SLC25A4 Gene Mutation Linked to Mild Mitochondrial Myopathy in Children, Case Study Shows

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by Alice Melão |

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SLC25A4, mild myopathy

A new mutation identified in the SLC25A4 gene has been linked to childhood-onset mild myopathy (muscle disease) in a case study from the Children’s Hospital of Philadelphia (CHOP).

The finding was published in a report titled, “Expanding the phenotype of de novo SLC25A4-linked mitochondrial disease to include mild myopathy,” in the journal Neurology Genetics.

The SLC25A4 gene encodes a mitochondrial protein called adenine nucleotide translocase type 1, or ANT1, an important mediator of the energy-producing mechanism.

Changes in the SLC25A4  sequence have been linked to disorders including an eye condition called progressive external ophthalmoplegia, heart disease (cardiomyopathy), and skeletal muscle weakness (myopathy).

A 2-year-old girl was admitted to the Children’s Hospital of Philadelphia with low muscle tone and strength (hypotonia) and mild gross motor delays. /A/ neurological evaluation revealed no additional symptoms.

Blood tests showed that her creatine kinase levels were about two times higher than normal, plus lactic acidosis, with levels about 1.9 times higher than normal. Both suggest muscle damage. Researchers subsequently performed a muscle tissue biopsy and genetic testing.

Analysis of the tissue sample showed a mitochondria deficiency involving complexes 1 and 4  of the energy-producing mechanism, called oxidative phosphorylation. The toddler showed a reduction of about 40% in the amount of mitochondrial DNA compared to age-matched healthy controls.

Tests showed she had a genetic mutation on one of the copies of the SLC25A4 gene, which was found not to have been inherited from her parents. The variant resulted from a substitution of the essential amino acid lysine in position 33 for the nonessential amino acid glutamine (Lys33Gln).

Her condition remained stable, with no development of cardiac or eye problems or cognitive impairment. She continued to show only mild muscle weakness, mostly affecting the proximal muscles — those closer to the body’s midline — and elevated levels of creatine kinase plus lactic acidosis.

To better understand the effect of this new mutation on the encoded protein, researchers conducted experiments with genetically engineered bacteria. They found that by introducing the Lys33Gln mutation, the ANT1 protein would not function, although it was being produced in normal amounts.

Given the role of ANT1 in mitochondria’s activity, the team expected such a mutation to have more health-threatening effects. But the child showed only mild muscle weakness.

Researchers think this might be due to the presence of other proteins that could substitute for ANT1 and do at least part of its job, sustaining mitochondria’s activity to less damaging levels.

“This report expands the clinical phenotype [manifestation] for SLC25A4-associated mitochondrial disease, with the mildest childhood-onset presentation to date,” the researchers wrote.