Aromatic L-amino acid decarboxylase deficiency

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Aromatic L-amino acid decarboxylase deficiency
Other namesAADC deficiency
Specialty Neurology   OOjs UI icon edit-ltr-progressive.svg
Symptoms Dystonia, oculogyric crises, developmental delay, parkinsonism, dysautonomia
Usual onsetInfancy
CausesAutosomal recessive DDC mutation
Diagnostic method Lumbar puncture for neurotransmitter analysis; enzyme assay; genetic testing

Aromatic L-amino acid decarboxylase deficiency, also known as AADC deficiency, is a rare genetic disorder caused by mutations in the DDC gene, which encodes an enzyme called aromatic L-amino acid decarboxylase.

Contents

Signs and symptoms

Biosynthesis and breakdown of serotonin and the catecholamines, and the metabolic block in aromatic L-amino acid decarboxylase deficiency, Wassenberg et al., 2017. Biosynthesis and breakdown of serotonin and the catecholamines, and the metabolic block in AADC deficiency.png
Biosynthesis and breakdown of serotonin and the catecholamines, and the metabolic block in aromatic L-amino acid decarboxylase deficiency, Wassenberg et al., 2017.

Babies with severe aromatic L-amino acid decarboxylase deficiency usually present to clinicians during the first few months of life. Symptoms can include:

Some people may develop cerebral folate deficiency, because O-methylation of the excessive amounts of L-DOPA can deplete methyl donors such as S-adenosyl methionine and levomefolic acid. This deviation can be detected by measuring the levels of levomefolic acid in the cerebrospinal fluid, and can be corrected by folinic acid. [1]

Genetics

Aromatic L-amino acid decarboxylase deficiency has an autosomal recessive pattern of inheritance Autorecessive.svg
Aromatic L-amino acid decarboxylase deficiency has an autosomal recessive pattern of inheritance

Aromatic L-amino acid decarboxylase deficiency is an autosomal recessive condition, meaning an individual needs to have two faulty copies of the DDC gene in order to be affected. Usually, one copy is inherited from each parent. [3]

Pathophysiology

The aromatic L-amino acid decarboxylase deficiency enzyme is involved in the synthesis of dopamine and serotonin, both of which are important neurotransmitters.

Diagnosis

There are three core diagnostic tools: [1]

  1. molecular genetics - proving compound heterozygous or homozygous disease causing variants in the DDC gene
  2. CSF examination - low levels of 5-HIAA, HVA, and MHPG, increased levels of 3-OMD, L-DOPA and 5-HTP, and normal levels of pterins
  3. serum examination - decreased AADC enzyme activity

To establish the diagnosis of AADCD, patient must have positive genetic testing (1st criterion) while also fulfilling either one of the other two criterions.

Elevated 3-OMD levels in serum can be used as a simple and sensitive screening test, positive result of which must be confirmed by the diagnostic criteria above. [1]

Treatment

There is no cure for aromatic L-amino acid decarboxylase deficiency, but medical and multidisciplinary treatment can relieve some of the symptoms.[ medical citation needed ] Individuals will require physiotherapy, occupational therapy, and speech and language therapy.[ medical citation needed ] Some will need enteral feeding (for example, a gastrostomy or jejunostomy) due to difficulties with chewing and swallowing.[ medical citation needed ]

Various medications can help compensate for the missing neurotransmitters. Dopamine agonists such as rotigotine or pramipexole and monoamine oxidase inhibitors such as selegiline are commonly used.[ medical citation needed ] Individuals may also need to take a range of other medications to control dyskinesia, constipation and other symptoms. [1]

In July 2021, results of a small gene therapy phase I study reported observation of dopamine restoration on seven participants between 4 and 9 years old. [4] [5] [6]

In July 2022, the gene therapy product eladocagene exuparvovec was approved in the European Union for use in patients aged 18 months or older. [7]

Related Research Articles

<span class="mw-page-title-main">Catecholamine</span> Class of chemical compounds

A catecholamine is a monoamine neurotransmitter, an organic compound that has a catechol and a side-chain amine.

<small>L</small>-DOPA Chemical compound

l-DOPA, also known as l-3,4-dihydroxyphenylalanine and used medically as levodopa, is made and used as part of the normal biology of some plants and animals, including humans. Humans, as well as a portion of the other animals that utilize l-DOPA, make it via biosynthesis from the amino acid l-tyrosine.

Aromatic <small>L</small>-amino acid decarboxylase Class of enzymes

Aromatic L-amino acid decarboxylase, also known as DOPA decarboxylase (DDC), tryptophan decarboxylase, and 5-hydroxytryptophan decarboxylase, is a lyase enzyme, located in region 7p12.2-p12.1.

<span class="mw-page-title-main">Carbidopa</span> Chemical compound

Carbidopa (Lodosyn) is a drug given to people with Parkinson's disease in order to inhibit peripheral metabolism of levodopa. This property is significant in that it allows a greater proportion of administered levodopa to cross the blood–brain barrier for central nervous system effect, instead of being peripherally metabolised into substances unable to cross said barrier.

<span class="mw-page-title-main">Methyldopa</span> Medication used to treat high blood pressure

Methyldopa, also known as α-methyl-L-DOPA and sold under the brand name Aldomet among others, is a medication used for high blood pressure. It is one of the preferred treatments for high blood pressure in pregnancy. For other types of high blood pressure including very high blood pressure resulting in symptoms other medications are typically preferred. It can be given by mouth or injection into a vein. Onset of effects is around 5 hours and they last about a day.

<span class="mw-page-title-main">Benserazide</span> Chemical compound often used as medication

Benserazide is a peripherally acting aromatic L-amino acid decarboxylase or DOPA decarboxylase inhibitor, which is unable to cross the blood–brain barrier.

<span class="mw-page-title-main">Tyrosine hydroxylase</span> Enzyme found in Homo sapiens that converts l-tyrosine to l-dopa, the precursor of cathecolamines

Tyrosine hydroxylase or tyrosine 3-monooxygenase is the enzyme responsible for catalyzing the conversion of the amino acid L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA). It does so using molecular oxygen (O2), as well as iron (Fe2+) and tetrahydrobiopterin as cofactors. L-DOPA is a precursor for dopamine, which, in turn, is a precursor for the important neurotransmitters norepinephrine (noradrenaline) and epinephrine (adrenaline). Tyrosine hydroxylase catalyzes the rate limiting step in this synthesis of catecholamines. In humans, tyrosine hydroxylase is encoded by the TH gene, and the enzyme is present in the central nervous system (CNS), peripheral sympathetic neurons and the adrenal medulla. Tyrosine hydroxylase, phenylalanine hydroxylase and tryptophan hydroxylase together make up the family of aromatic amino acid hydroxylases (AAAHs).

<span class="mw-page-title-main">Aromatic amino acid</span> Amino acid having an aromatic ring

An aromatic amino acid is an amino acid that includes an aromatic ring.

Catechol-<i>O</i>-methyltransferase inhibitor Medication

A catechol-O-methyltransferase inhibitor is a drug that inhibits the enzyme catechol-O-methyltransferase. This enzyme methylates catecholamines such as dopamine, norepinephrine and epinephrine. It also methylates levodopa. COMT inhibitors are indicated for the treatment of Parkinson's disease in combination with levodopa and an aromatic L-amino acid decarboxylase inhibitor. The therapeutic benefit of using a COMT inhibitor is based on its ability to prevent the methylation of levodopa to 3-O-methyldopa, thus increasing the bioavailability of levodopa. COMT inhibitors significantly decrease off time in people with Parkinson's disease also taking carbidopa/levodopa.

<span class="mw-page-title-main">PTC Therapeutics</span> Pharmaceutical company

PTC Therapeutics, Inc. is a US pharmaceutical company focused on the development of orally administered small molecule drugs and gene therapy which regulate gene expression by targeting post-transcriptional control (PTC) mechanisms in orphan diseases.

<span class="mw-page-title-main">Droxidopa</span> Synthetic amino acid/norepinephrine prodrug

Droxidopa, also known as L-threo-dihydroxyphenylserine (L-DOPS) and sold under the brand names Northera and Dops among others, is sympathomimetic medication which is used in the treatment of hypotension and for other indications. It is taken by mouth.

<span class="mw-page-title-main">Levodopa</span> Dopaminergic medication

Levodopa, also known as L-DOPA and sold under many brand names, is a dopaminergic medication which is used in the treatment of Parkinson's disease and certain other conditions like dopamine-responsive dystonia and restless legs syndrome. The drug is usually used and formulated in combination with a peripherally selective aromatic L-amino acid decarboxylase (AAAD) inhibitor like carbidopa or benserazide. Levodopa is taken by mouth, by inhalation, through an intestinal tube, or by administration into fat.

Aromatic <small>L</small>-amino acid decarboxylase inhibitor

An aromatic L-amino acid decarboxylase inhibitor (synonyms: DOPA decarboxylase inhibitor, extracerebral decarboxylase inhibitor, DDCI and AAADI) is a medication of type enzyme inhibitor which inhibits the synthesis of dopamine by the enzyme aromatic L-amino acid decarboxylase (AADC, AAAD, or DOPA decarboxylase). It is used to inhibit the decarboxylation of L-DOPA to dopamine outside the brain, i.e. in the blood. This is primarily co-administered with L-DOPA to combat Parkinson's disease. Administration can prevent common side-effects, such as nausea and vomiting, as a result of interaction with D2 receptors in the vomiting center (or cheomoreceptor trigger zone) located outside the blood–brain barrier.

Dopamine-responsive dystonia (DRD) also known as Segawa syndrome (SS), is a genetic movement disorder which usually manifests itself during early childhood at around ages 5–8 years.

Sepiapterin reductase deficiency is an inherited pediatric disorder characterized by movement problems, and most commonly displayed as a pattern of involuntary sustained muscle contractions known as dystonia. Symptoms are usually present within the first year of age, but diagnosis is delayed due to physicians lack of awareness and the specialized diagnostic procedures. Individuals with this disorder also have delayed motor skills development including sitting, crawling, and need assistance when walking. Additional symptoms of this disorder include intellectual disability, excessive sleeping, mood swings, and an abnormally small head size. SR deficiency is a very rare condition. The first case was diagnosed in 2001, and since then there have been approximately 30 reported cases. At this time, the condition seems to be treatable, but the lack of overall awareness and the need for a series of atypical procedures used to diagnose this condition pose a dilemma.

Gene therapy in Parkinson's disease consists of the creation of new cells that produce a specific neurotransmitter (dopamine), protect the neural system, or the modification of genes that are related to the disease. Then these cells are transplanted to a patient with the disease. There are different kinds of treatments that focus on reducing the symptoms of the disease but currently there is no cure.

3-<i>O</i>-Methyldopa Chemical compound

3-O-Methyldopa (3-OMD) is one of the most important metabolites of L-DOPA, a drug used in the treatment of the Parkinson's disease.

Dihydropteridine reductase deficiency (DHPRD) is a genetic disorder affecting the tetrahydrobiopterin (BH4) synthesis pathway, inherited in the autosomal recessive pattern. It is one of the six known disorders causing tetrahydrobiopterin deficiency, and occurs in patients with mutations of the QDPR gene.

<span class="mw-page-title-main">Monoamine precursor</span>

Monoamine precursors are precursors of monoamines and monoamine neurotransmitters in the body. The amino acids L-tryptophan and L-5-hydroxytryptophan are precursors of serotonin and melatonin, while the amino acids L-phenylalanine, L-tyrosine, and L-DOPA (levodopa) are precursors of dopamine, epinephrine (adrenaline), and norepinephrine (noradrenaline).

Eladocagene exuparvovec, sold under the brand name Upstaza among others, is a gene therapy product for the treatment of aromatic L‑amino acid decarboxylase (AADC) deficiency. It infuses the gene encoding for the human aromatic L-amino acid decarboxylase enzyme into the putamen region of the brain. The subsequent expression of aromatic L-amino acid decarboxylase results in dopamine production and, as a result, development of motor function in people with aromatic L-amino acid decarboxylase deficiency. Eladocagene exuparvovec is an adeno-associated virus vector-based gene therapy.

References

  1. 1 2 3 4 5 Wassenberg T, Molero-Luis M, Jeltsch K, Hoffmann GF, Assmann B, Blau N, et al. (January 2017). "Consensus guideline for the diagnosis and treatment of aromatic l-amino acid decarboxylase (AADC) deficiency". Orphanet J Rare Dis. 12 (1): 12. doi: 10.1186/s13023-016-0522-z . PMC   5241937 . PMID   28100251.
  2. Korenke, GC; Christen, HJ; Hyland, K; Hunneman, DH; Hanefeld, F (1997). "Aromatic L-amino acid decarboxylase deficiency: an extrapyramidal movement disorder with oculogyric crises". Eur J Paediatr Neurol. 1 (2–3): 67–71. doi:10.1016/S1090-3798(97)80065-7. PMID   10728198.
  3. Montioli, Riccardo; Dindo, Mirco; Giorgetti, Alejandro; Piccoli, Stefano; Cellini, Barbara; Voltattorni, Carla Borri (2014). "A comprehensive picture of the mutations associated with aromatic amino acid decarboxylase deficiency: From molecular mechanisms to therapy implications". Human Molecular Genetics. 23 (20): 5429–5440. doi: 10.1093/hmg/ddu266 . PMID   24865461.
  4. Pearson TS, Gupta N, San Sebastian W, Imamura-Ching J, Viehoever A, Grijalvo-Perez A, et al. (July 2021). "Gene therapy for aromatic L-amino acid decarboxylase deficiency by MR-guided direct delivery of AAV2-AADC to midbrain dopaminergic neurons". Nature Communications. 12 (1): 4251. Bibcode:2021NatCo..12.4251P. doi:10.1038/s41467-021-24524-8. ISSN   2041-1723. PMC   8275582 . PMID   34253733.
  5. Ibrahim, Mennatalla (2021-07-14). "Gene therapy restores missing dopamine in children with rare brain disease". Science. Retrieved 2021-07-18.
  6. "Gene therapy trial points to a wider window to alter course of rare disease". STAT. 2021-07-12. Retrieved 2021-07-18.
  7. Keam, S. J. (2022). "Eladocagene Exuparvovec: First Approval". Drugs. 82 (13): 1427–1432. doi:10.1007/s40265-022-01775-3. PMID   36103022. S2CID   252213561.