Hyperleptinemia in children with autosomal recessive spinal muscular atrophy type I-III

Abstract

BackgroundAutosomal-recessive proximal spinal muscular atrophies (SMA) are disorders characterized by a ubiquitous deficiency of the survival of motor neuron protein that leads to a multisystemic disorder, which mostly affects alpha motor neurons. Disease progression is clinically associated with failure to thrive or weight loss, mainly caused by chewing and swallowing difficulties. Although pancreatic involvement has been described in animal models, systematic endocrinological evaluation of the energy metabolism in humans is lacking.MethodsIn 43 patients with SMA type I-III (8 type I; 22 type II; 13 type III), aged 0.6–21.8 years, auxological parameters, pubertal stage, motor function (Motor Function Measurement 32 –MFM32) as well as levels of leptin, insulin glucose, hemoglobin A1c, Homeostasis Model Assessment index and an urinary steroid profile were determined.ResultsHyperleptinemia was found in 15/35 (43%) of our patients; 9/15 (60%) of the hyperleptinemic patients were underweight, whereas 1/15 (7%) was obese. Hyperleptinemia was associated with SMA type (p = 0.018). There was a significant association with decreased motor function (MFM32 total score in hyperleptinemia 28.5%, in normoleptinemia 54.7% p = 0.008, OR 0.969; 95%-CI: 0.946–0.992). In addition, a higher occurrence of hirsutism, premature pubarche and a higher variability of the urinary steroid pattern were found.ConclusionHyperleptinemia is highly prevalent in underweight children with SMA and is associated with disease severity and decreased motor function. Neuronal degradation of hypothalamic cells or an increase in fat content by muscle remodeling could be the cause of hyperleptinemia.

Diagnosis and management of spinal muscular atrophy: Part 2: Pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics

“…As reported in the part on nutritional care, occasional cases of pancreatic dysfunction including diabetes and alterations in glucose metabolism have been reported in SMA patients [56]. Hyperleptinemia has been identified in SMA patients with types 1, 2 and 3 [57]. Mitochondrial dysfunction has been described in patients and human neuronal cell lines [21,58,59].…”

Low-Intensity Running and High-Intensity Swimming Exercises Differentially Improve Energy Metabolism in Mice With Mild Spinal Muscular Atrophy

“…The high variability in metabolic alterations in SMA patients (Dahl and Peters, 1975; Bruce et al, 1995; Tein et al, 1995; Crawford et al, 1999; Berger et al, 2003; Sproule et al, 2009; Zolkipli et al, 2012; Davis et al, 2015; Bertoli et al, 2017; Kolbel et al, 2017) and mouse models (Bowerman et al, 2012, 2014; Ripolone et al, 2015) can preclude or limit the application, design or efficiency of therapies, including active exercise. Thus, deciphering the origin and mechanisms involved in those metabolic alterations and the way to modulate them appeared crucial.…”

“…It is admitted today that the metabolic status of SMA patients are diverse, notably in terms of diabetes, obesity or insulinemia (Davis et al, 2015; Kolbel et al, 2017), resulting in different abilities for them to perform active exercise. Therefore, particular attention should be paid to the exercise paradigm used, in order to fit the training protocol to the expected metabolic adaptation of each patient.…”

Pathogenic commonalities between spinal muscular atrophy and amyotrophic lateral sclerosis: Converging roads to therapeutic development

“…While it remains unclear whether intrinsic metabolic defects in specific cells and tissues such as motoneurons, skeletal muscle, glial cells and lymphoid organs or a systemic metabolic dysregulation are the source of dyshomeostasis in SMA and ALS, patients nevertheless present syndromes that have well-documented severe functional consequences. Indeed, instances of hyperinsulinemia (Bowerman et al, 2014;Davis et al, 2015), insulin resistance (Davis et al, 2015;Reyes et al, 1984), hyperlipidemia (Dahl and Peters, 1975;Dedic et al, 2012), hyperglycemia (Melissa Bowerman et al, 2012;Shimizu et al, 2011), hyperleptinemia (Kölbel et al, 2017), aberrant fatty acid metabolism (Pradat et al, 2010;Zolkipli et al, 2012), hypoglycemia (Bruce et al, 1995), hyperglucagonemia (Melissa Bowerman et al, 2012;Hubbard et al, 1992), glucose intolerance (Davis et al, 2015;Pradat et al, 2010) and development of diabetes (Borkowska et al, 2015;Hamasaki et al, 2015) have all been reported in SMA and ALS patients and animal models. As we move along therapeutic progress for both diseases, it will be interesting to see if the gene-targeted therapies correct the metabolic abnormalities described herein or if they will have to be complemented with interventions aimed at restoring metabolic homeostasis.…”