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

Aromatic l-amino acid decarboxylase (AADC) deficiency is a rare neurometabolic disorder with heterogeneous phenotypic spectrum resulting from disease-causing variants of the dihydroxyphenylalanine (l-DOPA) decarboxylase (DDC) gene [1‐4]. The AADC enzyme is required for the final decarboxylation step that results in synthesis of monoamine neurotransmitters, most importantly dopamine [5]. Decreased activity of the AADC enzyme results in severe dopamine deficits, is directly linked to a wide range of neurologic and cognitive impairments [5], and ultimately results in the failure of patients with AADC deficiency to achieve developmental motor milestones [3].

Little is known at this time about global prevalence of AADC deficiency. Taiwan is the site of a potential founder mutation (IVS6 + 4A > T), and the incidence of AADC deficiency in Taiwan has been estimated at 1/32,000 births [6]. A recent analysis of the estimated prevalence of AADC deficiency in the United States, European Union, and Japan demonstrated conservative population prevalence (2016 data) of 840, 853, and 125, respectively [7]. In a separate evaluation of disease prevalence, 36 new patients with AADC deficiency were identified via screening of biological samples obtained between 2008 and 2016 from 19,684 US patients with neurologic deficits of unknown origin [8].

In general, patients with AADC deficiency exhibit arrested motor development with no full head control and no ability to sit, stand, or walk [9]. Consensus guidelines specifically describe clinical features associated with the central and autonomic nervous systems (CNS, ANS) [3, 10]. Key symptoms associated with CNS dysfunction include truncal hypotonia, poor head control, limb hypertonia, dyskinesia, dystonia, oculogyric crisis, hypokinesia and/or bradykinesia, delayed developmental milestones (motor, cognitive, and speech), irritability, dysphoria, and insomnia. Clinical features associated with ANS dysfunction include ptosis, miosis, profuse drooling, postural hypotension, excessive sweating, temperature instability, nasal congestion, impairment of sympathetic blood pressure modulation, feeding/swallowing problems, gastroesophageal reflux, constipation, and diarrhea [3, 10, 11]. Importantly, many of the neurological features associated with AADC deficiency may be observed in seizure disorders and cerebral palsy, which may lead to an incorrect diagnosis of these more commonly occurring conditions [12‐14]. AADC deficiency is typically diagnosed through analysis of neurotransmitter metabolite levels in cerebrospinal fluid (CSF) according to consensus guidelines [15]. Because clinical presentation typically begins soon after birth [16], efforts have been made to standardize analysis of dried bloodspots for routine screening of AADC deficiency in newborns [6]. Currently, limited treatment options are available for individuals diagnosed with AADC deficiency and none are curative. Patients require lifelong care, and premature death typically occurs prior to the age of 10 years [17]. However, gene therapies are currently being developed clinically as potential novel treatment options for these patients.

The purpose of this case report is to describe the clinical presentation and diagnosis of 2 previously unknown patients with AADC deficiency.

AADC deficiency is a rare and life-threatening neurometabolic disorder with no currently available curative treatment options. It is commonly misdiagnosed, and little is known at this time about its global prevalence. In addition to observation of the previously described clinical symptoms, there are currently 3 main methodologies used to diagnose AADC deficiency [3]. The first involves the measurement of serotonin and catecholamine metabolites in CSF. Homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) are drastically reduced in the CSF of patients with AADC deficiency. In addition, their precursors, 3-O-methyldopa (3-OMD), l-DOPA, and 5-hydroxytryptophan (5-HTP), are typically increased [3]. The second methodology involves the measurement of AADC enzyme activity in plasma [18]. A marked decrease in AADC plasma activity has been observed in all AADC cases where it has been measured [3]. A third diagnostic measure is genetic testing. There are currently 82 DDC variants listed in the Pediatric Neurotransmitter Disease database (PNDdb; available at: http://​biopku.​org/​pnddb/​home.​asp), including 79 variants that may be associated with the disease phenotype [19]. Current guidelines recommend that genetic testing be performed to diagnose AADC deficiency. To confirm diagnosis, 2 of the 3 previously described diagnostic measurements should be positive [3]. Additional diagnostic methodologies for AADC deficiency include measurement of 3-OMD in blood or dried blood spots. Levels of 3-OMD have been shown to be highly elevated in dried blood spots from newborns with AADC deficiency, and this methodology has potential as a newborn screening tool [6]. In addition, elevated urine levels of vanillactic and vanilpyruvic acids and N-acetylvanilalanine may be suggestive of AADC deficiency [20].

In this case report, we described 2 previously unknown patients with AADC deficiency: 2 siblings with 2 new DDC gene variants. Both siblings presented with developmental deficiencies within the first few months of life. In the first reported case, elevations in urine vanillactic acid, vanilpyruvic acid, and N-acetylvanilalanine levels suggested AADC deficiency and were confirmed by genetic sequencing of the DDC gene. Further testing confirmed reduced AADC activity. In the second reported case, an initial diagnosis was made at an earlier age due to the older sister’s diagnosis and was based on DDC gene sequencing, confirmed by plasma analysis of AADC activity.

While a number of management strategies, treatments, and therapeutic modalities have been aimed at ameliorating the effects of AADC deficiency, they have all been based on small populations and have shown widely varying degrees of success. Current consensus guidelines suggest selective dopamine agonists, monoamine oxidase (MAO) inhibitors, and PLP/pyridoxine (i.e., vitamin B6) as first-line treatment agents. Symptomatic treatment agents include anticholinergic agents, melatonin, benzodiazepines, and alpha-adrenoceptor blockers. The use of multiple concurrent treatments is needed in most cases, but even with multiple treatments the management of symptoms is often ineffective [3]. There are currently no curative treatments available for AADC deficiency; the long-term benefits of symptomatic treatments in patients with AADC deficiency in terms of quality of life and prognosis remain unclear. There is also a dearth of clinical trials investigating treatment of this rare disease.

A recombinant adeno-associated viral vector serotype 2 carrying the gene for the human AADC protein (AAV2-hAADC) has recently been tested in children with AADC deficiency. Results have been promising, with improvements seen in cognitive abilities, neuromotor abilities, and body weight [21].

Gene therapy appears to be a viable treatment option with promising results. More research is needed to create a comprehensive gene therapy approach to the treatment of AADC deficiency [21]. The parents of the 2 patients described in this case report are appreciative of the treatment their children have received and have also requested to be involved in any kind of treatment-related research that could potentially benefit their children, demonstrating the support among families affected by AADC deficiency for improved treatment options.