3-Methylglutaconic Aciduria with Deafness, Encephalopathy, and Leigh-Likesyndrome; MEGDEL

What is 3-Methylglutaconic Aciduria with Deafness, Encephalopathy, and Leigh-Likesyndrome; MEGDEL?

3-Methylglutaconic Aciduria with Deafness, Encephalopathy, and Leigh-Likesyndrome; MEGDEL is a rare disease. It is also known as 3-methylglutaconic Aciduria, Type Vi; Mgca6 MEGDEL syndrome.

Wortmann et al., (2006) reported four patients (there was consanguinity in three) with a combination of 3-Methylglutaconic aciduria, deafness, encephalopathy, and radiological evidence of Leigh disease (MEGDEL). The children failed to thrive, had severe infections and three had neonatal hypoglycemia. CSF lactate was raised. All were delayed and floppy, but then became spastic and showed extrapyramidal features. Basal ganglia showed hyperintense lesions. There was biochemical evidence of mitochondrial dysfunction. 3-methylglutaconic aciduria type I, Barth syndrome, and Costeff syndromes were excluded, as the activity of 3-methylglutaconyl-CoA hydratase, the cardiolipin levels were normal and no mutations were found in OPA3 gene. Similar cases were reported by Broide et al., (1997) and Al Aqueel et al., (1994).
Four individuals from two consanguineous families all presented with hypotonia and liver dysfunction including symptomatic hypoglycemia and lactic acidosis (Sarig et al., 2013). From 13 to 22 months there was progressive deafness and extrapyramidal features. There were episodes of respiratory insufficiency and general regression. Hyperdensities in basal ganglia were observed. Mutations were found in SERAC1 (Wortmann et al., 2012). It is important in phospholipid exchange; analysis of fibroblasts showed elevated concentrations of phosphatidylglycerol - 34:1.
Wortmann et al., (2015) show the evolution of the MRI basal ganglia lesions. There were stages: 1) stage 1 - T2 signal changes of the pallidum; 2) stage 2 - swelling of the putamen and caudate; 3) stage 3 - the dorsal putamen shows an "eye" with no signal alteration. 4) stage 4 - this "eye" area becomes smaller leaving a small, probably gliotic remnant.
Radha Rama Devi et al. (2017) described two unrelated patients from consanguineous families with dystonia and intellectual disability due to biallelic mutations in the SERAC1 gene. Clinical characteristics included neonatal respiratory distress, seizures, generalized severe increasing dystonia, failure to thrive, swallowing difficulty, spasticity and flexion contractures. Laboratory findings were metabolic acidosis, high liver transaminases, elevated tyrosine metabolites, lactic acidosis, and elevated urinary 3-MGA. Percutaneous liver biopsy revealed histological changes of neonatal hepatitis with nonspecific changes and portal inflammation. Brain MRI, described as Leigh-like, showed focal areas of bright signal involving the anterior parts of the putamina and heads of the caudate nuclei; later, atrophy of the putamina and caudate nuclei, with changes of gliosis in the putamina was observed.
Roeben et al. (2017) described six patients from a consanguineous family with spastic paraplegia due to a homozygous splice-site mutation in the SERAC1 gene. Age of onset was before seven years. Clinical characteristics included cognitive delay, spasticity (predominantly in lower limbs), tremor, febrile seizures, and peripheral neuropathy. Brain MRI showed progressive atrophy of the caudate nucleus, and progressive T2-hyperintense lesions of the putamen (putaminal eye). Another unrelated patient with biallelic mutations in the same gene exhibited MEGDEL features: neonatal onset, hyperbilirubinemia, hyperammonemia, lactic acidosis, spasticity of lower limbs, cognitive delay, dystonia, sensorineural deafness, and liver failure.
Sequeira et al. (2017) described a female patient with MEGDEL syndrome due to compound heterozygous protein-truncating mutations in the SERAC1 gene. Clinical characteristics included IUGR, developmental delay, microcephaly, hypotonia, spastic tetraparesis, dystonia, myoclonic epilepsy, lethargy, failure to thrive, breathing difficulty, abdominal distention, progressive worsening of consciousness and jaundice. Muscle biopsy showed decreased activity of complexes II, IV, and V. Laboratory findings included transient hypoglycemia, mild elevated transaminases, metabolic acidosis, increased lactate, hyperammonemia, and 3-methylglutaconic aciduria. Electroencephalography revealed multifocal paroxysmal activity; CT scan suggested diffuse cerebral edema. Brain MRI revealed symmetric bilateral lesions in caudate nucleus, pallidum, and putamen, white matter hyperintensities on T2 and hypointense on T1, with pallidal lesions with restricted diffusion. Additional investigations showed high lactate peak in the basal ganglia, pulvinar thalamus, and white matter.

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What gene changes cause 3-Methylglutaconic Aciduria with Deafness, Encephalopathy, and Leigh-Likesyndrome; MEGDEL?

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 - 614739 (please check the OMIM page for updated information)

The syndrome can be caused by mutations in the following gene/s location/s:
SERAC1 - 6q25.3

What are the main symptoms of 3-Methylglutaconic Aciduria with Deafness, Encephalopathy, and Leigh-Likesyndrome; MEGDEL?

The typical symptoms of the syndrome are:
Failure to thrive, Abnormality of extrapyramidal motor function, Feeding difficulties in infancy, Developmental regression, Dystonia, Encephalopathy, Recurrent infections, Spasticity, Brain atrophy, Muscular hypotonia, Intellectual disability, 3-Methylglutaconic aciduria, Increased serum lactate, Lactic acidosis, Aplasia/Hypoplasia involving the central nervous system, Cerebellar atrophy, Hypoglycemia, Hyperammonemia, Global developmental delay, Autosomal recessive inheritance, Sensorineural hearing impairment, Seizure

How does someone get tested for 3-Methylglutaconic Aciduria with Deafness, Encephalopathy, and Leigh-Likesyndrome; MEGDEL?

The initial testing for 3-Methylglutaconic Aciduria with Deafness, Encephalopathy, and Leigh-Likesyndrome; MEGDEL 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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