Preliminary observations of mitochondrial dysfunction in Prader–Willi syndrome

Abstract

Prader-Willi syndrome (PWS) is a complex multi-system disorder due to errors in genomic imprinting with severe hypotonia, decreased muscle mass, poor suckling, feeding problems and failure to thrive during infancy, growth and other hormone deficiency, childhood-onset hyperphagia and subsequent obesity. Decreased energy expenditure in PWS is thought to contribute to reduced muscle mass and physical activity but may also relate to cellular metabolism and disturbances in mitochondrial function. We established fibroblast cell lines from six children and adults with PWS and six healthy controls for mitochondrial assays. We used Agilent Seahorse XF extra-cellular flux technology to determine real-time measurements of several metabolic parameters including cellular substrate utilization, ATP-linked respiration and mitochondrial capacity in living cells. Decreased mitochondrial function was observed in the PWS patients compared to the healthy controls with significant differences in basal respiration, maximal respiratory capacity and ATP-linked respiration. These results suggest disturbed mitochondrial bioenergetics in PWS although a low number of studied subjects will require a larger subject population before a general consensus can be reached to identify if mitochondrial dysfunction is a contributing factor in PWS.

Increased brain age in adults with Prader-Willi syndrome

“…A recent report of gene expression in post-mortem hypothalamic tissue in PWS reported a transcriptomic profile similar to that seen in neurodegenerative conditions and the aging brain, with downregulated genes mainly found in neuronal cells and involved in neurogenesis and synaptic plasticity, while upregulated genes were mainly microglial and associated with inflammatory responses ( Bochukova et al, 2018 ). In addition, a recent small study found decreased ex vivo mitochondrial function in fibroblast cell lines from patients with PWS (especially in those with deletion genotype) that might also play a pathogenic role in accelerated brain aging if also seen in other cell types ( Butler et al, 2018 ).…”

Analysis of the Prader–Willi syndrome imprinting center using droplet digital PCR and next‐generation whole‐exome sequencing

“…PWS2 possessed a single autosomal recessive gene variant ( TTC19 ) involving mitochondrial complex III deficiency which may have functional relevance in an individual with PWS. Recently, mitochondrial dysfunction has been reported in living cells from individuals with PWS (Butler, Hartin et al, ; Butler, Hossain et al, ). This specific gene variant has not been associated with a disorder and is classified as having an uncertain clinical significance.…”

“…The most recent PWS frequency data shows the 15q11‐q13 deletion is lower at 60% of cases while mUPD15 is higher at 36% than previously reported, potentially due to advanced maternal age. Imprinting center defects including microdeletions or failure to establish the correct methylation pattern (epimutations) are seen in the remaining 4% of individuals with PWS (Butler, Hartin et al, ; Butler, Hossain, Tessman, & Krishnamurthy, ). Earlier literature suggested that 15%–20% of those with PWS and IC defects are caused by a microdeletion in the IC (Buiting et al, ; Sutcliffe et al, ), associated with the 50% recurrence risk.…”

“…Techniques such as high‐resolution chromosomal single nucleotide polymorphism (SNP) MAs are used to detect deletions and to determine the three mUPD15 subclasses (total isodisomy, segmental isodisomy, and heterodisomy). The MA‐based analyses often have clinically required cutoff parameters including identification of a 100 kbp fragment with 50 or more DNA probes, before deletions are diagnostically considered confirmed (Butler, Hartin et al, ; Butler, Hossain et al, ). Furthermore, the number of probes in the PWS‐SRO region may be sparse or absent in oligonucleotide arrays and not helpful in distinguishing between different IC defects (microdeletions or epimutations).…”

Prolapsed Rectum and Risk Factors in Prader–Willi Syndrome: A Case-Based Review

“…Hormone deficiencies are also recognized in PWS along with a lower metabolic rate. 19 Confounding predisposing factors for developing rectal damage and prolapse besides chronic constipation may include obsessivecompulsions, self-stimulation and self-injury, rectal picking, and digital manipulation along with a lower pain sensation compared with the general population. 3 Skin picking behavior in PWS can be pronounced leading to significant comorbidities including bleeding and loss of tissue at the wound sites with infections and ulcerations requiring medical and/or surgical intervention.…”