Hereditary sensory and autonomic neuropathy type III, or familial dysautonomia [FD; Online Mendelian Inheritance in Man (OMIM) 223900], affects the development and long-term viability of neurons in the peripheral nervous system (PNS) and retina. FD is caused by a point mutation in the gene IKBKAP/ELP1 that results in a tissue-specific reduction of the IKAP/ELP1 protein, a subunit of the Elongator complex. Hallmarks of the disease include vasomotor and cardiovascular instability and diminished pain and temperature sensation caused by reductions in sensory and autonomic neurons. It has been suggested but not demonstrated that mitochondrial function may be abnormal in FD. We previously generated an Ikbkap/Elp1 conditional-knockout mouse model that recapitulates the selective death of sensory (dorsal root ganglia) and autonomic neurons observed in FD. We now show that in these mice neuronal mitochondria have abnormal membrane potentials, produce elevated levels of reactive oxygen species, are fragmented, and do not aggregate normally at axonal branch points. The small hydroxylamine compound BGP-15 improved mitochondrial function, protecting neurons from dying in vitro and in vivo, and promoted cardiac innervation in vivo. Given that impairment of mitochondrial function is a common pathological component of neurodegenerative diseases such as amyotrophic lateral sclerosis and Alzheimer's, Parkinson's, and Huntington's diseases, our findings identify a therapeutic approach that may have efficacy in multiple degenerative conditions.T he autonomic nervous system is essential for homeostasis, and its disruption in familial dysautonomia (FD) can have fatal consequences resulting from cardiovascular instability, respiratory dysfunction, and/or sudden death during sleep (1-3). In addition to developmental decreases in the number of sensory and autonomic neurons, FD patients undergo a progressive loss of peripheral neurons and retinal ganglion cells. The latter loss may ultimately lead to blindness (4, 5). More than 98% of FD cases result from a single base substitution (IVS20+6T > C) in the IKBKAP/ELP1 gene (3, 6). This mutation is carried by 1 in 27 to 1 in 32 Ashkenazi Jews (3, 6). The protein encoded by the IKBKAP/ELP1 gene, IKAP/ELP1, is a scaffolding protein for the six-subunit Elongator complex (ELP1-ELP6), which modifies tRNAs during translation (7). Why reduction in the IKAP/ ELP1 protein results in neuronal death is unknown, and we have sought to elucidate the cellular and molecular mechanisms that cause progressive neurodegeneration in FD to help identify treatments that improve neuronal function and viability.Accumulating evidence indicates that cells from FD patients and from mouse models with deletions in the Elongator subunits Ikbkap/Elp1 or Elp3 experience intracellular stress (4,5,(8)(9)(10) resulting from the direct and/or indirect consequences of impaired translation (7, 11). The C terminus of IKAP/ELP1 has been shown to bind c-Jun N-terminal kinase (JNK) and to regulate JNK cytosolic stress signaling (12)....

Since Riley and Day first described the clinical phenotype of patients with familial dysautonomia (FD) over 60 years ago, the field has made considerable progress clinically, scientifically, and translationally in treating and understanding the etiology of FD. FD is classified as a hereditary sensory and autonomic neuropathy (HSAN Type III) and is both a developmental and a progressive neurodegenerative condition that results from an autosomal recessive mutation in the gene IKBKAP, also known as ELP1. FD primarily impacts the peripheral nervous system but also manifests in central nervous system disruption, especially in the retina and optic nerve. While the disease is rare, the rapid progress being made in elucidating the molecular and cellular mechanisms mediating the demise of neurons in FD should provide insight into degenerative pathways common to many neurological disorders. Interestingly, the protein encoded by IKBKAP/ELP1, IKAP or ELP1, is a key scaffolding subunit of the six-subunit Elongator complex, and variants in other Elongator genes are associated with amyotrophic lateral sclerosis (ALS), intellectual disability, and Rolandic Epilepsy. Here we review the recent model systems that are revealing the molecular and cellular pathophysiological mechanisms mediating FD. These powerful model systems can now be used to test targeted therapeutics for mitigating neuronal loss in FD and potentially other disorders.

In a region with insufficient alimentary iodine supply (Kiel, Northern Germany) the prevalence of thyroid nodules was studied by means of ultrasonography in 212 healthy women (36-50 years old) in four groups of 53 women each with 0, 1, 2, and 3-5 previous pregnancies. Goiters were found in 28.3% (15 of 53) of the women without children and in 28.9% (46 of 159) of the women with children. There was no significant increase of goiter prevalence according to the number of pregnancies. We detected thyroid nodules in 21.2% (45 of 212). Only 9.4% (5 of 53) of the women without previous pregnancies had thyroid nodules, but 25.1% (40 of 159) of the women with pregnancies in the past had nodules, the difference being statistically significant (p < 0.05). We observed nodules in 11 of 53 women with 1 child (20.7%), in 11 of 53 women with 2 children (20.7%), and in 18 of 53 women with 3-5 previous pregnancies (33.9%). We propose that, in regions with borderline or insufficient alimentary iodine supply, accentuated iodine deficiency during pregnancies due to increase of iodine requirement is a probable cause for the higher prevalence of thyroid nodules in women with previous pregnancies.

Ultrasound scans of the thyroid were performed in 106 women of mean age 41.9 (36-50) years, 53 with and 53 without a history of previous pregnancy, with the object of ascertaining the prevalence of goitre and thyroid nodules. Goitres (defined as a thyroid volume exceeding 18 ml) were found in 22 of the women with previous pregnancies (41.5%). Thyroid nodules were found in 23 of the 106 women (21.6%). Whereas only five of the 53 women without previous pregnancies (9.4%) had thyroid nodules, they were noted in 18 of the 53 women who had had children (33.9%), the difference being statistically significant (P less than 0.05). Thyroid cysts were found in 12 of the 106 women (11.3%), though there was no significant difference between the two groups. Thyroid calcification was noted in only one woman. The results highlight the consequences of iodine deficiency in a region where iodine intake is inadequate (Kiel) and show that the deficiency is accentuated during pregnancy.

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