Award Title: Eladocagene exuparvovec for treating aromatic L-amino acid decarboxylase deficiency [ID3791]
Funder: Department of Health and Social Care

Abstract: Aromatic L-amino acid decarboxylase (AADC) deficiency is an extremely rare autosomal recessive neurometabolic ‘Parkinsonism’ disorder. AADC deficiency is caused by mutations in the gene that produces the AADCenzyme which is involved in the synthesis of the neurotransmitters serotonin and dopamine in the brain. Multiple genetic mutations can cause AADC deficiency, each resulting in different severity of symptoms and levels of response to treatment[1] . Symptoms of AADC deficiency often present in the first year of life and include developmental delays, lack of muscle tone, movement disorders, oculogyric crisis, and problems affecting the autonomic nervous system, such as excessive sweating and nasal congestion[2],[3] . Most cases of AADC deficiency present with severe symptoms [3] . It is often difficult to accurately determine prognosis because of variability in the severity of symptoms and the rarity of the condition. Life expectancy for people with AADC deficiency is unknown because of the variability and rarity of the disease but it can result in premature death. While published survival estimates are limited, it is reported that patients with severe AADC deficiency live for less than 10 years from birth[3],[5],[6] . Most people with AADC deficiency in the UK are children and young adults, but some people with AADC deficiency can live to adulthood. _x000D_
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The disease is reported to have a worldwide incidence of 1 in 55,000,000 with about 150-200 people diagnosed in 30 countries[4] . However, the incidence rate may be higher because there are likely people who are undiagnosed. No UK incidence rate has been reported but there are believed to be less than 10 people with AADC deficiency in the UK. AADC deficiency is more prevalent in people of East Asian family origin[7] . _x000D_
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Treatments for AADC deficiency do not treat the underlying cause of the disease and focus on managing symptoms, usually treating dopamine and serotonin deficiency. Medical treatment options include dopamine agonists, monoamine oxidase inhibitors, pyridoxine, anticholinergic agents, folinic acid, L-Dopa, benzodiazepines, and melatonin[3] . Treatment usually involves a combination of drugs depending on symptoms [3] . Other supportive treatments include physiotherapy, speech therapy, occupational therapy, feeding and nutritional assessment and psychological treatment[3] . Usually, only mild forms of AADC deficiency respond to treatment and not all symptoms can be relieved._x000D_
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References_x000D_
1 Helman G, Pappa M, and Pearl P (2014) Widening Phenotypic Spectrum of AADC Deficiency, a Disorder of Dopamine and Serotonin Synthesis. JIMD Reports 17: 23-27._x000D_
2 Brun L, Ngu L, Keng W et al. (2010) Clinical and biochemical features of aromatic L-amino acid decarboxylase deficiency. Neurology 75(1): 64-71._x000D_
3 Wassenberg T, Molero-Luis M, Jeltsch K et al. (2017) Consensus guideline for the diagnosis and treatment of aromatic L-amino acid decarboxylase (AADC) deficiency. Orphanet Journal of Rare Diseases 12(1): 12._x000D_
4 AADC Research Trust website (Accessed 28/04/2021)_x000D_
5 Hwu W-L, Muramatsu S, Tseng S-H, et al. Gene therapy for aromatic L-amino acid decarboxylase deficiency. Sci Transl Med 2012. 4: 134ra61._x000D_
6 Das S, Huang S & Lo AW. Acceleration of rare disease therapeutic development: a case study of AGIL-AADC. Drug Discov Today 2019. 24: 678–684._x000D_
7 Hyland K and Reott M (2020) Prevalence of Aromatic L-Amino Acid Decarboxylase Deficiency in At-Risk Populations. Pediatric Neurology 106: 38-42.

Lay Abstract: To evaluate the benefits and costs of eladocagene exuparvovec within its marketing authorisation for treating aromatic L-amino acid decarboxylase deficiency for national commissioning by NHS England.

Research Activity Codes: 6.2 CELLULAR AND GENE THERAPIES
Health Categories: NEUROLOGICAL