Growth hormone treatment in children with familial dysautonomia

Introduction Familial dysautonomia (FD) is a rare hereditary sensory and autonomic neuropathy (type III). The disease is caused by a point mutation in the IKBKAP gene that affects the splicing of the elongator-1 protein (also known as IKAP). Patients have dramatic blood pressure instability due to baroreflex failure, chronic kidney disease, and impaired swallowing leading to recurrent aspiration pneumonia, which results in chronic lung disease. Diminished pain and temperature perception results in neuropathic joints and thermal injuries. Impaired proprioception leads to gait ataxia. Optic neuropathy and corneal opacities lead to progressive visual loss. Areas covered This article reviews current therapeutic strategies for the symptomatic treatment of FD, as well as the potential of new gene modifying agents. Expert opinion Therapeutic focus on FD is centered on reducing the catecholamine surges caused by baroreflex failure. Managing neurogenic dysphagia with effective protection of the airway passages and prompt treatment of aspiration pneumonias is necessary to prevent respiratory failure. Sedative medications should be used cautiously due to risk of respiratory depression. Non-invasive ventilation during sleep effectively manages apneas and prevents hypercapnia. Clinical trials of compounds that increase levels of IKAP (ELP-1) are underway and will determine whether they can reverse or slow disease progression.

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“…Six of nine patients treated for more than one year grew >5 cm/year. 85 Spinal curvature tends to worsen at times of accelerated growth.…”

Section: Growthmentioning

confidence: 99%

Current treatments in familial dysautonomia

Palma

Kaufmann

Fuente-Mora

et al. 2014

Expert Opinion on Pharmacotherapy

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“…Similar to FD patients, TgFD9; Ikbkap Δ20/flox mice showed reduced growth rate (Fig. 2B) (47) and skeletal abnormalities (Fig. 2C-G) (48).…”

Section: Generating a New Phenotypic Mouse Model For Fdmentioning

confidence: 55%

“…The rigorous characterization of this mouse revealed that TgFD9; Ikbkap Δ20/flox is an excellent model for FD. In fact, it recapitulates many of the primary FD phenotypic hallmarks, including reduced growth (47), reduced number of fungiform papillae on the tongue (10,49), spinal abnormalities (48) and sensory and autonomic impairment. The examination of E18.5 TgFD9; Ikbkap Δ20/flox embryos showed that the pathogenesis of the disease starts during the embryogenesis.…”

Section: Discussionmentioning

confidence: 73%

Sensory and autonomic deficits in a new humanized mouse model of familial dysautonomia

et al. 2016

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Familial dysautonomia (FD) is an autosomal recessive neurodegenerative disease that affects the development and survival of sensory and autonomic neurons. FD is caused by an mRNA splicing mutation in intron 20 of the IKBKAP gene that results in a tissue-specific skipping of exon 20 and a corresponding reduction of the inhibitor of kappaB kinase complex-associated protein (IKAP), also known as Elongator complex protein 1. To date, several promising therapeutic candidates for FD have been identified that target the underlying mRNA splicing defect, and increase functional IKAP protein. Despite these remarkable advances in drug discovery for FD, we lacked a phenotypic mouse model in which we could manipulate IKBKAP mRNA splicing to evaluate potential efficacy. We have, therefore, engineered a new mouse model that, for the first time, will permit to evaluate the phenotypic effects of splicing modulators and provide a crucial platform for preclinical testing of new therapies. This new mouse model, TgFD9; Ikbkap(Δ20/flox) was created by introducing the complete human IKBKAP transgene with the major FD splice mutation (TgFD9) into a mouse that expresses extremely low levels of endogenous Ikbkap (Ikbkap(Δ20/flox)). The TgFD9; Ikbkap(Δ20/flox) mouse recapitulates many phenotypic features of the human disease, including reduced growth rate, reduced number of fungiform papillae, spinal abnormalities, and sensory and sympathetic impairments, and recreates the same tissue-specific mis-splicing defect seen in FD patients. This is the first mouse model that can be used to evaluate in vivo the therapeutic effect of increasing IKAP levels by correcting the underlying FD splicing defect.

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“…Most patients with FD still have a low body mass index (BMI), slow growth rates, and short stature in adulthood (18).…”

Section: What Is Newmentioning

confidence: 99%

“…Aggressive surgical management with fundoplication to prevent vomiting and gastrostomy nutrition (17), however, has not reduced the prevalence of malnutrition in the population. Most patients with FD still have a low body mass index (BMI), slow growth rates, and short stature in adulthood (18).…”

mentioning

confidence: 99%

Resting Energy Expenditure in Patients With Familial Dysautonomia

Aluma

Norcliffe‐Kaufmann

Sarouk

et al. 2019

J. pediatr. gastroenterol. nutr.

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Objectives: Familial dysautonomia (FD) is a rare hereditary sensory and autonomic neuropathy characterized by chronic lung disease and cyclic vomiting due to hyper-adrenergic crises. Most FD patients are in a depleted nutritional state; however, the phenotype of the disease is quite different between patients, as for the severity of lung disease and the intensity and frequency of these pathognomonic crises. In this study we wanted to investigate whether resting energy expenditure (REE) levels are increased in this population, and if correlations exist between REE levels and phenotype severity. Methods: Data was collected from 12 FD patients (6/6 m/f). REE measurements were conducted by indirect calorimeter. Measured REE % predicted were correlated with pulmonary function, severity of the scoliosis, serum C-reactive protein, yearly frequency of hyperadrenergic crisis, hospital admissions and the use of nocturnal noninvasive positive pressure ventilation. Results: Mean REE was 112 ±13% predicted with 50% being in a hypermetabolic state (REE/HB > 110%). Body mass index (BMI) was below normal range in 75% of patients, and reduced energy intake was also decreased in 75%. No significant correlations to disease severity factors were found. When dividing the subjects to REE levels above or below 125% predicted, Patients with REE above 125% predicted presented with significantly lower inspiratory capacity (42.7% predicted vs 62.8% predicted; P = 0.04). Conclusions: Hypermetabolic state was described in 50% of FD patients. The Low BMI is explained by combination of relative anorexia and increased REE. The REE levels are related to the underling respiratory disease.

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Growth hormone treatment in children with familial dysautonomia

Cited by 11 publications

References 17 publications

Current treatments in familial dysautonomia

Current treatments in familial dysautonomia

Sensory and autonomic deficits in a new humanized mouse model of familial dysautonomia

Resting Energy Expenditure in Patients With Familial Dysautonomia

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