Recurrent Myoglobinuria Research Articles

McArdle's Disease: A Differential Diagnosis of Metabolic Myopathies.

McArdle's disease, also known as glycogen storage disease type V or McArdle syndrome, is a pure muscle myopathy with an autosomal recessive inheritance pattern. It is caused by mutations in the gene that encodes muscle phosphorylase. Symptoms typically begin in late adolescence or early adulthood, presenting as exercise intolerance. This review focuses on the diagnosis of McArdle's disease, initially manifesting as a clinical picture of rhabdomyolysis in an 18-year-old male patient with a history of minor thalassemia who had been followed in pediatric consultation since age three for failure to thrive. After excluding common causes such as alcohol consumption, drug use, traumatic muscle compression, and other conditions, the diagnosis of McArdle's disease was considered. The diagnosis was supported by laboratory tests showing myoglobinuria and elevated creatine kinase levels, as well as the absence of increased serum lactate following ischemic exercise. Genetic testing confirmed the presence of mutations in the PYGM gene, corroborating the diagnosis. Treatment includes administering a diet rich in slow-absorbing carbohydrates, regular low-intensity physical exercise, and, in some cases, supplementation with vitamin B6 and creatine. The prognosis is generally favorable with proper disease management, although vigorous exercise should be avoided to prevent complications such as severe muscle injury and rhabdomyolysis. Although McArdle's disease is a rare condition, it is likely underdiagnosed. Ideally, it should be considered in the differential diagnosis of rhabdomyolysis in all patients with symptoms of exercise intolerance and/or recurrent myoglobinuria.

Protocolo diagnóstico de las mialgias

Myalgia, or muscle pain, is a common complaint among the adult population. Diffuse myalgias are more frequent than localized myalgias. Excessive physical effort, trauma, medications, and viral infections are among the most common causes. Myalgias are most often benign, but in a certain percentage of cases, they are the symptom of muscle disease (myopathy) or muscle inflammation (myositis). Myaglias caused by a primary muscle disorder are generally triggered with exercise and are accompanied by other signs/symptoms. In patients with carbohydrate metabolism disorders, muscle symptoms are triggered by brief isometric exercise or less intense, sustained dynamic exercise and can cause cramps and recurrent myoglobinuria. In lipid metabolism disorders, the symptoms tend to be induced by infections, fever, prolonged or intense exercise, and prolonged fasting. These patients do not develop true muscle cramps or contractures and do not experience the phenomenon known as “second wind.”

Rare Cause of Arrhythmia and Seizures in a Late-Preterm Newborn

Rare Cause of Arrhythmia and Seizures in a Late-Preterm Newborn

EP.09Hypersomnia-featured very long-chain acyl-coenzyme a dehydrogenase deficiency caused by a homozygous R428H mutation of ACADVL

Very long-chain acyl-coenzyme a dehydrogenase deficiency (VLCADD) is an autosomal recessive inherited disorder of mitochondrial fatty-acid β-oxidation. It can be severe infantile-onset cardiac, childhood-onset hypoglycemic, and adolescent/adult-onset myopathic. The myopathic VLCADD as shown in present patient usually presents with muscle pain and myoglobinuria after fasting or exercise, but to our knowledge, hypersomnia as a main symptom in any type of VLCADD has never been reported before. We report an unusual case involving a patient with hypersomnia. A 52-year-old man presented with recurrent myalgia, weakness, myoglobinuria and hypersomnia triggered by excessive exercise. Muscle pathology showed mild necrosis and regeneration. A homozygous mutation c. 1283G>A (p.R428H) in the very long chain acyl-coenzyme dehydrogenase (VLCAD) gene was found by next-generation sequencing, which has been proved pathogenic. Given that R428H mutation caused the loss of the catalytic ability of VLCAD and that the accumulation of acyl-carnitine reduces the carnitine level as a consequence of the defect of VLCAD, the impairment of the FAO process resulting in low level of free carnitine in VLCADD may plausibly explain the hypersomnia in our patient, though further studies are required for the molecular basis of the hypersomnia in VLCADD. Our report, therefore, broadens the phenotypic spectrum of VLCADD and suggests an awareness of VLCADD as a causative factor in the differential diagnosis and treatment of hypersomnia disorder.

Neuromuscular Manifestations in Mitochondrial Diseases in Children

Mitochondrial diseases exhibit significant clinical and genetic heterogeneity. Mitochondria are highly dynamic organelles that are the major contributor of adenosine triphosphate, through oxidative phosphorylation. These disorders may be developed at any age, with isolated or multiple system involvement, and in any pattern of inheritance. Defects in the mitochondrial respiratory chain impair energy production and almost invariably involve skeletal muscle and peripheral nerves, causing exercise intolerance, cramps, recurrent myoglobinuria, or fixed weakness, which often affects extraocular muscles and results in droopy eyelids (ptosis), progressive external ophthalmoplegia, peripheral ataxia, and peripheral polyneuropathy. This review describes the main neuromuscular symptomatology through different syndromes reported in the literature and from our experience. We want to highlight the importance of searching for the "clue clinical signs" associated with inheritance pattern as key elements to guide the complex diagnosis process and genetic studies in mitochondrial diseases.

Molecular analysis of LPIN1 in Jordanian patients with rhabdomyolysis

Recessive mutations in LPIN1, which encodes a phosphatidate phosphatase enzyme, are a frequent cause of severe rhabdomyolysis in childhood. Hence, we sequenced the 19 coding exons of the gene in eight patients with recurrent hereditary myoglobinuria from four unrelated families in Jordan. The long-term goal is to facilitate molecular genetic diagnosis without the need for invasive procedures such as muscle biopsies. Three different mutations were detected, including the novel missense mutation c.2395G>C (Gly799Arg), which was found in two families. The two other mutations, c.2174G>A (Arg725His) and c.1162C>T (Arg388X), have been previously identified, and were found to cosegregate with the disease phenotype in the other two families. Intriguingly, patients homozygous for Arg725His were also homozygous for the c.1828C>T (Pro610Ser) polymorphism, and were exercise-intolerant between myoglobinuria episodes. Notably, patients homozygous for Arg388X were also homozygous for the c.2250G>C silent variant (Gly750Gly). Taken together, the data provide family-based evidence linking hereditary myoglobinuria to pathogenic variations in the C-terminal lipin domain of the enzyme. This finding highlights the functional significance of this domain in the absence of structural information. This is the first analysis of LPIN1 in myoglobinuria patients of Jordanian origin, and the fourth such analysis worldwide.

Metabolic Myoglobinuria

One large group of hereditary myopathies characterized by recurrent myoglobinuria, almost invariably triggered by exercise, comprises metabolic disorders of two main fuels, glycogen and long-chain fatty acids, or mitochondrial diseases of the respiratory chain. Differential diagnosis is required to distinguish the three conditions, although all cause a crisis of muscle energy. Muscle biopsy may be useful when performed well after the episode of rhabdomyolysis. Molecular genetics is increasingly the diagnostic test of choice to discover the underlying genetic basis.

Exercise Intolerance and Myoglobinuria Associated with a Novel Maternally Inherited MT-ND1 Mutation.

The most common clinical phenotype caused by a mtDNA mutation in complex I of the mitochondrial respiratory chain is Leber hereditary optic neuropathy. We report a family with a novel maternally inherited homoplasmic mtDNA m.4087A>G mutation in the ND1 gene (MT-ND1) associated with isolated myopathy, recurrent episodes of myoglobinuria, and rhabdomyolysis. DNA from blood in seven family members and muscle from four family members were PCR amplified and sequenced directly and assessed for the m.4087A>G variation in MT-ND1. Mitochondrial enzyme activity in all muscle biopsies was measured. PCR and direct sequencing of the MT-ND1 genes from blood showed that all seven family members were homoplasmic for the m.4087A>G mutation (NC_012920.1:c.781A>G). The mutation predicts a threonine to alanine substitution at position 261 (p.T261A). The same mutation was found in muscle of all four family members available for muscle biopsy, and biochemical analyses revealed an isolated complex I defect in muscle of all family members (range 22-52% of normal). Muscle morphology showed severe myopathic changes with internal nuclei in multiple fibers of all family members. Monosymptomatic myopathy with recurrent myoglobinuria is a rare phenotype of mitochondrial myopathies. We report this phenotype in a family affected by a novel homoplasmic mutation in MT-ND1. It is the first time such a phenotype has been associated with complex I gene mutations and a homoplasmic mutation of mtDNA.

Recurrent myoglobinuria and deranged acylcarnitines due to a mutation in the mtDNA MT-CO2 gene

Mitochondrial myopathies commonly present with exercise intolerance typified by breathlessness and fatigue on exercise. In contrast, exercise-induced rhabdomyolysis and myoglobinuria occur rarely. We present a 43-year-old man with a lifelong history of exercise intolerance associated with myalgia and recurrent episodes of exercise-induced myoglobinuria. From early childhood, he had weekly episodes of myoglobinuria, which became infrequent (every 3 months) as an adult. Carnitine transporter defect was suspected, because carnitine levels were low in muscle. During childhood, he was treated with carnitine (4-5 g daily), but without effect. With the advent of acylcarnitines, profiles mimicking but not diagnostic for multiple acyl-CoA dehydrogenase deficiency (MADD) were found. This led to treatment with riboflavin (100 mg/day for 3 years), again without effect. Clinical examination, including echocardiography, revealed no signs of involvement from other organs, and all relatives were asymptomatic.

G.P.115 Recurrent myoglobinuria and deranged acyl-carnitines due to mutation of the COII gene of mtDNA

Abstract Mitochondrial myopathies generally present with exercise intolerance in which the typical symptoms constitute breathlessness and fatigue on exercise. Exercise-induced rhabdomyolysis and myoglobinuria occur very rarely. This case presents the story of a 43-year old man with a life-long history of exercise intolerance, associated with recurrent episodes of exercise-induced myoglobinuria. His parents sought medical assistance when he as a young boy could not keep up with his younger sister when walking. He was believed to be affected by multiple acyl-CoA dehydrogenase deficiency (MADD), because of his symptoms, and because his acyl-carnitine profiles looked typical for MADD. He was treated with riboflavin, which however, worsened his symptoms. Results: On testing, the patient had a normal neurological examination, except for mild weakness in hip flexion bilaterally. Resting plasma lactate ranged from normal to 3.8 mmol/L. A muscle biopsy showed only mild myopathic changes, no abnormal lipid accumulation, approximately 40% COX-negative fibers, and a few ragged blue fibers and multiple fibers with subsarcolemmal accumulation of mitochondria. Biochemical assessment showed a selective complex IV deficiency (20% of normal). No mutation in the three genes responsible for MADD could be found, but sequencing of the mitochondrial genome revealed a novel, frame-shifting mutation in the COII subunit gene (8156dupG). The mutation load in muscle was 56%. The mutation was not present in fibroblasts or blood from the patient. In accordance with the exercise intolerance, the patient had a peak oxygen uptake of 23 ml O 2 /min/kg on cycle testing, which is about 60% of normal for the age. Mutations in COII of mtDNA have only been reported in a handful of patients, and the present case demonstrates that a phenotype of a disorder of lipid oxidation can be mimicked with this defect, with recurrent episode of myoglobinuria and acyl-carnitine profiles reminiscent of MADD.

Disorders of phospholipids, sphingolipids and fatty acids biosynthesis: toward a new category of inherited metabolic diseases

We wish to delineate a novel, and rapidly expanding, group of inborn errors of metabolism with neurological/muscular presentations: the defects in phospholipids, sphingolipids and long chain fatty acids biosynthesis. At least 14 disorders have been described so far. Clinical presentations are diverse but can be divided into (1) diseases of the central nervous system; (2) peripheral neuropathies; and (3) muscular/cardiac presentations. (1) Leukodystrophy and/or iron deposits in basal ganglia is a common feature of phospholipase A2 deficiency, fatty acid hydroxylase deficiency, and pantothenate kinase-associated neurodegeneration. Infantile epilepsy has been reported in GM3 synthetase deficiency. Spastic quadriplegia with ichthyosis and intellectual disability are the presenting signs of the elongase 4 deficiency and the Sjogren-Larsson syndrome caused by fatty aldehyde dehydrogenase deficiency. Spastic paraplegia and muscle wasting are also seen in patients with mutations in the neuropathy target esterase gene. (2) Peripheral neuropathy is a prominent feature in PHARC syndrome due to α/β-hydrolase 12 deficiency, and in hereditary sensory autonomic neuropathy type I due to serine palmitoyl-CoA transferase deficiency. (3) Muscular/cardiac presentations include recurrent myoglobinuria in phosphatidate phosphatase 1 (Lipin1) deficiency; cardiomyopathy and multivisceral involvement in Barth syndrome secondary to tafazzin mutations; congenital muscular dystrophy due to choline kinase deficiency, Sengers syndrome due to acylglycerol kinase deficiency and Chanarin Dorfman syndrome due to α/β- hydrolase 5 deficiency. These synthesis defects of complex lipid molecules stand at the frontier between classical inborn errors of metabolism and other genetic diseases involving the metabolism of structural proteins.

Fluorescence spectroscopy measures yeast PAH1-encoded phosphatidate phosphatase interaction with liposome membranes

Phosphatidate (PA) phosphatase, the enzyme that catalyzes the penultimate step in triacylglycerol synthesis, is a cytosolic enzyme that must associate with the membrane where its substrate PA resides. Fluorescence spectroscopy was used to measure the interaction of yeast PAH1-encoded PA phosphatase with model liposome membranes. PA phosphatase contains five tryptophan residues and exhibited inherit fluorescence that increased upon interaction with phosphatidylcholine liposomes. The interaction was enhanced by inclusion of other phospholipids and especially the substrate PA. Interaction was dependent on both the concentration of phosphatidylcholine-PA liposomes as well as the surface concentration of PA in liposomes. Mg(2+) ions, which were required for catalysis, did not affect PA phosphatase interaction with phosphatidylcholine-PA liposomes. PA phosphatase was a substrate for protein kinase A, protein kinase C, and casein kinase II, and these phosphorylations decreased PA phosphatase interaction with phosphatidylcholine-PA liposome membranes.

Genotypic and phenotypic features of McArdle disease: insights from the Spanish national registry

BackgroundPublished genotype/phenotype data on McArdle disease are limited in sample size. A single national (Spanish) registry of patients with McArdle disease was created with the purpose of analysing their genotypic...

Recurrent myoglobinuria in a sporadic patient with a novel mitochondrial DNA tRNAIle mutation

The differential diagnosis of myoglobinuria includes multiple etiologies, such as infection, inflammation, trauma, endocrinopathies, drugs toxicity, and primary metabolic disorders. Metabolic myopathies can be due to inherited disorders of glycogen metabolism or to defects of fatty acid oxidation. Primary respiratory chain dysfunction is a rare cause of myoglobinuria, but it has been described in sporadic cases with mutations in genes encoding cytochrome b or cytochrome c oxidase (COX) subunits and in four cases with tRNA mutations. We describe a 39-year-old woman with myalgia and exercise-related recurrent myoglobinuria, who harbored a novel mitochondrial DNA mutation at nucleotide 4281 (m.4281A>G) in the tRNA-isoleucine gene. Her muscle biopsy revealed ragged-red and COX-deficient fibers. No deletions or duplication were detected by Southern blot analysis. The m.4281A>G mutation was present in the patient's muscle with a mutation load of 46% and was detected in trace amounts in urine and cheek mucosa. Single-fiber analysis revealed significantly higher levels of the mutation in COX-deficient (65%) than in normal fibers (45%). This novel mutation has to be added to the molecular causes of recurrent myoglobinuria.

Genotype-phenotype correlations in a large series of patients with muscle type CPT II deficiency

<title/>Objectives: The adult or ‘muscular’ form of carnitine-palmitoyl-transferase II (CPT II) deficiency presents with recurrent rhabdomyolytic episodes and myoglobinuria, usually triggered by prolonged exercise. The aim of this study was to investigate a large series of patients in order to provide genotype-phenotype correlations.Methods: Our muscle tissue bank was surveyed for patients showing attacks of rhabdomyolysis with myoglobinuria. After exclusion of cases affected with toxic myoglobinuria, McArdle's disease and Becker muscular dystrophy, over 100 patients were selected for isotope-exchange radioenzymatic assay of CPT enzyme activity in muscle, and 25 cases resulted to be defective. Acylcarnitine profile was performed in five patients using tandem mass spectrometry. Mutations in the CPT2 gene were identified using DNA sequencing.Results: Although the clinical features were rather homogeneous, some patients presented life-threatening events (acute renal failure) and muscle weakness, and low levels of residual CPT activity. The typical acylcarnitine profile found in mutant patients confirmed its value as a screening method for further diagnostic investigations. We found a high frequency of the common p.Ser113Leu mutation, the recurrence of the rare p.Arg631Cys mutation in a genetic isolate in Southern Italy, and identified four novel mutations. In some affected patients only one mutant allele was found, suggesting either incomplete mutation detection or the possibility they are symptomatic carriers.Discussion: Null mutations and homozygous mutations were frequently associated with a more severe phenotype and biochemical defect. The identification of symptomatic obligate heterozygous carriers might suggest that additional epigenetic or environmental factors may contribute to determine the phenotype.

Necrotizing Vacuolar Myopathy Presenting with Recurrent Myoglobinuria

ABSTRACTMyoglobinuria occurs in a variety of systemic and neurological disorders and can pose diagnostic challenges. We report on a 23-year-old man in whom recurrent myoglobinuria was observed due to necrotizing vacuolar myopathy confirmed on muscle biopsy. Histopathologically the intramuscular vacuoles lacked the typical findings reported in vacuolar myopathy due to disorders of glycogen and lipid metabolism. We discuss the management approach to recurrent myoglobinuria. Recurrent myoglobinuria in the absence of toxin or drug exposure and seizure is more often due to primary muscle disease. Recognizing the presence of myoglobinuria and the proximate cause is essential in preventing the development of renal dysfunction and the future recurrence of symptoms.

A Diagnostic Algorithm for Metabolic Myopathies

Metabolic myopathies comprise a clinically and etiologically diverse group of disorders caused by defects in cellular energy metabolism, including the breakdown of carbohydrates and fatty acids to generate adenosine triphosphate, predominantly through mitochondrial oxidative phosphorylation. Accordingly, the three main categories of metabolic myopathies are glycogen storage diseases, fatty acid oxidation defects, and mitochondrial disorders due to respiratory chain impairment. The wide clinical spectrum of metabolic myopathies ranges from severe infantile-onset multisystemic diseases to adult-onset isolated myopathies with exertional cramps. Diagnosing these diverse disorders often is challenging because clinical features such as recurrent myoglobinuria and exercise intolerance are common to all three types of metabolic myopathy. Nevertheless, distinct clinical manifestations are important to recognize as they can guide diagnostic testing and lead to the correct diagnosis. This article briefly reviews general clinical aspects of metabolic myopathies and highlights approaches to diagnosing the relatively more frequent subtypes (Fig. 1). Fig. 1 Clinical algorithm for patients with exercise intolerance in whom a metabolic myopathy is suspected. CK-creatine kinase; COX-cytochrome c oxidase; CPT-carnitine palmitoyl transferase; cyt b-cytochrome b; mtDNA-mitochondrial DNA; nDNA-nuclear DNA; PFK-phosphofructokinase; PGAM-phosphoglycerate mutase; PGK-phosphoglycerate kinase; PPL-myophosphorylase; RRF-ragged red fibers; TFP-trifunctional protein deficiency; VLCAD-very long-chain acyl-coenzyme A dehydrogenase.

Homozygous female Becker muscular dystrophy

We report, for the first time, on a female Becker muscular dystrophy (BMD) patient with homozygous dystrophin deletion. The 14-year-old patient, product of consanguineous parents, presented with a 7-year history of exercise intolerance and recurrent myoglobinuria. Although CK was elevated to 1,800 U/L, no muscle weakness, atrophy, or hypertrophy was seen on examination. Muscle pathology demonstrated a minimal dystrophic change and faint dystrophin staining pattern. Semi-quantitative PCR of dystrophin revealed a homozygous dystrophin deletion of exons 45-55, which is predicted to remove 593 amino acids without frame shifting. Western blot analysis of skeletal muscle for dystrophin showed a 306 kDa band; thus, we made a diagnosis of female BMD. We confirmed identical deletion in both father and mother, in hemizygous and heterozygous modes, respectively. Neither female Duchenne muscular dystrophy (DMD) nor BMD due to homozygous dystrophin mutation has ever been identified although female DMD has been found in patients with Turner syndrome or unilateral parental disomy for X chromosome. Our results indicate that dystrophinopathy can also be caused in females by homozygosity, albeit rare.

Myopathic form of phosphoglycerate kinase (PGK) deficiency: A new case and pathogenic considerations

We describe an 18-year-old man with muscle cramps and recurrent exertional myoglobinuria, without hemolytic anemia or brain dysfunction. Phosphoglycerate kinase (PGK) deficiency was documented in muscle and erythrocytes and molecular analysis of the PGK1 gene identified a novel mutation, T378P. This is the ninth case presenting with isolated myopathy, whereas most other patients show hereditary non-spherocytic hemolytic anemia alone or associated with brain dysfunction, and a few patients have myopathy plus brain involvement. Although the diverse tissue involvement in PGK deficiency remains unclear, all mutations in myopathic patients tend to cluster in the C terminal domain, adjacent to the substrate-binding pocket. This may lead to a failure in the closure of the N terminal and C terminal domains and loss of stability due to lack of inter-domain communication during the catalytic process.

LeaPIN’ toward the cause of myoglobinuria in childhood

Mutations in LPIN1 cause recurrent acute myoglobinuria in childhood Zeharia et al. (2008) The American Journal of Human Genetics 83: 1–6