Metabolic and Nutritional Issues Associated with Spinal Muscular Atrophy

Abstract

Spinal muscular atrophy (SMA), the main genetic cause of infant death, is a neurodegenerative disease characterized by the selective loss of motor neurons in the anterior horn of the spinal cord, accompanied by muscle wasting. Pathomechanically, SMA is caused by low levels of the survival motor neuron protein (SMN) resulting from the loss of the SMN1 gene. However, emerging research extends the pathogenic effect of SMN deficiency beyond motor neurons. A variety of metabolic abnormalities, especially altered fatty acid metabolism and impaired glucose tolerance, has been described in isolated cases of SMA; therefore, the impact of SMN deficiency in metabolic abnormalities has been speculated. Although the life expectancy of these patients has increased due to novel disease-modifying therapies and standardization of care, understanding of the involvement of metabolism and nutrition in SMA is still limited. Optimal nutrition support and metabolic monitoring are essential for patients with SMA, and a comprehensive nutritional assessment can guide personalized nutritional therapy for this vulnerable population. It has recently been suggested that metabolomics studies before and after the onset of SMA in patients can provide valuable information about the direct or indirect effects of SMN deficiency on metabolic abnormalities. Furthermore, identifying and quantifying the specific metabolites in SMA patients may serve as an authentic biomarker or therapeutic target for SMA. Here, we review the main epidemiological and mechanistic findings that link metabolic changes to SMA and further discuss the principles of metabolomics as a novel approach to seek biomarkers and therapeutic insights in SMA.

Metabolic Dysfunction in Spinal Muscular Atrophy

“…Low-fat diets with high sucrose content had the best effect in normalizing abnormal readouts (such as ketones), suggesting that this led to lesser reliance on fat as an energy source [ 41 ]. However, some discordant studies exist and have been discussed more extensively elsewhere [ 41 , 62 , 257 ]. An early small study looking at a low-fat/high carbohydrate diet claimed positive results [ 92 ], but concerns about its validity remain as this was ahead of genetic testing and the classification of patients was unclear.…”

Nutritional, Gastrointestinal and Endo-Metabolic Challenges in the Management of Children with Spinal Muscular Atrophy Type 1

“…Many studies have reported various forms of undernutrition and overnutrition in SMA patients, suggesting a multifactorial impairment that can produce different nutritional phenotypes [ 25 , 26 ]. For this reason, energy needs should be properly evaluated in each patient.…”

“…Another interesting role of artificial nutrition in SMA1 has been explained by MC Ørngreen et al [ 42 ]. This study shows how in SMA1, as in all neurodegenerative diseases, a greater tendency to develop hypoglycemia during the fasting phases can be observed; the reason of this phenomenon seems to be to the lack of muscle mass as an important supplier of substrates for gluconeogenesis; therefore, due to the extremely reduced muscle mass, gluconeogenesis is less effective in these patients [ 26 ]. For this reason, an important role of artificial nutrition is to prevent prolonged fasting and, subsequently, hypoglycemia.…”

“…One of the major metabolic problems is the dysregulation of lipid profile. An increasing number of studies have shown that patients with severe forms of SMA have metabolic abnormalities involving the metabolism of fatty acids [ 26 , 80 ].…”

“…In fact, in most SMA patients, a normal profile of both acylcarnitine and ketones, which is typically altered in classical disorders of fatty acid transport and mitochondrial oxidation, can be observed. This evidence seems to reflect a correct utilization of fatty acids by the liver under conditions of fasting or stress [ 26 ]. However, aciduria of small and medium chained fatty acids has been more strongly associated with SMA1 if compared to milder types of SMA, suggesting that metabolic abnormalities may depend on SMA severity [ 82 , 83 ].…”