Острый рабдомиолиз

Rhabdomyolysis results from the rapid breakdown of skeletal muscle fibers, which leads to leakage of potentially toxic cellular contents into the systemic circulation. Acquired causes by direct injury to the sarcolemma are the most frequent. The inherited causes are: metabolic with failure of energy production, including mitochondrial fatty acid ß-oxidation defects, LPIN1 mutations, inborn errors of glycogenolysis and glycolysis, more rarely mitochondrial respiratory chain deficiency, purine defects and peroxysomalα-Methylacyl-CoA-racemase defect (AMACR); dystrophinopathies and myopathies; calcic causes with RYR1 mutations; inflammatory with myositis. Irrespective of the cause of rhabdomyolysis, the pathophysiologic events follow a common pathway, the ATP depletion leading to an increased intracellular calcium concentration and necrosis. Most episodes of rhabdomyolysis are triggered by an environmental stress, mostly fever. This condition is associated with two events, elevated temperature and high circulating levels of pro-inflammatory mediators such as cytokines and chemokines. We describe here an example of rhabdomyolysis related to high temperature, aldolase deficiency, in 3 siblings with episodic rhabdomyolysis without hemolytic anemia. Myoglobinuria was always triggered by febrile illnesses. We show that the underlying mechanism involves an exacerbation of aldolase A deficiency at high temperatures that affected myoblasts but not erythrocytes. Thermolability was enhanced in patient myoblasts compared to control. The aldolase A deficiency was rescued by arginine supplementation in vitro. Lipid droplets accumulated in patient myoblasts relative to control and this was increased by cytokines. Lipotoxicity may participate to myolysis. Our results expand the clinical spectrum of aldolase A deficiency to isolated temperature-dependent rhabdomyolysis, and suggest that thermolability may be tissue specific. We also propose a treatment for this severe disease. Some other diseases involved in rhabdomyolysis may implicate pro-inflammatory cytokines and may be proinflammatory diseases.Острый рабдомиолиз – драматичное внезапное разрушение мышечных волокон скелетных мышц. К генетическим этиологическим факторам относят: метаболические расстройства, сопровождаемые дефицитом окисления жирных кислот, дефицитом липина-1, аномалии гликогенолиза и гликолиза, реже – дефицит митохондриальной дыхательной цепи, дефицит пурина и пероксизмальный дефицит α-метил-ацил-КоА-рацемазы (α-methyl-acyl-CoA-acemase, AMACR); структурные патологии в рамках дистрофинопатий и миопатий; аномалии кальциевого обмена с мутациями в гене RYR1; воспалительные реакции, ассоциированные с миозитом. Независимо от причины, дефицит аденозинтрифосфата в миоците приводит к повышению содержания внутриклеточного кальция и некрозу мышечных волокон. Провоцирующим фактором рабдомиолиза могут быть экзогенные факторы, среди которых травматизация мышц является самой частой причиной рабдомиолиза метаболического генеза. В случае лихорадки следует учитывать 2 фактора: повышение температуры тела и существование провоспалительных цитокинов. В статье описан случай рабдомиолиза у 3 детей от близкородственного брака, спровоцированный гипертермией и вызванный дефицитом альдолазы А, не сопровождаемой гемолитической анемией. В рассматриваемом случае миоглобинурия была всегда вызвана фебрильной температурой. В свою очередь, фермент альдолаза-А обладает тканеспецифичной термолабильностью: при тестируемых температурах он обнаружен в миобластах, но не в эритроцитах, что объясняет специфическую симптоматику у описываемых пациентов. Существуют предположения, что в клеточной липотоксичности участвуют так называемые жировые капли. В ходе исследований in vitro дефицит альдолазы А был возмещен добавлением аргинина. Другие типы рабдомиолиза метаболического генеза, вероятно, являются провоспалительными заболеваниями.перевод: Мария Олеговна Ковальчу

Acute rhabdomyolysis

Rhabdomyolysis results from the rapid breakdown of skeletal muscle fibers, which leads to leakage of potentially toxic cellular contents into the systemic circulation. Acquired causes by direct injury to the sarcolemma are the most frequent. The inherited causes are: metabolic with failure of energy production, including mitochondrial fatty acid ß-oxidation defects, LPIN1 mutations, inborn errors of glycogenolysis and glycolysis, more rarely mitochondrial respiratory chain deficiency, purine defects and peroxysomalα-Methylacyl-CoA-racemase defect (AMACR); dystrophinopathies and myopathies; calcic causes with RYR1 mutations; inflammatory with myositis. Irrespective of the cause of rhabdomyolysis, the pathophysiologic events follow a common pathway, the ATP depletion leading to an increased intracellular calcium concentration and necrosis. Most episodes of rhabdomyolysis are triggered by an environmental stress, mostly fever. This condition is associated with two events, elevated temperature and high circulating levels of pro-inflammatory mediators such as cytokines and chemokines. We describe here an example of rhabdomyolysis related to high temperature, aldolase deficiency, in 3 siblings with episodic rhabdomyolysis without hemolytic anemia. Myoglobinuria was always triggered by febrile illnesses. We show that the underlying mechanism involves an exacerbation of aldolase A deficiency at high temperatures that affected myoblasts but not erythrocytes. Thermolability was enhanced in patient myoblasts compared to control. The aldolase A deficiency was rescued by arginine supplementation in vitro. Lipid droplets accumulated in patient myoblasts relative to control and this was increased by cytokines. Lipotoxicity may participate to myolysis. Our results expand the clinical spectrum of aldolase A deficiency to isolated temperature-dependent rhabdomyolysis, and suggest that thermolability may be tissue specific. We also propose a treatment for this severe disease. Some other diseases involved in rhabdomyolysis may implicate pro-inflammatory cytokines and may be proinflammatory diseases

Mutations in human lipoyltransferase gene LIPT1 cause a Leigh disease with secondary deficiency for pyruvate and alpha-ketoglutarate dehydrogenase.

International audienceBACKGROUND: Synthesis and apoenzyme attachment of lipoic acid have emerged as a new complex metabolic pathway. Mutations in several genes involved in the lipoic acid de novo pathway have recently been described, but no mutation was found so far in genes involved in the specific process of attachment of lipoic acid to apoenzymes pyruvate dehydrogenase (PDHc), alpha-ketoglutarate dehydrogenase (alpha-KGDHc) and branched chain alpha-keto acid dehydrogenase (BCKDHc) complexes. METHODS: Exome capture was performed in a boy who developed Leigh disease following a gastroenteritis and had combined PDH and alpha-KGDH deficiency with a unique amino acid profile that partly ressembled E3 subunit (dihydrolipoamide dehydrogenase / DLD) deficiency. Functional studies on patient fibroblasts were performed. Lipoic acid administration was tested on the LIPT1 ortholog lip3 deletion strain yeast and on patient fibroblasts. RESULTS: Exome sequencing identified two heterozygous mutations (c.875C > G and c.535A > G) in the LIPT1 gene that encodes a mitochondrial lipoyltransferase which is thought to catalyze the attachment of lipoic acid on PDHc, alpha-KGDHc, and BCKDHc. Anti-lipoic acid antibodies revealed absent expression of PDH E2, BCKDH E2 and alpha-KGDH E2 subunits. Accordingly, the production of 14CO2 by patient fibroblasts after incubation with 14Cglucose, 14Cbutyrate or 14C 3OHbutyrate was very low compared to controls. cDNA transfection experiments on patient fibroblasts rescued PDH and alpha-KGDH activities and normalized the levels of pyruvate and 3OHbutyrate in cell supernatants. The yeast lip3 deletion strain showed improved growth on ethanol medium after lipoic acid supplementation and incubation of the patient fibroblasts with lipoic acid decreased lactate level in cell supernatants. CONCLUSION: We report here a putative case of impaired free lipoic acid attachment due to LIPT1 mutations as a cause of PDH and alpha-KGDH deficiencies. Our study calls for renewed efforts to understand the mechanisms of pathology of lipoic acid-related defects and their heterogeneous biochemical expression, in order to devise efficient diagnostic procedures and possible therapies

A Thermolabile Aldolase A Mutant Causes Fever-Induced Recurrent Rhabdomyolysis without Hemolytic Anemia

International audienceAldolase A deficiency has been reported as a rare cause of hemolytic anemia occasionally associated with myopathy. We identified a deleterious homozygous mutation in the ALDOA gene in 3 siblings with episodic rhabdomyolysis without hemolytic anemia. Myoglobinuria was always triggered by febrile illnesses. We show that the underlying mechanism involves an exacerbation of aldolase A deficiency at high temperatures that affected myoblasts but not erythrocytes. The aldolase A deficiency was rescued by arginine supplementation in vitro but not by glycerol, betaine or benzylhydantoin, three other known chaperones, suggesting that arginine-mediated rescue operated by a mechanism other than protein chaperoning. Lipid droplets accumulated in patient myoblasts relative to control and this was increased by cytokines, and reduced by dexamethasone. Our results expand the clinical spectrum of aldolase A deficiency to isolated temperature-dependent rhabdomyolysis, and suggest that thermolability may be tissue specific. We also propose a treatment for this severe disease

Study of LPIN1, LPIN2 and LPIN3 in rhabdomyolysis and exercise-induced myalgia

BACKGROUND: Recessive LPIN1 mutations were identified as a cause of severe rhabdomyolysis in pediatric patients. The human lipin family includes two other closely related members, lipin-2 and 3, which share strong homology and similar activity. The study aimed to determine the involvement of the LPIN family genes in a cohort of pediatric and adult patients (n = 171) presenting with muscular symptoms, ranging from severe (CK >10 000 UI/L) or moderate (CK <10 000 UI/L) rhabdomyolysis (n = 141) to exercise-induced myalgia (n = 30), and to report the clinical findings in patients harboring mutations. METHODS: Coding regions of LPIN1, LPIN2 and LPIN3 genes were sequenced using genomic or complementary DNAs. RESULTS: Eighteen patients harbored two LPIN1 mutations, including a frequent intragenic deletion. All presented with severe episodes of rhabdomyolysis, starting before age 6 years except two (8 and 42 years). Few patients also suffered from permanent muscle symptoms, including the eldest ones (≥ 40 years). Around 3/4 of muscle biopsies showed accumulation of lipid droplets. At least 40% of heterozygous relatives presented muscular myalgia. Nine heterozygous SNPs in LPIN family genes were identified in milder phenotypes (mild rhabdomyolysis or myalgia). These variants were non-functional in yeast complementation assay based on respiratory activity, except the LPIN3-P24L variant. CONCLUSION: LPIN1-related myolysis constitutes a major cause of early-onset rhabdomyolysis and occasionally in adults. Heterozygous LPIN1 mutations may cause mild muscular symptoms. No major defects of LPIN2 or LPIN3 genes were associated with muscular manifestations

Reported cases of Aldolase A deficiency with the described mutations.

<p>*: normal range. In the first case reported by Beutler et al in 1973 with no described mutation, the red cell aldolase activity was 16% of normal mean.</p><p>Reported cases of Aldolase A deficiency with the described mutations.</p

1A: Family tree showing the 3 affected children.

<p>1B: Crystal structure of human muscle aldolase complexed with fructose 1,6-bisphosphate (isoenzyme A, PDB code 4ALD) superimposed with the tetrameric crystal structure of human brain aldolase (isoenzyme C, PDB code 1XFB), which is similar to the muscle isoenzyme. Chains A, B, C and D of isoenzyme C are shown in orange, light blue, light green and pink, respectively. Monomeric isoenzyme A is shown in grey and is superimposed on chain D of the tetrameric isoenzyme C. Fructose 1,6-bisphosphate co-crystallized with isoenzyme A is shown in yellow. The mutated residue described in this report (red arrow) and the mutated amino acids previously described are highlighted in the magnified structure. The structural and functional consequences of the mutations are described in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004711#pgen-1004711-t001" target="_blank">Table 1</a>. 1C: aldolase A, glucose-6-phosphate dehydrogenase (G6PD) and hexokinase activities in the erythrocytes of the parents, the healthy sibling and the 3 affected patients (*: patients 2, 3, 4). 1D: in vitro muscle study of anaerobic glycogenolysis and glycolysis (only patient 3); results of lactate production (µmol/g muscle in 30 minutes) after incubation with various substrates.</p

<i>ALDOA</i> expression and activity.

<p>3A:<i>ALDOA</i> mRNA expression in control myoblasts (C, white bars) and the patient myoblasts (P, grey bars) under basal conditions, with TNFα+Ilβ treatment (left) or at a high temperature (right, 40°C); Aldolase A protein levels (lower panel) under basal conditions, with TNFα+Ilβ treatment or at a high temperature. 3B: Aldolase A activity in control and the patients' myoblasts under the same conditions: basal conditions, TNFα+Ilβ treatment and at different temperatures. The results are shown as the mean value ±SD from 3 independent experiments. 3C: Aldolase A activity in control and patients erythrocytes under basal conditions and at different temperatures. The results are shown as the mean value of two independent experiments. 3D: Aldolase A activity (upper) and protein level (below) in the patient myoblasts under basal condition and after arginine (Arg) treatment.*: p<0,05).</p