Fatty acid oxidation defects presenting as primary myopathy and prominent dropped head syndrome

Vengalil, Seena; Preethish‐Kumar, Veeramani; Polavarapu, Kiran; Christopher, Rita; Gayathri, Narayanappa; Natarajan, Archana; Mahadevappa, Manjunath; Nashi, Saraswati; Prasad, Chandrajit; Nalini, Atchayaram

doi:10.1016/j.nmd.2017.08.004

Cited by 19 publications

(10 citation statements)

References 41 publications

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“…All suspected LSD cases were subjected to blood‐based tandem mass spectrometry for quantitative analysis of abnormal lipid metabolism as part of routine diagnostics, as described previously (Vengalil et al . ).…”

Section: Methodsmentioning

confidence: 97%

Mitochondrial dysfunction in human skeletal muscle biopsies of lipid storage disorder

Bandopadhyay

Kumar

Prasad

et al. 2018

Journal of Neurochemistry

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Mitochondria regulate the balance between lipid metabolism and storage in the skeletal muscle. Altered lipid transport, metabolism and storage influence the bioenergetics, redox status and insulin signalling, contributing to cardiac and neurological diseases. Lipid storage disorders (LSDs) are neurological disorders which entail intramuscular lipid accumulation and impaired mitochondrial bioenergetics in the skeletal muscle causing progressive myopathy with muscle weakness. However, the mitochondrial changes including molecular events associated with impaired lipid storage have not been completely understood in the human skeletal muscle. We carried out morphological and biochemical analysis of mitochondrial function in muscle biopsies of human subjects with LSDs (n = 7), compared to controls (n = 10). Routine histology, enzyme histochemistry and ultrastructural analysis indicated altered muscle cell morphology and mitochondrial structure. Protein profiling of the muscle mitochondria from LSD samples (n = 5) (vs. control, n = 5) by high-throughput mass spectrometric analysis revealed that impaired metabolic processes could contribute to mitochondrial dysfunction and ensuing myopathy in LSDs. We propose that impaired fatty acid and respiratory metabolism along with increased membrane permeability, elevated lipolysis and altered cristae entail mitochondrial dysfunction in LSDs. Some of these mechanisms were unique to LSD apart from others that were common to dystrophic and inflammatory muscle pathologies. Many differentially regulated mitochondrial proteins in LSD are linked with other human diseases, indicating that mitochondrial protection via targeted drugs could be a treatment modality in LSD and related metabolic diseases. Cover Image for this Issue: doi: 10.1111/jnc.14177.

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Section: Methodsmentioning

confidence: 97%

Mitochondrial dysfunction in human skeletal muscle biopsies of lipid storage disorder

Bandopadhyay

Kumar

Prasad

et al. 2018

Journal of Neurochemistry

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“…3 Misdiagnoses with polymyositis and psychiatric disorder, as well as delay of precise diagnosis, are reported. 3,4 In our patient, the blood acylcarnitine profile was normal. This test is generally helpful when lipid metabolism disorder is suspected; it must be performed after at least a 12-hour fasting period, and it usually reveals the accumulation of all types of acylcarnitines (C4-C18).…”

Section: Discussionmentioning

confidence: 52%

Pearls & Oy-sters: A curable myopathy manifesting as exercise intolerance and respiratory failure

et al. 2018

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Few forms of severe genetic myopathies can successfully be treated, although multiple acyl-CoA dehydrogenase deficiency (MADD) is highly responsive to riboflavin supplementation. c Muscle MRI and muscle biopsy play important roles in patients with exercise intolerance and dyspnea when metabolic myopathy is suspected. Oysters c EMG and serum creatine kinase (CK) levels may be normal in metabolic myopathies. Muscle biopsy may be the only abnormal ancillary examination. c MADD must be considered in cases of rapidly progressive respiratory insufficiency, as this condition is potentially treatable. Case report A 32-year-old woman presented with a 2-year history of progressive exercise intolerance and lower limb myalgia. She noted progressive difficulty in walking long distances and climbing stairs as well as dyspnea. No relevant familial history or consanguinity was reported. The patient's motor development was unremarkable.

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“…We also observed increased lipid accumulation in cardiac muscle and in glycolytic type IIb fibers of the genioglossus (tongue) muscle in fasted and exercised VLCADD mice compared to WT controls. The tongue was included in our study because VLCADD patients may have bulbar weakness . This is one of the most important bulbar muscles and plays an important role in breathing.…”

Section: Discussionmentioning

confidence: 99%

“…The tongue was included in our study because VLCADD patients may have bulbar weakness. 21 This is one of the most important bulbar muscles and plays an important role in breathing. Specifically, contraction of extrinsic tongue muscles, particularly the genioglossus, can dilate and/or stiffen the pharyngeal lumen, thereby minimizing airway narrowing and/or collapse in the face of negative inspiratory pressures.…”

Section: Impact Of Vlcadd On Musclementioning

confidence: 99%

AAV9 gene replacement therapy for respiratory insufficiency in very‐long chain acyl‐CoA dehydrogenase deficiency

Zieger

Keeler

Flotte

et al. 2019

J of Inher Metab Disea

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Very‐long chain acyl‐CoA dehydrogenase (VLCAD) deficiency (VLCADD) is an autosomal recessive disorder of fatty acid oxidation. Fatty acids are a major source of energy during catabolic stress, so the absence of VLCAD can result in a metabolic crises and respiratory insufficiency. The etiology of this respiratory insufficiency is unclear. Thus, our aims were: (1) to characterize respiratory pathophysiology in VLCADD mice (VLCAD−/−), and (2) to determine if AAV9‐mediated gene therapy improves respiratory function. For the first aim, VLCAD−/− and wild‐type (WT) mice underwent an exercise/fast “stress protocol” and awake spontaneous breathing was evaluated using whole‐body plethysmography (WBP) both at baseline and during a hypercapnic respiratory challenge (FiO2: 0.21; FiCO2: 0.07; nitrogen balance). During hypercapnia, VLCAD −/− mice had a significantly lower frequency, tidal volume, minute ventilation, and peak inspiratory and expiratory flow, all of which indicate respiratory insufficiency. Histologically, the cardiac and respiratory muscles of stressed VLCAD −/− animals had an accumulation of intramyocellular lipids. For the second aim, a single systemic injection of AAV9‐VLCAD gene therapy improved this respiratory pathology by normalizing breathing frequency and enhancing peak inspiratory flow. In addition, following gene therapy, there was a moderate reduction of lipid accumulation in the respiratory muscles. Furthermore, VLCAD protein expression was robust in cardiac and respiratory muscle. This was confirmed by immuno‐staining with anti‐human VLCAD antibody. In summary, stress with exercise and fasting induces respiratory insufficiency in VLCAD−/− mice and a single injection with AAV9‐VLCAD gene therapy ameliorates breathing.

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Fatty acid oxidation defects presenting as primary myopathy and prominent dropped head syndrome

Cited by 19 publications

References 41 publications

Mitochondrial dysfunction in human skeletal muscle biopsies of lipid storage disorder

Mitochondrial dysfunction in human skeletal muscle biopsies of lipid storage disorder

Pearls & Oy-sters: A curable myopathy manifesting as exercise intolerance and respiratory failure

AAV9 gene replacement therapy for respiratory insufficiency in very‐long chain acyl‐CoA dehydrogenase deficiency

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