Clinical Profile and Outcome of Indian Children with Aromatic L-Amino Acid Decarboxylase Deficiency: A primary CSF Neurotransmitter Disorder Mimicking as Dyskinetic Cerebral Palsy

Abstract

Aromatic L-amino acid decarboxylase (AADC) deficiency is a disorder of neurotransmitter synthesis. It presents with psychomotor delay, dystonia, oculogyric crisis, and autonomic features. There is paucity of literature on this disorder. Hence, we are reporting this series with an objective to study profile and outcome of Indian children with AADC deficiency. In this retrospective review, all case records of genetically confirmed cases of AADC deficiency at the pediatric neurology department in a tertiary care hospital, from March 2014 to March 2020, were analyzed. The data were extracted in a predesigned proforma and analyzed. Out of seven cases, five were males. Median age of onset of symptoms was 4 months but median age of diagnosis was 12 months. All of them had developmental delay, oculogyric crisis, dystonia, increased sweating, intermittent fever, feeding and sleep disturbance, irritability, failure to thrive, axial hypotonia with dyskinetic quadriparesis, and normal magnetic resonance imaging (MRI) of brain and electroencephalogram (EEG). All of them were treated with pyridoxal 5-phosphate, trihexyphenidyl and pramipexole and six cases, in addition, were given bromocriptine. One case was additionally treated with selegiline. One case showed good improvement, five showed partial improvement, and one case expired. In conclusion, AADC deficiency should be suspected in any child with dyskinetic quadriparesis, oculogyric crisis, autonomic disturbances like increased sweating, intermittent fever, and sleep disturbance with normal neuroimaging.

Keywords

AADC - neurotransmitter - dyskinetic - oculogyric - DDC

Publication History

Received: 28 April 2020

Accepted: 09 June 2020

Article published online:
27 July 2020

• References

• 1 Brun L, Ngu LH, Keng WT. et al. Clinical and biochemical features of aromatic L-amino acid decarboxylase deficiency. Neurology 2010; 75 (01) 64-71
• 2 Helman G, Pappa MB, Pearl PL. Widening phenotypic spectrum of AADC deficiency, a disorder of dopamine and serotonin synthesis. JIMD Rep 2014; 17: 23-27
• 3 Wassenberg T, Molero-Luis M, Jeltsch K. et al. Consensus guideline for the diagnosis and treatment of aromatic l-amino acid decarboxylase (AADC) deficiency. Orphanet J Rare Dis 2017; 12 (01) 12
• 4 Tay SK, Poh KS, Hyland K. et al. Unusually mild phenotype of AADC deficiency in 2 siblings. Mol Genet Metab 2007; 91 (04) 374-378
• 5 Lee HF, Tsai CR, Chi CS, Chang TM, Lee HJ. Aromatic L-amino acid decarboxylase deficiency in Taiwan. Eur J Paediatr Neurol 2009; 13 (02) 135-140
• 6 Hyland K, Clayton PT. Aromatic amino acid decarboxylase deficiency in twins. J Inherit Metab Dis 1990; 13 (03) 301-304
• 7 Pons R. The phenotypic spectrum of paediatric neurotransmitter diseases and infantile parkinsonism. J Inherit Metab Dis 2009; 32 (03) 321-332
• 8 Leuzzi V, Mastrangelo M, Polizzi A. et al. Report of two never treated adult sisters with aromatic L-amino acid decarboxylase deficiency: a portrait of the natural history of the disease or an expanding phenotype?. JIMD Rep 2015; 15: 39-45
• 9 Verbeek MM, Geurtz PB, Willemsen MA, Wevers RA. Aromatic L-amino acid decarboxylase enzyme activity in deficient patients and heterozygotes. Mol Genet Metab 2007; 90 (04) 363-369
• 10 Himmelreich N, Montioli R, Bertoldi M. et al. Aromatic amino acid decarboxylase deficiency: Molecular and metabolic basis and therapeutic outlook. Mol Genet Metab 2019; 127 (01) 12-22
• 11 Chien Y-H, Lee N-C, Tseng S-H. et al. Efficacy and safety of AAV2 gene therapy in children with aromatic L-amino acid decarboxylase deficiency: an open-label, phase 1/2 trial. Lancet Child Adolesc Health 2017; 1 (04) 265-273
• 12 Abdenur JE, Abeling N, Specola N. et al. Aromatic l-aminoacid decarboxylase deficiency: unusual neonatal presentation and additional findings in organic acid analysis. Mol Genet Metab 2006; 87 (01) 48-53
• 13 Maller A, Hyland K, Milstien S, Biaggioni I, Butler IJ. Aromatic L-amino acid decarboxylase deficiency: clinical features, diagnosis, and treatment of a second family. J Child Neurol 1997; 12 (06) 349-354
• 14 Pons R, Ford B, Chiriboga CA. et al. Aromatic L-amino acid decarboxylase deficiency: clinical features, treatment, and prognosis. Neurology 2004; 62 (07) 1058-1065
• 15 Swoboda KJ, Saul JP, McKenna CE, Speller NB, Hyland K. Aromatic L-amino acid decarboxylase deficiency: overview of clinical features and outcomes. Ann Neurol 2003; 54 (Suppl. 06) S49-S55
• 16 Manegold C, Hoffmann GF, Degen I. et al. Aromatic L-amino acid decarboxylase deficiency: clinical features, drug therapy and follow-up. J Inherit Metab Dis 2009; 32 (03) 371-380
• 17 Arnoux JB, Damaj L, Napuri S. et al. Aromatic L-amino acid decarboxylase deficiency is a cause of long-fasting hypoglycemia. J Clin Endocrinol Metab 2013; 98 (11) 4279-4284
• 18 Bräutigam C, Hyland K, Wevers R. et al. Clinical and laboratory findings in twins with neonatal epileptic encephalopathy mimicking aromatic L-amino acid decarboxylase deficiency. Neuropediatrics 2002; 33 (03) 113-117
• 19 Mills PB, Surtees RA, Champion MP. et al. Neonatal epileptic encephalopathy caused by mutations in the PNPO gene encoding pyridox(am)ine 5′-phosphate oxidase. Hum Mol Genet 2005; 14 (08) 1077-1086
• 20 Ng J, Papandreou A, Heales SJ, Kurian MA. Monoamine neurotransmitter disorders--clinical advances and future perspectives. Nat Rev Neurol 2015; 11 (10) 567-584
• 21 Hwu WL, Chien YH, Lee NC, Li MH. Natural history of aromatic L-amino acid decarboxylase deficiency in Taiwan. JIMD Rep 2018; 40: 1-6
• 22 Chang YT, Sharma R, Marsh JL. et al. Levodopa-responsive aromatic L-amino acid decarboxylase deficiency. Ann Neurol 2004; 55 (03) 435-438
• 23 Hwu WL, Muramatsu S, Tseng SH. et al. Gene therapy for aromatic L-amino acid decarboxylase deficiency. Sci Transl Med 2012; 4 (134) 134ra61
• 24 Kojima K, Nakajima T, Taga N. et al. Gene therapy improves motor and mental function of aromatic l-amino acid decarboxylase deficiency. Brain 2019; 142 (02) 322-333
• 25 San Sebastian W, Kells AP, Bringas J. et al. Safety and tolerability of MRI-guided infusion of AAV2-HAADC into the mid-brain of non-human primate. Mol Ther Methods Clin Dev 2014; 3: 14049