Aromatic L‑amino acid decarboxylase (AADC) deficiency is an ultra-rare genetic disorder. It is associated with a wide range of severe symptoms mainly affecting the central nervous system, autonomic nervous system, gastrointestinal system and endocrine system. It is caused by a mutation in the DDC gene. This results in a lack of the AADC enzyme, which leads to severe deficiency in dopamine and other neurotransmitters essential for normal development. Dopamine deficiency is considered to be key in the pathology of AADC deficiency. It is also the precursor for adrenaline and noradrenaline. Lack of these neurotransmitters is known to affect mood, attention, sleeping habits and learning. Serotonin deficiency is also known to contribute to symptoms of the condition, although the extent of its role relative to dopamine is uncertain. AADC deficiency typically presents from birth, with symptoms becoming apparent in the first few months of life. The condition is often difficult to diagnose because of its rarity and the wide range of possible symptoms. The mean age at diagnosis is usually around 3.5 years, but can range from 2 months to 23 years. AADC deficiency is characterised by oculogyric crises, which are episodes of involuntary muscle spasm that results in upwards deviation of the eyes. These episodes can last several hours, and people with the condition are often misdiagnosed as having epilepsy, which can delay appropriate treatment. In the UK, a final diagnosis is often confirmed through genetic testing of the DDC gene. About 80% of people with AADC deficiency present with a severe phenotype, broadly defined by international consensus guidelines as reaching no or very limited developmental milestones, and full dependence on carers. The company's submission proposed that a severe phenotype may also be defined as having no or poor head control at 24 months of age. In very severe cases, people may be bedridden with little or no motor function, and be at high risk of premature death within the first 2 decades of life. Because of the rarity of AADC deficiency, there is little evidence about its effect on survival. But clinical expert opinion suggests that most people die within the first decade of life. Causes of death vary, but include comorbidities associated with the condition such as multiple organ failure, pneumonia, acute complications during an oculogyric crisis episode and asphyxia. The committee noted that AADC is a spectrum of conditions, and that most people present with a severe phenotype.