Clinical profile and outcome of Indian children with aromatic L-amino acid decarboxylase deficiency: A primary CSF neurotransmitter disorder mimicking as dyskinetic cerebral palsy
Gowda VK, et al. J Pediatr Genet. 2020;10(2):85–91.
Publication Date | July 2020
Authors | Gowda VK, Vegda H, Nagarajan BB, Shivappa SK.
Citation | J Pediatr Genet. 2020;10(2):85–91.
A recent study by researchers from the Indira Gandhi Institute of Child Health explores the clinical manifestations of aromatic L–amino acid decarboxylase (AADC) deficiency, and outcomes of therapy for seven children in India.
AADC deficiency is a rare, autosomal recessive, genetic disorder of neurotransmitter synthesis. Symptoms of this complex syndrome include psychomotor delay, dystonia, oculogyric crisis and autonomic dysfunction. Notably, symptoms can mimic dyskinetic cerebral palsy, and can make diagnosis challenging, especially in a resource–limited developing country such as India. The researchers highlight that an early, confirmed diagnosis of AADC deficiency is important for patients. However, as noted in this study, current treatment strategies are often of limited benefit to patients.
Consensus guidelines recommend two out of three tests should be positive for a diagnosis of AADC deficiency. These analyses are the genetic confirmation of DDC mutation; a cerebrospinal fluid (CSF) metabolite panel indicating reduced levels of homovanillic acid (HVA), 5–hydroxyindoleacetic acid (5–HIAA), and 3–methoxy–4–hydroxyphenylglycol (MHPG) concentrations with corresponding increase in the concentrations of L–Dopa, 5-hydroxytryptophan (5–HTP), 3–O–methyldopa (3–OMD) and normal pterins; and reduced AADC enzyme activity in plasma.2 One limitation of this study was the inability to secure CSF metabolite panels for all patients or AADC enzyme activity, although genetic analysis was positive for DDC mutation in all subjects.1
A retrospective review of six years of paediatric clinical notes was carried out to identify patients with AADC deficiency (from March 2014–March 2020). Diagnosis was made based on clinical and neuroimaging findings and confirmed by genetic sequencing in every case. Seven patients with AADC deficiency were identified – five males, two females.
Upon genetic sequencing of the DDC gene in the study population, two novel variants (c.1060G > T and c.175G > A) which had not been previously described in the literature were found. A c.140C > A mutation was identified in four patients (two homozygous and two compound heterozygous). One patient had the novel c.175G > A mutation, another patient’s genotype showed a c.208C > T pathogenic variant, and the final patient had the newly identified c.1060G > T mutation.
Median age of diagnosis was 12 months (interquartile range: 11–36 months). All patients exhibited developmental, motor and autonomic symptoms characteristic of AADC deficiency, manifesting in the first months of life (mean age 5 months [standard deviation: 2.8]), similar to other reports of patients with the condition (Table 1). All patients had been treated previously with antiepileptic medication, based on an initial diagnosis of dyskinetic cerebral palsy with epilepsy before AADC deficiency was confirmed.
Table 1: Clinical manifestations of AADC deficiency in an Indian population (N=7)
|Oculogyric crisis||7 (100)|
|Axial hypotonia with dyskinetic quadriparesis||7 (100)|
|Excessive sweating||7 (100)|
|Behavioural and other symptoms|
|Feeding difficulties||7 (100)|
|Failure to thrive||7 (100)|
|Global development delay||7 (100)|
|Sleep disturbances||7 (100)|
|Intermittent fever||7 (100)|
|Diurnal variation||2 (28.5)|
Regarding patient medical history, all seven patients had a normal birth history, brain magnetic resonance imaging (MRI) and electroencephalogram (EEG), arterial blood gas, serum lactate, serum ammonia, and tandem mass spectrometry. Consanguinity and a positive family history were seen in two of seven patients and neonatal concerns, including exchange transfusion for pathological jaundice and admission to neonatal intensive care, occurred in three. While all seven patients presented with clinical manifestations observed in Table 1, none had ptosis and nasal congestion.
All seven patients were initiated on a polytherapy treatment regimen (Table 2). On treatment, one patient (14.2%) showed overall good improvement, with cessation of oculogyric crises, marked improvement in dystonia and all other autonomic and behavioural symptoms. Cognition also improved. The patient attained head control and the ability to sit with support, along with response to commands and the showing of emotion through facial expression. Five patients (71.4%) showed partial improvement of symptoms with polytherapy treatment. Mild reductions of dystonia and oculogyric crises were reported. Autonomic symptoms of irritability, feeding difficulties and sleep disturbance also showed mild improvement, along with cognition.
One patient (14.2%) died from aspiration pneumonia within 2 months of diagnosis.
Table 2: Therapeutics given to patients prior to follow–up (N=7)
|Pyridoxal 5–phosphate||7 (100)|
Concluding, the researchers recommended that patients with a diagnosis of dyskinetic cerebral palsy – a noted mimic of AADC deficiency – of unknown aetiology should be further investigated to secure a definitive diagnosis to rule out another neurological disorder for which therapies are available. AADC deficiency should be considered especially in patients presenting with oculogyric crisis, dyskinetic quadriparesis, autonomic symptoms and sleep disturbance who have normal neuroimaging. The authors conclude that a timely definitive diagnosis would allow therapy to be initiated earlier which, in turn, may improve patient outcomes.
- Gowda VK, et al. J Pediatr Genet. 2020;10(2):85–91.
- Wassenberg T, et al. Orphanet J Rare Dis. 2017;12.