RESUMEN:

La enfermedad de Parkinson (EP) es la causa más frecuente de parkinsonismo (rigidez, temblor en reposo, bradicinesia y pérdida de reflejos posturales). Existe evidencia de la participación de factores ambientales y genéticos en la patogénesis de la EP.

El estudio de los factores genéticos se inició con las investigaciones de agregación familiar que, en general, han demostrado antecedentes familiares de EP en cerca de 15% de los familiares de primer grado de los pacientes en comparación con 1% en poblaciones controles. Los estudios en gemelos muestran una mayor concordancia en gemelos monocigotos (MZ) que en dicigotos (DZ), en casos de EP de inicio temprano (antes de los 40 años). Sin embargo, en los estudios de neuroimagen funcional en gemelos con Tomografía por Emisión de Positrones (PET, por sus siglas en inglés) con [¹⁸F]dopa, se ha observado que la herencia también cumple un papel importante en casos de EP con inicio tardío

A la fecha se han identificado nueve loci y clonado seis genes involucrados en la EP familiar con patrón de herencia mendeliana. El primero fue el gen de la α-sinucleína (PARK1), que se hereda con un patrón autosómico dominante; sin embargo, las mutaciones de este gen son poco frecuentes. Las mutaciones en el gen de la parkina (PARK2) producen EP con patrón de herencia autosómica recesiva y se encuentran con relativa frecuencia en pacientes con inicio de los síntomas a edad temprana. Actualmente se considera que en la mayoría de los casos la susceptibilidad genética para desarrollar EP es producto de variantes normales (polimorfismos) de algunos genes que, bajo la influencia de ciertos factores ambientales aún no identificados, participan en la patogénesis de la enfermedad.

Algunos estudios de asociación con genes candidatos han encontrado polimorfismos que, al menos en las poblaciones estudiadas, se asocian con ciertas características clínicas, entre las que destacan un mayor riesgo de presentar la enfermedad y el desarrollo de efectos adversos al tratamiento con levodopa. Los genes candidatos se han seleccionado con base en el conocimiento actual de la fisiopatología de la enfermedad e incluyen principalmente a los genes involucrados en la síntesis, transporte y degradación de la dopamina, destoxificación de xenobióticos y otras toxinas en las neuronas dopaminérgicas, en el metabolismo mitocondrial, así como genes que codifican para factores de transcripción o neurotróficos involucrados en el desarrollo del sistema dopaminérgico en el mesencéfalo.

En un futuro, el mapa de haplotipos del genoma humano ayudará a la mejor planeación de estudios genéticos de asociación. El descubrimiento de los genes involucrados en la susceptibilidad para desarrollar EP será un importante paso para encontrar medidas para su prevención, diagnóstico y tratamiento.

Actualmente no se recomienda la realización de pruebas genéticas para diagnóstico de EP a menos que existan argumentos de peso que sugieran una etiología genética de la enfermedad (p. ej. algún miembro de la familia es portador de una mutación ya conocida como responsable de la enfermedad, consanguinidad en los padres o dos o más hermanos afectados con inicio de los síntomas en la segunda o tercera década de la vida) o que el inicio de los síntomas haya sido a edad temprana (antes de los 40 años).

Esta es una revisión sobre los factores genéticos involucrados en la susceptibilidad para desarrollar la EP.

Palabras clave: Enfermedad de Parkinson; genética; polimorfismo; haplotipo; diagnóstico molecular

SUMMARY:

Parkinson’s disease (PD) is the main cause of parkinsonism (rigidity, resting tremor, bradykinesia and loss of postural reflexes). There is evidence highlighting the importance of the interaction between environmental factors and genetics on the pathogenesis of PD. The research about the role of genetics in Parkinson’s disease began with familial aggregation studies, which have shown that approximately 10-15% of patients with PD have a positive firstdegree family history of PD; this proportion is higher than a 1% found in controls.

Twins studies have found a larger concordance rate in monozygotic twins with early-onset PD (symptoms onset before 40 years of age). Nevertheless, dopaminergic functional studies in twins using PET (Positron Emission Tomography) with [¹⁸F]dopa have also shown a substantial role for inheritance in late-onset, sporadic PD. In one of these studies with clinically discordant twins (monozygotic and dizygotic), the concordance rate at baseline for subclinical striatal dopaminergic dysfunction was higher in monozygotic than dizygotic twin pairs (55% vs 18%, respectively) using functional neuroimaging criteria.

Nine loci have been so far identified and six genes inherited as a Mendelian fashion have been cloned.

Also, α-synuclein (PARK1) gene mutations were found to be pathogenic and responsible for a rare PD with an autosomal dominant inheritance in a large Greek-Italian family (the Contursi kindred). These findings have not been reproduced in patients with late-onset, sporadic PD. Mutations in the gene encoding for parkin (PARK2) are responsible for PD with an autosomal recessive trait and are relatively common in patients with early-onset PD.

Mutations in α-synuclein and parkin genes suggest that the dysfunction of the ubiquitine-proteasome system, that mediates degradation of proteins, plays an important role in the pathogenesis of PD. Ubiquitine is a key component of this system and is attached to the proteins by ubiquitine-ligases in order to mark them to be cleaved by the proteasome. The production of freeubiquitine involves a type of proteins called ubiquitine-hydrolases. Mutations in a gene that encodes for one of these proteins, UCHL1, have been also involved in familial PD.

Cellular death models in PD have been centered in oxidative stress and excitoxicity mechanisms. Even though these mechanisms are still considered important, the models that highlight the abnormal aggregation of proteins and the failure of the ubiquitine proteolytic system are more consistent with available experimental data. The product of DJ-1 (PARK7) was recently involved in familial PD. This could protect dopaminergic neurons from damage due to oxidative stress as suggested by its structure similarity with the stress-induced bacterial chaperone (Hsp-31); it also could help in the appropriate folding of proteins. Other studies suggest DJ-1 mutations could contribute to the elevated levels of oxidative stress seen in PD.

Theories about the pathogenesis of PD have been developed independently of the findings in the genetics field. One particularly prominent model suggests that various mitochondrial alterations that produce failure in the production of cellular energy or elevated free radicals levels or both have an important role in PD pathogenesis, and some recent genetic findings support this theory. Mutations in the gene encoding for PINK1 (PARK6), a mitochondrial protein-kinase, have been found in some patients with familial PD. Recently, a gene localized in PARK8 (LRRK2/dardarine) has been cloned. It is responsible for familial PD with autosomal dominant inheritance, typical age of onset and clinical findings similar to the ones found in idiopathic PD.

Association studies with candidate genes have discovered the influence of some polymorphisms on certain PD clinical features, at least in the populations studied. The relative risk and age of onset of PD, as well as the levodopa induced dyskinesia, are among these characteristics. Candidate genes were chosen because of their alleged role on the pathogenesis of PD. The major candidate genes studied so far are related to dopamine synthesis, transport and metabolism, xenobiotics and other neuronal toxins detoxification, mitochondrial metabolism, and also transcription factors and neurotrophic genes involved in the mesencephalic dopaminergic system development.

Of the susceptibility genes so far studied, only the MAO-B >188 bp allele has shown a significant association in a meta-analysis. Additionally, only six genes (DRD2, ND3, BNDF, α-synuclein, UCHL1 and Nurr-1) have shown important associations with PD in several studies and have fulfilled the criteria for their replication and meta-analysis.

These mixed results could be related to differences in sample size, ethnical background and methodology as to make it almost impossible to summarize independent studies. Other possible contributions are populations stratification, biologic credibility of the association between the gene and the phenotype and gene to gene interactions.

However, these mutations are not found in the great majority of patients with sporadic PD. In these patients, normal gene polymorphisms must confer susceptibility to PD, and certain, not-yetidentified, environmental factors must interact with them in order to produce clinically PD.

Normally, each subject receives one maternal and one paternal allele for each gene. During meiosis, the chromosomal recombination is undertaken in such a way the probability of two loci being transmitted together to the next generation is indirectly proportional to the distance in the chromosome between them.

The group of alleles inherited as a cluster are known as haplotype and the study and knowledge of haplotypes present in the populations could be associated with clinical phenotypes.

If loci are inherited as stable fragments, association studies can be developed for each haplotype and not for each locus, which saves time, money, human and material resources. The HapMap will contribute to a better design of genetic association studies with clinical phenotypes.

A better understanding of the genetics involved in the relative risk of PD will be an important step to improve its prevention, diagnosis and treatment.

Genetic testing for PD may be premature and is not currently recommended unless the patient has a strong family history, a family member is known to be carrier of a causal mutation, there is parental consanguinity, or the patient exhibits symptoms at an unusually early age (before 40 years of age).

Presymptomatic testing for such an incurable neurodegenerative disease must always be accompanied by proper education and counseling and must be carried out at a center with expertise in this area. Currently there are no well-standardized presymptomatic protocols for PD genetic testing; therefore, it is recommended to follow the Huntington’s disease protocol.

This review summarizes relative risk of genetics in PD.

Key words: Parkinson’s disease; genetics; polymorphisms; haplotype; genetic testing