Aromatic L-amino Acid Decarboxylase Deficiency Research Articles

Streamlined determination of 3-O-methyldopa in dried blood spots: Prospective screening for aromatic l-amino-acid decarboxylase deficiency

BackgroundAromatic L-amino-acid decarboxylase (AADC) deficiency diagnosis is often delayed by low disease awareness and specific laboratory examinations. We demonstrated that an elevated concentration of L-dopa metabolite 3-O-methyldopa (3-OMD) in dried blood spots could be integrated into a newborn screening program to detect AADC deficiency. MethodsDBS samples for amino acid and acylcarnitine analysis using NeoBase™2 reagents were also analyzed for the 3-OMD concentration using 13C6-phenylalanine as an internal standard. For samples exceeding the pre-defined cutoffs, an additional spot was punched from the original filter paper for second-tier 3-OMD measurement by high performance liquid chromatography (HPLC)-MS/MS assay. Newborns with a 3-OMD concentration exceeding 500 ng/mL were referred for confirmatory testing. ResultsFrom Feb. 2020 to Dec. 2022, 157,371 newborns were screened for AADC deficiency. Eight newborns exhibited an elevated 3-OMD concentration (839–5170 ng/mL). Among them, six newborns were confirmed to carry two pathogenic DDC variants, indicating an incidence of AADC deficiency of ∼1:26,000 (95% confidence interval: 1 in 12,021 to 1 in 57,228). During the follow-up period, all six patients developed typical symptoms of AADC deficiency. ConclusionThe screening for 3-OMD, a target for AADC deficiency, could be easily integrated into the existing newborn screening programs and facilitate the future application for early diagnosis and effective treatment.

Aromatic l-amino acid decarboxylase deficiency in Taiwan.

Aromatic l-amino acid decarboxylase (AADC) deficiency is a rare inherited disorder that affects neurotransmitter biosynthesis. A DDC founder mutation c.714 + 4A > T (IVS6 + 4A > T) is prevalent in the Chinese population. This study investigated the epidemiology of AADC deficiency in Taiwan by analyzing data from National Taiwan University Hospital (NTUH), a central institution for diagnosing and treating the disease. From January 2000 to March 2023, 77 patients with AADC deficiency visited NTUH. Among them, eight were international patients seeking a second opinion, and another two had one or both non-Chinese parents; all others were ethnically Chinese. The c.714 + 4A > T mutation accounted for 85% of all mutated alleles, and 94% of patients exhibited a severe phenotype. Of the 77 patients, 31 received gene therapy at a mean age of 3.76 years (1.62-8.49) through clinical trials, and their current ages were significantly older than those of the remaining patients. Although the combined incidence of AADC deficiency in this study (1:66491 for 2004 and later) was lower than that reported in newborn screening (1:31997 to 1:42662), case surges coincided with the launch of clinical trials and the implementation of newborn screening. Currently, many young patients are awaiting for treatment.

Human aromatic amino acid decarboxylase is an asymmetric and flexible enzyme: Implication in aromatic amino acid decarboxylase deficiency.

Human aromatic amino acid decarboxylase (AADC) is a pyridoxal 5'-phosphate-dependent enzyme responsible for the biosynthesis of dopamine and serotonin, essential neurotransmitters involved in motor and cognitive abilities. Mutations in its gene lead to AADC deficiency, a monogenic rare neurometabolic childhood parkinsonism characterized by severe motor and neurodevelopmental symptoms. Here, for the first time, we solved the crystal structure of human holoAADC in the internal aldimine (1.9 Å) and in the external aldimine (2.4 Å) of the substrate analog L-Dopa methylester. In this intermediate, the highly flexible AADC catalytic loop (CL) is captured in a closed state contacting all protein domains. In addition, each active site, composed by residues of both subunits, is connected to the other through weak interactions and a central cavity. By combining crystallographic analyses with all-atom and coarse-grained molecular dynamics simulations, SAXS investigations and limited proteolysis experiments, we realized that the functionally obligate homodimeric AADC enzyme in solution is an elongated, asymmetric molecule, where the fluctuations of the CL are coupled to flexibility at the edge between the N-terminal and C-terminal domains. The structural integrity of this peripheral protein region is essential to catalysis, as assessed by both artificial and 37 AADC deficiency pathogenic variants leading to the interpretation that structural dynamics in protein regions far from the active site is essential for CL flexibility and the acquirement of a correct catalytically competent structure. This could represent the molecular basis for pathogenicity prediction in AADC deficiency.

Gene therapy for aromatic L-amino acid decarboxylase deficiency: Requirements for safe application and knowledge-generating follow-up.

The autosomal recessive defect of aromatic L-amino acid decarboxylase (AADC) leads to a severe neurological disorder with manifestation in infancy due to a pronounced, combined deficiency of dopamine, serotonin and catecholamines. The success of conventional drug treatment is very limited, especially in patients with a severe phenotype. The development of an intracerebral AAV2-based gene delivery targeting the putamen or substantia nigra started more than 10 years ago. Recently, the putaminally-delivered construct, Eladocagene exuparvovec has been approved by the European Medicines Agency and by the British Medicines and Healthcare products Regulatory Agency. This now available gene therapy provides for the first time also for AADC deficiency (AADCD) a causal therapy, leading this disorder into a new therapeutic era. By using a standardized Delphi approach members of the International Working Group on Neurotransmitter related Disorders (iNTD) developed structural requirements and recommendations for the preparation, management and follow-up of AADC deficiency patients who undergo gene therapy. This statement underlines the necessity of a framework for a quality-assured application of AADCD gene therapy including Eladocagene exuparvovec. Treatment requires prehospital, inpatient and posthospital care by a multidisciplinary team in a specialized and qualified therapy center. Due to lack of data on long-term outcomes and the comparative efficacy of alternative stereotactic procedures and brain target sites, a structured follow-up plan and systematic documentation of outcomes in a suitable, industry-independent registry study are necessary.

Prevalence of DDC genotypes in patients with aromatic L-amino acid decarboxylase (AADC) deficiency and in silico prediction of structural protein changes.

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive genetic disorder affecting the biosynthesis of dopamine, a precursor of both norepinephrine and epinephrine, and serotonin. Diagnosis is based on the analysis of CSF or plasma metabolites, AADC activity in plasma and genetic testing for variants in the DDC gene. The exact prevalence of AADC deficiency, the number of patients, and the variant and genotype prevalence are not known. Here, we present the DDC variant (n=143) and genotype (n=151) prevalence of 348 patients with AADC deficiency, 121 of whom were previously not reported. In addition, we report 26 new DDC variants, classify them according to the ACMG/AMP/ACGS recommendations for pathogenicity and score them based on the predicted structural effect. The splice variant c.714+4A>T, with a founder effect in Taiwan and China, was the most common variant (allele frequency=32.4%), and c.[714+4A>T];[714+4A>T] was the most common genotype (genotype frequency=21.3%). Approximately 90% of genotypes had variants classified as pathogenic or likely pathogenic, while 7% had one VUS allele and 3% had two VUS alleles. Only one benign variant was reported. Homozygous and compound heterozygous genotypes were interpreted in terms of AADC protein and categorized as: i) devoid of full-length AADC, ii) bearing one type of AADC homodimeric variant or iii) producing an AADC protein population composed of two homodimeric and one heterodimeric variant. Based on structural features, a score was attributed for all homodimers, and a tentative prediction was advanced for the heterodimer. Almost all AADC protein variants were pathogenic or likely pathogenic.

Exome sequencing data screening to identify undiagnosed Aromatic l-amino acid decarboxylase deficiency in neurodevelopmental disorders

Aromatic l-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive neurometabolic disorder caused by biallelic pathogenic variants in the DDC gene and mainly characterized by developmental delay, hypotonia, and oculogyric crises. Early diagnosis is crucial for correct patient management; however, many patients remain misdiagnosed or undiagnosed due to the rarity and clinical heterogeneity of the disorder especially in the milder forms. Here, we applied exome sequencing approach by screening 2000 paediatric patients with neurodevelopmental disorders to identify possible new AADC variants and AADC deficiency patients. We identified five distinct DDC variants in two unrelated individuals. Patient #1 harboured two compound heterozygous DDC variants: c.436-12T > C and c.435 + 24A>C and presented with psychomotor delay, tonic spasms, and hyperreactivity. Patient #2 had three homozygous AADC variants: c.1385G > A; p.Arg462Gln, c.234C > T; p.Ala78 = , and c.201 + 37A > G and presented with developmental delay and myoclonic seizures. The variants were classified as benign class I variants and therefore non-causative according to the ACMG/AMP guidelines. Since the AADC protein is a structural and functional obligate homodimer, we evaluated the possible AADC polypeptide chain combinations in the two patients and determined the effects resulting from the amino acid substitution Arg462Gln. Our patients carrying DDC variants presented clinical manifestations not precisely overlapped to the classical symptoms exhibited by the most severe AADC deficiency cases. However, screening data derived from exome sequencing in patients featuring wide-range symptoms related to neurodevelopmental disorders may help to identify AADC deficiency patients, especially when applied to larger cohorts.

Carrier frequency and incidence of aromatic L-amino acid decarboxylase deficiency: a gnomAD-based study.

Aromatic L-amino acid decarboxylase (AADC) deficiency is an autosomal recessive neurotransmitter metabolism disorder and is clinically characterized by infancy hypotonia, ophthalmic crisis, and developmental delay. With the emergence of gene therapy for AADC deficiency, accurate prediction of AADC deficiency is required. This study aimed to analyze the carrier frequency and expected incidence of AADC deficiency using exome data from the Genome Aggregation Database (gnomAD). We analyzed 125,748 exomes from gnomAD, including 9197 East Asian exomes, for the DDC gene. All identified variants were classified according to the 2015 American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines. The worldwide carrier frequency of AADC deficiency was 0.17%; the highest frequency was observed in East Asians at 0.78%, and the lowest was in Latinos at 0.07%. The estimated incidence of AADC deficiency was 1 in 1,374,129 worldwide and 1 in 65,266 in East Asians. The results demonstrated that East Asians have a higher carrier frequency of AADC deficiency than other ethnic groups. The variant spectrum of DDC genes in East Asian populations differed greatly from those of other ethnic groups. Our data will serve as a reference for further investigation of AADC deficiency. This study analyzed exome data from the Genome Aggregation Database (gnomAD) to estimate the carrier frequency and expected incidence of aromatic L-amino acid decarboxylase (AADC) deficiency. The article provides updated carrier frequency and incidence estimates for AADC deficiency, particularly in East Asian populations, and emphasizes the significant differences in the variant spectrum of DDC genes in this population compared to other ethnic groups. The study provides important information for accurate prediction and early diagnosis of AADC deficiency, particularly in high-risk populations, and may aid in the development of more effective targeted screening programs and gene therapies for this disorder.

EPH127 Understanding the Burden of Aromatic L-Amino Acid Decarboxylase Deficiency (AADCD): Results from a Clinician Expert Survey

Aromatic L-amino acid decarboxylase deficiency (AADCd) is a life-limiting and acutely debilitating rare genetic neurological disorder that causes widespread central nervous system dysfunction and developmental delay. Eladocagene exuparvovec is a gene therapy, approved in Europe, which bilaterally delivers a functional DDC gene directly into the putamen improving patient motor function. Due to the disease rarity and paucity of surrounding data, clinician experts were surveyed on evaluating the importance of motor development in AADC deficiency progression and outcomes.

Gene Therapy for Dopamine Dyshomeostasis: From Parkinson's to Primary Neurotransmitter Diseases.

Neurological disorders encompass a broad range of neurodegenerative and neurodevelopmental diseases that are complex and almost universally without disease modifying treatments. There is, therefore, significant unmet clinical need to develop novel therapeutic strategies for these patients. Viral gene therapies are a promising approach, where gene delivery is achieved through viral vectors such as adeno-associated virus and lentivirus. The clinical efficacy of such gene therapies has already been observed in two neurological disorders of pediatric onset; for spinal muscular atrophy and aromatic L-amino acid decarboxylase (AADC) deficiency, gene therapy has significantly modified the natural history of disease in these life-limiting neurological disorders. Here, we review recent advances in gene therapy, focused on the targeted delivery of dopaminergic genes for Parkinson's disease and the primary neurotransmitter disorders, AADC deficiency and dopamine transporter deficiency syndrome (DTDS). Although recent European Medicines Agency and Medicines and Healthcare products Regulatory Agency approval of Upstaza (eladocagene exuparvovec) signifies an important landmark, numerous challenges remain. Future research will need to focus on defining the optimal therapeutic window for clinical intervention, better understanding of the duration of therapeutic efficacy, and improved brain targeting. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Eladocagene Exuparvovec Gene Therapy Improves Motor Development in Patients With Aromatic L-Amino Acid Decarboxylase Deficiency (S34.004)

<h3>Objective:</h3> Investigate the efficacy and safety of eladocagene exuparvovec in patients with aromatic l-amino acid decarboxylase deficiency (AADCd). <h3>Background:</h3> AADCd results from mutations in the dopa decarboxylase gene leading to reduced AADC enzyme activity; it is characterized by motor impairments and inability to attain developmental milestones. Eladocagene exuparvovec is a recombinant adeno-associated viral vector serotype 2 carrying the coding sequence for human AADC. <h3>Design/Methods:</h3> Eladocagene exuparvovec was infused bilaterally in the putamina of 30 children with AADC deficiency in 3 studies (AADC-CU/1601 [n=8], AADC-010 [n=10], and AADC-011 [n=12] in patients aged 18–102 months. Data were extracted on January 4, 2022. Patients receiving a total of 1.8 × 10¹¹ vg (n=21) or 2.4 × 10¹¹ vg (n=9; AADC-011) were followed for up to 120 months and assessed for motor milestone attainment using the Peabody Developmental Motor Scale, 2nd edition (PDMS-2). Specific motor skill items of the PDMS-2 were used to assess motor milestones including head control (partial or full), sitting (supported or independently), standing (with/away from support; up from cross-legged position), and walking (with/without assistance; 10 feet; taped line) Motor milestones and development were measured every 3 months for 1 year following gene therapy, then every 6–12 months for ≤120 months. <h3>Results:</h3> At baseline, no patients mastered head control or more advanced milestones. At year 1 of follow-up, patients were gaining the following skills (n): partial head control (26); full head control (15), sitting unassisted (7), supported standing (2). Progression of development was noted at years 5 and 10. By year 5, more advanced milestones were achieved (n): full head control (24), sitting unassisted (21) assisted walking (5), walking 10 feet (3), or walking up stairs (3). These abilities were maintained for as long as 10 years <h3>Conclusions:</h3> These data indicate eladocagene exuparvovec can provide a durable, positive impact on motor development in patients with AADCd. <b>Disclosure:</b> Mrs. Russell has received personal compensation for serving as an employee of PTC Therapeutics. Mrs. Russell has stock in PTC Therapeutics. Prof. ROUBERTIE has received personal compensation in the range of $500-$4,999 for serving as a Consultant for PTC. Prof. ROUBERTIE has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for PTC. Yin-Hsiu Chien has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi Genzyme. Yin-Hsiu Chien has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Yin-Hsiu Chien has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Yin-Hsiu Chien has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Amicus. Yin-Hsiu Chien has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi. Yin-Hsiu Chien has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sanofi Genzyme. Yin-Hsiu Chien has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Avexis/Norvatis. Yin-Hsiu Chien has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Biogen. The institution of Yin-Hsiu Chien has received research support from Sanofi Genzyme. Ni-Chung Lee has nothing to disclose. Dr. Sierra has received personal compensation for serving as an employee of PTC Therapeutics Inc. Dr. Sierra has stock in PTC Therapeutics Inc. Dr. Turna has received personal compensation for serving as an employee of PTC Therapeutics. Dr. Turna has stock in PTC Therapeutics. Dr. Wang has received personal compensation for serving as an employee of PTC Therapeutics. Dr. Wang has received stock or an ownership interest from PTC Therapeutics, Inc.. The institution of Chun-Hwei Tai has received research support from National Taiwan University Hospital. Paul Wuh-Liang Hwu has received personal compensation in the range of $500-$4,999 for serving as a Consultant for PTC Therapeutics Inc.. Paul Wuh-Liang Hwu has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for PTC therapeutics. The institution of Paul Wuh-Liang Hwu has received research support from PTC therapeutics.

Aromatic L-amino acid decarboxylase deficiency in countries in the Middle East: a case series and literature review

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare inherited neurometabolic disorder that can lead to severe physical and developmental impairment. This report includes 16 patients from the Middle East and is the largest series of patients with confirmed AADC deficiency from this region reported to date. The patients displayed a range of signs and symptoms at presentation and almost all failed to reach major motor milestones. Missed and delayed diagnoses were common leading to the late introduction of targeted treatments. Eight unique variants were identified in the DDC gene, including six missense and two intronic variants. A previously undescribed variant was identified: an intronic variant between exons 13 and 14 (c.1243-10A>G). The patients were mostly treated with currently recommended medications, including dopamine agonists, vitamin B6, and monoamine oxidase inhibitors. One patient responded well, but treatment outcomes were otherwise mostly limited to mild symptomatic improvements. Five patients had died by the time of data collection, confirming that the condition is associated with premature mortality. There is an urgent need for earlier diagnosis, particularly given the potential for gene therapy as a transformative treatment for AADC deficiency when provided at an early age. Conclusions: Delays in the diagnosis of AADC deficiency are common. There is an urgent need for earlier diagnosis, particularly given the potential for gene therapy as a transformative treatment for AADC deficiency when provided at an early age.What is Known:• Aromatic L-amino acid decarboxylase deficiency is a rare neurometabolic disorder that can lead to severe physical and developmental impairment.• Currently recommended medications provide mostly mild symptomatic improvements.What is New:• The clinical presentation of sixteen patients with confirmed AADC deficiency varied considerably and almost all failed to reach major motor milestones.• There is an urgent need for earlier diagnosis, given the potential for gene therapy as a transformative treatment for AADC deficiency when provided at an early age.

AAV vectors applied to the treatment of CNS disorders: Clinical status and challenges.

In recent years, adeno-associated virus (AAV) has become the most important vector for central nervous system (CNS) gene therapy. AAV has already shown promising results in the clinic, for several CNS diseases that cannot be treated with drugs, including neurodegenerative diseases, neuromuscular diseases, and lysosomal storage disorders. Currently, three of the four commercially available AAV-based drugs focus on neurological disorders, including Upstaza for aromatic l-amino acid decarboxylase deficiency, Luxturna for hereditary retinal dystrophy, and Zolgensma for spinal muscular atrophy. All these studies have provided paradigms for AAV-based therapeutic intervention platforms. AAV gene therapy, with its dual promise of targeting disease etiology and enabling 'long-term correction' of disease processes, has the advantages of immune privilege, high delivery efficiency, tissue specificity, and cell tropism in the CNS. Although AAV-based gene therapy has been shown to be effective in most CNS clinical trials, limitations have been observed in its clinical applications, which are often associated with side effects. In this review, we summarized the therapeutic progress, challenges, limitations, and solutions for AAV-based gene therapy in 14 types of CNS diseases. We focused on viral vector technologies, delivery routes, immunosuppression, and other relevant clinical factors. We also attempted to integrate several hurdles faced in clinical and preclinical studies with their solutions, to seek the best path forward for the application of AAV-based gene therapy in the context of CNS diseases. We hope that these thoughtful recommendations will contribute to the efficient translation of preclinical studies and wide application of clinical trials.

Intraputaminal Gene Delivery in Two Patients with Aromatic L-Amino Acid Decarboxylase Deficiency.

Aromatic l-amino acid decarboxylase deficiency (AADCD) is a rare, early-onset, dyskinetic encephalopathy mostly reflecting a defective synthesis of brain dopamine and serotonin. Intracerebral gene delivery (GD) provided a significant improvement among AADCD patients (mean age, ≤6 years). We describe the clinical, biological, and imaging evolution of two AADCD patients ages >10 years after GD. Eladocagene exuparvovec, a recombinant adeno-associated virus containing the human complimentary DNA encoding the AADC enzyme, was administered into bilateral putamen by stereotactic surgery. Eighteen months after GD, patients showed improvement in motor, cognitive and behavioral function, and in quality of life. Cerebral l-6-[18F] fluoro-3, 4-dihydroxyphenylalanine uptake was increased at 1 month, persisting at 1 year compared to baseline. Two patients with a severe form of AADCD had an objective motor and non-motor benefit from eladocagene exuparvovec injection even when treated after the age of 10 years, as in the seminal study.

Burden of illness in aromatic l‐amino acid decarboxylase deficiency

AbstractObjectivesDeficiency of aromatic l‐amino acid decarboxylase (AADC), a key enzyme in monoamine synthesis, is an ultrarare disorder of monoamine synthesis estimated to affect fewer than 50 patients in the United States, although rates of misdiagnosis may be high. In its severe form, this congenital hypodopaminergic state results in profound hypotonia, developmental impairment, oculogyric crises, dystonia, dysautonomia, hypoglycemia, and premature death. The present study assesses the burden of illness for patients and caregivers by assessment of medical resource utilization (MRU) and quality of life (QOL) measures to enable future health technology assessment activities for emerging therapeutic options.MethodsData from patients’ medical records from the prior two years were examined to estimate burden in terms of direct costs; indirect care burden (including caregiver impact on sleep, health, and vocational opportunities) and QOL were also assessed using the BURQOL‐RD, AQoL‐6, and Visual Analogue Scale questionnaires.ResultsData were available for five US cases (three males, two females; age, 2–24 years, median, 5 years). MRU ranged from $6162.73 to $49 043.94 annually per patient. Although the proportion of costs (inpatient and outpatient visits, labs/tests, drugs, devices/durable medical equipment, and speech/physical therapy) varied greatly, the average annual direct cost of healthcare was approximately $25 000. Caregivers described profound care burden and QOL effects, with an average indirect care burden cost assessment of nearly $43 000 yearly. The mean economic burden of AADC deficiency per year was estimated at $68 000.ConclusionMRU and QOL varied considerably by patient. This is attributable to the disease's variable phenotypic severity and differing patient needs. Frequent contact with the healthcare system, however, is a constant for patients with AADC deficiency and their caregivers. Quantifying MRU and QOL for rare genetic diseases is critical for assessing the value of emerging targeted therapies.

Adeno-associated virus-mediated gene therapy for rare pediatric neurogenetic diseases: Current status and outlook.

Rare pediatric neurogenetic diseases always have early onset, no specific therapy, high mortality, and pose a severe risk to the health and survival of children. Adeno-associated virus (AAV)-mediated gene therapy, a type of disease-modifying therapy, provides a new option for the treatment of rare pediatric neurogenetic diseases and represents a significant advancement in the field. Currently, the US Food and Drug Administration (FDA) and the European Medicines Association (EMA) have approved AAV-mediated gene therapy medications for treating spinal muscular atrophy, aromatic L-amino acid decarboxylase deficiency, and Duchenne muscular dystrophy. Numerous preclinical and clinical trial research findings from recent years indicate that AAV-mediated gene therapy has a promising future in treating genetic disorders. The quick approval process for rare diseases medications may bring hope for the treatment of children with rare neurogenetic diseases. AAV-mediated gene therapy is an emerging technology with certain risks and challenges. It is necessary to establish a standardized regulatory system and a sound long-term follow-up system to evaluate the efficacy and safety of gene therapy.

Adeno-associated virus vector-based gene therapies for pediatric diseases.

Gene therapy using adeno-associated virus (AAV) is a rapidly developing technology with widespread treatment potential. AAV2 vectors injected directly into the brain by stereotaxic brain surgery have shown good results in treating aromatic l-amino acid decarboxylase deficiency. Moreover, gene therapy using the AAV9 vector, which crosses the blood-brain barrier, has been performed in more than 2000 patients worldwide as a disease-modifying therapy for spinal muscular atrophy. AAV vectors have been applied to the development of gene therapies for various pediatric diseases. Gene therapy trials for hemophilia and ornithine transcarbamylase deficiency are underway. Clinical trials are planned for glucose transporter I deficiency, Niemann-Pick disease type C, and spinocerebellar ataxia type 1. The genome of AAV vectors is located in the episome and is rarely integrated into chromosomes, making the vectors safe. However, serious adverse events such as hepatic failure and thrombotic microangiopathy have been reported, and ongoing studies are focusing on developing more efficient vectors to reduce required dosages.

Molecular Neurosurgery: Introduction to Gene Therapy and Clinical Applications

AbstractTo date, more than 100 clinical trials have used sequence-based therapies to address diseases of the pediatric central nervous system. The first targeted pathologies share common features: the diseases are severe; they are due (mostly) to single variants; the variants are well characterized within the genome; and the interventions are technically feasible. Interventions range from intramuscular and intravenous injection to intrathecal and intraparenchymal infusions. Whether the therapeutic sequence consists of RNA or DNA, and whether the sequence is delivered via simple oligonucleotide, nanoparticle, or viral vector depends on the disease and the involved cell type(s) of the nervous system. While only one active trial targets an epilepsy disorder—Dravet syndrome—experiences with aromatic L-amino acid decarboxylase deficiency, spinal muscular atrophy, and others have taught us several lessons that will undoubtedly apply to the future of gene therapy for epilepsies. Epilepsies, with their diverse underlying mechanisms, will have unique aspects that may influence gene therapy strategies, such as targeting the epileptic zone or nodes in affected circuits, or alternatively finding ways to target nearly every neuron in the brain. This article focuses on the current state of gene therapy and includes its history and premise, the strategy and delivery vehicles most commonly used, and details viral vectors, current trials, and considerations for the future of pediatric intracranial gene therapy.

Mild Aromatic L-Amino Acid Decarboxylase Deficiency: As A Reason For Hypoketotic Hypoglycemia In A 4-Year-Old Girl.

Aromatic L-amino acid decarboxylase (AADC) deficiency is a disease in which neurological findings are dominant due to deficiencies in neurotransmitter synthesis; hypoglycemia caused by autonomic dysfunction is one of the symptoms that may be encountered. Here we report a mild AADC deficiency presenting with hypoglycemia without a neurological sign. A 4-year-old girl presented with recurrent hypoglycemia. Her growth and development were normal. Plasma insulin and cortisol values were normal in the sample at the time of hypoglycemia. The C8:1-Carnitine elevation was detected in the acylcarnitine profile. The clinic exome panel was performed with the suggestion of a fatty acid oxidation defect. However, a homozygous variant in the DDC gene was detected. On top of that, CSF neurotransmitter analysis revealed low 5-hydroxy indol acetic ( 5 HIAA ) and homovanillic acid ( HVA ) and high 3-O-methyl-dopa and methyltetrahydrofolate ( 5 MTHF ) consistent with AADC deficiency. Plasma AADC enzyme activity was low. The episodes of hypoglycemia were treated with uncooked cornstarch. Our case emphasizes that AADC deficiency should be considered in patients with hypoglycemia.

Diagnosis of Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency via Epilepsy Gene Panel Screening in a Patient with Atypical Presentation

We describe an atypical presentation of a girl with aromatic L-amino acid decarboxylase (AADC) deficiency identified via a genetic testing program for children with epilepsy. At 21 months of age, she presented with poor head control, diffuse hypotonia, poor fixation, developmental delay, and dysphagia. She was lost to follow-up, then presented back at 3 years of age with staring spells and brief episodes of upward eye deviation. The diagnosis of unprovoked epilepsy allowed her to be included in a genetic testing program, which identified two heterozygous variants in the dopa decarboxylase (DCC) gene. Based on the genetic testing, plasma AADC enzyme activity and plasma 3-O-methyldopa results, a diagnosis of AADC deficiency was made when she was 4 years and 2 months of age. This case report shows that AADC deficiency can be the underlying diagnosis in patients with suspected epilepsy.

Oromandibular Dystonia is a Prominent Feature in Patients with Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency

Oromandibular Dystonia is a Prominent Feature in Patients with Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency