Man’s case shows mild symptoms may sometimes mark AADC deficiency
Diagnosis underscores importance of genetic testing, clinicians say
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Symptoms of aromatic L-amino acid decarboxylase (AADC) deficiency can be mild and may occur alongside other genetic conditions, according to a team of researchers who reported the case of a young man from the Baltic region whose diagnosis was made only after “comprehensive” testing.
While the man had drooping eyelids and muscle weakness — signs of the nervous system disorder — he did not show many of the developmental delays or other symptoms that typically characterize the disease. His AADC deficiency diagnosis came after genetic testing, done when other tests suggested a potential muscular disease, the researchers noted.
“This case highlights the clinical variability of AADC deficiency and underscores the importance of comprehensive genetic and biochemical investigations to achieve an accurate diagnosis and inform personalised management,” the scientists, from Latvia, wrote.
The man’s “unusual presentation” eased after treatment with daily vitamin B6 and folic acid, which led to “substantial clinical improvement, including reduced gastrointestinal symptoms, increased muscle strength and improved quality of life,” the team noted.
Their report, titled “Mild form of aromatic L-amino acid decarboxylase deficiency,” was published in the journal BMJ Case Reports.
AADC deficiency is caused by mutations in the DDC gene, which provides instructions for producing the AADC enzyme. This enzyme is needed for producing serotonin and catecholamines, chemicals in the brain that are important for the body’s movement and automatic processes such as digestion. AADC needs vitamin B6 to function properly.
The disease is inherited in an autosomal recessive pattern, meaning a person must inherit a disease-causing mutation from both parents. When AADC is missing or does not function properly, serotonin and catecholamine become scarce, while chemicals normally processed by the enzyme, such as 3-O-methyl-L-dopa, build up.
Symptoms of AADC deficiency usually start in infancy
Most patients develop symptoms of the condition during infancy. These may include low tone in the muscles supporting the body, developmental delays, and so-called oculogyric crises, in which the eyes involuntarily move upward. Some patients also develop drooping eyelids, called ptosis, and involuntary muscle tightening known as dystonia. Problems with automatic bodily processes can also occur.
The case of this man in his early 30s was unusual because he had a milder form of AADC deficiency, according to the researchers. The man had ptosis and had undergone seven surgeries on his eyelids. He also had naturally light skin, mild hearing loss, muscle weakness and wasting, and severe digestive problems involving frequent diarrhea and constipation.
Despite these symptoms, his early development was relatively normal. He began walking at about 18 months, and his other motor development was normal. However, his muscle weakness limited his physical activities at school. An electromyogram, a test that measures the electrical activity of muscles, showed changes consistent with a muscular disease, the researchers noted.
Doctors initially investigated whether a mitochondrial disease — affecting the structures inside cells that produce energy — might explain his symptoms. However, testing of his mitochondrial DNA and the number of mitochondrial DNA copies did not identify a cause. At age 26, worsening muscle weakness and continued digestive problems led to further genetic testing.
Whole-exome sequencing, which tests most genes that provide instructions for producing proteins, identified mutations in three genes. Two mutations in the GJB2 gene explained the man’s hearing loss. Mutations in the TYR gene supported a diagnosis of type IB oculocutaneous albinism, which affects the production of melanin, the pigment responsible for much of the color of the skin, hair, and eyes. That accounted for the man’s light skin.
The genetic test also found the same mutation in both copies of the DDC gene. While it was initially considered a mutation of uncertain significance, blood testing showed that the man’s level of 3-O-methyl-L-dopa was three times higher than normal. Together, these findings supported a diagnosis of AADC deficiency, the team noted.
Treatment with vitamin B6 led to marked improvements
Treatment was started with vitamin B6 at 100 mg daily and folic acid at 5,000 micrograms daily. After treatment, the man improved significantly: His bowel movements decreased from as many as 15 per day to three or four, and muscle strength in his face, arms, and legs was normal. His quality of life also improved, the team noted.
According to the researchers, this case demonstrates that AADC deficiency can range from severe disease beginning in infancy to a much milder condition. The disease’s severity, the team noted, may depend on how much of the enzyme’s activity remains.
This man’s genetic mutation may have allowed some AADC enzyme to remain functional, the researchers noted.
Detailed genetic and biochemical analyses are essential for accurate diagnosis.
His hearing loss and albinism were caused by separate genetic diseases, showing why comprehensive testing is important when symptoms do not fit the typical pattern, per the scientists.
“Detailed genetic and biochemical analyses are essential for accurate diagnosis,” the researchers wrote. Getting the correct diagnosis can also help doctors provide more personalized treatment, the team noted.
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