U.S. flag

An official website of the United States government

Format

Send to:

Choose Destination

3-methylglutaconic aciduria type 9(MGCA9)

MedGen UID:
1622927
Concept ID:
C4540171
Disease or Syndrome
Synonym: 3-METHYLGLUTACONIC ACIDURIA, TYPE IX
SNOMED CT: 3-methylglutaconic aciduria, epilepsy, spasticity, severe intellectual disability syndrome (1222672002); 3-methylglutaconic aciduria type 9 (1222672002)
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).
 
Gene (location): TIMM50 (19q13.2)
 
Monarch Initiative: MONDO:0044724
OMIM®: 617698
Orphanet: ORPHA505216

Definition

3-Methylglutaconic aciduria type IX (MGCA9) is an autosomal recessive disorder characterized by early-onset seizures, severely delayed psychomotor development and intellectual disability. Patients have hypotonia or spasticity, and laboratory investigations show increased serum lactate and 3-methylglutaconic aciduria, suggestive of a mitochondrial defect (summary by Shahrour et al., 2017). For a phenotypic description and a discussion of genetic heterogeneity of 3-methylglutaconic aciduria, see MGCA type I (250950). [from OMIM]

Clinical features

From HPO
Urinary incontinence
MedGen UID:
22579
Concept ID:
C0042024
Finding
Loss of the ability to control the urinary bladder leading to involuntary urination.
3-Methylglutaric aciduria
MedGen UID:
463302
Concept ID:
C3151952
Finding
An abnormally increased level of 3-hydroxy-3-methylglutaric acid in the urine.
3-Methylglutaconic aciduria
MedGen UID:
777186
Concept ID:
C3696376
Disease or Syndrome
An increased amount of 3-methylglutaconic acid in the urine.
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Aggressive behavior
MedGen UID:
1375
Concept ID:
C0001807
Individual Behavior
Behavior or an act aimed at harming a person, animal, or physical property (e.g., acts of physical violence; shouting, swearing, and using harsh language; slashing someone's tires).
Clonus
MedGen UID:
40341
Concept ID:
C0009024
Sign or Symptom
A series of rhythmic and involuntary muscle contractions (at a frequency of about 5 to 7 Hz) that occur in response to an abruptly applied and sustained stretch.
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.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Intellectual disability, severe
MedGen UID:
48638
Concept ID:
C0036857
Mental or Behavioral Dysfunction
Severe mental retardation is defined as an intelligence quotient (IQ) in the range of 20-34.
Choreoathetosis
MedGen UID:
39313
Concept ID:
C0085583
Disease or Syndrome
Involuntary movements characterized by both athetosis (inability to sustain muscles in a fixed position) and chorea (widespread jerky arrhythmic movements).
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
Areflexia
MedGen UID:
115943
Concept ID:
C0234146
Finding
Absence of neurologic reflexes such as the knee-jerk reaction.
Cerebral atrophy
MedGen UID:
116012
Concept ID:
C0235946
Disease or Syndrome
Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.
Delayed ability to walk
MedGen UID:
66034
Concept ID:
C0241726
Finding
A failure to achieve the ability to walk at an appropriate developmental stage. Most children learn to walk in a series of stages, and learn to walk short distances independently between 12 and 15 months.
Delayed speech and language development
MedGen UID:
105318
Concept ID:
C0454644
Finding
A degree of language development that is significantly below the norm for a child of a specified age.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Hypsarrhythmia
MedGen UID:
195766
Concept ID:
C0684276
Finding
Hypsarrhythmia is abnormal interictal high amplitude waves and a background of irregular spikes. There is continuous (during wakefulness), high-amplitude (>200 Hz), generalized polymorphic slowing with no organized background and multifocal spikes demonstrated by electroencephalography (EEG).
Abnormal cerebral white matter morphology
MedGen UID:
181756
Concept ID:
C0948163
Pathologic Function
An abnormality of the cerebral white matter.
Persistent head lag
MedGen UID:
256151
Concept ID:
C1141883
Finding
The Premie-Neuro and the Dubowitz Neurological Examination score head lag in the same manner. Scoring for both is as follows
Increased CSF lactate
MedGen UID:
257904
Concept ID:
C1167918
Finding
Increased concentration of lactate in the cerebrospinal fluid.
Epileptic spasm
MedGen UID:
315948
Concept ID:
C1527366
Disease or Syndrome
A sudden flexion, extension, or mixed extension-flexion of predominantly proximal and truncal muscles that is usually more sustained than a myoclonic movement but not as sustained as a tonic seizure. Limited forms may occur
Absent speech
MedGen UID:
340737
Concept ID:
C1854882
Finding
Complete lack of development of speech and language abilities.
Hypertonia
MedGen UID:
10132
Concept ID:
C0026826
Finding
A condition in which there is increased muscle tone so that arms or legs, for example, are stiff and difficult to move.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Muscle weakness
MedGen UID:
57735
Concept ID:
C0151786
Finding
Reduced strength of muscles.
Frontal bossing
MedGen UID:
67453
Concept ID:
C0221354
Congenital Abnormality
Bilateral bulging of the lateral frontal bone prominences with relative sparing of the midline.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Increased circulating lactate concentration
MedGen UID:
332209
Concept ID:
C1836440
Finding
Abnormally increased level of blood lactate (2-hydroxypropanoic acid). Lactate is produced from pyruvate by lactate dehydrogenase during normal metabolism. The terms lactate and lactic acid are often used interchangeably but lactate (the component measured in blood) is strictly a weak base whereas lactic acid is the corresponding acid. Lactic acidosis is often used clinically to describe elevated lactate but should be reserved for cases where there is a corresponding acidosis (pH below 7.35).
High palate
MedGen UID:
66814
Concept ID:
C0240635
Congenital Abnormality
Height of the palate more than 2 SD above the mean (objective) or palatal height at the level of the first permanent molar more than twice the height of the teeth (subjective).
Short neck
MedGen UID:
99267
Concept ID:
C0521525
Finding
Diminished length of the neck.
Long eyelashes
MedGen UID:
342955
Concept ID:
C1853738
Finding
Mid upper eyelash length >10 mm or increased length of the eyelashes (subjective).
Wide intermamillary distance
MedGen UID:
473489
Concept ID:
C1827524
Finding
A larger than usual distance between the left and right nipple.
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.
Strabismus
MedGen UID:
21337
Concept ID:
C0038379
Disease or Syndrome
A misalignment of the eyes so that the visual axes deviate from bifoveal fixation. The classification of strabismus may be based on a number of features including the relative position of the eyes, whether the deviation is latent or manifest, intermittent or constant, concomitant or otherwise and according to the age of onset and the relevance of any associated refractive error.

Recent clinical studies

Etiology

Wortmann SB, Ziętkiewicz S, Kousi M, Szklarczyk R, Haack TB, Gersting SW, Muntau AC, Rakovic A, Renkema GH, Rodenburg RJ, Strom TM, Meitinger T, Rubio-Gozalbo ME, Chrusciel E, Distelmaier F, Golzio C, Jansen JH, van Karnebeek C, Lillquist Y, Lücke T, Õunap K, Zordania R, Yaplito-Lee J, van Bokhoven H, Spelbrink JN, Vaz FM, Pras-Raves M, Ploski R, Pronicka E, Klein C, Willemsen MA, de Brouwer AP, Prokisch H, Katsanis N, Wevers RA
Am J Hum Genet 2015 Feb 5;96(2):245-57. Epub 2015 Jan 15 doi: 10.1016/j.ajhg.2014.12.013. PMID: 25597510Free PMC Article
Sarig O, Goldsher D, Nousbeck J, Fuchs-Telem D, Cohen-Katsenelson K, Iancu TC, Manov I, Saada A, Sprecher E, Mandel H
Am J Med Genet A 2013 Sep;161A(9):2204-15. Epub 2013 Aug 5 doi: 10.1002/ajmg.a.36059. PMID: 23918762
Chitayat D, Chemke J, Gibson KM, Mamer OA, Kronick JB, McGill JJ, Rosenblatt B, Sweetman L, Scriver CR
J Inherit Metab Dis 1992;15(2):204-12. doi: 10.1007/BF01799632. PMID: 1382150

Diagnosis

Catteruccia M, Verrigni D, Martinelli D, Torraco A, Agovino T, Bonafé L, D'Amico A, Donati MA, Adorisio R, Santorelli FM, Carrozzo R, Bertini E, Dionisi-Vici C
Mol Genet Metab 2014 Mar;111(3):353-359. Epub 2014 Jan 8 doi: 10.1016/j.ymgme.2014.01.001. PMID: 24485043
Sarig O, Goldsher D, Nousbeck J, Fuchs-Telem D, Cohen-Katsenelson K, Iancu TC, Manov I, Saada A, Sprecher E, Mandel H
Am J Med Genet A 2013 Sep;161A(9):2204-15. Epub 2013 Aug 5 doi: 10.1002/ajmg.a.36059. PMID: 23918762
Mercimek-Mahmutoglu S, Tucker T, Casey B
Mol Genet Metab 2011 Nov;104(3):410-3. Epub 2011 Jul 26 doi: 10.1016/j.ymgme.2011.07.021. PMID: 21840233
Mack M, Schniegler-Mattox U, Peters V, Hoffmann GF, Liesert M, Buckel W, Zschocke J
FEBS J 2006 May;273(9):2012-22. doi: 10.1111/j.1742-4658.2006.05218.x. PMID: 16640564
Chitayat D, Chemke J, Gibson KM, Mamer OA, Kronick JB, McGill JJ, Rosenblatt B, Sweetman L, Scriver CR
J Inherit Metab Dis 1992;15(2):204-12. doi: 10.1007/BF01799632. PMID: 1382150

Therapy

Catteruccia M, Verrigni D, Martinelli D, Torraco A, Agovino T, Bonafé L, D'Amico A, Donati MA, Adorisio R, Santorelli FM, Carrozzo R, Bertini E, Dionisi-Vici C
Mol Genet Metab 2014 Mar;111(3):353-359. Epub 2014 Jan 8 doi: 10.1016/j.ymgme.2014.01.001. PMID: 24485043

Prognosis

Wortmann SB, Ziętkiewicz S, Kousi M, Szklarczyk R, Haack TB, Gersting SW, Muntau AC, Rakovic A, Renkema GH, Rodenburg RJ, Strom TM, Meitinger T, Rubio-Gozalbo ME, Chrusciel E, Distelmaier F, Golzio C, Jansen JH, van Karnebeek C, Lillquist Y, Lücke T, Õunap K, Zordania R, Yaplito-Lee J, van Bokhoven H, Spelbrink JN, Vaz FM, Pras-Raves M, Ploski R, Pronicka E, Klein C, Willemsen MA, de Brouwer AP, Prokisch H, Katsanis N, Wevers RA
Am J Hum Genet 2015 Feb 5;96(2):245-57. Epub 2015 Jan 15 doi: 10.1016/j.ajhg.2014.12.013. PMID: 25597510Free PMC Article
Catteruccia M, Verrigni D, Martinelli D, Torraco A, Agovino T, Bonafé L, D'Amico A, Donati MA, Adorisio R, Santorelli FM, Carrozzo R, Bertini E, Dionisi-Vici C
Mol Genet Metab 2014 Mar;111(3):353-359. Epub 2014 Jan 8 doi: 10.1016/j.ymgme.2014.01.001. PMID: 24485043

Clinical prediction guides

Wortmann SB, Ziętkiewicz S, Kousi M, Szklarczyk R, Haack TB, Gersting SW, Muntau AC, Rakovic A, Renkema GH, Rodenburg RJ, Strom TM, Meitinger T, Rubio-Gozalbo ME, Chrusciel E, Distelmaier F, Golzio C, Jansen JH, van Karnebeek C, Lillquist Y, Lücke T, Õunap K, Zordania R, Yaplito-Lee J, van Bokhoven H, Spelbrink JN, Vaz FM, Pras-Raves M, Ploski R, Pronicka E, Klein C, Willemsen MA, de Brouwer AP, Prokisch H, Katsanis N, Wevers RA
Am J Hum Genet 2015 Feb 5;96(2):245-57. Epub 2015 Jan 15 doi: 10.1016/j.ajhg.2014.12.013. PMID: 25597510Free PMC Article

Supplemental Content

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...