the function of mitochondria, resulting in the accumulation and excretion of 3-methylglutaconic acid, and the presence of 3-methylglutaric acid in the urine.
Optic atrophy
MedGen UID:
18180
Concept ID:
C0029124
Disease or Syndrome
A disorder characterized by loss of optic nerve fibers. It may be inherited or acquired. Acquired causes include ischemia, optic nerve neuropathy, glaucoma, trauma, radiation, brain tumors, and multiple sclerosis. It leads to vision disturbances.
Visual impairment
MedGen UID:
22663
Concept ID:
C0042798
Finding
Reduced ability to perceive visual stimuli.
Reduced visual acuity
MedGen UID:
65889
Concept ID:
C0234632
Finding
Diminished clarity of vision.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGV3-Methylglutaconic aciduria type 3
Follow this link to review classifications for 3-Methylglutaconic aciduria type 3 in Orphanet.

Recent clinical studies

Therapy

Costeff H, Apter N, Elpeleg ON, Prialnic M, Böhles HJ
Brain Dev 1998 Jan;20(1):33-5. PMID: 9533558

Clinical prediction guides

Costeff H, Apter N, Elpeleg ON, Prialnic M, Böhles HJ
Brain Dev 1998 Jan;20(1):33-5. PMID: 9533558
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. PMID: 9097959

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