Spectrum of DDC variants causing aromatic l-amino acid decarboxylase (AADC) deficiency and pathogenicity interpretation using ACMG-AMP/ACGS recommendations.

Pathogenic variants in dopa decarboxylase (DDC), the gene encoding the aromatic l-amino acid decarboxylase (AADC) enzyme, lead to a severe deficiency of neurotransmitters, resulting in neurological, neuromuscular, and behavioral manifestations clinically characterized by developmental delays, oculogyric crises, dystonia, and severe neurologic dysfunction in infancy. Historically, therapy has been aimed at compensating for neurotransmitter abnormalities, but response to pharmacologic therapy varies, and in most cases, the therapy shows little or no benefit. A novel human DDC gene therapy was recently approved in the European Union that targets the underlying genetic cause of the disorder, providing a new treatment option for patients with AADC deficiency. However, the applicability of human DDC gene therapy depends on the ability of laboratories and clinicians to interpret the results of genetic testing accurately enough to diagnose the patient. An accurate interpretation of genetic variants depends in turn on expert-guided curation of locus-specific databases. The purpose of this research was to identify previously uncharacterized DDC variants that are of pathologic significance in AADC deficiency as well as characterize and curate variants of unknown significance (VUSs) to further advance the diagnostic accuracy of genetic testing for this condition. DDC variants were identified using existing databases and the literature. The pathogenicity of the variants was classified using modified American College of Medical Genetics and Genomics/Association for Molecular Pathology/Association for Clinical Genomic Science (ACMG-AMP/ACGS) criteria. To improve the current variant interpretation recommendations, in silico variant interpretation tools were combined with structural 3D modeling of protein variants and applied comparative analysis to predict the impact of the variant on protein function. A total of 422 variants were identified (http://biopku.org/home/pnddb.asp). Variants were identified on nearly all introns and exons of the DDC gene, as well as the 3' and 5' untranslated regions. The largest percentage of the identified variants (48%) were classified as missense variants. The molecular effects of these missense variants were then predicted, and the pathogenicity of each was classified using a number of variant effect predictors. Using ACMG-AMP/ACGS criteria, 7% of variants were classified as pathogenic, 32% as likely pathogenic, 58% as VUSs of varying subclassifications, 1% as likely benign, and 1% as benign. For 101 out of 108 reported genotypes, at least one allele was classified as pathogenic or likely pathogenic. In silico variant pathogenicity interpretation tools, combined with structural 3D modeling of variant proteins and applied comparative analysis, have improved the current DDC variant interpretation recommendations, particularly of VUSs.

Clinical Features in Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency: A Systematic Review.

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare congenital autosomal recessive metabolic disorder caused by pathogenic homozygous or compound heterozygous variants in the dopa decarboxylase (DDC) gene. Adeno-associated viral vector-mediated gene transfer of the human AADC gene into the putamina has become available. This systematic review on PubMed, Scopus databases, and other sources is aimed at describing the AADC whole phenotypic spectrum in order to facilitate its early diagnosis. Literature reviews, original articles, retrospective and comparative studies, large case series, case reports, and short communications were considered. A database was set up using Microsoft Excel to collect clinical, molecular, biochemical, and therapeutic data. By analysing 261 patients from 41 papers with molecular and/or biochemical diagnosis of AADC deficiency for which individuality could be determined with certainty, we found symptom onset to occur in the first 6 months of life in 93% of cases. Hypotonia and developmental delay are cardinal signs, reported as present in 73.9% and 72% of cases, respectively. Oculogyric crises were seen in 67% of patients while hypokinesia in 42% and ptosis in 26%. Dysautonomic features have been revealed in 53% and gastrointestinal symptoms in 19% of cases. With 37% and 30% of patients reported being affected by sleep and behavioural disorders, it seems to be commoner than previously acknowledged. Although reporting bias cannot be excluded, there is still a need for comprehensive clinical descriptions of symptoms at onset and during follow-up. In fact, our review suggests that most of the neurological and extraneurological symptoms and signs reported, although quite frequent in this condition, are not pathognomonic, and therefore, ADCC deficiency can remain an underdiscovered disorder.

Evaluación económica de tecnologías para retrasar la aparición del deterioro funcional en pacientes con enfermedad de Parkinson en Colombia / Economic evaluation of technologies to delay the onset of functional deterioration in patients with Parkinson's disease in Colombia

INTRODUCCIÓN: La Enfermedad de Parkinson (EP) es la segunda enfermedad neurodegenerativa más frecuente después del Alzheimer. Es una enfermedad crónica, degenerativa y progresiva, cuyas características fundamentales son la aparición de alteraciones motoras y no motoras como el temblor en reposo, la bradicinesia, la rigidez y la inestabilidad postural, así como alteraciones en la función cognitiva, en la expresión de las emociones y en la función autónoma. Los síntomas anteriores se producen por la pérdida de neuronas dopaminérgicas en la sustancia nigra pars compacta. Su padecimiento puede estar asociado a factores genéticos y ambientales que llevan a estrés oxidativo y la consecuente producción de radicales libres, lesión mitocondrial y cambios en las proteínas que tienen un rol central en la patogénesis, aunque los mecanismos exactos no han sido dilucidados. TRATAMIENTO: La condición tiene una evolución progresiva e irreversible con una secuencia de tres momentos claves en el deterioro funcional de los pacientes: el paso de manifestaciones unilaterales a bilaterales, la aparición de desequilibrio y finalmente la pérdida de independencia funcional. El esfuerzo terapéutico se enfoca generalmente en frenar la progresión de la enfermedad, el alivio de los síntomas motores y no motores y la prevención de fluctuaciones motoras y discinesias. Para los dos últimos objetivos, las opciones se agrupan en medicamentos anticolinérgicos, agonistas dopaminérgicos derivados o no de la ergotamina y Levodopa acompañada de inhibidores de la descarboxilasa. Las indicaciones varían según la edad del paciente, la gravedad de la condición al inicio del tratamiento y el tiempo de evolución. POBLACIÓN: Pacientes (independientemente del sexo) con enfermedad de Parkinson inicial y avanzada. Se considerarán pacientes con las diferentes definiciones diagnósticas adoptadas por los estudios seleccionados, y con edad de inicio de síntomas posteriores a los 45 años. INTERVENCIÓN: La(s) intervención(es) a evaluar dependerá(n) de los resultados obtenidos en el informe de seguridad y efectividad. Dicho informe evaluará las siguientes tecnologías: -Levodopa más inhibidor de la DOPA descarboxilasa (benserazida),- Pramipexol en monoterapia o en terapia combinada con levodopa. -Rasagilina en monoterapia o en terapia combinada con levodopa, -Rotigotina en monoterapia o en terapia combinada con levodopa. PERSPECTIVA: Se empleará la perspectiva del sistema de salud colombiano, es decir, serán incluidos los costos médicos directos asociados al uso de las tecnologías en salud que son objeto de la evaluación y los beneficios en salud percibidos directamente por los pacientes. DESENLACES Y VALORACIÓN: De acuerdo con las recomendaciones del manual metodológico del IETS, en esta evaluación se propone emplear los AVAC (años de vida ajustados por calidad) como medida de desenlace. La información de las ponderaciones de utilidad se obtendrá de la literatura. En caso que no sea factible emplear AVAC, se emplearán otros desenlaces, que serán justificados en el informe. COSTOS: Se tendrán en cuenta todos los costos asociados a las tecnologías evaluadas y a los desenlaces en salud incluidos en el modelo de decisión planteado. Se utilizarán como fuentes de información bases de datos institucionales de validez nacional, consulta directa y otras fuentes, tal como lo estipula el manual metodológico del IETS. MODELO DE DECISIONES: Se diseñará un modelo de decisión analítico a partir de la revisión de literatura económica existente, los resultados de la evaluación de efectividad y seguridad elaborada por el IETS y la consulta a expertos clínicos y otros actores del sistema de salud relacionados con las tecnologías e indicación de interés. PRESENTACIÓN DE RESULTADOS: En el caso de tecnologías no dominadas, se calcularán las razones incrementales de costo-utilidad o costo-efectividad. Para efectos de interpretación, y de acuerdo con las recomendaciones del manual metodológico del IETS, se realizarán comparaciones entre la razón incremental y 1 PIB per cápita y 3 PIB per cápita en Colombia de acuerdo con las estimaciones actuales del Banco de la República. ANÁLISIS DE SENSIBILIDAD: Se evaluará la incertidumbre en las estimaciones mediante análisis de sensibilidad univariados y probabilísticos. Los resultados de las simulaciones de Montecarlo se presentarán mediante un diagrama de dispersión en el plano de costoefectividad y los resultados del análisis de sensibilidad probabilístico mediante curvas de aceptabilidad.

Lergotrile in Parkinson disease: further studies.

Lergotrile was administered to 53 patients with advanced Parkinson disease (PD), who had increasing disability despite optimal treatment with levodopa/carbidopa (Sinemet). Thirty-nine patients who could tolerate at least 20 mg per day lergotrile (thus considered "adequately treated") had significant descreases in rigidity, tremor, bradykinesia, gait disturbance, and total score without increased involuntary movements. Twenty-one of these 39 patients improved by at least one stage. Among the 39 patients, 23 had "on-off" effects, and in 13 of these the "on-off" effects decreased on lergotrile. The mean daily dose of lergotrile in adequately treated patients was 49 mg, permitting a 10 percent reduction in the dose of levodopa. Lergotrile was discontinued in 33 of the 53 patients because of adverse effects, including hepatotoxicity (11 patients), mental changes (12 patients) and orthostatic hypotension (8 patients). Although lergotrile, when added to levodopa, has a definite antiparkinsonian effect, the incidence of adverse effects, particularly hepatotoxicity, makes it unlikely that this ergot alkaloid will become widely available for the treatment of PD. Analogues of lergotrile have been synthesized, and it is hoped that they will duplicate the antiparkinsonian effect of this drug without its toxicity.

[Haloperidol, reserpine, l-dopa and amantidine in the treatment of Huntington chorea (author's transl)]. / Terapia della chorea di Huntington azione del serenase, reserpina, l-dopa, amatadina sulle ipercinesie coreiche

Two drugs that should reduce striatal dopamine activity (haloperidol and reserpine) and two other drugs that should increase it (L-Dopa and amantadine) have been successively adminstered to six patients suffering from Huntington's Chorea. The most effective treatment in reducing hyperkinesis was haloperidol, followed by reserpine. Treatment with L-Dopa did not have appreciable effect, on this type of involuntary movements. Against some theoretical expectations administration of amantadine was followed by a slight improvement in the control of involuntary activity.