About Aromatic Amino Acid Decarboxylase deficiency (AADCd)

AADCd is a genetically inherited neurological disorder affecting the brains ability to produce neurotransmitters, dopamine and serotonin; two of the most essential neurotransmitters needed for every day living! AADC deficiency presents early in life with hypotonia, hypokinesia, Oculogyric Crisis (known as a spell/attack), autonomic dysfunction, dysphoric mood, and sleep disturbance.

Affected children can also show a number of movement disorders, most frequently dystonia. Diurnal fluctuation and improvement of symptoms after sleep is a characteristic of AADC.  The severity of symptoms experienced by each affected child varies, but the majority of children show minimal motor development in the absence of treatment.

What does AADC deficiency stand for?

AADC is an abbreviated term used by medical professionals around the World when presenting, discussing and writing about the disease:

Aromatic Amino Acid Decarboxylase Deficiency

In some countries Aromatic Amino Acid Decarboxylase Deficiency can also be known as:

  • AAD

  • AADC

  • AADCd

  • ALADD

  • DDC Deficiency

  • DOPA Decarboxylase Deficiency

Are there other medical terms used to describe AADC deficiency?

What is the disease 'Aromatic Amino Acid Decarboxylase (AADCd) deficiency'?

AADC deficiency is rare metabolic neurotransmitter disease.

AADC is an essential enzyme, which is involved in the decarboxylation of aromatic amino acids; if the enzyme is defective, formation of the neurotransmitters dopamine and serotonin is impaired and the passage and signalling within the brain is disrupted.

In AADC Deficiency there is a failure to convert the chemicals L-dopa and 5-hydroxytryptophan to the active neurotransmitter chemicals Dopamine and Serotonin. These are two of the brains main neurotransmitters needed for everyday living.

 

Dopamine
Dopamine can be converted further to the neurotransmitters

norepinephrine (noradrenaline)and epinephrine (adrenaline). 

Collectively this group of neurotransmitters are known as catecholamines.

Serotonin
Serotonin can also be converted to melatonin, which may also

theoretically be deficient in AADC deficiency.

Absent or decreased amounts of neurotransmitters such as those described above have catastrophic affects leaving an AADC affected child with profound disabilities


(more information can be found under ‘Symptoms of AADC Deficiency’)

What are Neurotransmitters?

Neurotransmitters are naturally occurring chemical substances found in the brain which are used to transfer messages between different brain cells.

Neurotransmitters relay, amplify and modulate signals from one brain cell (Neuron) to another and work in unison to balance the body’s motor co-ordination, pain mechanisms, behaviour, blood flow and many other biochemical and physiologic properties.

Dopamine, epinephrine (also known as adrenaline), norepinephrine (also known as noradrenaline) and serotonin are some of the major neurotransmitters implicated in AADC deficiency.

How does AADC deficiency affect the brains neurotransmitters?

Neurotransmitters are a sensitive chain of signals along pathways in the brain which ultimately lead to a correct instruction for bodily function. In AADC deficiency these sensitive chains of signals fail to complete.

L-Dopa and 5-Hydoxytryptophan need correct AADC function to convert them to the active neurotransmitters; Dopamine and Serotonin respectively.

Lack of Dopamine and Serotonin means the brain is also deficient of other neurotransmitters such as:

Norepinephrine (noradrenaline)

Epinephrine (adrenaline)

Melatonin

In addition to the lack of essential neurotransmitters there is a superfluity of the precursor's L-dopa and 5 Hydroxytryptophan which accumulates in the brain and other body tissues. It is still unknown as to how exactly this may affect a child with AADC deficiency.

 

What neurotransmitters and pathways are implicated in AADC deficiency?

 

In AADC deficiency pathways associated with the following are affected in some way and to varying degrees from child to child:

L-Dopa - (excess of)

5 Hydroxytrptophan - (excess of)

Dopamine - (lack of)

Norepinephrine - (lack of)

Epinephrine - (lack of)

Serotonin - (lack of)

Melatonin - (lack of)

S-adenosylmethionine (lack of)

5-methyltetrahydrofolate (lack of)

It’s very hard to quantify exactly what and how many other neurotransmitters and pathways are implicated in AADC deficiency, as there is still much more research needed to understand this disease.

The Symptoms associated with AADC deficiency

AADC deficiency presents early in life with hypotonia, hypokinesia, oculogyric crisis, autonomic dysfunction, dysphoric mood, and sleep disturbance. There may be a number of movement disorders, most frequently dystonia. Diurnal fluctuation and improvement of symptoms after sleep is a characteristic of AADC deficiency. The majority of affected children show minimal motor development in the absence of treatment.

 

The presentation of symptoms presents in varying degrees of severity:

 

Neonatal Period

Feeding difficulties

Autonomic dysfunction

Hypotonia

 

Motor symptoms

Axial hypotonia (decreased tone or floppy - trunk, head and limbs)

Limb hypertonia (increased tone to the limbs)

Fluctuating limb tone

Hypokinesia (decreased spontaneous movements)

 

Oculogyric crises (a spasmodic attack and fixation of the eyeballs upwards)

 

Other movement disorders

Limb dystonia (disorder of muscle control)

Stimulus-provoked dystonia

Cervicofacial dystonia

Myoclonus/prominent startle

Distal chorea

Choreoathetosis

Athetosis

Parkinsonism

Flexor spasms

Tremor

Drug-induced dyskinesias

Chorea

Dystonia (disorder of muscle control)

 

Diurnal

variation/improvement of neurologic symptoms after sleep

 

Autonomic dysfunction

Diaphoresis

Temperature instability

Nasal congestion

Ptosis/pupillary changes (droopy eyelids)

Hypotension/bradyarrhythmia

RAD/GI dysmotility (Gastrointestinal symptoms including gastroesophageal reflux, constipation, diarrhoea and dysmotility and absorption (inability to pass food through the gastrointestinal tract because muscles do not work properly)),

 

Dysphoria general feeling of unwell, unhappy and emotional lability

 

Sleep disturbance

Nobody knows the life expectancy of a child living with AADC deficiency. Symptoms vary greatly from child to child and because there are so few children currently diagnosed with the disorder it is impossible to say what the long-term affect of AADC deficiency is going to be. 

We do know that AADC deficiency has already cost children their lives. 

AADC deficiency is considered to be a fairly new scientific discovery and because of the similarity in some of the symptoms shared with Parkinson’s disease we can only hope that a major breakthrough in the treatment of Parkinson’s disease could have potential benefits in treating a child with AADC deficiency. However, it also possible that by researching the biochemical mechanisms involved in AADC, new insights into our understanding and treatment of Parkinson’s disease could occur. 

Will my child survive living with AADC Deficiency?

Can any Physician/Consultant diagnose AADC Deficiency?

A specialist physician/consultant cannot confirm diagnosis of AADC deficiency by symptoms alone.

When a child first presents with a neurological disorder and a dopamine related disease is suspected then the treating physician/consultant will arrange the correct and necessary tests.

Warning: Many specialists are still not yet aware that AADC deficiency even exists. If you suspect your child may have this condition please direct your physician to this web site.

How is AADC Deficiency diagnosed?

The clinical picture in AADC is similar to that of tyrosine hydroxylase deficiency (TH), guanosine triphosphate cyclohydrolase (GTPCH) deficiency, sepiapterin reductase (SR) deficiency as well as other dopamine related diseases. CSF analysis of certain neurotransmitter metabolites can help distinguish between all of these conditions and each of these conditions requires separate therapies. This is why it is best to have the lumbar puncture.

1) Cerebrospinal Fluid/CSF (lumbar Puncture)

A sample of cerebrospinal fluid (CSF) is taken from a child suspected of having AADC deficiency (or other similar dopamine related disease). The CSF can provide an almost conclusive positive result for AADC deficiency as well as eliminating other dopamine related diseases. There are just a few laboratories in the world able to confirm AADC deficiency by measuring HVA, 5-HIAA, 3-O-methylDOPA, L-DOPA, 5-hydroxytryptophan (5-HTP) and vanillyllactic acid in a CSF sample.

An example of a positive AADC result from CSF using:

HPLC Diagnosis of AADC Deficiency (High Performance Liquid Chromatography with Electrochemical Detection) measures:

 

5-HIAA = 5-hydroxyindoleacetic acid - a serotonin metabolite (LOW)
HVA = homovanillic acid = a dopamine metabolite (LOW)
5HTP = 5-hydroxytryptophan - a serotonin precursor that accumulates in AADC deficiency (HIGH)

L-DOPA = Levodopa - a dopamine precursor that accumulates in AADC deficiency (HIGH)
3-OMD = 3-O-methyldopa a methylated derivative of levodopa that accumulates in AADC deficiency (HIGH).

2) Blood Test (plasma enzyme assay)

Although a lumbar puncture is preferred (because it can distinguish between several diseases that present with similar symptoms) a blood test to determine enzyme activity can also be used to give a diagnosis of AADC deficiency.

This procedure can be used to confirm the findings of an already performed lumbar puncture or confirm a diagnosis of AADC deficiency if a parent of a child suspected to have this condition refuses to allow a lumbar to be performed.

This test will determine how active AADC function is and a diagnosis of AADC will be confirmed if the activity of AADC function is almost undetectable.

The parents of an affected AADC child can have the same test to conclusively confirm their child's diagnosis and confirm that they are carriers of a mutated gene allele for AADC deficiency. See ‘Is AADC Deficiency an inherited disease’.

The same test is also available to other family members (including the siblings of an AADC affected child) to determine if they are carriers of the same mutated gene allele for AADC deficiency.

This test requires strict collection procedures. Blood should be drawn according to the specific procedure policies provided by each of the laboratories in the section ‘where does my child’s sample go to confirm diagnosis’.

3) Blood Test (DNA Analysis)

The gene for AADC deficiency maps to chromosome 7p12.1-p12.3. Blood can be collected and DNA extracted which can allow sequencing of the whole of the coding region for the AADC gene (exon/exon-intron boundary sequencing). This means that if a mutation(s) is/are found an absolutely diagnosis is made. Detection of mutations in an affected child also means that prenatal diagnosis should be available for subsequent pregnancies.

This test requires strict collection procedures. Blood should be drawn according to the specific procedure policies provided by each of the laboratories in the section ‘where does my child’s sample go to confirm diagnosis’.

4) Urine collection (to measure neurotransmitter activity)

Although a urine sample is not the usual or widely used method to confirm (or make the initial diagnosis) of AADC deficiency (descriptions 1, 2 and 3 are the preferred) there is some evidence that this may be possible. A diagnosis of AADC Deficiency has been confirmed using a urine sample alone measuring HVA, 5-HIAA, pteridines, L-DOPA, 5-HTP, vanillactic acid and 3-0-methylDOPA. Further studies are necessary to measure how accurate this method is. Urine measurement of vanillactic acid can also detect AADC deficiency but elevations of vanillactic acid are small and it requires laboratories to specifically look for this chemical.

Who gets AADC ?

In 1992 the first two children (twins) were correctly diagnosed with AADC Deficiency (see Hyland K. Surtees R.A.H. Rodeck C. and Clayton P.T. (1992). Aromatic L Amino acid decarboxylase deficiency: Clinical features, diagnosis and treatment of a new inborn error of neurotransmitter amine synthesis. Neurology 42, 1980-1988.) 

Subsequent to this approx 130-150 children, around the World, have been diagnosed with the disease. 

AADC does not discriminate in its choice of sufferers and affects males and females equally. 

Some of the countries where AADC deficiency has been diagnosed include:-

Argentina / Israel / Portugal / Australia / Italy / Singapore / Austria / Ireland / Switzerland / Belgium / Japan / Taiwan / Canada / Jordan / UK / France / Malaysia / USA / Germany / Netherlands / Zanzibar / Estonia / India / Pakistan / Russia / UAE / China / Thailand / Spain / Brazil / Philippines / Cambodia / Turkey / Iran

Is AADC an inherited condition?

yes it is...

The gene for AADC deficiency maps to 7p12.1-p12.3 and is composed of 15 exons spanning 85 kilobases. Every gene consists of two alleles. One that comes from the father and one that comes from the mother. AADC deficiency is an inherited autosomal recessive trait – this means that each parent has a bad AADC allele that they pass on to their affected child.

Example 1:-


A child born to the parents below will not be affected by disease, as the parents are not carriers of a defective gene.

Example 2:-

A child born to the parents below has a 25% chance of inheriting AADC Deficiency, a 50% chance of becoming a carrier and a 25% chance of being free from any defective allele. Like the parents, a child who becomes a carrier is not usually expected to show any symptoms.

What medications are available to treat AADC Deficiency?

Each affected AADC child reacts differently to medications used to treat the disorder. Below is some information that may help you understand a little more about their benefits when treating this disease. Please do not use this information to self diagnose or self medicate your child and discuss in detail with your child’s treating physician/consultants the potential benefits to your child.

 

Dopamine Receptor Agonists

 

Dopamine is normally released from the end of a nerve. It crosses the gap (synapse) between this nerve and the next one where it binds to receptors causing the receptors to ‘fire’. This process allows signals to transfer from one nerve to another. In AADC deficiency, dopamine levels are insufficient to allow this passage of signals to occur. Dopamine agonists are an artificial form of naturally produced dopamine. The agonists mimic the action of the naturally produced dopamine and they act by attaching and stimulating dopamine receptors in the brain.

 

Dopamine agonists used to treat AADC deficiency include ergot and non-ergot derived forms. Recently it has been reported that ergot forms of dopamine agonists, such as pergolide and bromocriptine can cause a serious fibrotic reaction. The newer forms of non-ergot dopamine agonists, pramipexole and ropinirole, are now more favoured in the treatment of AADC deficiency but do not necessarily have the same benefits as the ergot forms. This should be discussed in more detail with your affected child’s treating physician/consultant and with the help of an AADC medical expert.

 

Monoamine Oxidase Inhibitors (MAOI)

 

In AADC deficiency there is always a very small amount of dopamine and serotonin that is produced. MAO inhibitors are used to inhibit the monoamine oxidase enzyme that would normally break down dopamine and serotonin. In the presence of MAOI’s the small amounts of dopamine and serotonin can accumulate and hence improve the neurotransmission process.

 

Usually whilst taking MAO inhibitors you are advised to avoid certain foods and medications. Although, we do know of at least one child affected by AADC, on an MAO inhibitor, who continues to eat all food groups without adverse reaction.

 

Vitamin B6 – Pyridoxine

 

Vitamin B6 – otherwise known as pyridoxine is a precursor that the body converts into pyridoxal -5’ phosphate. This pyridoxal 5’-phosphate is required for the normal functioning of AADC. By increasing the amount of B6 it is hoped that it may help stimulate AADC function to facilitate some production of natural dopamine and serotonin. In AADC deficiency the benefit of high doses of B6 is unknown.

 

Anticholinergic Agents

 

Theoretically anticholinergics agents such as Trihexyphenidyl are used to improve the imbalance between the acetylcholine and dopamine. In children with AADC deficiency, these medications have been reported to help reduce the increased sweating and possibly ameliorate the limb dystonia.

 

It has been reported that it may help in the smoothing out of motor fluctuations.

 

Antiepilectics

 

Used for the treatment of seizures – seizures are rarely present in AADC deficiency.

 

Serotonergic Medications

 

Selective Serotonin Re-uptake Inhibitors (SSRI) or Serotonin Agonists may be used to treat AADC deficiency. Serotonergic medications may cause an adverse reaction if used in conjunction with MAO inhibitors. This should be discussed in more detail with your affected child's treating physician/consultant and with the help of an AADC medical expert.

 

Gastrointestinal Medications

 

There are many gastrointestinal medications and interventions, once your child has been fully assessed for gastrointestinal symptoms and treatments or procedures recommended, try and resource all the information you can about their benefits and risks.

 

Folate

 

In AADC deficiency there is accumulation of L-dopa. The removal of this L-dopa requires methylfolate. For every molecule of L-dopa that accumulates you need one molecular of methylfolate. For this reason, if the intake of folate in the diet is inadequate a patient with AADC deficiency can slowly become folate deficient. It is recommended that you discuss this with your physician and regularly check your child’s folate status.

 

Note

 

This list is not an exhausted list of medications and we encourage you to use the medline link provided to explore more about each medication and its potential benefit and risk when being used to treat your child. This can prove difficult, as some of the medications above are not routinely used to treat children.

 

If you have specific concerns about medications used to treat your affected child then it may be useful to refer your child’s treating physician/consultant to an AADC medical expert to find out more.

How successful are those medications?

Children who have been able to tolerate medication have had varying degrees of improvement in the symptoms of AADC deficiency. At the extreme end, a wheelchair bound affected child improved to such a degree that he was able to learn to walk and talk with the help of medication. However, there are many children living with AADC deficiency who have not been able to tolerate even the smallest amount of medication that has been given to try and help improve their state.

 

Each child affected with AADC Deficiency is unique and subsequently so is each child’s reaction to medication. More research is necessary to understand the reasons why some children respond more favourably to medication than others.

What are the long-term affects of medication?

It is still currently unclear what the long term effects of the various medications will be.

Will medication need to be adjusted?

Medication may have to be adjusted on a regular basis just after diagnosis in order to allow ‘fine tuning’. Also as your child becomes older the amounts of medication will likely have to be increased due to their increase in size and weight.

Does having a child affected by AADC Deficiency affect our decision to have more children?

Yes probably...

If you have a child affected by AADC deficiency, this may influence your decision for more children. 

If the parents have another child there is a 25% chance that the child will be affected by AADC deficiency, a 50% chance that the child will be a heterozygote carrier and a 25% chance that the child will have a completely normal AADC gene. See ‘is AADC an inherited disease’ for more information.

It is not always possible to pinpoint the exact location of the mutated allele on the AADC gene even after a child has a confirmed diagnosis of AADC deficiency. If the mutation(s) have been located in your affected child, pre-natal diagnosis may be possible. Please consult with your physician and genetic counsellor.

If my child is diagnosed with AADC will the whole family have to have a test?

AADC deficiency is an autosomal recessive condition. Everybody has one AADC gene and each AADC gene is made of two parts (alleles).

 

One allele comes from one parent and the other comes from the other parent.

 

In a child affected with AADC deficiency both alleles have a mutation, one mutation came from the mother and the other from the father. This means that the mother and father have one normal allele and the other allele carries a mutation – they are known as carriers for AADC deficiency.

 

This does not affect AADC function in the parents.

 

If the same parents have another child, there is a 25% chance that the child will be affected by AADC deficiency, a 50% chance that the child will be a carrier and a 25% chance that the child will have a completely normal AADC gene.


It is up to the parents to decide if they wish to know if other family members are carriers for an AADC mutation or if they are completely unaffected

Testing for carrier status can be done by measuring AADC activity in blood – see the link ‘how is AADC diagnosed’ for more information about this test.

Where can I go for help to find out more about AADC deficiency?

www.pubmed.com can be used to help find out more about AADC using the key words 'AADC deficiency'


Other web sites which may also be helpful include:

www.BH4.org

www.PNDassoc.org

quick links

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