Abnormal fatty acid metabolism in childhood spinal muscular atrophy

Abstract

Our previous experience with abnormal fatty acid metabolism in several children with spinal muscular atrophy (SMA) prompted evaluation of fatty acid metabolism in a larger cohort. Thirty‐three infants with severe infantile SMA were shown to have a significantly increased ratio of dodecanoic to tetradecanoic acid in plasma compared with normal infants and 6 infants affected with equally debilitating, non‐SMA denervating disorders. Seventeen children with milder forms of SMA had normal fatty acid profiles. In addition, all 5 infants with severe SMA evaluated in a fasting state developed a distinctive and marked dicarboxylic aciduria, including saturated, unsaturated, and 3‐hydroxy forms, comparable in severity with the dicarboxylic aciduria of children with primary defects of mitochondrial fatty acid β‐oxidation. Nine children with chronic SMA and 23 control patients did not develop an abnormal dicarboxylic aciduria during fasting. No known disorder of fatty acid metabolism explains all of the abnormalities we find in SMA. Our data suggest, however, that the abnormalities are not a consequence of SMA‐related immobility, systemic illness, muscle denervation, or muscle atrophy. These abnormalities in fatty acid metabolism may be caused by changes in cellular physiology related to the molecular defects of the SMA‐pathogenic survival motor neuron gene or neighboring genes. Ann Neurol 1999;45:337–343

Congenital heart disease is a feature of severe infantile spinal muscular atrophy

“…Other neurodegenerative disorders are associated with extra-neuronal manifestations in their most severe expression. In this context it is worth noting that an abnormal fatty acid metabolism was found in infants with severe SMA but not in milder forms or controls 24. Further studies are required to investigate the impact of SMN on different steps of cardiogenesis and more specifically of cardiac septation.…”

Defects in pancreatic development and glucose metabolism in SMN-depleted mice independent of canonical spinal muscular atrophy neuromuscular pathology

“…Past reports have identified metabolic abnormalities in SMA patients, including metabolic acidosis, abnormal fatty acid metabolism, hyperlipidemia and hyperglycemia (50–53). Here, we highlight the fact that patients with milder forms of SMA (types II, III and IV), may, overtime, exhibit metabolic dysfunction that is a direct result of ‘low’ level Smn protein reduction.…”

Is spinal muscular atrophy a disease of the motor neurons only: pathogenesis and therapeutic implications?

“…The most common metabolic defect reported consists of alterations in fatty acid metabolism, which occurs in severe patients and some younger SMA Type II patients [143,144]. Abnormal fatty acid metabolism is characterized by mild to moderate dicarboxylic aciduria and increased levels of esterified carnitine.…”

“…These data suggest that the fatty acid metabolism dysfunction in SMA is not the consequence of SMA-related immobility, systemic illness, muscle denervation, or muscle atrophy. Rather these abnormalities may be directly related to the loss of SMN1 or neighboring genes [144]. The importance of SMN protein in the development and function of the liver was demonstrated by Vitte and colleagues in 2004 using the Δ7 SMA in vivo model.…”