Familial dysautonomia: History, genotype, phenotype and translational research.
Familial dysautonomia (FD) is a rare neurological disorder caused by a splice mutation in the IKBKAP gene. The mutation arose in the 1500s within the small Jewish founder population in Eastern Europe and became prevalent during the period of rapid population expansion within the Pale of Settlement. The carrier rate is 1:32 in Jews descending from this region. The mutation results in a tissue-specific deficiency in IKAP, a protein involved in the development and survival of neurons. Patients homozygous for the mutations are born with multiple lesions affecting mostly sensory (afferent) fibers, which leads to widespread organ dysfunction and increased mortality. Neurodegenerative features of the disease include progressive optic atrophy and worsening gait ataxia. Here we review the progress made in the last decade to better understand the genotype and phenotype. We also discuss the challenges of conducting controlled clinical trials in this rare medically fragile population. Meanwhile, the search for better treatments as well as a neuroprotective agent is ongoing.
Department of Neurology, New York University School of Medicine, New York, NY, USA.
Lucy
L
Norcliffe-Kaufmann
Center for Human Genetic Research, Massachusetts General Hospital Research Institute and Department of Neurology, Harvard Medical School, Boston, MA, USA.
Susan A
SA
Slaugenhaupt
Department of Neurology, New York University School of Medicine, New York, NY, USA. Electronic address: horacio.kaufmann@nyumc.org.
Horacio
H
Kaufmann
D000818:Animals; D055808:Drug Discovery / Q000639:trends*; D004402:Dysautonomia, Familial / Q000188:drug therapy* / Q000235:genetics*; D019317:Evidence-Based Medicine; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing / Q000379:methods*; D005838:Genotype; D006801:Humans; D057170:Translational Research, Biomedical / Q000639:trends*; D016896:Treatment Outcome
D005819:Genetic Markers