Aromatic amino acid decarboxylase deficiency: Molecular and metabolic basis and therapeutic outlook

Himmelreich, Nastassja; Montioli, Riccardo; Bertoldi, Mariarita; Carducci, Carla; Leuzzi, Vincenzo; Gemperle, Corinne; Berner, Todd; Hyland, Keith; Thöny, Beat; Hoffmann, Georg F.; Voltattorni, Carla Borri; Blau, Nenad

doi:10.1016/j.ymgme.2019.03.009

Cited by 75 publications

(120 citation statements)

References 46 publications

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“…A third diagnostic measure is genetic testing. There are currently 82 DDC variants listed in the Pediatric Neurotransmitter Disease database (PNDdb; available at: http://biopku.org/pnddb/home.asp), including 79 variants that may be associated with the disease phenotype [19]. Current guidelines recommend that genetic testing be performed to diagnose AADC deficiency.…”

Section: Discussionmentioning

confidence: 99%

Case report: discovery of 2 gene variants for aromatic L-amino acid decarboxylase deficiency in 2 African American siblings

Monteleone

Hyland

2020

BMC Neurol

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Background: Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare genetic disorder with heterogeneous phenotypic spectrum resulting from disease-causing variants in the dopa decarboxylase (DDC) gene. Consensus guidelines recommend dopamine agonists, monoamine oxidase inhibitors, and other symptomatic treatments, but most patients have an unrelenting disease course with no response to these therapies. Case presentation: We describe 2 African American siblings with AADC deficiency and identify 2 DDC gene variants not previously associated with the disorder. The patients were evaluated for cognitive and neurologic impairments. Diagnosis of AADC deficiency was initially based on evaluation of urine and plasma metabolites, followed by targeted DDC gene sequencing. The first patient, a firstborn African American female, had moderate elevations of vanillactic and vanilpyruvic acids, and slight elevation of N-acetylvanilalanine in urine. The second patient, an African American female and younger sibling of the first patient, had low AADC enzyme activity and elevated 3-O-methyldopa levels in plasma. Genetic testing confirmed that both siblings possessed the same 2 DDC gene variants, which were identified as NM_000790.3: c.48C > A (p.Tyr16Ter) and NM_000790.3: c.116G > C (p.Arg39Pro). Conclusions: This report describes 2 previously unknown patients with AADC deficiency and confirmed the presence of 2 DDC gene variants not previously associated with this disorder. Further research is needed to identify disease-modifying treatments for this devastating neurometabolic disorder. Gene therapy with a recombinant adeno-associated viral vector serotype 2 carrying the gene for the human AADC protein (AAV2-hAADC) is currently in clinical development.

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Section: Discussionmentioning

confidence: 99%

Case report: discovery of 2 gene variants for aromatic L-amino acid decarboxylase deficiency in 2 African American siblings

Monteleone

Hyland

2020

BMC Neurol

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“…3,9 Treatment is based on compensating the lack of AADC activity and the treatment options include dopamine agonists, monoamine oxidase (MAO) inhibitors, pyridoxal-5 phosphate, anticholinergics, and other supportive treatment. 10 Gene therapy has been used recently in cases of AADC deficiency and it has shown promising results. 11 All our seven cases typically presented with a severe phenotype, with onset of symptoms in the first few months of life, as reported in literature.…”

Section: Discussionmentioning

confidence: 99%

Clinical Profile and Outcome of Indian Children with Aromatic L-Amino Acid Decarboxylase Deficiency: A primary CSF Neurotransmitter Disorder Mimicking as Dyskinetic Cerebral Palsy

et al. 2020

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Aromatic L-amino acid decarboxylase (AADC) deficiency is a disorder of neurotransmitter synthesis. It presents with psychomotor delay, dystonia, oculogyric crisis, and autonomic features. There is paucity of literature on this disorder. Hence, we are reporting this series with an objective to study profile and outcome of Indian children with AADC deficiency. In this retrospective review, all case records of genetically confirmed cases of AADC deficiency at the pediatric neurology department in a tertiary care hospital, from March 2014 to March 2020, were analyzed. The data were extracted in a predesigned proforma and analyzed. Out of seven cases, five were males. Median age of onset of symptoms was 4 months but median age of diagnosis was 12 months. All of them had developmental delay, oculogyric crisis, dystonia, increased sweating, intermittent fever, feeding and sleep disturbance, irritability, failure to thrive, axial hypotonia with dyskinetic quadriparesis, and normal magnetic resonance imaging (MRI) of brain and electroencephalogram (EEG). All of them were treated with pyridoxal 5-phosphate, trihexyphenidyl and pramipexole and six cases, in addition, were given bromocriptine. One case was additionally treated with selegiline. One case showed good improvement, five showed partial improvement, and one case expired. In conclusion, AADC deficiency should be suspected in any child with dyskinetic quadriparesis, oculogyric crisis, autonomic disturbances like increased sweating, intermittent fever, and sleep disturbance with normal neuroimaging.

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“…The DDC gene is associated with maintaining adequate levels of monoamine neurotransmitters and the production of AADC [22,23]. There are homozygous mutations that lead to loss of function in the DDC gene, thereby depleting the pools of the decarboxylase and causing a person to develop a fatal form of infantile Parkinsonism, known as AADC deficiency [22].…”

Section: Antisocial Personality Disorder and Somatic Symptom Disordermentioning

confidence: 99%

“…The loss of function mutations have been shown to be an inherited disorder, and its symptoms include movement abnormalities, developmental delays, and autonomic system dysfunction, all of which are incompatible with normal life [7,22]. Additionally, hypotonia, oculogyric crisis, and dystonia are experienced by those with AADC enzyme deficiency [23]. When there is minimally active AADC present, the individual fails to produce adequate levels of the monoamine neurotransmitters, resulting in reduced dopamine levels and even lower serotonin levels, a characteristic of both APSD and SSD [23].…”

Section: Antisocial Personality Disorder and Somatic Symptom Disordermentioning

confidence: 99%

“…Additionally, hypotonia, oculogyric crisis, and dystonia are experienced by those with AADC enzyme deficiency [23]. When there is minimally active AADC present, the individual fails to produce adequate levels of the monoamine neurotransmitters, resulting in reduced dopamine levels and even lower serotonin levels, a characteristic of both APSD and SSD [23].…”

Section: Antisocial Personality Disorder and Somatic Symptom Disordermentioning

confidence: 99%

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A Systematic Literature Review of the Association Between Somatic Symptom Disorder and Antisocial Personality Disorder

Espiridion¹,

Kerbel²

2020

Cureus

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Somatic symptom disorder (SSD) and antisocial personality disorder (APSD) are found at higher rates within families compared to the general population. Both disorders are characterized by low serotonin levels, which may be attributed to polymorphisms in the dopa decarboxylase (DDC) gene. The polymorphism rs11575542 of the gene leads to decreasing the efficiency of aromatic l-amino decarboxylase (AADC) and serotonin levels in a person. The polymorphism is also associated with the development of somatic symptoms and sensation-seeking behavior, a trait underlying APSD. Hence, the role of this polymorphism as an underlying feature that may predispose a person to develop APSD or SSD should be explored further in future studies.

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Aromatic amino acid decarboxylase deficiency: Molecular and metabolic basis and therapeutic outlook

Cited by 75 publications

References 46 publications

Case report: discovery of 2 gene variants for aromatic L-amino acid decarboxylase deficiency in 2 African American siblings

Case report: discovery of 2 gene variants for aromatic L-amino acid decarboxylase deficiency in 2 African American siblings

Clinical Profile and Outcome of Indian Children with Aromatic L-Amino Acid Decarboxylase Deficiency: A primary CSF Neurotransmitter Disorder Mimicking as Dyskinetic Cerebral Palsy

A Systematic Literature Review of the Association Between Somatic Symptom Disorder and Antisocial Personality Disorder

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