Case report: discovery of 2 gene variants for aromatic L-amino acid decarboxylase deficiency in 2 African American siblings

Abstract

Background: Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare genetic disorder with heterogeneous phenotypic spectrum resulting from disease-causing variants in the dopa decarboxylase (DDC) gene. Consensus guidelines recommend dopamine agonists, monoamine oxidase inhibitors, and other symptomatic treatments, but most patients have an unrelenting disease course with no response to these therapies. Case presentation: We describe 2 African American siblings with AADC deficiency and identify 2 DDC gene variants not previously associated with the disorder. The patients were evaluated for cognitive and neurologic impairments. Diagnosis of AADC deficiency was initially based on evaluation of urine and plasma metabolites, followed by targeted DDC gene sequencing. The first patient, a firstborn African American female, had moderate elevations of vanillactic and vanilpyruvic acids, and slight elevation of N-acetylvanilalanine in urine. The second patient, an African American female and younger sibling of the first patient, had low AADC enzyme activity and elevated 3-O-methyldopa levels in plasma. Genetic testing confirmed that both siblings possessed the same 2 DDC gene variants, which were identified as NM_000790.3: c.48C > A (p.Tyr16Ter) and NM_000790.3: c.116G > C (p.Arg39Pro). Conclusions: This report describes 2 previously unknown patients with AADC deficiency and confirmed the presence of 2 DDC gene variants not previously associated with this disorder. Further research is needed to identify disease-modifying treatments for this devastating neurometabolic disorder. Gene therapy with a recombinant adeno-associated viral vector serotype 2 carrying the gene for the human AADC protein (AAV2-hAADC) is currently in clinical development.

Atypical Presentation of Aromatic L-Amino Acid Decarboxylase Deficiency with Developmental Epileptic Encephalopathy

“…The prevalence of AADC deficiency is uncertain, especially given the high probability of delayed or inaccurate diagnosis. 1,2 The estimated prevalence in the United States, European Union, and Japan demonstrated a conservative population prevalence of 840, 853, and 125. 1 The incidence in Taiwan, considered the site of a potential founder mutation (IVS6 þ 4A > T), has been estimated at 1/32.000 births.…”

“…1,2 The estimated prevalence in the United States, European Union, and Japan demonstrated a conservative population prevalence of 840, 853, and 125. 1 The incidence in Taiwan, considered the site of a potential founder mutation (IVS6 þ 4A > T), has been estimated at 1/32.000 births. 1 To date, over than 135 cases have been described worldwide [6][7][8] and 88 DDC variants were listed in the Pediatric Neurotransmitter Disease database (PNDdb; available at: http://biopku.org/pnddb/home.asp).…”

“…1 The incidence in Taiwan, considered the site of a potential founder mutation (IVS6 þ 4A > T), has been estimated at 1/32.000 births. 1 To date, over than 135 cases have been described worldwide [6][7][8] and 88 DDC variants were listed in the Pediatric Neurotransmitter Disease database (PNDdb; available at: http://biopku.org/pnddb/home.asp). 1,2 The phenotypic spectrum of AADC deficiency ranges from relatively mild to extremely severe manifestations.…”

“…1 To date, over than 135 cases have been described worldwide [6][7][8] and 88 DDC variants were listed in the Pediatric Neurotransmitter Disease database (PNDdb; available at: http://biopku.org/pnddb/home.asp). 1,2 The phenotypic spectrum of AADC deficiency ranges from relatively mild to extremely severe manifestations. It is typically associated with the central and autonomic nervous system, 1,2,7 including truncal hypotonia, movement disorders (e.g., oculogyric crisis, dystonia), poor head control, delayed developmental milestones, excessive sweating, and behavioral problems (i.e., irritability, dysphoria, excessive crying, and autism-like symptoms).…”

“…Aromatic L-amino acid decarboxylase deficiency (AADCD; OMIM #608643) is a rare, autosomal recessive neurotransmitter disease caused by mutations in the dopa decarboxylase (DDC) gene (OMIM Ã 107930). [1][2][3][4] The DDC gene, located on chromosome 7p12.1-12.3, encodes AADC or DDC (E.C. 4.1.1.28), a homodimeric pyridoxal 5′-phosphate (PLP)-dependent enzyme that converts L-3,4-dihydroxyphenylalanine (L-Dopa) and L-5-hydroxytryptophan (5-HTP) to dopamine and serotonin, and CO 2 .…”