Abstract & Commentary
Source: Vockley J, Whiteman DAH. Defects of mitochondrial beta-oxidation: A growing group of disorders. Neuromuscul Disord. 2002;12:235-246.
First described in 1973, at least 22 inborn disorders of fatty acid metabolism are currently recognized, many of which produce myopathy or neuropathy, and are, thus, of interest to the neurologist. Beta-oxidation denotes the process by which free fatty acids (FFAs) lose 2 carbon units at a time, with the end result being generation of ATP by hydrogen ion transfer down the electron transport chain. FFAs, derived from the diet or fat stores, are metabolized in peroxisomes if carbon length is more than 20, and in mitochondria if carbon length is 20 or less.
FFAs enter the cell cytoplasm from blood by a poorly characterized specific transport process and must be transformed into acyl-CoA thioesters, by acyl-CoA synthase, prior to entering the mitochondria. Carnitine palmitoyl transferase I (CPT I), located on the inner aspect of the outer mitochondrial membrane, conjugates carnitine with the acyl-CoA thioester forming acylcarnitine and, by carnitine-acylcarnitine translocase (CAT), passes it onto CPT II, located in the inner mitochondrial membrane, allowing acylcarnitine to enter the mitochondrial matrix. Importantly, carnitine itself must be transported into the cell from blood by a specific transporter protein. Once inside the mitochondria, 2 carbon acetyl-CoA units are sequentially cleaved from acylcarnitine via beta-oxidation. ACDs (acyl-CoA dehydrogenases) catalyze the removal of the 2 carbon fragments, with 4 specific enzymes being involved: VLCAD, LCAD, MCAD, and SCAD responsible for very long chain, long chain, medium chain, and short chain acyl-CoA dehydrogenation, respectively. Energy (ATP) is ultimately generated when acetyl-CoA is oxidized to carbon dioxide and water in the citric acid cycle. This releases hydrogen ions which are transported down the respiratory chain to generate ATP. Defects at all these levels have been described and those of potential interest to neurologists are synopsized.
Defective Cellular FFA Uptake. Acute liver failure and impaired FFA uptake in fibroblasts has been described in 2 patients, supporting a likely defect of cellular FFA uptake. Efforts to identify the gene defect are ongoing.
Cellular Carnitine Deficiency Due to Defective Uptake. Progressive muscle weakness, hypertrophic cardiomyopathy, and muscle lipid storage in the first year of life have been reported with deficiency of the plasma membrane carnitine transport protein, precluding carnitine entry into the cell. Plasma carnitine is low but supplementation is therapeutic.
CPT II Deficiency. Recurrent myoglobinuria from rhabdomyolysis precipitated by exercise, fasting, high fat intake, viral illness, or stress is the hallmark of this disorder, the most common of the group. It presents in late childhood or early adulthood and may be severe enough to result in acute renal failure. Characteristically, plasma carnitine is low with elevated acylcarnitine. Carnitine supplementation is of no benefit. CPT I deficiency rarely causes muscle symptoms.
ACD Defects. Myopathy, cardiomyopathy, or recurrent rhabdomyolysis beginning in adolescence may be seen in VLCAD deficiency. A variety of genetic defects have been described but genotype/phenotype correlation remains questionable. MCAD deficiency may present as Reye syndrome, sudden infant death syndrome, isolated hypoglycemia, or episodic muscle weakness with lipid excess in muscle and is one of the most common inborn errors of metabolism in some northern European populations. SCAD deficiency has been described in multicore myopathy, hypotonia, and developmental delay.
Mitochondrial Matrix Beta-oxidation Enzyme Defects. Myopathy, recurrent myoglobinuria, or peripheral neuropathy may be seen with deficiency of long chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD). Short chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD) deficiency is rare and may result in acute liver failure and sudden death. Further studies are needed to confirm this relationship. Developmental delay and muscle weakness is described in 3 patients with 3-ketoacyl-CoA thiolase deficiency but definitive enzyme studies were not performed. Multiple acyl-CoA dehydrogenation disorder (MADD) causes a potpourri of clinical abnormalities including, among others, severe hypotonia, lipid storage myopathy, and structural brain abnormalities (cerebellar vermis agenesis, hypoplastic temporal lobes, focal cerebral cortical dysplasia). Mutational analysis has revealed a variety of abnormalities but with no clear correlation between gene defect and clinical severity.
Pregnancy and Beta-oxidation Defects. Twenty-one pregnancies complicated by acute fatty liver of pregnancy (AFLP) or hypertension, elevated liver enzymes, low platelets (HELLP) have been reported where the child subsequently born was found to have a defect of FFA metabolism, supporting the notion that AFLP or HELLP should trigger a work-up for a beta-oxidation defect.
Treatment of mitochondrial beta-oxidation disorders centers on the avoidance of fasting thereby avoiding the need for fat metabolism to generate energy. Healthy individuals should restrict fat intake to 25% or less of total caloric intake, and during illness carbohydrate intake should be increased by intravenous or nasogastric means if necessary. Dietary supplementation is generally of little benefit in these disorders but carnitine, 300 mg/kg/d or 100 mg/kg/d, is warranted in carnitine transporter deficiency and secondary carnitine deficiency, respectively. Glycine has been suggested for multiple dehydrogenase deficiency but may be toxic. Riboflavin, 200 mg/kg/d, may be helpful in MADD.
Commentary
Muscle, given its high energy requirement, is often affected in mitochondrial disorders. Several mitochondrial cytopathies have been described, which do not involve beta-oxidation, and myopathy is prominent in most. Progressive external ophthalmoplegia (PEO) is extremely suggestive of a mitochondrial disorder, as is dysfunction of the central nervous system including ataxia, seizures, and sensorineural deafness. Short stature, diabetes, and cardiomyopathy are common expressions of mitochondrial dysfunction, and pigmentary retinopathy ("salt and pepper" pigmentation with normal vision) may be seen in up to one third of such patients. Exertional headache and nausea, with weakness or myalgia, are particularly suggestive. Other clues include unexplained lactic acidosis and myopathy in association with peripheral neuropathy. Colorful abbreviations incorporating each abnormality have been appended to these disorders and include, among others, myoclonus epilepsy with ragged-red fibers (MERFF), mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), and neuropathy, ataxia, and retinitis pigmentosa (NARP). MNGIE has also been referred to as polyneuropathy, ophthalmoplegia, leucoencephalopathy, and intestinal-pseudo-obsruction (POLIP) and mitochondrial encephalomyopathy, sensorimotor polyneuropathy, ophthalmoplegia, and pseudo-obsruction (MEPOP). Muscle biopsy is helpful in most instances, demonstrating ragged red fibers, subsarcolemmal accumulations of mitochondria, on modified Gomori trichrome stain. Recently, molecular genetics has identified numerous mitochondrial mutations providing specific genetic diagnoses, indeed creating a new classification system for mitochondrial myopathies. —Michael Rubin
Dr. Rubin, Professor of Clinical Neurology, New York Presbyterian Hospital-Cornell Campus, is Assistant Editor of Neurology Alert.
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