Triple A Syndrome: Preliminary Response to the Antioxidant N-Acetylcysteine Treatment in a Child

Abstract

Introduction: Triple A syndrome (AAAS) is a rare autosomal recessive disorder characterized by alacrima, achalasia, ACTH-resistant adrenal insufficiency, autonomic dysfunction, and progressive neurodegeneration. Increased oxidative stress, demonstrated in patients’ fibroblasts in vitro, may be a central disease mechanism. N-acetylcysteine protects renal function in patients with kidney injuries associated with increased oxidative stress and improves viability of AAAS-knockdown adrenal cells in vitro. Patient and Results: A boy diagnosed with AAAS presented with short stature and increased oxidative stress in vivo assessed by increased thiobarbituric acid reactive substances (TBARS), which are markers of lipid peroxidation, and by the susceptibility of LDL to oxidation and the capacity of HDL to prevent it. A homozygous missense germline mutation (c.523G>T, p.Val175Phe) in AAAS was identified. N-acetylcysteine (600 mg orally, twice daily) decreased oxidative stress but did not change the patient’s growth pattern. Conclusions: An increase in oxidative stress is reported for the first time in vivo in an AAAS patient. N-acetylcysteine was capable of decreasing TBARS levels, reducing the susceptibility of LDL to oxidation and improving the antioxidant role of HDL. The long-term effect of antioxidant treatment should be evaluated to determine the real benefit for the prevention of the degenerative process in AAAS.

Compensation for Chronic Oxidative Stress in Aladin Null Mice

“…Previous studies have demonstrated that ALADIN employs a crucial role in the redox response of the cell in vitro [12][13][14][15][16][17]. Triple A patients as well suffer from increased cellular oxidative stress as preliminary shown by Fragoso et al [28]. Thus, we hypothesized that chronic oxidative stress will unmask the distinct phenotype in ALADIN null mice.…”

The Retina in Patients With Triple A Syndrome: A Window Into Neurodegeneration?

“…Deficiency of ALADIN Impairs Redox Homeostasis in vitro in Adrenal and neuronal cells. ( 22 ) and markers of oxidative stress have been measured in a child with Triple A syndrome ( 10 ).…”

“…The oxidative stress was assessed by measurements of a lipid peroxidation product, thiobarbituric acid reactive substances in plasma and measurement of reduced glutathione in whole blood. N-acetylcysteine was shown to lower lipid peroxidation products and increase reduced glutathione levels in the patient ( 5 , 10 ). Our study documenting severe thinning of the retinal layers in children and adults with Triple A syndrome points towards OCT as a useful follow-up tool in these patients.…”

“…ALADIN has also been shown to interact directly with progesterone receptor membrane component 2 (PGRMC2), a microsomal protein known to regulate cytochrome P450 hydroxylases and oxidoreductases, which are critical for maintaining the cellular oxidative state and for generating precursors for hormones like cortisol ( 9 ). In vivo , a study in one patient revealed oxidative stress, evidenced by lipid peroxidation and LDL oxidation measurements ( 10 ).…”

Compensation for chronic oxidative stress in ALADIN null mice

“…Previous studies have demonstrated that ALADIN employs a crucial role in the redox response of the cell in vitro ( Hirano et al, 2006 ; Jühlen et al, 2015 ; Kind et al, 2010 ; Koehler et al, 2013 ; Prasad et al, 2013 ; Storr et al, 2009 ). Triple A patients also suffer from increased cellular oxidative stress, as shown by Fragoso et al (2017) . Thus, we hypothesized that chronic oxidative stress would unmask the distinct phenotype in ALADIN null mice.…”