Extensive investigation of a large Brazilian pedigree of 11778/haplogroup J Leber hereditary optic neuropathy.
OBJECTIVE
To conduct systematic epidemiologic, neuro-ophthalmologic, psychophysical, and mitochondrial DNA (mtDNA) genetic examinations on a newly identified pedigree with Leber hereditary optic neuropathy (LHON).


METHODS
Observational population cohort study.


METHODS
A prospective investigation of an entire Brazilian LHON family.


METHODS
A field investigation by an international team conducted in a remote part of Brazil.


METHODS
We evaluated 265 (both eyes) of the 328 living family members of this LHON pedigree. Only members of this pedigree were studied. Those entering the pedigree as spouses were used as controls.


METHODS
We conducted epidemiologic interviews emphasizing possible environmental risk factors, comprehensive neuro-ophthalmologic examinations, psychophysical tests, Humphrey visual field studies, fundus photography, and blood testing for mitochondrial genetic analysis.


RESULTS
We reconstructed a seven-generation maternal lineage descended from a common ancestor dating to the 1870s. All maternally related family members were invariably homoplasmic 11778 with a haplogroup J mtDNA, 33 being affected, of which 22 are still living. With each subsequent generation, there was a progressive decrease of penetrance, and only males were affected in the last two generations. A significant exposure (greater than 95% confidence intervals) to a variety of environmental risk factors characterized the affected individuals, with smoking as the most common (P <.01). Both affected and carriers (95% confidence intervals) presented with a significantly lower incidence of hypertension and high cholesterol compared with the control group (P <.05).


CONCLUSIONS
Almost 95% of a 328-living-member pedigree with LHON 11778/J haplogroup was comprehensively studied. Our initial results indicate the strong influence of environmental risk factors. The remarkably reduced incidence of cardiovascular risk in the maternal lineage is discussed. Further genetic analysis may reveal a role for the nuclear genome.
Sadun
Alfredo A
AA
Keck-University of Southern California School of Medicine/Doheny Eye Institute, Los Angeles, CA 90033, USA. Asadun@usc.edu
Carelli
Valerio
V
Salomao
Solange R
SR
Berezovsky
Adriana
A
Quiros
Peter A
PA
Sadun
Federico
F
DeNegri
Anna Maria
AM
Andrade
Rafael
R
Moraes
Milton
M
Passos
Angelo
A
Kjaer
Patrícia
P
Pereira
Josenilson
J
Valentino
Maria Lucia
ML
Schein
Stan
S
Belfort
Rubens
R
D000293:Adolescent; D001938:Brazil / Q000453:epidemiology; D015331:Cohort Studies; D003118:Color Perception; D015350:Contrast Sensitivity; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics; D005260:Female; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D029242:Optic Atrophy, Hereditary, Leber / Q000453:epidemiology* / Q000235:genetics*; D010375:Pedigree; D016133:Polymerase Chain Reaction; D012307:Risk Factors; D014792:Visual Acuity; D014794:Visual Fields
D004272:DNA, Mitochondrial