Diagnosis of Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency via Epilepsy Gene Panel Screening in a Patient with Atypical Presentation

Abstract

We describe an atypical presentation of a girl with aromatic L-amino acid decarboxylase (AADC) deficiency identified via a genetic testing program for children with epilepsy. At 21 months of age, she presented with poor head control, diffuse hypotonia, poor fixation, developmental delay, and dysphagia. She was lost to follow-up, then presented back at 3 years of age with staring spells and brief episodes of upward eye deviation. The diagnosis of unprovoked epilepsy allowed her to be included in a genetic testing program, which identified two heterozygous variants in the dopa decarboxylase (DCC) gene. Based on the genetic testing, plasma AADC enzyme activity and plasma 3-O-methyldopa results, a diagnosis of AADC deficiency was made when she was 4 years and 2 months of age. This case report shows that AADC deficiency can be the underlying diagnosis in patients with suspected epilepsy.

Keywords

developmental delay inborn errors of metabolism mutation

Introduction

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive neurometabolic disorder associated with a wide range of neurological and cognitive impairments.¹ It results from pathogenic variants in the dopa decarboxylase (DDC) gene, which encodes the enzyme required for the final step in the biosynthesis of the monoamine neurotransmitters dopamine and serotonin.² AADC deficiency is usually characterized by oculogyric crises, sleep disorder, mood disturbance, gastrointestinal symptoms, autonomic dysfunction and profound motor impairment.^3,4 Typically, individuals with AADC deficiency present with signs and symptoms within the first year of life¹; however, median age at diagnosis is approximately 2.75 years old.⁵

Current consensus guidelines describe three core diagnostic tests for identifying AADC deficiency: 1) compound heterozygous or homozygous pathogenic variants in the DDC gene; 2) decreased AADC enzyme activity in plasma; and 3) low cerebrospinal fluid (CSF) levels of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG), high CSF levels of 3-O-methyldopa (3-OMD), I-3,3-dihydroxyphenylalanine (L-Dopa) and 5-hydroxytryptophan (5-HTP), and normal CSF pterins.¹ To diagnose AADC deficiency, genetic testing should be performed and at least two of the three core diagnostic tests should be positive.¹

Here, we describe identification of AADC deficiency in a girl with atypical presentation who was diagnosed using a no-cost to patient epilepsy gene panel.

Case

The patient is a 4-year-old African American girl, born to nonconsanguineous parents at term via spontaneous vaginal delivery. At 21 months of age, she presented with poor head control, diffuse hypotonia, poor fixation, developmental delay and dysphagia and was referred to a child neurologist. She was lost to follow-up, then presented back at 3 years of age with staring spells and brief episodes of upward eye deviation concerning for seizures. Her gait was ataxic at that time. Developmentally, she held her head up at 9 months, sat independently at 12 months, and walked at 24 months of age. She said her first word by 12 months of age; however, by 4 years of age, she had not progressed to speaking in sentences.

An electroencephalogram performed at 3 years of age showed seizures from the left and right posterior temporal/occipital regions. Clinical correlation with upward gaze deviation events were consistent with focal electroclinical seizures arising from the occipital region with either left or right and bilateral synchronization. Brain magnetic resonance imaging at 3 years of age was normal.

The diagnosis of unprovoked epilepsy at 3 years of age allowed her to be included in a genetic testing program for children with epilepsy. At the time, the selected epilepsy panel comprised 151 genes including the DDC gene. Two heterozygous DDC variants were identified: c.116G > C (p.Arg39Pro) and c.272C > T (p.Ala91Val).

Laboratory test results are summarized in Table 1. Array comparative genomic hybridization was performed at 21 months of age and returned no abnormalities. Additionally, analyses of plasma amino acids and urine organic acids returned normal results. Serum lactic acid, creatine kinase, very long chain fatty acids, complete blood count and blood comprehensive metabolic panel results were also normal. However, plasma 3-OMD was elevated at > 5000 nmol/L (normal range, 64-280 nmol/L). Analysis of AADC enzyme activity provided a dopamine level of < 0.22 pmol/min/mL (normal range, 36-129 pmol/min/mL). Based on the genetic testing, plasma AADC enzyme activity and plasma 3-OMD results, a diagnosis of AADC deficiency was made when the girl was 4 years and 2 months of age.

Table 1.

Laboratory Results Used to Build the Diagnostic Profile of the Patient.

Laboratory test	Result	Normal range
AADC enzyme activity in plasma (dopamine level)	< 0.22 pmol/min/mL	36–129 pmol/min/mL
Plasma 3-OMD	> 5000 nmol/L	64–280 nmol/L
DDC variant analysis	c.116G > C (p.Arg39Pro) heterozygous c.272C > T (p.Ala91Val) heterozygous	–
Array comparative genomic hybridization	No abnormalities	–
Urine organic acids	Normal	–

Note: AADC, aromatic L-amino acid decarboxylase; DDC, dopa decarboxylase; 3-OMD, 3-O-methyldopa.

Following the diagnosis of AADC deficiency, the patient was prescribed pyridoxine 50 mg twice daily and pramipexole 0.25 mg three times daily, with a plan to also prescribe a monoamine oxidase (MAO) inhibitor. Follow-up to assess treatment response is ongoing with monitoring every 4–6 months. The girl's family is faced with geographic (living 4 h from the specialist neurology center) and financial barriers that have had an impact on their ability to attend appointments.

Discussion

In this case report, we describe an atypical presentation of AADC deficiency identified via a genetic testing program for children with epilepsy. Sequencing of the DDC gene revealed two heterozygous variants: c.116G > C (p.Arg39Pro) and c.272C > T (p.Ala91Val). The first variant, c.116G > C (p.Arg39Pro), is currently listed as a ‘variant of uncertain significance’.⁶ It has been identified previously in two siblings, who also had a second heterozygous variant (c.48C > A; pTyr16Ter).⁷ Both patients had decreased AADC enzyme activity and elevated plasma 3-OMD.⁷ Algorithms developed to predict the effect of missense changes on protein structure and function suggest that this variant is disruptive, but confirmatory functional studies have not been published.⁶

The second variant, c.272C > T (p.Ala91Val), is currently listed as ‘likely pathogenic’,⁸ having been reclassified one month after our patient was tested. The variant is present in population databases (rs137853211) and has been identified in published cases of AADC deficiency.^9,10 One of these studies also provides comprehensive functional and biochemical evidence for the pathogenicity of this variant.¹⁰

The diagnosis of AADC deficiency was confirmed in our patient by analysis of plasma AADC enzyme activity, in line with diagnostic guidelines.¹ Significant elevation of plasma 3-OMD in this patient provided supporting biochemical evidence of the diagnosis. However, this biomarker is not yet considered a core diagnostic test for AADC deficiency.¹ Urine organic acid analysis did not show elevations in AADC deficiency related metabolites, such as vanillactic acid (VLA).

The lack of elevated VLA levels in a confirmed AADC deficiency case is atypical but has been reported previously.¹¹ Dopamine plays a critical role in natriuresis and sodium homeostasis¹² and renal AADC activity is normally very high. In AADC deficient patients, residual AADC activity appears sufficient to produce normal or even elevated levels of dopamine in the urine.¹³ This could potentially result in normal or near-normal VLA and/or vanillylmandelic acid excretion in some AADC deficiency cases.

Our case highlights that concurrent epilepsy is rare but can be present in AADC deficiency and that biochemical evidence of this diagnosis may not always be identified using standard urine organic acid analysis. In a retrospective analysis of an international cohort of 63 patients, 27% were initially misdiagnosed with epilepsy and/or had a history of treatment with antiepileptic medication before the diagnosis of AADC deficiency was confirmed.³ Additionally, it may be difficult to distinguish seizures from oculogyric crises and paroxysmal dystonia in some cases.¹⁴ However, in the current case, the initial epilepsy diagnosis was instrumental in achieving the correct diagnosis of AADC deficiency because of the inclusion of DDC in the epilepsy gene panel.

Our case, therefore, supports future inclusion of DDC in other gene panels and access to genetic testing for children with epilepsy. It also adds to the evidence base showing that AADC deficiency has a broad phenotypic spectrum,^3,15–19 which has implications for accurate and timely clinical diagnosis. A limitation of the current report is that follow-up data on the impact of treatments are not yet available.

AADC deficiency remains a severe, life-limiting disease. Responses to the most frequently used drugs (including dopamine agonists, MAO inhibitors, pyridoxal phosphate, pyridoxidine, anticholinergic agents, folinic acid and L-Dopa) are inconsistent and have frequently been disappointing.¹ However, gene therapy techniques are being developed^20,21 and Upstaza^TM (eladocagene exuparvovec) was granted marketing authorization by the European Commission as the first disease-modifying treatment for AADC deficiency in July 2022.¹⁹ This case report highlights the value of a gene panel approach for detailed exploration of epilepsy diagnoses, the specific relevance of genetic testing for AADC deficiency in these patients, and that standard urine organic acid analysis may not identify abnormal metabolites in all cases.

Footnotes

Acknowledgments

The authors would like to thank John Moore, MS, at the Biochemical Genetics Laboratory, University of Alabama at Birmingham, AL, USA for performing the urine organic acid analyses and Jeff Kopesky, MS, CGC, from PTC Therapeutics, Inc., for his initiative in publishing this case report and for his guidance and logistical support.

Author Contributions

All authors provided clinical data, contributed to the article, revised all drafts and have approved the submitted version. The concept for the manuscript and decision to submit it for publication was agreed between PTC Therapeutics and the authors. Medical writing was provided by Tove Anderson, PhD, of PharmaGenesis London, London, UK.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethical Approval

Our institution does not require ethical approval for reporting individual cases or case series.

Funding

AADC deficiency testing was funded by PTC Therapeutics and performed by MNG Laboratories, Atlanta, Georgia, USA. The Behind the Seizure genetic testing program was developed and funded by Invitae, San Francisco, California, USA. Medical writing was provided by Tove Anderson, PhD, of PharmaGenesis London, London, UK, and was funded by PTC Therapeutics.

PTC Therapeutics, Invitae, PharmaGenesis London.

Informed Consent

Verbal informed consent was obtained from a legally authorized representative for anonymized patient information to be published in this article.

Trial Registration

Not applicable, because this article does not contain any clinical trials.

ORCID iD

Tony M. McGrath

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