A very large Brazilian pedigree with 11778 Leber's hereditary optic neuropathy.
OBJECTIVE
We conducted extensive epidemiological, neuro-ophthalmological, psychophysical, and blood examinations on a newly discovered, very large pedigree with molecular analysis showing mtDNA mutation for Leber's hereditary optic neuropathy (LHON).


METHODS
Four patients representing four index cases from a remote area of Brazil were sent to Sao Paulo, where complete ophthalmological examinations strongly suggested LHON. Molecular analysis of their blood demonstrated that they were LHON, homoplasmic 11778, J-haplogroup. They had an extensive family that all lived in one rural area in Brazil. To investigate this family, we drew on a number of international experts to form a team that traveled to Brazil. This field team also included several members of the Federal University of Sao Paulo, and together we evaluated 273 of the 295 family members that were still alive. We conducted epidemiological interviews emphasizing possible environmental risk factors, comprehensive neuro-ophthalmological examinations, psychophysical tests, Humphrey visual field studies, fundus photography, and blood testing for both mitochondrial genetic analysis and nuclear gene linkage analysis.


RESULTS
The person representing the first-generation case immigrated from Verona, Italy, to Colatina. Subsequent generations demonstrated penetrance rates of 71%, 60%, 34%, 15%, and 9%. The percentages of males were 60%, 50%, 64%, 100%, and 100%. Age at onset varied from 10 to 64 years, and current visual acuities varied from LP to 20/400.


CONCLUSIONS
Almost 95% of a nearly 300-member pedigree with LHON 11778 were comprehensively studied. Analysis of environmental risk factors and a nuclear modifying factor from this group may help address the perplexing mystery of LHON: Why do only some of the genetically affected individuals manifest the disease? This fully described database may also provide an excellent opportunity for future clinical trials of any purported neuroprotective agent.
Sadun
Alfredo A
AA
University of Southern California-Keck School of Medicine/Doheny Eye Institute, Los Angeles, USA.
Carelli
Valerio
V
Salomao
Solange R
SR
Berezovsky
Adriana
A
Quiros
Peter
P
Sadun
Federico
F
DeNegri
Anna-Maria
AM
Andrade
Rafael
R
Schein
Stan
S
Belfort
Rubens
R
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D001938:Brazil / Q000453:epidemiology; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D029242:Optic Atrophy, Hereditary, Leber / Q000208:ethnology* / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D012307:Risk Factors; D014792:Visual Acuity; D014794:Visual Fields
D004272:DNA, Mitochondrial