Selective Serotonin Reuptake Inhibitor Treatment Post Gene Therapy for an Ultrarare Neurometabolic Disorder (AADC Deficiency)

Abstract

Aromatic L-amino acid decarboxylase (AADC) deficiency is an ultrarare genetic disorder affecting 1 in 500,000 individuals. It causes complete absence of monoamine neurotransmitter synthesis, profound motor impairment, and developmental delays. Treatment guidelines recommend against selective serotonin re-uptake inhibitors (SSRIs) in AADC deficiency, given reports of movement-related side effects and no benefits. Newly developed disease modifying gene therapy for this condition substantially improves motor symptoms. Herein, we describe a case of beneficial treatment response to SSRIs for anxiety in a child post AADC gene therapy. The child was diagnosed with AADC deficiency in infancy during investigations for hypotonia. Between 6 months and 5 years of age, she experienced severe irritability and sleep disturbance, severe hypotonia (no voluntary motor movements or head control, g-tube fed), and several hours of dystonic episodes weekly. At age 5 years, she received gene therapy that delivered an adeno-associated viral gene vector (AAV2-AADC) to the midbrain, resulting in marked improvements in motor function. At age 6 and 7 years, standardized developmental assessment estimated cognitive skills in the 10-month range, and she was diagnosed with autism spectrum disorder and an anxiety disorder. A cautious trial of sertraline 12.5 mg titrated to 75 mg over 4 months was well tolerated and substantially reduced anxiety and emotional lability, without adverse effects. This report is illustrative of the challenges and opportunities posed by genetic therapies, including a need to systematically revisit existing evidence and treatment guidelines in the emerging era of genomic medicine.