Background
Methods
Composition of the guideline working group and timeline
Developing topics and key questions
Systematic literature search
Grading of evidence and recommendations
Levels of evidence | |
---|---|
1++ | High quality meta-analyses, systematic reviews of RCTs or RCTs with a very low risk of bias |
1+ | Well conducted meta-analyses, systematic reviews, or RCTs with a low risk of bias |
1- | Meta-analyses, systematic reviews, or RCTs with a high risk of bias |
2++ | High quality systematic reviews of case control or cohort studies |
High quality case control or cohort studies with a very low risk of confounding or bias and a high probability that the relationship is causal | |
2+ | Well conducted case control or cohort studies with a low risk of confounding bias and a moderate probability that the relationship is causal |
2- | Case control or cohort studies with a high risk of confounding or bias and a significant risk that the relationship is not causal |
3 | Non-analytic studies, e.g. case reports, case series |
4 | Expert opinion |
Judgment | Recommendation |
---|---|
Undesirable consequences clearly outweigh desirable consequences | Strong recommendation against |
Undesirable consequences probably outweigh desirable consequences | Conditional recommendation against |
Balance between desirable and undesirable consequences is closely balanced or uncertain | Recommendation for research and possibly conditional recommendation for use restricted to trials |
Desirable consequences probably outweigh undesirable consequences | Conditional recommendation for |
Desirable consequences clearly outweigh undesirable consequences | Strong recommendation for |
Disclaimer
Part I: Clinical presentation
Number of reports; literature search
Ethnic origin
Age of onset and age of diagnosis
Symptom/ sign | Neo natal | Infancy | Child hood | Adolescence | Adulthood | ||
---|---|---|---|---|---|---|---|
CNS | Tone regulation | Floppy infant | + | ++ | |||
Hypotonia (mainly truncal) | + | ++ | ++ | ++ | ++ | ||
Poor head control | + | + | + | + | + | ||
Hypertonia (mainly limbs) | + | + | + | + | + | ||
Movement disorders | Dyskinesia (eg hyperkinesia, chorea, athetosis) | ± | + | + | + | + | |
Dystonia | - | ++ | ++ | ++ | ++ | ||
Oculogyric crisis | ± | ++ | ++ | ++ | ++ | ||
Hypokinesia and/ or bradykinesia | ± | ++ | ++ | ++ | ++ | ||
Myoclonus | ± | ± | ± | ± | ± | ||
Tremor | ± | ± | ± | ± | ± | ||
Developmental Delay | Delayed motor development | ± | ++ | ++ | ++ | ++ | |
Delayed cognitive development | ± | + | + | + | |||
Delayed speech development | ± | + | + | + | |||
Behavioural Problems | Irritability | ++ | ++ | + | + | + | |
Autistic features | ± | ± | ± | ||||
Dysphoria/ Mood problems | ± | ± | ± | ± | ± | ||
Excessive crying | + | ++ | + | - | - | ||
Sleeping Problems | Insomnia and or hypersomnia | + | + | + | + | ||
Other | Epileptic seizures | - | ± | ± | ± | ± | |
Fatiguability | ± | ± | ± | ± | ± | ||
Diurnal fluctuation | ± | ± | ± | ± | |||
Dysarthria | ± | ± | ± | ||||
Poor eye fixation | + | + | + | + | |||
Increased startle | ± | ± | ± | ± | ± | ||
ANS | Eyes | Ptosis | + | + | + | + | + |
Miosis | ± | ± | ± | ± | ± | ||
Upper respiratory tract | Nasal congestion | - | + | + | ± | ± | |
Excessive drooling | - | + | + | ± | ± | ||
Stridor | ± | ± | ± | ± | ± | ||
Skin | Excessive sweating | - | + | + | + | + | |
Homeostasis | Temperature instability | + | + | + | + | + | |
Cardiovascular | (Orthostatic) Hypotension | - | - | ± | + | + | |
Bradycardia | ± | ± | ± | ± | ± | ||
Heart rhytm abnormalities | ± | ± | ± | ± | |||
Gastrointestinal | Diarrhea | ± | + | + | + | ± | |
Obstipation | ± | + | + | + | ± | ||
Metabolic/ endocrine | Hypoglycemia | ± | ± | ± | - | - | |
Hyperprolactinemia | ± | ± | ± | ± | ± | ||
General | Feeding/ Swallowing Problems | + | + | + | + | + | |
Gastrointestinal reflux | + | + | + | ± | ± | ||
Gastrointestinal problems unspecified | + | ++ | + | + | + | ||
Failure to thrive | ± | + | + | + | |||
Contractures | - | - | - | ± | ± | ||
Small hand and feet | ± | ± | ± | ± | ± |
Key symptoms and signs
Other neurological findings
Additional clinical findings
Phenotypic spectrum and clinical course
Phenotype correlations with genotype or biochemical phenotype
Part IIa: Diagnosis: laboratory tests
Key diagnostic tests: CSF, AADC activity and genetic testing
Lumbar puncture
AADC activity in plasma
Molecular diagnosis
Concluding statements regarding key diagnostic tests
Other diagnostic tests in AADCD
Prolactin
Neurotransmitter (metabolites) in blood
Dried blood spot measurement of 3-OMD
Urine measurements of neurotransmitter metabolites
Other diagnostic tests
Part IIb: Diagnosis: imaging and electroencephalography
Magnetic resonance imaging (MRI) of the brain
Electroencephalography (EEG)
Other imaging modalities
Part III: Treatment
IIIa: Medical treatment
Available evidence
First line treatment
Dopamine agonists
MAO inhibitors
Pyridoxine / pyridoxal phosphate (PLP)
Additional symptomatic treatment
Anticholinergic drugs
Melatonin
Benzodiazepines
Other symptomatic treatment
Other treatment options
L-Dopa with or without carbidopa
Folinic acid
5-Hydroxytryptophan
Selective serotonin reuptake inhibitors (SSRIs)
Class | Drug | Mechanism | Dose recommendation | Precaution/comments | |
---|---|---|---|---|---|
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 |