A Cephalometric Evaluation of Craniofacial Morphology in Familial Dysautonomia

Mass, Eliyahu; Brin, Ilana; Belostoky, Leon; Maayan, Channa; Gadoth, Natan

doi:10.1597/1545-1569(1998)035<0120:aceocm>2.3.co;2

Cited by 10 publications

(6 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Wnt1-cKO mice showed no body dysmorphisms, but could be readily distinguished from littermates by a slightly recessed mandible (retrognathia; Fig. 2D, arrowhead), similar to humans with FD (Mass et al, 1998), their labored breathing (supplementary material Movie 1) and their distended abdomen (Fig. 2D, arrow).…”

Section: Generating Viable Elp1 Conditional Knockout Micementioning

confidence: 84%

A neuron autonomous role for the familial dysautonomia geneELP1in sympathetic and sensory target tissue innervation

Jackson¹,

Gruner

Qin

et al. 2014

Development

View full text Add to dashboard Cite

Familial dysautonomia (FD) is characterized by severe and progressive sympathetic and sensory neuron loss caused by a highly conserved germline point mutation of the human ELP1/IKBKAP gene. Elp1 is a subunit of the hetero-hexameric transcriptional elongator complex, but how it functions in disease-vulnerable neurons is unknown. Conditional knockout mice were generated to characterize the role of Elp1 in migration, differentiation and survival of migratory neural crest (NC) progenitors that give rise to sympathetic and sensory neurons. Loss of Elp1 in NC progenitors did not impair their migration, proliferation or survival, but there was a significant impact on post-migratory sensory and sympathetic neuron survival and target tissue innervation. Ablation of Elp1 in post-migratory sympathetic neurons caused highly abnormal target tissue innervation that was correlated with abnormal neurite outgrowth/branching and abnormal cellular distribution of soluble tyrosinated α-tubulin in Elp1-deficient primary sympathetic and sensory neurons. These results indicate that neuron loss and physiologic impairment in FD is not a consequence of abnormal neuron progenitor migration, differentiation or survival. Rather, loss of Elp1 leads to neuron death as a consequence of failed target tissue innervation associated with impairments in cytoskeletal regulation.

show abstract

Section: Generating Viable Elp1 Conditional Knockout Micementioning

confidence: 84%

A neuron autonomous role for the familial dysautonomia geneELP1in sympathetic and sensory target tissue innervation

Jackson¹,

Gruner

Qin

et al. 2014

Development

View full text Add to dashboard Cite

show abstract

“…S2 A and B). Children with FD can exhibit retrognathism of the mandible and a resulting reduced inferior facial angle (24). Because the Wnt1 + cranial crest orchestrates and contributes to much of the cranial facial morphology (23), we measured the inferior facial angle and the position of the mandible relative to the most anterior point on the face (25) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Familial dysautonomia model reveals Ikbkap deletion causes apoptosis of Pax3 ⁺ progenitors and peripheral neurons

George

Chaverra

Wolfe

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

159

View full text Add to dashboard Cite

Familial dysautonomia (FD) is a devastating developmental and progressive peripheral neuropathy caused by a mutation in the gene inhibitor of kappa B kinase complex-associated protein (IKBKAP). To identify the cellular and molecular mechanisms that cause FD, we generated mice in which Ikbkap expression is ablated in the peripheral nervous system and identify the steps in peripheral nervous system development that are Ikbkap-dependent. We show that Ikbkap is not required for trunk neural crest migration or pathfinding, nor for the formation of dorsal root or sympathetic ganglia, or the adrenal medulla. Instead, Ikbkap is essential for the second wave of neurogenesis during which the majority of tropomyosin-related kinase A (TrkA + ) nociceptors and thermoreceptors arise. In its absence, approximately half the normal complement of TrkA + neurons are lost, which we show is partly due to p53-mediated premature differentiation and death of mitotically-active progenitors that express the paired-box gene Pax3 and give rise to the majority of TrkA + neurons. By the end of sensory development, the number of TrkC neurons is significantly increased, which may result from an increase in Runx3 + cells. Furthermore, our data demonstrate that TrkA + (but not TrkC + ) sensory and sympathetic neurons undergo exacerbated Caspase 3-mediated programmed cell death in the absence of Ikbkap and that this death is not due to a reduction in nerve growth factor synthesis. In summary, these data suggest that FD does not result from a failure in trunk neural crest migration, but rather from a critical function for Ikbkap in TrkA progenitors and TrkA + neurons.H ereditary sensory and autonomic neuropathies (HSANs) are a group of five phenotypically diverse but overlapping disorders of the peripheral nervous system (PNS) that result from mutations in 12 distinct genes (1). HSAN type 3, or familial dysautonomia (FD) (also called Riley-Day syndrome), results from an intronic mutation (IVS20 + 6T > C; 99.5% of patients) in a gene called inhibitor of kappa B kinase complex-associated protein or IKBKAP, causing mis-splicing and subsequent tissuespecific reductions in IKAP protein (2, 3). FD is marked by tachycardia, blood pressure lability, autonomic vomiting "crises," decreased pain and temperature sensation, and commonly death during early adulthood (4). The function of IKAP in the nervous system is unclear, nor is it understood why deletions in this broadly expressed gene primarily devastate the PNS. The earliest pathology study, performed on a 2-y-old child with FD, showed that ∼90% of cells in the dorsal root and sympathetic ganglia (SG) were missing (5). To identify IKAP's function in the developing PNS, we first need to establish the steps in which it is essential.The vertebrate PNS derives primarily from the neural crest, a multipotent, heterogeneous cell population that delaminates from the neural tube and migrates throughout the embryo (6). Those neural crest cells that stop laterally to the neural tube give rise to the chain of sensory...

show abstract

“…described craniofacial anomalies in FD patients, with retrognathic position of the maxilla and particularly the mandibular, reclination of the lower incisors, and small jaws, which frequently cause difficulties in airway management during sedation or anesthesia. 21 Similarly, thoracic deformities are frequent in FD patients and may compromise respiration. 20 Kyphoscoliosis of FD patients, with forward inclination of the head and neck, aggravates the risk of airway collapse upon sedation or sleep.…”

Section: Obstructive Apneas Were More Common Than Central Apneas In Omentioning

confidence: 99%

“…5 While obstructive apneas can be treated with continuous positive airway pressure (CPAP), this treatment is less successful in central sleep apneas. 9,10 In FD patients, the pathology with central and peripheral autonomic dysfunction, 2,4,[11][12][13][14][15][16][17][18][19] kyphoscoliosis, 20 and craniofacial abnormalities 21 may give rise to both central and obstructive sleep apneas.…”

Section: Introductionmentioning

confidence: 99%

Obstructive Sleep-Disordered Breathing Is More Common than Central in Mild Familial Dysautonomia

Hilz

Moeller

Buechner

et al. 2016

Journal of Clinical Sleep Medicine

View full text Add to dashboard Cite

Study Objectives:In familial dysautonomia (FD) patients, sleep-disordered breathing (SDB) might contribute to their high risk of sleep-related sudden death. Prevalence of central versus obstructive sleep apneas is controversial but may be therapeutically relevant. We, therefore, assessed sleep structure and SDB in FD-patients with no history of SDB. Methods: 11 mildly affected FD-patients (28 ± 11 years) without clinically overt SDB and 13 controls (28 ± 10 years) underwent polysomnographic recording during one night. We assessed sleep stages, obstructive and central apneas (≥ 90% air flow reduction) and hypopneas (> 30% decrease in airflow with ≥ 4% oxygen-desaturation), and determined obstructive (oAI) and central (cAI) apnea indices and the hypopnea index (HI) as count of respective apneas/hypopneas divided by sleep time. We obtained the apnea-hypopnea index (AHI4%) from the total of apneas and hypopneas divided by sleep time. We determined differences between FD-patients and controls using the U-test and within-group differences between oAIs, cAIs, and HIs using the Friedman test and Wilcoxon test. Results: Sleep structure was similar in FD-patients and controls. AHI4% and HI were significantly higher in patients than controls. In patients, HIs were higher than oAIs and oAIs were higher than cAIs. In controls, there was no difference between HIs, oAIs, and cAIs. Only patients had apneas and hypopneas during slow wave sleep. Conclusions: In our FD-patients, obstructive apneas were more common than central apneas. These findings may be related to FD-specific pathophysiology. The potential ramifications of SDB in FD-patients suggest the utility of polysomnography to unveil SDB and initiate treatment. Commentary: A commentary on this article appears in this issue on page 1583. Keywords: familial dysautonomia, hereditary sensory and autonomic neuropathy type III, obstructive sleep apnea, sleep-disordered breathing Citation: Hilz MJ, Moeller S, Buechner S, Czarkowska H, Ayappa I, Axelrod FB, Rapoport DM. Obstructive sleep-disordered breathing is more common than central in mild familial dysautonomia.

show abstract

A Cephalometric Evaluation of Craniofacial Morphology in Familial Dysautonomia

Abstract: The results suggest an insufficiency of the expected dentoalveolar compensatory mechanism that usually helps to bridge skeletal discrepancies. It is postulated that the neuropathy is probably the important factor in the lack of this compensatory mechanism.

Cited by 10 publications

References 0 publications

A neuron autonomous role for the familial dysautonomia geneELP1in sympathetic and sensory target tissue innervation

A neuron autonomous role for the familial dysautonomia geneELP1in sympathetic and sensory target tissue innervation

Familial dysautonomia model reveals Ikbkap deletion causes apoptosis of Pax3 ⁺ progenitors and peripheral neurons

Obstructive Sleep-Disordered Breathing Is More Common than Central in Mild Familial Dysautonomia

Contact Info

Product

Resources

About

A Cephalometric Evaluation of Craniofacial Morphology in Familial Dysautonomia

Abstract: The results suggest an insufficiency of the expected dentoalveolar compensatory mechanism that usually helps to bridge skeletal discrepancies. It is postulated that the neuropathy is probably the important factor in the lack of this compensatory mechanism.

Cited by 10 publications

References 0 publications

A neuron autonomous role for the familial dysautonomia geneELP1in sympathetic and sensory target tissue innervation

A neuron autonomous role for the familial dysautonomia geneELP1in sympathetic and sensory target tissue innervation

Familial dysautonomia model reveals Ikbkap deletion causes apoptosis of Pax3 + progenitors and peripheral neurons

Obstructive Sleep-Disordered Breathing Is More Common than Central in Mild Familial Dysautonomia

Contact Info

Product

Resources

About

Familial dysautonomia model reveals Ikbkap deletion causes apoptosis of Pax3 ⁺ progenitors and peripheral neurons