AADC Deficiency May Impact Brain Development of Children, Study Says

Catarina Silva, MSc avatar

by Catarina Silva, MSc |

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AADC deficiency and gene therapy

Microstructural changes were observed in brain regions related to language and motor function in children with aromatic L-amino acid decarboxylase (AADC) deficiency, suggesting that this enzyme shortage can influence brain development, researchers have found.

Their study, “Microstructural Changes of Brain in Patients with Aromatic L-Amino Acid Decarboxylase Deficiency,” was published in Human Brain Mapping.

Patients with AADC deficiency usually experience developmental delays, severe movement disorders, and an inability to speak. Because the AADC enzyme is involved in the production of several brain chemical messengers, such as dopamine and serotonin, its deficiency may lead to abnormal development of the brain.

Previous research has failed to demonstrate significant brain changes in patients with AADC deficiency. However, a study using positron emission tomography (PET) scan revealed that the disease severely affects the frontal cortex, which is involved in language, and the striatum, which controls movement.

Researchers from National Taiwan University Hospital sought to analyze magnetic resonance images of children with AADC deficiency, specifically their frontal lobe and striatum, and investigate the relationship between their findings and the patients’ symptoms. Magnetic resonance imaging (MRI), including diffusion tensor imaging (DTI), is a non-invasive way to study the brain’s structure.

Twelve children with AADC deficiency (6 boys and 6 girls, from 9 to 50 months old) and 15 age- and sex-matched controlled subjects were included in the study.

All AADC-deficient patients had generalized low muscle tone, involuntary muscle contractions, and involuntary movement of the eyeballs. About 67% of the patients experienced excessive sweating, and 33% had sleep apnea — a disorder where breathing is intermittently interrupted during sleep.

In total, 15 magnetic resonance examinations, including three follow-up studies, were performed.

Results showed 40% (6 of 15 scans) had reduced brain volume, 67% (10 of 15) had significantly dilated brain ventricles (fluid-filled interconnected brain cavities), and 80% (12 of 15) had an abnormally small amount of myelin (insulation of the brain’s wiring), compared with the control group.

Volume of part of the striatum, called the caudate nucleus, was also significantly smaller than that of control subjects.

“Follow-up MRI also revealed progressive decrease of the volume of caudate nucleus in one patient,” suggesting that AADC deficiency could impact striatum development and lead to progressive atrophy of this brain structure.

In the patients, the thickness of the back portion of the corpus callosum — the anatomical bridge between the left and right sides of the brain — was significantly increased. In addition, the corpus callosum’s front portion (genu) was smaller in the patients, compared with the control subjects.

Morphology studies suggest that the genu of corpus callosum mainly projects to prefrontal cortex. Consequently, atrophy of genu of corpus callosum is expected to cause frontal lobe atrophy, and thus affect its function in patients with AADC deficiency.

Using DTI, researchers then evaluated the disease’s effect on white matter development. The brain contains gray and white matter, where white matter consists of nerve cell projections, known as axons or fibers, connecting distinct parts of gray matter. The condition of the fibers influences the way the brain processes information.

Scientists reported “significant decrease of fiber density indices in major white matter fiber tracts,” including language-related tracts and those related to motor function.

“Damage to (these tracks) could … induce deficits in object naming, phonological language function and writing,” the investigators wrote.

Five patients (one older than a year) cooed, and did not develop babbling in speech. The children with AADC deficiency, who were older than 12 months, did not speak words or phrases with significant meaning, suggesting possible speech and motor impairment, which was corroborated by the DTI findings.

“AADC deficiency may have significant impact on brain development, especially the frontal lobe and fiber tracts related to language function and motor function. Long-term follow-up of brain MRI in patients with AADC deficiency may clarify the possible effect of AADC deficiency on brain development,” the study stated.