Paula and Bobby
Parents of Lillie
What is 3-Methylglutaconic Aciduria?
This rare disease is a very rare genetic metabolic disorder. There are currently less than 20 cases recorded worldwide, to date.
Generally symptoms of this rare disease may be present in childhood, but for others symptoms may not appear until early adulthood. This can make it difficult to diagnose, based on its symptoms alone.
Developmental delay is a major symptom of the syndrome, and this presents in childhood.
What gene changes cause 3-Methylglutaconic Aciduria?
Mutations in the AUH, HTRA2, DNACJ19, SERAC1, CLPB, TIMM50, OPA3, TAZ and MGCA1 genes are responsible for causing the syndrome.
These mutations affect the ability of the body to produce enough of the enzyme necessary to prevent a build up of 3-Methylglutaconic acid. This leads to a build up of the acid in the blood and the urine also.
However research into the condition continues as some individuals present with syndromes only in early adulthood, while others affected with syndromes since childhood sometimes show an improvement in their condition and health.
It is inherited in an autosomal recessive pattern. 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.
What are the main symptoms of 3-Methylglutaconic Aciduria?
Symptoms may present in childhood for some affected individuals, while for others symptoms to not appear until early adulthood.
The main symptoms include, delayed development including motor and speech.
Involuntary muscle cramping, spasms and weakness of the arms and legs often referred to as spasticity are also symptoms.
Optic atrophy is another possible major syndrome and affects the nerves which transmit information from the eyes to the brain.
When symptoms present in early adulthood, the major symptom is leukoencephalopathy which is damage to the white matter of the brain. This affects speech, leg and arm control and may also present with dementia or signs of it.
How does someone get tested for 3-Methylglutaconic Aciduria?
The initial testing for 3-Methylglutaconic Aciduria syndrome can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. 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.
Medical information on 3-Methylglutaconic Aciduria
This is a relatively benign condition manifesting with delayed speech development and macrocephaly. There may be some motor delay and symptomatic hypoglycaemia. The patient reported by Illsinger et al., (2004) presented with fever-associated epilepsy. Increased amounts of 3-methylglutaconic acid can be demonstrated in the urine and the enzyme 3-methylglutaconyl-CoA hydratase has been demonstrated to be deficient. Another patient with speech delay as the presenting sign was reported by Ensenauer et al., (2000).
Ijlst et al., (2002) showed that 3-methylglutaconyl-CoA hydratase is encoded by the AUH gene, an AU-specific RNA-binding protein. Mutation analysis of AUH in two patients revealed a nonsense mutation (R197X) and a splice-site mutation (IVS8-1G-->A).
Tavasoli et al. (2017) described a 3.5 years old male patient from consanguineous family with 3-Methylglutaconic Aciduria and a novel homozygous mutation in the AUH gene. At age of 22 months, the patient had central hypotonia and intention tremor. He walked a few steps with the help of parents and spoke just a few words. He also had moderate sensorineural hearing loss. Brain MRI at the age of two years showed delayed myelination in trigone region and nonspecific hypersignal intensities in centrum semiovale. Urine organic acid analysis revealed high level of 3-methylglutaconic and 3-hydroxyisovaleric acids. Acylcarnitine profile showed increased level of 3-hydroxyisovalerylcarnitine. The patient was treated with restricted leucine diet (60 mg/kg/day) and carnitine (100 mg/kg/day in three doses). At the age of 3.5 years, the patient was able to walk, he had only some incoordination during running, the speech and cognition were normal. Brain MRI showed improvement of myelination in trigone area.
* This information is courtesy of the L M D.
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