Marie-catherine Boll - Academia.edu (original) (raw)

Papers by Marie-catherine Boll

Revista Mexicana de Neurociencia, Apr 24, 2017

Parkinsonism is defined as the presence of bradykinesia and at least one of the following: rest t... more Parkinsonism is defined as the presence of bradykinesia and at least one of the following: rest tremor, rigidity, or postural instability. Most of the parkinsonism seen at neurological centers represent Parkinson's disease (PD). Differential diagnosis can be complicated, particularly in early stages when features of PD may overlap with those seen in other movement disorders. Atypical parkinsonian disorders are a group of clinical syndromes with atypical features beyond the classic PD. Progressive supranuclear palsy (PSP), multiple system atrophy (MSA), dementia with Lewy bodies (DLB) and corticobasal degeneration (CBD) are the most prevalent. They all share parkinsonian features which make early diagnosis a challenge for the neurologist. However, it is important to guide management and predict prognosis.

Archivos de neurociencias, 2008

Revista Mexicana de Neurociencia, Dec 10, 2020

By the end of 2019, a peculiar epidemic appeared in China; it was of the flu-type and revealed a ... more By the end of 2019, a peculiar epidemic appeared in China; it was of the flu-type and revealed a lethal zoonosis caused by a beta coronavirus. In this study, we review the history of this new pandemic starting from its origin; we describe how COVID-19 spread its symptoms, especially the neurological ones, and the investigations currently underway.

Interdisciplinary Neurosurgery, Dec 1, 2019

Trigeminal neuralgia is described by the International Headache Classification 3rd edition as a c... more Trigeminal neuralgia is described by the International Headache Classification 3rd edition as a chronic, painful, and sporadic condition characterized by electric shock-like hemifacial pain. The initial management of trigeminal neuralgia is with medication, if there is persistence of pain, surgical management is the gold standard. Microvascular decompression is a non-destructive technique that improves pain in 98% of cases.). In the literature, only 5 cases of CMT-associated trigeminal neuralgia that were surgically managed with microvascular decompression have been published.

Epilepsy & Behavior, 2020

Background: Retigabine is an antiepileptic drug developed for the adjunctive treatment of adults ... more Background: Retigabine is an antiepileptic drug developed for the adjunctive treatment of adults with epilepsy and partial-onset seizures (POS). Following its approval in 2011, reports of ophthalmological/dermatological pigmentation/discoloration led to a restriction of the indication in 2013, and in 2017, retigabine was voluntarily withdrawn from the market because of its limited usage. Here, data are reported from four open-label extension studies focusing on long-term safety with particular emphasis on ophthalmological and dermatological events. Methods: Studies 113413 (NCT01336621), 114873 (NCT01777139), 115097 (NCT00310388), and 115098 (NCT00310375) were multicenter, open-label extension studies of retigabine (300-1200 mg/day) for the adjunctive treatment of adults with POS. Safety assessments included monitoring treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs). When new safety issues were identified, protocols were amended to include additional on-treatment safety evaluations, including ophthalmological and dermatological examinations. Patients who had abnormal retinal pigmentation, unexplained vision change, pigmentation of nonretinal ocular tissue, or abnormal discoloration of skin, lips, nails, and/or mucosa at the end of the treatment phase were asked to enter a safety follow-up continuation phase comprising 6-monthly ophthalmological/dermatological assessments. Results: The safety population (patients receiving ≥1 dose of retigabine in the open-label phase) comprised 98, 30, 376, and 181 patients for studies 113413, 114873, 115097, and 115098, respectively. Mean (standard deviation) treatment exposure ranged from 529 (424) to 1129 (999) days. In total, 68%-96% and 4%-27% of patients across the studies experienced TEAEs and TE SAEs, respectively. There were seven on-treatment deaths and two after discontinuation. Overall, 14%-73% of patients had an on-treatment eye examination, of whom 8/53, 4/22, 17/54, and 14/36 had abnormal retinal pigmentation and 15/53, 7/22, 15/54, and 11/36 had nonretinal ocular pigmentation in studies 113413, 114873, 115097, and 115098, respectively. Four patients had confirmed acquired vitelliform maculopathy. In patients with unresolved events at discontinuation and ≥1 posttreatment follow-up, retinal pigmentation resolved completely in 1/3, 0/3, 0/10, and 1/7 patients and nonretinal ocular pigmentation in 1/4, 0/3, 8/10, and 4/6 patients, respectively. Overall, 12%-83% of patients had an on-treatment dermatological examination, of whom 11/58, 0/25, 23/46, and 23/37 had any-tissue discoloration, respectively. In patients with unresolved events at discontinuation and ≥1 posttreatment follow-up, discoloration of skin, lips, nails, and/or mucosa resolved completely in 2/3, 0/0, 7/13, and 1/11 patients, respectively.

Archivos - Instituto nacional de neurología y neurocirugía, Sep 1, 2016

Degenerative ataxias consist of a heterogeneous group of diseases that are divided into a majorit... more Degenerative ataxias consist of a heterogeneous group of diseases that are divided into a majority of hereditary entities and also sporadic forms. In an effort to make a thorough study and to improve the quality of care of these patients, we have designed a new clinical protocol that attempts to characterize the condition of each patient, considering monitoring and future treatments. The collection of this data will allow us to ascertain the entities that occur in our environment and make the best algorithm. We present here an analysis of 147 cases studied during the last 2 years with 85 cases of hereditary ataxias, of which the most common are dominant: SCA2 (20%) followed by SCA3 (12.3%) and recessive of which 6 confirmed FA cases and 1 case with pending molecular diagnostic, and finally, an important group of sporadic ataxias (62 cases) in which we have individualized "Friedreich ataxia-like" syndromes in young adults and cases pointing out mitochondrial diseases while in subjects over age 40, multiple system atrophies predominate. To diagnose these entities we applied the algorithm first introduced in the Medical-Surgical Meeting in December 2014 and in this publication. Our effort is only starting and we have to coordinate with geneticists especially in the study of sporadic early-onset ataxias. This report reflects the current status of ataxias followed in the INNN-MVS. It highlights the requirement for special attention to these patients as well as highly specialized studies to better define these conditions and not to forget those with specific treatment.

American Journal of Neuroradiology, Aug 11, 2016

BACKGROUND AND PURPOSE: There is a scarcity of information on the effect of white matter degenera... more BACKGROUND AND PURPOSE: There is a scarcity of information on the effect of white matter degeneration in patients with spinocerebellar ataxia type 7. Therefore, we investigated the WM integrity in a large group of patients with spinocerebellar ataxia type 7 by using Tract-Based Spatial Statistics. MATERIALS AND METHODS: Thirty-three patients with a molecular diagnosis of spinocerebellar ataxia type 7 and their age-and sex-matched healthy controls participated in this study. The patients' ataxia severity was evaluated with the Scale for the Assessment and Rating of Ataxia. Voxelwise analyses of diffusion metrics, including fractional anisotropy and mean diffusivity, were performed with Tract-Based Spatial Statistics. The correlation between WM abnormalities and ataxia severity was then calculated. RESULTS: Tract-Based Spatial Statistics analysis revealed WM abnormalities in the cerebellum and the cerebellar peduncles, as well as in other major cortical and subcortical pathways. Further analysis between the Scale for the Assessment and Rating of Ataxia score and WM mean diffusivity showed significant associations only in key areas related to motor control and visuospatial processing, including the cerebellar WM, the middle occipital WM, the superior cerebellar peduncle, and bilateral anterior thalamic radiation. No significant associations between fractional anisotropy and the Scale for the Assessment and Rating of Ataxia were found. CONCLUSIONS: These results suggest a significant contribution of local cerebellar and cerebellar-midbrain connections to ataxic impairment in spinocerebellar ataxia type 7. The results also suggest an involvement of cortical WM abnormalities including tracts within the occipital and frontal cortices. These findings contribute to a more comprehensive view of the clinical impact of the white matter degeneration in spinocerebellar ataxia type 7. ABBREVIATIONS: FA ϭ fractional anisotropy; MD ϭ mean diffusivity; SARA ϭ Scale for the Assessment and Rating of Ataxia; SCA ϭ spinocerebellar ataxia; SCA7 ϭ spinocerebellar ataxia type 7; TBSS ϭ Tract-Based Spatial Statistics S pinocerebellar ataxia type 7 (SCA7) is an autosomal dominant cerebellar ataxia caused by a mutation consisting in the expansion of the cytosine-adenine-guanine trinucleotide in the codon region of the chromosome 3p21, encoding the protein ataxin 7. 1

Movement Disorders, Jul 1, 2012

Parkin mutations in patients with early-onset Parkinson&amp;amp;amp;amp;amp;amp;amp;amp;a... more Parkin mutations in patients with early-onset Parkinson&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (EOPD) are estimated to occur in 49% of familial cases and 18% of sporadic cases. We analyzed the entire sequence-coding region and dosage mutations of parkin in 63 Mexican-mestizo EOPD patients and 120 controls. Parkin mutations were present in 34 patients (54.0%). Exon rearrangements, predominantly spanning exons 9 and 12 (31.7% and 19.0%, respectively) were present in 32 patients, with 17.5% carrying simple heterozygous and 25.4% carrying compound heterozygous parkin mutations. A higher frequency of parkin exon rearrangements than of sequence mutations was observed. Patients with parkin exons 9 and 12 rearrangements showed a later age at onset than did cases with other regions affected (40.3 ± 4.5 vs 30.1 ± 8.8; P = .005), suggesting a mutational hot spot in the etiology of Mexican-mestizo patients with EOPD. To our knowledge, this study represents the largest sampling of Mexican-mestizo patients with EOPD cases for which parkin sequence and dosage alterations were analyzed. .

Neurología, Feb 1, 2021

Introduction: Neuroinflammation is involved in the pathophysiology of various neurological disord... more Introduction: Neuroinflammation is involved in the pathophysiology of various neurological disorders, in particular Alzheimer disease (AD) and Parkinson's disease (PD). Alterations in the blood-brain barrier may allow peripheral blood lymphocytes to enter the central nervous system; these may participate in disease pathogenesis. Objective: To evaluate the peripheral blood lymphocyte profiles of patients with AD and PD and their association with the disease and its progression. Methods: The study included 20 patients with AD, 20 with PD, and a group of healthy individuals. Ten of the patients with AD and 12 of those with PD were evaluated a second time 17 to 27 months after the start of the study. Lymphocyte subpopulations and their activation status were determined by flow cytometry. All patients underwent neurological examinations using internationally validated scales. Results: Compared to healthy individuals, patients with AD and PD showed significantly higher levels of activated lymphocytes, lymphocytes susceptible to apoptosis, central memory T cells, and regulatory T and B cells. As the diseases progressed, there was a significant decrease in activated cells (CD4+ CD38+ and CD8+ CD38+ in PD and AD, CD4+ CD69+ and CD8+ CD69+ in PD), T cells susceptible to apoptosis, and some regulatory populations (CD19+ CD5+ IL10+ in PD and AD, CD19+ CD5+ IL10+ FoxP3+, CD4+ FoxP3+ CD25+ CD45RO+ in PD). In patients with AD, disease progression was associated with lower percentages of CD4+ CD38+ cells and higher percentages of effector CD4 cells at the beginning of the study. Significant differences were observed between both diseases.

Canadian Journal of Neurological Sciences, Feb 6, 2019

Background: Amyotrophic lateral sclerosis (ALS) is a devastating disease that targets motor neuro... more Background: Amyotrophic lateral sclerosis (ALS) is a devastating disease that targets motor neurons. Upper motor neurons degeneration is pathologically characterized by brain iron accumulation. Signal attenuation in the shape of a ribbon at the posterior border of the precentral gyrus can be observed on conventional magnetic resonance imaging (MRI) sequences including T2-weighted sequence. Methods: With the aim to know the qualities of this potential marker of ALS, we conducted a prospective study. Patients with definite ALS in the age range of 40-70 years and healthy controls underwent 3T brain MRI using a standardized sequence. A second MRI was performed 18 months later under the same conditions in the patients with ALS. Results: Most of the patients with ALS (91.66%) exhibited a "black ribbon" (BR) with an average area of 79.98 mm 3. Signal attenuation discriminated ALS with a mean value of 63.97 arbitrary units (AU) on the left BR (95% CI: 60.67-67.27), a mean value of 59.15 AU (95% CI: 54.78-63.53) on the right BR, and a significant difference with control subjects presenting a mean value of 107.85 AU (p < 0.001). The optimal cutoff point for differentiating patients with ALS from controls (sensitivity, 0.92; specificity, 0.93) was 83 AU. Forced vital capacity and muscle strength in the contralateral upper extremity were significantly correlated with the ribbon intensity in ALS. Patients who underwent a second study exhibited significant changes in the BR related to the rapid evolution of the disease. Conclusions: This marker represents a valuable tool for the selection of candidates and their follow-up in clinical trials. RÉSUMÉ: L'hypo-intensité du cortex moteur est-elle une des caractéristiques de la sclérose latérale amyotrophique? Contexte: La sclérose latérale amyotrophique (SLA) est une maladie dévastatrice qui affecte les neurones moteurs. Sur le plan pathologique, la dégénérescence de ces neurones est caractérisée par une accumulation de fer dans le cerveau. L'affaiblissement du potentiel nerveux lié à cette maladie prend la forme d'un ruban situé à la limite postérieure du gyrus précentral. Un tel symptôme peut être observé au moyen de séquences tirées d'examens d'IRM conventionnelle, ce qui inclut la pondération T2. Méthodes: Nous avons mené une étude prospective avec l'objectif de mieux connaître les propriétés de ce marqueur potentiel de la SLA. Ainsi, des patients clairement atteints de SLA et âgés de 40 à 70 ans, de même que des témoins en bonne santé, ont subi une IRM 3T en vertu d'une séquence conventionnelle. Dix-huit mois plus tard, dans les mêmes conditions, une deuxième IRM a été effectuée dans le cas des patients atteints de SLA. Résultats: La plupart de ces patients, soit 91,66 % d'entre eux, ont donné à voir une forme de « ruban noir » dont la superficie moyenne atteignait 79,98 mm3. L'affaiblissement du potentiel nerveux a aussi permis de distinguer la SLA, la valeur moyenne, en unités arbitraires (UA), étant de 63,97 pour la section gauche du « ruban noir » (IC 95 % : 60,67-67,27) et de 59,15 (IC 95 % : 54,78-63,53) pour la section droite de ce même ruban. Une différence notable a été observée par rapport aux témoins, ces derniers donnant à voir une valeur moyenne de 107,85 (UA) (p < 0,001). Pour distinguer les patients atteints de SLA et les témoins, nous avons aussi déterminé que la limite optimale d'inclusion se situait à 83 (UA) (sensibilité : 0,92 ; spécificité : 0,93). Tant la capacité vitale forcée (CVF) que la force musculaire du membre supérieur controlatéral se sont révélées fortement corrélées à l'intensité du ruban associé à la SLA. Les patients ayant participé à une deuxième étude ont quant à eux présenté des modifications importantes en ce qui a trait à ce ruban en raison de l'évolution accélérée de leur maladie. Conclusions: Ce marqueur représente donc un outil précieux en vue de la sélection et du suivi de candidats devant participer à des essais cliniques.

Neurología (English Edition)

Reviews in the Neurosciences

Huntington’s disease (HD), a neurodegenerative disorder caused by an expansion of the huntingtin ... more Huntington’s disease (HD), a neurodegenerative disorder caused by an expansion of the huntingtin triplet (Htt), is clinically characterized by cognitive and neuropsychiatric alterations. Although these alterations appear to be related to mutant Htt (mHtt)-induced neurotoxicity, several other factors are involved. The gut microbiota is a known modulator of brain-gut communication and when altered (dysbiosis), several complaints can be developed including gastrointestinal dysfunction which may have a negative impact on cognition, behavior, and other mental functions in HD through several mechanisms, including increased levels of lipopolysaccharide, proinflammatory cytokines and immune cell response, as well as alterations in Ca2+ signaling, resulting in both increased intestinal and blood-brain barrier (BBB) permeability. Recently, the presence of dysbiosis has been described in both transgenic mouse models and HD patients. A bidirectional influence between host brain tissues and the ...

Revista de investigación clínica; organo del Hospital de Enfermedades de la Nutrición

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the presence of mot... more Parkinson's disease (PD) is a neurodegenerative disorder characterized by the presence of motor disturbances, derived from the striatal dopamine depletion. Previously, we reported that CuSO4 pretreatment blocked an oxidative stress marker (lipid peroxidation) and prevented the striatal dopamine depletion induced by the administration of the 1-methyl-4-phenylpiridinium (MPP+), the toxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a model of PD. . To determine if tyrosine hydroxylase (TH), the rate-limiting synthetic enzyme of dopamine, is implicated in the neuroprotective effect of CuSO4 pretreatment, and if this neuroprotective effect is able to prevent the hypokinetic state (measured as spontaneous locomotor activity, SLA) induced by the experimental model of PD. C57 Black/6J mice received a single dose of CuSO4 (2.5 mg/kg, i.p.) either 16 or 24 h before the administration of MPP+ (18 microg/3 microl, i.c.v.). Twenty four hours later, mice SLA was registe...

Neurochemical Research, 2001

Neurodegenerative effects of MPP+, the main metabolite of MPTP include dopamine (DA) depletion an... more Neurodegenerative effects of MPP+, the main metabolite of MPTP include dopamine (DA) depletion and enhanced lipid peroxidation (LPO) in mice striata, both associated to free radicals overproduction. Since copper is related to several antioxidant enzymes, we tested its neuroprotective effect against MPP+-induced neurotoxicity (20 µg/3 µl). CuSO4 pretreatment was administrated by either acute (2.5 mg/kg, i.p) or chronic (350 or

European Journal of Neuroscience, Jun 1, 2013

Genetic Testing and Molecular Biomarkers, Dec 1, 2009

Huntington&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;am... more Huntington&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (HD) is an autosomal dominant progressive, disabling neurodegenerative disorder, for which there is no effective treatment. Predictive testing (PT) for this illness began in 1986 and by 1993 it became more precise after cloning of the gene and the discovery of a CAG repeat expansion as the underlying cause. The objective of this paper is to illustrate the implementation and results of a PT program in a group of at-risk Mexican individuals with 12 years of follow-up. Our PT program conforms to the guidelines proposed by the International Huntington Association and the HD Working group of the World Federation of Neurology. Seventy-five individuals requested the testing, four of them did not fulfill the inclusion criteria, and five abandoned the program voluntarily before receiving the test results. Therefore, 66 results were delivered to 41 noncarriers and 25 mutation carriers. We did not have any catastrophic event, but 4 individuals with normal results and 11 mutation carriers were depressed. Even if this is a small sample, it is the first report of PT in a Latin-American population in which we have been faced with the same problems referred to in larger series.

Journal of Chromatography B, May 1, 2007

Citrulline and nitric oxide (NO) are synthesized by NO synthase (NOS) in a 1:1-stoichiometry. In ... more Citrulline and nitric oxide (NO) are synthesized by NO synthase (NOS) in a 1:1-stoichiometry. In this study, we determined by HPLC arginine and citrulline concentrations by fluorescence detection and nitrate levels by UV absorbance detection in the cerebrospinal fluid (CSF) from patients with acute hydrocephalus that underwent ventricular drainage. We found increased citrulline concentration (50.6+/-17.2 versus 20.9+/-2.0 microM) and decreased arginine/citrulline molar ratio (0.42+/-0.11 versus 1.12+/-0.16) in hydrocephalus patients, while arginine and nitrate concentrations and citrulline/nitrate molar ratio remained with little change. Citrulline has been determined as a marker of NOS activity in some studies, but it remains to be determined the extent at which this statement holds true, since other biochemical pathways also regulate the concentration of this amino acid. Our results suggest that citrulline is primarily synthesized from NOS in acute hydrocephalus. The evaluation of sample deproteinization by addition of methanol for the analysis of amino acids in CSF is also reported.

Archives of Medical Research, 1999

Treatment of Parkinson's Disease (PD) has been attempted by others by transplanting eithe... more Treatment of Parkinson's Disease (PD) has been attempted by others by transplanting either the patient's own adrenal medullary tissue or fetal substantia nigra into caudate or putamen areas. However, the difficulties inherent in using the patient's own adrenal gland, or the difficulty in obtaining human fetal tissue, has generated the need to find alternative methods. We report here of an alternative to both procedures by using as transplant material cultured human adrenal chromaffin cells differentiated into neuron-like cells by extremely low frequency magnetic fields (ELF MF). The results of this study show that human differentiated chromaffin cells can be grafted into the caudate nucleus of a PD patient, generating substantial clinical improvement, as measured by the Unified Rating Scale for PD, which correlated with glucose metabolism and D2 DA receptor increases as seen in a PET scan, while allowing a 70% decrease in L-Dopa medication. This is the first preliminary report showing that transplants of cultured differentiated neuron-like cells can be successfully used to treat a PD patient.

Neurología, 2019

NRL-1273; No. of Pages 12 2 S. Garfias et al. Conclusiones: Este estudio proporciona evidencia de... more NRL-1273; No. of Pages 12 2 S. Garfias et al. Conclusiones: Este estudio proporciona evidencia de cambios en los fenotipos de linfocitos periféricos asociados a EA y EP y a su gravedad. Teniendo en cuenta la comunicación efectiva sangre-cerebro, nuestros resultados abren nuevas vías para explorar terapias de inmunomodulación para tratar estas enfermedades.

American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 2014

Mutations in PARK2, PINK1, and DJ-1 have been associated with autosomal recessive early-onset Par... more Mutations in PARK2, PINK1, and DJ-1 have been associated with autosomal recessive early-onset Parkinson's disease. Here, we report the prevalence of sequence and structural mutations in these three main recessive genes in Mexican Mestizo patients. The complete sequences of these three genes were analyzed by homo/heteroduplex DNA formation and direct sequencing; exon dosage was determined by multiplex ligation-dependent probe amplification and real-time PCR in 127 patients belonging to 122 families and 120 healthy Mexican Mestizo controls. All individuals had been previously screened for the three most common LRRK2 mutations. The presence of two mutations in compound heterozygous or homozygous genotypes was found in 16 unrelated patients, 10 had mutations in PARK2, six in PINK1, and none in DJ-1. Two PARK2-PINK1 and one PARK2-LRRK2 digenic cases were observed. Novel mutations were identified in PARK2 and PINK1 genes, including PINK1 duplication for the first time. Exon dosage deletions were the most frequent mutations in PARK2 (mainly in exons 9 and 12), followed by those in PINK1. The high prevalence of heterozygous mutations in PARK2 (12.3%) and the novel heterozygous and homozygous point mutations in PINK1 observed in familial and sporadic cases from various states of Mexico support the concept that single heterozygous mutations in recessive Parkinson's disease genes play a pathogenic role. These data have important implications for genetic counseling of Mexican Mestizo patients with earlyonset Parkinson's disease. The presence of digenic inheritance underscores the importance of studying several genes in this disease. A step-ordered strategy for molecular diagnosis is proposed.