Boy’s rare, mild disease case not identified for more than 6 years

Symptoms followed exercise, and initial genetic testing skipped DDC gene

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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A unusually mild case of aromatic l-amino acid decarboxylase (AADC) deficiency, one characterized by exercise-induced episodes of involuntary muscle contractions, was described in a recent report.

Scientists suspect that this atypical presentation was responsible for a substantial delay in the boy’s AADC deficiency diagnosis, arrived at when he was 15 years old.

His case was described along with that of a more traditional, severely affected child seen at the same clinic in Belgium. Both were diagnosed via genetic testing, which found previously unreported disease-causing mutations in the DDC gene.

The study, “Novel presentation of AADC deficiency as a mild phenotype with exercise-induced dystonic crises: A case report,” was published in Heliyon.

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Likely disease-causing, but novel, mutations found in two children in Belgium

People with AADC deficiency lack a working AADC enzyme, which is critical for the production of important brain signaling chemicals, or neurotransmitters, due to disease-causing mutations in both copies of the DDC gene

In turn, a neurotransmitter deficiency drives the wide range of neurological symptoms seen with AADC. Among them are movement disorders such as dystonia, marked by involuntary muscle contractions, and oculogyric crises, where muscle spasms cause the eyes’ gaze to be fixed upward.

Patients also commonly experience developmental delays, sleep problems, mood disorders, seizures, and disturbances in involuntary bodily processes. Symptoms of this very rare disease — with fewer than 350 cases reported to date — are typically severe and emerge in the first year of life. Only a few cases of milder disease have been reported.

A team of researchers in Belgium described two new cases of AADC deficiency: one with a more typical and severe presentation and the other with an atypical, milder presentation.

In the more severe case, a baby boy of Afghan origin born to blood-related parents, came to the researchers’ hospital at 4.5 months of age due to seizures. He was found to have noisy breathing, severe motor developmental delays, low muscle tone, circular movements in the hands, and abnormal positioning of the spine and limbs.

After a number of clinical tests came back normal, a neurotransmitter disorder was suspected. Genetic testing revealed a mutation in both copies of the DDC gene. Called c.170T>G, the mutation had not been previously reported in AADC deficiency patients, but was predicted to be disease causing.

Additional body fluid tests showed reductions in AADC activity and in levels of two end products of the enzyme’s metabolic pathway, confirming a disease diagnosis. The boy received several treatments, was given a feeding tube, and underwent surgery for his breathing problems.

At the time of the report, the child was 3 years old and continued to have severe developmental delays, dystonia, feeding problems, breathing issues, and oculogyric crises.

His current treatment regimen included selegiline, which works to increase neurotransmitter production, trihexyphenidyl to prevent muscle spasms, as well as melatonin and hydroxyzine for sleep issues. Treatment has eased his dystonic and oculogyric crises, the team noted.

Missed ‘subtle signs’ could have led to earlier AADC deficiency diagnosis

The second case, a 15-year-old boy of Turkish origin, had a notably less severe presentation. He first came to the hospital at age 6 with signs of mild intellectual disability, delayed language, problems with concentration, and fatigue. However, a clinical exam was normal.

A year later, his walking pattern changed, with abnormal rotation of the feet and involuntarily flexed muscles at the elbows and wrists. He also showed progressively worsening involuntary eye movements. Still, brain imaging and activity tests came back normal.

Genetic tests looking for mutations in more than 150 genes related to epilepsy with or without intellectual disability, but not including the DDC gene, came back negative.

At age 12, the boy experienced persistent fatigue, worsening walking problems and dystonia crises that were triggered by exercise and were more frequent later in the day.

Additional genetic testing identified a novel mutation (c.941T>C) in both DDC gene copies that again was predicted to be disease causing. An AADC deficiency diagnosis was made after lab tests indicated substantially reduced AADC activity.

The boy was started on vitamin B6, a first-line treatment that can increase AADC activity, as well as pramipexole, which mimics the activity of a key neurotransmitter that’s lacking in AADC deficiency. His exercise capacity improved and his dystonia crises eased.

Researchers believe this patient’s atypical presentation is responsible for the more than six-year delay between his initial genetic test and the test that led to a definitive diagnosis.

“Retrospectively, subtle signs of the disease were present earlier in life,” the team wrote. These included nasal congestion, an upward gaze as a baby, and an inability to sit up at 9 months of age.

“These findings highlight the importance of a detailed medical history,” the researchers wrote.

“We expand the [clinical profile] of this neurometabolic disorder by reporting on a pediatric patient with a mild [presentation] with atypical exercise-induced dystonic crises, a feature that has not been described in AADC deficiency up till now,” they added.

Scientists also emphasized that in both mild and severe cases, genetic testing was important for confirming a diagnosis and enabling the start of treatment.

“The correct treatment can undoubtedly have significant effects on the quality of life of AADC patients and their families,” the researchers concluded.