Recent findings suggest a significant effect of the cerebellar circuit deterioration on the clinical manifestation of Huntington's disease, calling for a better understanding of the cerebellar degeneration in this disorder. Recent... more
Recent findings suggest a significant effect of the cerebellar circuit deterioration on the clinical manifestation of Huntington's disease, calling for a better understanding of the cerebellar degeneration in this disorder. Recent brain imaging analyses have provided conflicting results regarding the cerebellar changes during the progression of this disease. To help in resolving this controversy, we examined the cerebellar gray matter structural integrity from a cohort of HD patients. Whole brain voxel-based morphometry (VBM) and spatially unbiased atlas template of the human cerebellum (SUIT) analyses were done from T1-weighted brain images. Our results showed a significant cerebellar degeneration without any sign of volume increase. The highest cerebellar degeneration was identified in Crus I right lobule, Crus II bilaterally, and left VIIb, and left VIIIa lobules. The cerebellar degeneration signature, which controls for severity of degeneration, showed a degeneration pattern that included regions I-IV, Crus II, VIIb, VIIIa, VIIIb and X.
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Objective: To reanalyze seizure phenotypes in families with childhood absence epilepsy (CAE) and juvenile myoclonic epilepsy (JME) using artificial intelligence tools and results of Whole Exome/Genome Sequencing (WES/WGS). Background:... more
Objective: To reanalyze seizure phenotypes in families with childhood absence epilepsy (CAE) and juvenile myoclonic epilepsy (JME) using artificial intelligence tools and results of Whole Exome/Genome Sequencing (WES/WGS). Background: Since 1992, the Genetic Epilepsy StudieS Consortium (GENESS) and collaborators have collected phenotype data on CAE and JME families from Los Angeles, CA (USA), Mexico, Honduras, El Salvador, Guatemala, Peru, Brazil, Spain, France, and Japan. Combining new informatics tools, the new 2016 ILAE classification of seizures and epilepsies and WES/WGS can help further reanalysis of cases. Design/Methods: The phenotypes of 268 probands with JME were reanalyzed using the RapidMiner tool. We studied the variables age, gender, seizure types, age at onset of each type, trigger factors, EEG findings, family history, and response to treatment. We used the pediatric age groups suggested by the National Institutes of Child Health and Human Development. Results: The s...
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OBJECTIVE To refine classification of Juvenile Myoclonic Epilepsy (JME) subsyndromes in 298 cases according to age at onset of absence seizures (ABS) and results of whole exome sequencing (WES). BACKGROUND The 2011 Avignon Workshop... more
OBJECTIVE To refine classification of Juvenile Myoclonic Epilepsy (JME) subsyndromes in 298 cases according to age at onset of absence seizures (ABS) and results of whole exome sequencing (WES). BACKGROUND The 2011 Avignon Workshop established the diagnostic criteria for JME as onset of awakening myoclonias and EEG 4-6Hz polyspike waves between 10-25 years of age. However, ABS with/without eyelid myoclonia (EM), astatic drop, and photosensitivity confound JME nosology. DESIGN/METHODS JME cases were regrouped according to age onset of ABS: early childhood (1-5 yr) [eCA/JME], childhood (6-11y) [CA/JME], adolescence [adolABS/JME] (12-21y), and JME with ABS in adulthood (22y+). WES of 12 large JME families followed linkage and haplotype analysis. Discovered epilepsy genes were then screened in the 298 cases. RESULTS Out of 298, 134 probands (45[percnt]) had classic JME (cJME), 60 (20[percnt]) had CA/JME, 70 (23[percnt]) had adolABS/JME, 20 (7[percnt]) had eCA/JME, 9 (3[percnt]) had asta...
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In juvenile myoclonic epilepsy, data are limited on the genetic basis of networks promoting convulsions with diffuse polyspikes on electroencephalography (EEG) and the subtle microscopic brain dysplasia called microdysgenesis. Using... more
In juvenile myoclonic epilepsy, data are limited on the genetic basis of networks promoting convulsions with diffuse polyspikes on electroencephalography (EEG) and the subtle microscopic brain dysplasia called microdysgenesis. Using Sanger sequencing, we sequenced the exomes of six members of a large family affected with juvenile myoclonic epilepsy and confirmed cosegregation in all 37 family members. We screened an additional 310 patients with this disorder for variants on DNA melting-curve analysis and targeted real-time DNA sequencing of the gene encoding intestinal-cell kinase ( ICK). We calculated Bayesian logarithm of the odds (LOD) scores for cosegregating variants, odds ratios in case-control associations, and allele frequencies in the Genome Aggregation Database. We performed functional tests of the effects of variants on mitosis, apoptosis, and radial neuroblast migration in vitro and conducted video-EEG studies in mice lacking a copy of Ick. A variant, K305T (c.914A→C), c...
Research Interests: Neurology, Malformations of Cortical Development, Electroencephalography, Adolescent, Medicine, and 15 moreHumans, Child, Mutation, Mice, Female, Animals, Male, Infant, Bayes Theorem, Neurosciences, Nervous System Diseases, Case Control Studies, Juvenile Myoclonic Epilepsy, Child preschool, and Medical and Health Sciences
The NR4A2 transcription factor is important in the development, survival and phenotype of dopaminergic neurons and it is postulated as a possible biomarker for Parkinson's disease (PD). Therefore, our aim was to analyze in a sample of... more
The NR4A2 transcription factor is important in the development, survival and phenotype of dopaminergic neurons and it is postulated as a possible biomarker for Parkinson's disease (PD). Therefore, our aim was to analyze in a sample of a Mexican population with idiopathic PD, mutations (in two hotspot mutation regions) and two polymorphisms (rs34884856 in promotor and rs35479735 intronic regions) of the NR4A2 gene. We also evaluate the levels of NR4A2 gene expression in peripheral blood for a Mexican population, and identify whether they are associated with NR4A2 gene polymorphisms. We conducted a case-control study, which included 227 idiopathic PD cases and 454 unrelated controls. Genetic variants of the NR4A2 gene were genotyped by high-resolution melting (HRM) and validated by an automated sequencing method. The gene expression was performed in peripheral blood using a real-time polymerase chain reaction. The rs35479735 polymorphism was associated with a higher risk of develo...
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Research Interests: Neuroscience, Psychology, Cognitive Science, Magnetic Resonance Imaging, Medicine, and 14 moreMovement disorders, Humans, Cerebellum, Cerebral Cortex, Functional Magnetic Resonance Imaging, Female, Spinocerebellar ataxia, Male, Clinical Sciences, Middle Aged, Adult, Neurosciences, Cognition disorders, and Psychomotor Performance
Fifty-eight, at-risk subjects were studied. 81% of the group wished to know whether they had inherited Huntington's disease, even though only 79% would undergo testing. The subjects reported a favorable attitude toward a probable... more
Fifty-eight, at-risk subjects were studied. 81% of the group wished to know whether they had inherited Huntington's disease, even though only 79% would undergo testing. The subjects reported a favorable attitude toward a probable positive result in 81% of cases. Nevertheless, 52% reported they would become depressed, and a small group referred suicidal ideation as response to a probable positive result. Regarding genetic counseling, 59% reported that an at-risk person should not have children, although this increased to 82% if the person knew with certainty that they would develop the disease. Prenatal testing was favored in 74%, and less than half would be willing to have an abortion. Genetic counseling must be insisted upon, the selection of at-risk subjects must be carefully made, and the characteristics of the Mexican population must be taken into account.
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OBJECTIVE: GENESS’ aim is to accelerate discovery of new genes causing classic juvenile myoclonic epilepsy (cJME). BACKGROUNG: JME is a common epilepsy, representing 3-12% of all epilepsies. In the last decade, six mutation-harboring... more
OBJECTIVE: GENESS’ aim is to accelerate discovery of new genes causing classic juvenile myoclonic epilepsy (cJME). BACKGROUNG: JME is a common epilepsy, representing 3-12% of all epilepsies. In the last decade, six mutation-harboring Mendelian genes (CaCNB4, CaCNa1, Ca Sensor receptor, GABRA1, GABRd and EFHC1), almost all unique to rare families, except EFHC1, have been identified in cJME. Consequently, there is no cure. Here, we report a new gene (myclonin 3) for JME using genome-wide linkage mapping combined with whole exome sequencing (WES). DESIGN/METHODS: We studied a four generation family with classic JME and 232 controls. Thirty-seven family members (four with cJME, four clinically asymptomatic but with EEG polyspike waves and 29 unaffecteds) participated in Genome-wide linkage mapping using Marshfield set 16,with 400 STRP9s and 6p11-12 fine mapping with 38 additional STRPs. Pair-end WES of four affected members and two “married-in” controls was performed by Illumina on a HiSeq 2000 sequencer..ANNOVAR program modified for epilepsy was used to annotate, filter and prioritize functional DNA variants. Mendelian inheritance segregation and Sanger sequencing confirmed the identified DNA variant. RESULTS: Two-point parametric genome-wide linkage scan suggested linkage to D6S1053 (LOD 2.30 at theta=0.05) and to D6S1017 (LOD 2.28 at theta=0.00). Fine mapping on 6p12 confirmed linkage to D6S257 (LOD 3.35) and D6S1573 (LOD 3.27). WES identified a heterozygous mutation of A914C/K305T in myclonin 3, which located perfectly in chromosome 6p12.2 identified by genome-wide linkage and 6p fine mapping. Heterozygous A914C/K305T in myclonin 3 segregates with eight clinically and EEG polyspike wave affected family members, four carriers in the four generation family and not in 232 controls. Six missense and one nonsense mutations in myoclonin 3 were identified in 8 other families and singletons. CONCLUSION: Our data strongly suggest myclonin 3 causes juvenile myoclonic epilepsy. Encoded protein and function of Myoclonin3 will be discussed. Study Supported by NIH-R01NS055057 and NHLBI Mammalian Genotyping Service. Disclosure: Dr. Bai has nothing to disclose. Dr. Medina has nothing to disclose. Dr. Duron has nothing to disclose. Dr. Bailey has nothing to disclose. Dr. Alonso has nothing to disclose. Dr. Suzuki has nothing to disclose. Dr. Tanaka has nothing to disclose. Dr. Martinez-Juarez has received personal compensation for activities with Abbott Laboratories, Inc. Dr. Ochoa has nothing to disclose. Dr. Jara-Prado has nothing to disclose. Dr. Serratosa has received personal compensation for activities with Eisai Inc., UCB Pharma, and Bial. Dr. Yamakawa has nothing to disclose. Dr. Escueta has nothing to disclose.
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Multiple Sclerosis (MS) is a highly polymorphic disease characterized by different neurologic signs and symptoms. In MS, racial and genetic factors may play an important role in the geographic distribution of this disease. Studies have... more
Multiple Sclerosis (MS) is a highly polymorphic disease characterized by different neurologic signs and symptoms. In MS, racial and genetic factors may play an important role in the geographic distribution of this disease. Studies have reported the presence of several protective alleles against the development of autoimmune disorders. In the case of MS, however, they help define MS as a complex disease, and confirm the importance of environmental agents as an independent variable not associated with ethnicity. We carried out an on-site epidemiological study to confirm the absence of MS or NMO among Lacandonians, a pure Amerindian ethnic group in Mexico. We administered a structured interview to 5,372 Lacandonians to assess by family background any clinical data consistent with the presence of a prior demyelinating event. Every participating subject underwent a comprehensive neurological examination by a group of three members of the research team with experience in the diagnosis and...
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Lafora disease (LD) is an autosomal recessive progressive myoclonus epilepsy with classic adolescent onset of stimuli sensitive seizures. Patients typically deteriorate rapidly with dementia, ataxia, vegetative failure and death by 25... more
Lafora disease (LD) is an autosomal recessive progressive myoclonus epilepsy with classic adolescent onset of stimuli sensitive seizures. Patients typically deteriorate rapidly with dementia, ataxia, vegetative failure and death by 25 years of age. LD is caused by homozygous mutations in EPM2A or EPM2B genes. We found four novel mutations in EPM2A - three in exon 4 (Q247X, H265R G279C) and one in exon 1 (Y86D) - and a previously described mutation in exon 4 (R241X). These five EPM2A mutations were found in four index cases and affected relatives. Patient 1 with classic LD was doubly heterozygous for H265R and R241X in exon 4; while Patient 2, who also had classic LD, was homozygous for Q247X in exon 4. Patient 3 with classic LD was homozygous for Y86D in exon 1, but the same mutation in his affected brother manifested an atypical earlier childhood onset. For the first time, we describe a later onset and slower progression of EPM2A-deficient LD seen in Patient 4 and her three sisters who were doubly heterozygous for R241X and G279C in exon 4. In these sisters, seizures started later at 21 to 28 years of age and progressed slowly with patients living beyond 30 years of age. Our observations suggest that variations in phenotypes of EPM2A-deficient LD, like an earlier childhood or adolescent or later adult onset with a rapid or slower course, depend on a second modifying factor separate from pathogenicity or exon location of EPM2A mutations. A modifying gene amongst the patient's genetic background or environmental factors may condition age of onset and rapid or slow progression of LD.
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Research Interests: Nutrition, Anthropometry, Medicine, Humans, Female, and 15 moreMale, Nutritional Status, Aged, Middle Aged, Dietary Assessment, Adult, Mastication, Dietary Carbohydrates, Huntington disease, Energy Intake, Case Control Studies, Dietary fats, Nutrition assessment, Deglutition disorders, and Medical and Health Sciences
Research Interests: Nutrition, Anthropometry, Dysphagia, Medicine, Appetite, and 15 moreHumans, Female, Body Composition, Male, Dietary Supplements, Nutritional Status, Body Mass Index, Aged, Middle Aged, Longitudinal Studies, Adult, Huntington disease, Energy Intake, Neurologic Examination, and Medical and Health Sciences
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Research Interests: Genetics, Magnetic Resonance Imaging, Electroencephalography, Medicine, Brain, and 14 moreHumans, Child, Differential Diagnosis, Phenotype, Genotype, Neuropediatrics, Huntington disease, Neurosciences, Cognition disorders, Nino, Neuropsychological Tests, Child preschool, alleles, and Paediatrics and reproductive medicine
Juvenile myoclonic epilepsy (JME) accounts for 3 to 12% of all epilepsies. In 2004, the GENESS Consortium demonstrated four missense mutations in Myoclonin1/EFHC1 of chromosome 6p12.1 segregating in 20% of Hispanic families with JME. To... more
Juvenile myoclonic epilepsy (JME) accounts for 3 to 12% of all epilepsies. In 2004, the GENESS Consortium demonstrated four missense mutations in Myoclonin1/EFHC1 of chromosome 6p12.1 segregating in 20% of Hispanic families with JME. To examine what percentage of consecutive JME clinic cases have mutations in Myoclonin1/EFHC1. We screened 44 consecutive patients from Mexico and Honduras and 67 patients from Japan using heteroduplex analysis and direct sequencing. We found five novel mutations in transcripts A and B of Myoclonin1/EFHC1. Two novel heterozygous missense mutations (c.755C>A and c.1523C>G) in transcript A occurred in both a singleton from Mexico and another singleton from Japan. A deletion/frameshift (C.789del.AV264fsx280) in transcript B was present in a mother and daughter from Mexico. A nonsense mutation (c.829C>T) in transcript B segregated in four clinically and seven epileptiform-EEG affected members of a large Honduran family. The same nonsense mutation (c.829C>T) occurred as a de novo mutation in a sporadic case. Finally, we found a three-base deletion (-364--362del.GAT) in the promoter region in a family from Japan. Nine percent of consecutive juvenile myoclonic epilepsy cases from Mexico and Honduras clinics and 3% of clinic patients from Japan carry mutations in Myoclonin1/EFCH1. These results represent the highest number and percentage of mutations found for a juvenile myoclonic epilepsy causing gene of any population group.
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Research Interests: Genetics, Biology, Adolescent, Intellectual Disability, Medicine, and 15 moreWestern blotting, Biological Sciences, Humans, Child, Haplotypes, Human Molecular Genetics, Pedigree, Phenotype, Genotype, Adult, HeLa cells, Protein Tyrosine Phosphatases, Exon, Child preschool, and Medical and Health Sciences
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Huntington&a... more
Huntington'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.
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Research Interests: Genetics, Epilepsy, Biology, Medicine, Gene expression, and 15 moreDNA, Humans, Mutation, Female, Male, Clinical Sciences, Family Health, Genotype, Amino Acid Profile, Base Sequence, Juvenile Myoclonic Epilepsy, Molecular Sequence Data, DNA mutational analysis, Nucleotide substitution, and Mutation analysis
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Huntington's disease (HD) is a degenerative disorder of the central nervous system with autosomal dominant inheritance. Genetic counseling has always been difficult in this disorder with anguish, depression and denial... more
Huntington's disease (HD) is a degenerative disorder of the central nervous system with autosomal dominant inheritance. Genetic counseling has always been difficult in this disorder with anguish, depression and denial being very common in both the patient and family members. The discovery of the causal gene has led to precise diagnostic procedures allowing homozygotes for the disease to be identified. Contrary to what occurs in some other autosomal dominant diseases, the course of the disease is not more severe in the homozygote than in the heterozygote. The present authors describe a family comparing two affected siblings: one is heterozygotic and the other homozygous for the HD mutation. They confirm that the age and symptoms of onset did not differ significantly between the subjects; however, the disease seemed to have a more severe progression in the heterozygote than in the homozygote. The authors discuss the ethical dilemma derived from the genetic counseling of a homozygotic patient, given the fact that all his offspring will be affected. Letting the offspring know about their 100% probability of inheriting the disorder is equivalent to delivering a non-requested predictive test, while not informing them constitutes withholding crucial information from the individual.
Research Interests: Genetics, Medicine, Genetic counseling, Humans, Clinical, and 15 moreDisease, Clinical Genetics, Pedigree, Clinical Sciences, Middle Aged, Family Health, Consanguinity, Genetic Disorder, Disease Progression, Huntington disease, Molecular Diagnostic Techniques, Offspring, Molecular Diagnosis, Age of Onset, and Heterozygote Advantage
We investigated the allele distribution of the polymorphic (CAG)n repeat in the IT15 gene in 96 normal subjects from the Mexican population and 83 unrelated patients with Huntington's disease. Our results show that the... more
We investigated the allele distribution of the polymorphic (CAG)n repeat in the IT15 gene in 96 normal subjects from the Mexican population and 83 unrelated patients with Huntington's disease. Our results show that the size distributions of normal and affected alleles do not overlap. Normal alleles range from 13 to 32 triplets, with 18 being the most frequent allele, while HD alleles contain 37 to 76 repeats with 42 being the most frequent. One allele in the range of intermediate alleles was found (32 repeats) in a normal subject. The juvenile onset cases in this study are associated with an expansion greater than 49 repeats. In the available parent-offspring pairs, paternal alleles show instability with an expansion of 28 repeats in one case.
Research Interests: Genetics, Biology, Adolescent, Medicine, Mexico, and 15 morePCR, Population, Humans, Child, Clinical, Clinical Genetics, Clinical Sciences, Aged, Middle Aged, Adult, MEXICO, Huntington disease, Allele, Age of Onset, and alleles
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Spinocerebellar ataxia type 17 (SCA17) is caused by expansion of a CAG/CAA repeat in the TBP gene. Most pathogenic alleles are interrupted and are stably transmitted from parent to offspring without anticipation. We identified three SCA17... more
Spinocerebellar ataxia type 17 (SCA17) is caused by expansion of a CAG/CAA repeat in the TBP gene. Most pathogenic alleles are interrupted and are stably transmitted from parent to offspring without anticipation. We identified three SCA17 families with expansion of uninterrupted alleles, thus greatly increasing the number of known intergenerational transmissions of such alleles. We found that uninterrupted SCA17 alleles are unstable, associated with anticipation, and show a paternal expansion bias that increases with age. Even small increments in repeat length resulted in inordinate increases in anticipation. Anticipation was also associated with childhood presentation. Sequencing of all SCA17 alleles is required for effective genetic counseling.
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Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant disorder caused by expansion of an unstable ATTCT repeat. SCA10 has been described as a pure cerebellar syndrome accompanied by seizures and has been recognized only in... more
Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant disorder caused by expansion of an unstable ATTCT repeat. SCA10 has been described as a pure cerebellar syndrome accompanied by seizures and has been recognized only in families of Mexican origin. We describe ...
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Juvenile myoclonic epilepsy is a common subtype of idiopathic epilepsy accounting for 4-11% of all epilepsies. We reported previously significant evidence of linkage between chromosome 6p12-11 microsatellites and the clinical epilepsy and... more
Juvenile myoclonic epilepsy is a common subtype of idiopathic epilepsy accounting for 4-11% of all epilepsies. We reported previously significant evidence of linkage between chromosome 6p12-11 microsatellites and the clinical epilepsy and EEG traits of JME families from Belize and Los Angeles. To narrow the JME region, we ascertained and genotyped 31 new JME families from Mexico using a later generation of Généthon microsatellites. Two point linkage analyses obtained significant Z(max) values of 3.70 for D6S1573 and 2.65 for D6S1714 at theta(m = f) = 0.10, and 3.49 for D6S465, 2.11 for D6S1960 at theta(m = f) = 0.05 assuming autosomal dominant inheritance with 70% age-dependent penetrance. Multipoint LOD score curve peaked at 4.21 for D6S1573. Haplotype and recombination analysis reduced the JME region to 3.5 cM flanked by D6S272 and D6S1573. These results provide confirmatory evidence that a major susceptibility gene for JME exists in chromosome 6p12 in Spanish-Amerinds of Mexico.
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Amongst idiopathic generalized epilepsies, juvenile myoclonic epilepsy (JME) is the most common, accounting for 12% to 30% of all epilepsies in the Western world. Classic JME consists of awakening myoclonias, grand mal convulsions and EEG... more
Amongst idiopathic generalized epilepsies, juvenile myoclonic epilepsy (JME) is the most common, accounting for 12% to 30% of all epilepsies in the Western world. Classic JME consists of awakening myoclonias, grand mal convulsions and EEG 4 to 6 Hz polyspike waves that appear in adolescence. Probands and affected family members do not have pyknoleptic 3Hz spike and wave absences. However, in 10 to 30% of patients, rare or spanioleptic polyspike wave absences appear. In 1988,1995,1996,we mapped classic JME to a 7 cM locus in chromosome 6p12 11, called EJM1, using families from Los Angeles and Belize. In 2001,we studied one large family from Belize and 21 new families from Los Angeles and Mexico Cities, aided by a BAC/PAC based physical map and 6 new dinucleotide repeats, to narrow EJM1 to an interval between D6S272 and D6S1573. In 2002, we found myoclonin, the putative gene for typical JME in 6p12. At the congress, we will reveal the identity of the myoclonin gene, its putative function and discuss the significance of this discovery in the JME population at large.