aromatic L-amino acid decarboxylase deficiency

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare, inherited disorder that affects the way nerve cells (neurons) transmit information to other cells [4][10]. This condition is caused by mutations in the DDC gene, which leads to a severe combined deficiency of neurotransmitters such as serotonin, dopamine, norepinephrine, and epinephrine [2][5].

The symptoms of AADC deficiency typically appear in the first six months of life and can include:

• Feeding difficulties
• Weak muscle tone (hypotonia)
• Sleep disturbances
• Developmental delay
• Movement disorders (such as oculogyric crisis, dystonia, and hypokinesia)
• Autonomic symptoms

AADC deficiency is an autosomal recessive condition, meaning that an individual needs to have two faulty copies of the DDC gene in order to be affected [11]. This means that a person must inherit one faulty copy from each parent.

The disorder affects the production of signals that allow cells in the nervous system to communicate with each other, leading to problems with the nervous system [12]. AADC deficiency is a rare genetic disorder that can have significant effects on an individual's quality of life.

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare genetic disorder that affects the production of certain neurotransmitters in the brain, leading to a range of symptoms. The signs and symptoms of AADC deficiency typically appear in early infancy and can vary from person to person.

Common Symptoms:

• Hypotonia: Weak muscle tone, which can lead to feeding difficulties and poor suckling.
• Developmental Delay: Delays in reaching developmental milestones, such as sitting, standing, or walking.
• Movement Disorders: Abnormal movements, including oculogyric crises (sudden, involuntary eye movements), dystonia (involuntary muscle contractions), and hypokinesia (reduced movement).
• Autonomic Symptoms: Problems with the autonomic nervous system, which can lead to issues such as:
  • Seizures
  • Behavioral problems
  • Sleep disturbances

Other Possible Symptoms:

• Feeding difficulties
• Poor suckling
• Delayed or absent speech development
• Abnormal gait or balance
• Sensory processing issues

It's essential to note that the severity and progression of symptoms can vary significantly from person to person, even within the same family. Early diagnosis and treatment are crucial for managing the condition and improving outcomes.

References:

[2] Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare, genetic disease. 1,2 A mutation in the DDC gene results in reduced activity of the AADC enzyme. 1,2 The AADC enzyme plays an important role in producing the key neurotransmitters, dopamine and serotonin. 2. In AADC deficiency, the reduction of these neurotransmitters causes the associated symptoms [6].

[9] Individuals with aromatic L-amino acid decarboxylase (AADC) deficiency typically have complex symptoms, including motor, behavioral, cognitive, and autonomic findings. Symptom onset is in early infancy, typically within the first six months of life. The most common initial symptoms are often nonspecific, and include feeding difficulties, hypotonia, and developmental delay [9].

[7] SIGNS AND SYMPTOMS · Hypotonia · Oculogyric crises · Delayed development · Unusual movements · Autonomic nervous system dysfunction · Seizures · Behavioral problems [7].

Diagnostic Tests for Aromatic L-Amino Acid Decarboxylase Deficiency

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare genetic disorder that requires accurate diagnosis to ensure proper treatment. Several diagnostic tests can help establish the presence of this condition.

• Measurement of 3-O-methyldopa concentrations: This test measures the levels of 3-O-methyldopa, a catabolic product of L-dopa that accumulates in individuals with AADC deficiency, in dried blood spots [4].
• Cerebrospinal fluid (CSF) neurotransmitter analysis: This test analyzes the levels of neurotransmitters such as dopamine and serotonin in the CSF to confirm the diagnosis [14].
• Enzyme activity essay in plasma: This test measures the activity of AADC enzyme in the plasma, which is typically decreased in individuals with AADC deficiency [6].
• Mutational analysis: This test identifies mutations in the DDC gene that cause AADC deficiency.
• Aromatic L-amino acid Decarboxylase Enzyme Analysis (ENZ01): This test is used for the diagnosis of AADC deficiency and measures the activity of the AADC enzyme [5].

Diagnostic Pathway

The diagnostic pathway for suspected AADC deficiency involves a series of tests, including:

1. Initial physical examination to identify key symptoms such as hypotonia, movement disorders, developmental delay, and autonomic symptoms.
2. Measurement of 3-O-methyldopa concentrations in dried blood spots.
3. CSF neurotransmitter analysis.
4. Enzyme activity essay in plasma.
5. Mutational analysis.

Specialist Referrals

Diagnostic teams for AADC deficiency may include genetics specialists who can provide guidance on genetic testing and counseling [10].

Treatment Options for Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare genetic disorder that affects the production of dopamine and other neurotransmitters in the brain. While there is no cure for this condition, various treatment options are available to manage its symptoms.

Dopamine Agonists

Treatment with dopamine agonists, such as levodopa/carbidopa, has been beneficial in managing the symptoms of AADC deficiency [4]. These medications work by increasing the levels of dopamine in the brain, which can help alleviate symptoms such as muscle weakness and tremors.

Monoamine Oxidase Inhibitors (MAOIs)

In addition to dopamine agonists, MAOIs have also been used to treat AADC deficiency. These medications inhibit the action of monoamine oxidase, an enzyme that breaks down dopamine and other neurotransmitters [4]. By inhibiting this enzyme, MAOIs can help increase the levels of dopamine in the brain.

Other Treatment Options

A complex treatment regimen including pyridoxine phosphate, anticholinergic, and antiepileptic drugs may also be used to manage the symptoms of AADC deficiency [6].

Gene Therapy

Recently, a gene therapy called eladocagene exuparvovec (Kebilidi) has been approved by the FDA for the treatment of AADC deficiency. This is the first FDA-approved gene therapy for this condition and represents a significant advancement in the field of gene therapy [9].

European Union Approval

Eladocagene exuparvovec (Upstaza) has also been approved in the European Union and United Kingdom for individuals aged 18 months and older diagnosed with AADC deficiency [1]. This approval marks an important milestone in the treatment of this rare genetic disorder.

References:

[1] The gene therapy eladocagene exuparvovec (Upstaza) has been approved in the European Union and United Kingdom for individuals aged 18 months and older diagnosed with AADC deficiency. [4] Treatment with dopamine agonists and MAO inhibitors is beneficial, yet long-term prognosis is unclear. [6] A complex treatment regimen including dopamine agonists, monoamine oxidase inhibitors, pyridoxine phosphate, anticholinergic and antiepileptic drugs are used to manage the symptoms of AADC deficiency. [9] Kebilidi is the first FDA-approved gene therapy for treatment of AADC deficiency.

Differential Diagnosis of Aromatic L-Amino Acid Decarboxylase Deficiency

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare genetic disorder that can be challenging to diagnose due to its overlapping symptoms with other neurological disorders. To establish an accurate diagnosis, it's essential to consider the differential diagnoses of AADC deficiency.

Possible Differential Diagnoses:

• Other movement disorders: Conditions like dystonia, chorea, and athetosis can present with similar symptoms to AADC deficiency.
• Autonomic dysfunction: Disorders such as multiple system atrophy (MSA) and Parkinson's disease can also exhibit autonomic dysfunction, which is a characteristic feature of AADC deficiency.
• Neurodegenerative disorders: Conditions like Huntington's disease and spinocerebellar ataxia can have overlapping symptoms with AADC deficiency.

Diagnostic Criteria:

To confirm the diagnosis of AADC deficiency, the following criteria should be met:

• Biogenic amine levels in CSF: Determination of biogenic amines such as dopamine, serotonin, and norepinephrine in cerebrospinal fluid (CSF) can help establish the diagnosis.
• Enzyme activity assay: Measuring the enzyme activity of AADC in plasma can also aid in confirming the diagnosis.
• Mutational analysis: Genetic testing to identify mutations in the DDC gene can provide conclusive evidence for AADC deficiency.

Recommended Evaluations Following Initial Diagnosis:

After establishing a diagnosis of AADC deficiency, it's essential to conduct further evaluations to determine the extent of the disorder and develop an effective treatment plan. These may include:

• Neurological examination: A thorough neurological examination can help assess the severity of symptoms.
• Imaging studies: Imaging techniques such as MRI or CT scans can aid in identifying any structural abnormalities in the brain.
• Genetic counseling: Genetic counseling can provide guidance on the inheritance pattern and potential risks for family members.

References:

[6] Wassenberg, T. (2017). Aromatic L-amino acid decarboxylase deficiency: a rare neurometabolic disorder. [online] Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5551113/ [Accessed 25 Nov. 2024].

[8] Summary of AADC deficiency. (n.d.). [online] Available at: https://www.healthline.com/health/aromatic-l-amino-acid-decarboxylase-deficiency [Accessed 25 Nov. 2024].

[9] Wen, Y. (2020). Aromatic L-amino acid decarboxylase deficiency: a rare genetic disorder. [online] Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541113/ [Accessed 25 Nov. 2024].