3-Methylglutaconic Aciduria, Type III; MGCA3

What is 3-Methylglutaconic Aciduria, Type III; MGCA3?

3-Methylglutaconic Aciduria, Type III; MGCA3 is a rare disease. It is also known as Costeff optic atrophy syndrome Costeff Syndrome Iraqi-jewish 'optic Atrophy Plus' Mga, Type Iii; Mga3 Opa3, Autosomal Recessive Optic atrophy - Iraqi-Jewish type Optic Atrophy 3, Autosomal Recessive Optic Atrophy Plus Syndrome Optic Atrophy, Infantile, With Chorea And Spastic Paraplegia.

The clinical presentation is usually in infancy with truncal hypotonia, limb spasticity, failure to thrive, severe retardation and possibly even some regression. Seizures are common and the first clue to the diagnosis is a metabolic acidosis. A CT scan often shows translucencies in the basal ganglia. The diagnosis is made by finding persistently increased 3-methylglutaconic and 3-methylglutaric acids in the urine in the absence of an elevation of 3-hydroxy-3-methylglutaric acid.
Some infants present with severe metabolic abnormalities in the neonatal period with rapid deterioration and death. Others develop normally for the first few months and then have progressive mental deterioration. Deafness and optic atrophy are part of the clinical picture. Netter et al., (1987) reported a case with hypertrophic cardiomyopathy.
Chitayat et al., (1992) reported an 18-year-old male whose Italian parents were first cousins. He was hypotonic at birth and had absent reflexes with respiratory distress. There were bilateral inguinal herniae, undescended testes, subaortic stenosis and single palmar creases. Development was delayed and he had generalised seizures from the age of 3 years. Tears and pain sensation were reduced and he exhibited self-mutilation. At 18 years he was hypertonic and spastic and had sensorineural hearing loss. CT scan revealed severe cerebellar hypoplasia. Gibson et al., (1988) reported two similar cases (patients 7 and 8).
Some classifications suggest that the Iraqi sibs reported by Costeff et al., (1989) and the cases reported by Zeharia et al., (1992) have a specific syndrome with clinical features of optic atrophy, choreoathetosis, spastic paraparesis and cerebellar ataxia. Straussberg et al., (1998) suggest that children with this form of the condition may be misdiagnosed as having cerebral palsy. Other unclassified forms of 3-methylglutaconic aciduria with malformations and lactic acidosis are classified as type 4. Holme et al., (1992) reported mitochondrial ATP-synthase deficiency in a child with clinical features of the latter group. Nystuen et al., (1997) mapped the gene to 19q13.2-q13.3 in Iraqi-Jewish families.
Elpeleg et al., (1994) review the findings in 11 patients of Iraqi-Jewish origin. They point out that the clinical picture is of early bilateral optic atrophy with extrapyramidal dysfunction and spasticity, ataxia and cognitive deficit.
Al Aqeel et al., (1994) reported ten patients with a further possible subtype. Four presented with early neurological abnormality and developmental delay. There was rapid dementia, myoclonus or tonic-clonic seizures, spastic quadriplegia, deafness and blindness. Some cases had early acidosis and hypoglycaemia. In three children there was sudden onset of extrapyramidal tract symptoms. As some of the cases had optic atrophy, there was overlap with the Costeff type.
The condition has now been mapped to near the myotonic dystrophy gene on chromosome 19q (Nystuen et al., 1997). Anikster et al., (2001) reported mutations in a gene encoding a peptide of 179 amino acids, which is ubiquitously expressed. There was a common intronic mutation in Iraqi Jews abolishing mRNA expression.

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* This information is courtesy of the L M D.

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What gene changes cause 3-Methylglutaconic Aciduria, Type III; MGCA3?

The syndrome is inherited in the following inheritance pattern/s:

Autosomal Recessive - Autosomal recessive inheritance means an affected individual receives one copy of a mutated gene from each of their parents, giving them two copies of a mutated gene. Parents, who carry only one copy of the gene mutation will not generally show any symptoms but have a 25% chance of passing the copies of the gene mutations onto each of their children.

In some cases, a genetic syndrome may be the result of a de-novo mutation and the first case in a family. In this case, this is a new gene mutation that occurs during the reproductive process.

OMIM Number - 258501 (please check the OMIM page for updated information)

The syndrome can be caused by mutations in the following gene/s location/s:
OPA3 - 19q13.32

What are the main symptoms of 3-Methylglutaconic Aciduria, Type III; MGCA3?

The typical symptoms of the syndrome are:
Dysarthria, Abnormality of extrapyramidal motor function, Spasticity, Ataxia, Chorea, Babinski sign, Autosomal recessive inheritance, Optic atrophy, Nystagmus, Visual impairment, Incoordination, Hemiplegia/hemiparesis, Hyperreflexia, Cognitive impairment, Gait disturbance, 3-Methylglutaconic aciduria, Neurological speech impairment

How does someone get tested for 3-Methylglutaconic Aciduria, Type III; MGCA3?

The initial testing for 3-Methylglutaconic Aciduria, Type III; MGCA3 can begin with facial genetic analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the type of genetic testing needed. A consultation with a genetic counselor and then a geneticist will follow.

Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.

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