Patients with only one mutated copy of the DDC gene may present delayed or milder symptoms of AADC deficiency — including behavioral abnormalities as sole manifestations — that often lead to late diagnosis and further complications, a case report shows.
The study, “When dysphoria is not a primary mental state: A case report of the role of the aromatic L-aminoacid decarboxylase,” was published in the journal Medicine.
Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare genetic disease caused by mutations in the DDC gene, which contains the instructions for making the aromatic L-amino acid decarboxylase (AADC) enzyme. Most of the cases reported to date were in the Asian population.
AADC is necessary for the correct production of neurotransmitters — substances produced in response to nerve signals that act as chemical messengers — such as dopamine and serotonin.
Symptoms of the disease include lack of movement control and low muscle tone that impair activities such as breathing, feeding, and swallowing. Typically, symptoms appear in the first months of life.
Behavioral problems such as mood swings, irritability, and excessive crying are also frequent, but have not been extensively studied.
The researchers reported the case of a 43-year-old Caucasian woman. She was the second child of a non-consanguineous marriage and presented behavioral disorders since adolescence, which were later found to be caused by a single mutated copy of the DDC gene.
The patient had personality changes, poor concentration, confusion, and anxiety since age 16 and was being treated with lithium carbonate, a medication for psychological disorders. Three months before admission, she had tremors and numbness in the four limbs, along with low potassium levels.
She was treated with muscle relaxants and potassium, with no results. The lithium carbonate was changed for olanzapine, an antipsychotic agent, but this change increased the behavioral disorders.
She also had fevers and increased difficulty moving. After being hospitalized, she had a slow heart rate alternating with arrhythmia and loss of consciousness.
A deeper investigation of the family history revealed that a sister had suddenly died and that two of her three children showed behavioral abnormalities.
Genome sequencing revealed that only one copy of the DDC gene carried a mutation called p.Ser250Phe, a common mutation in AADC deficiency. After the correct diagnosis, she was prescribed vitamin B6 and pramipexole, but the treatment was not undertaken because she suddenly died.
Investigators believe the patient developed only behavioral symptoms in her adolescence because only one copy of the gene was mutated, which probably led to the late diagnosis.
Patients with only one mutated copy present a “residual activity level of the enzyme of about 35% to 40%, [which often] seems sufficient and [is] not associated with clinical signs and symptoms,” researchers said.
Furthermore, olanzapine blocks the production of dopamine and serotonin, which are already lacking in AADC deficiency patients, so this might have contributed to the rapid worsening of her condition.
Researchers concluded that “in our patient, the … onset was with behavioral abnormalities. Early recognition of such clinical condition, especially when the onset is just psychiatric, is important in order to prevent possible complications related to disease progression.
“Indeed, a prompt … diagnosis is essential to screen other family members, especially for those who present with early onset psychiatric manifestations.”