Table 4 Recommended drugs and doses in AADC deficiency

FIRST LINE TREATMENT AGENTS

Vitamin B6

Pyridoxine (vit B6)

Cofactor, optimizes residual AADC activity

Start: 100 mg/d in 2 doses

Max 200 mg/d

May be preferred over pyridoxal 5-phosphate because of cost and availability

Maintain for 1 year, then discontinue when in stable circumstances. If no deterioration, leave discontinued.

Chronic use in high dose can cause severe sensorimotor polyneuropathy

Side effects: generally well tolerated, sometimes nausea, vomiting.

Pyridoxal 5-Phosphate

Cofactor, optimizes residual AADC activity

Start:100 mg/d in 2 doses.

Max 200 mg/d

Consider trial if pyridoxine gives too many side effects or is not effective.

Chronic use in high dose can cause severe sensorimotor polyneuropathy

Dopamine agonists

Pramipexole

Non-ergot derived D2-agonist with preference for D3 receptor subtype.

Start 0.005 – 0.010 mg/kg/d of BASE in 1-3 divided doses, increase every 3-7* days by 0.005 mg/kg/d, max 0.075 mg/kg or 3.3 mg/d of BASE

Distinction in salt and base content.

Take tablets with water, optional with food

High risk of drug-induced dyskinesias

Ropinirole

Non-ergot derived D2-agonist with preference for D3-receptor subtype.

Suggestion: Start 0.25 mg/d

1 daily 2 h before bedtime; increase every 3-7* days to 0.5-4.0 mg/d in 3 divided doses, max 0.3 mg/kg/d or 24 mg/d

Do not use in severe kidney failure

Take tablets with food

Very limited experience in AADC deficiency, physician should extrapolate and titrate carefully. Probably high risk of drug-induced dyskinesias as in other dopamine agonists.

Rotigotine patch

Non-ergot derived D2 agonist with preference for D3; also effect on D2, D1 and D5; and α2B and 5HT1A agonist.

>12 years and >15 kg:

Start 2 mg/d; weekly increase by 2 mg, max 8 mg/d.

No data available for use in children <12y/ <15 kg.

Do not cut patches.

Drug induced dyskinesias require a lower dose and/ or slower increase

Skin reactions occur often (about 30 %).

Sulphite can lead to allergic reactions

Remove patch during MRI/ electrocardioversion (aluminium content)

Bromocriptine

Ergot-derived D2-agonist with D1 receptor antagonist effect

Start 0.1 mg/kg/d (max 1.25 mg/d); increase weekly by 0.1 mg/kg/d (max 1.25 mg/d) up to 0.5 mg/kg/d (max 30 mg/d) in 2-3 divided doses.

Non-ergot derived dopamine agonists are preferred

Take tablets with food

Small risk of fibrotic complications, consider cardiac screening before and during use.

Higher risk with higher dose, dose restricted to 30 mg/d in adults. Maintain lowest effective dose.

Pergolide or cabergoline

Ergot-derived

None

Do not use because of higher risk of fibrotic complications

MAO-inhibitors

Selegiline

MAO-B inhibitor (non-selective in very high doses)

Start 0.1 mg/kg/d in 2-3 divided doses. Increase every 2 weeks by 0.1 mg/kg/d up to 0.3 mg/kg/d or 10 mg/d

Dose at breakfast and lunch, avoid night-time doses if insomnia is experienced.

Dose sublingual preparations much lower

Tranylcypromine

Non-selective MAO-A and -B inhibitor

Start 0.1 mg/kg/d in 2 doses. Increase every 2 weeks by 0.1 mg/kg/d up to 0.5 mg/kg/d (max 30 mg)

Dose at breakfast and lunch, avoid night-time doses if insomnia is experienced.

Occurrence of ‘cheese effect’ (hypertensive crises when foods with high content of tyramine are ingested) is very unlikely in patients with AADC deficiency due to their low levels of dopamine, norepinephrine and epinephrine.

ADDITIONAL SYMPTOMATIC TREATMENT

Anticholinergics

(dystonia/ autonomic symptoms)

Trihexyphenidyl

Anticholinergic agents, restores neurotransmitter disbalance

<15 kg: start 0.5-1 mg/d in 1 dose; increase every 3-7* days by 1 mg/d in 2-4 doses/d

>15 kg: start 2 mg/d in 2 doses; increase every 3-7* days by2mg/d in 2-4 divided doses.

Effective dose highly variable (6-60 mg)

Maximum dose: <10 kg 30 mg/d; >10 kg 60 mg/d

In general, the younger, the better tolerated; dosages often exceed recommended dose for adults (15 mg/d).

Maximum dose is dictated by side effects: e.g. dry mouth, dry eyes, blurred vision (mydriasis), urine retention, constipation. Sedation in high doses.

Benztropine

Centrally acting anticholinergic agent. Also dopaminergic effect by inhibiting presynaptic reuptake

Start 1 mg in 2 divided doses, increase weekly up to 4 mg/d

Anticholinergic side effects: e.g. dry mouth, dry eyes, blurred vision (mydriasis), urine retention, obstipation. Sedation in high doses.

Nasal congestion

Oxymetazoline or xylometazoline nosedrops

α-adrenergic agonist leading to local vasoconstriction

Use general dose guidelines for age, try to use lowest available dose in chronic use

Try to include intermittent weeks without treatment to prevent habituation

Hypertensive crises if used concomitantly with MAO-inhibitors is very unlikely in patients with AADC deficiency due to their levels of dopamine, norepinephrine and epinephrine

Sleeping problems

Melatonin

Regulates onset of sleep and day/night cycling

Start 3 mg/d, given 4 h before onset of sleep. Max dose 5-8 mg/d

Transient night terrors on initial treatment can occur (personal experience)

Availability differs between countries.

Irritability/ sleep disturbance

Clonidine

Centrally acting antihypertensive drug; imidazoline (I1-) and α2-agonist

Start 0.1 mg/d ante noctum, increase to max 3 mg/d ante noctum

Monitor blood pressure in higher dose

Sedative, therefore give AN

SPECIAL CASES ONLY

L-Dopa binding site variant

L-Dopa without carbidopa

Substrate for AADC to form dopamine; effective in certain binding site variants

Start 0.5-1 mg/kg/d in 3 divided doses, increase 2 weekly by 1 mg/kg to 5 mg/kg/d. Only if clinical effective, further increase to max 15 mg/kg/d

Start as first line treatment only if known binding site variant.

Otherwise, consider as third-line treatment trial for 2 months (or less if deterioration) when in stable clinical situation.

Monitor CSF during treatment, including 5-MTHF

Low 5-MTHF in CSF

Folinic acid (calcium folinate)

Methylation of excessive amounts of L-Dopa in AADCD may cause depletion of methyl donors.

1-2 mg/kg/d, max 20 mg/ d

Only supply if 5-MTHF is low in CSF

Monitor 5-MTHF in CSF during treatment with L-Dopa