Hereditary myopathy with lactic acidosis due to ISCU deficiency
General Information (adopted from Orphanet):
Synonyms, Signs:
MYOPATHY WITH DEFICIENCY OF SUCCINATE DEHYDROGENASE AND ACONITASE
MYOGLOBINURIA DUE TO ABNORMAL GLYCOLYSIS
HML
Iron-sulphur cluster deficiency myopathy
ISCU myopathy
myopathy with exercise intolerance, swedish type
Aconitase deficiency
The symptoms in patients with HML are restricted to skeletal muscle. The highest level of incorrectly spliced ISCU mRNA was found in skeletal muscle, while the normal splice form predominated in patient heart (PMID:21165651).
A single intronic change at position g.7044 G/C , has been shown to be homozygous in the 3 patients and heterozygous in the unaffected offspring (PMID:18304497).
Two brothers, showing a more severe clinical phenotype were found to be heterozygous for the deep intronic mutation and a novel c.149 G>A missense mutation in exon 3, changing a highly conserved glycine residue to a glutamate (PMID:19567699).
Hereditary myopathy with lactic acidosis is an autosomal recessive muscular disorder characterized by childhood onset of exercise intolerance with muscle tenderness, cramping, dyspnea, and palpitations. Biochemical features include lactic acidosis and, rarely, rhabdomyolysis. It is a chronic disorder ... Hereditary myopathy with lactic acidosis is an autosomal recessive muscular disorder characterized by childhood onset of exercise intolerance with muscle tenderness, cramping, dyspnea, and palpitations. Biochemical features include lactic acidosis and, rarely, rhabdomyolysis. It is a chronic disorder with remission and exacerbation of the muscle phenotype (summary by Sanaker et al., 2010).
Reporting from Umea in northern Sweden, Larsson et al. (1964) described 14 patients in 5 families with an apparently distinct form of myopathy. The disease appeared in childhood and ran a chronic course with exacerbations and remissions. It ... Reporting from Umea in northern Sweden, Larsson et al. (1964) described 14 patients in 5 families with an apparently distinct form of myopathy. The disease appeared in childhood and ran a chronic course with exacerbations and remissions. It was characterized by low physical performance. Physical exertion caused early exhaustion, dyspnea, and palpitations. In continued work the muscles became hard and tender with development of cramps and sometimes weakness. In its most severe form there was widespread weakness, severe acidosis, and sometimes myoglobinuria. Concentrations of lactate and pyruvate in the blood increased disproportionately for the workload. All the affected individuals were in single sibships and there was consanguinity in some of the families; recessive inheritance was thought likely. Linderholm et al. (1969) reported further findings in the same families. Haller et al. (1991) evaluated a 22-year-old man from the same coastal area of northern Sweden as that identified by Larsson et al. (1964) and Linderholm et al. (1969) with an identical clinical history and similar exercise pathophysiology as that of previously described patients. He had had lifelong exercise intolerance marked by premature exertional muscle fatigue, dyspnea, and cardiac palpitations as well as episodes lasting days to weeks of increased muscle fatigability and weakness associated with painful muscle swelling and pigmenturia (myoglobinuria). Cycle exercise testing revealed low maximal oxygen uptake with exaggerated increases in venous lactate and pyruvate in relation to oxygen uptake but low lactate/pyruvate ratios in maximal exercise. The patient studied by Schapira et al. (1990) showed some similarities; in that case (see 251945) it was speculated that iron-sulfur proteins of the mitochondrial respiratory chain may be encoded by nuclear genes and that a mutation in a single coding sequence might account for double deficiency. Haller et al. (1991) commented on the fact that myocardium and brain as well as vascular smooth muscle appeared to be spared in the deficiency of SDH/aconitase. Reichmann and Angelini (1993) studied 2 brothers, aged 25 and 19 years, with hypertrophic cardiomyopathy. Both showed proximal muscle weakness and myopathic features by EMG. CPK was elevated. Muscle histochemistry showed subsarcolemmal mitochondria and lipid accumulation. SDH staining was negative in all muscle fibers, regardless of whether cross-sections or longitudinal sections were performed. Biochemical investigation showed a complex II defect in the respiratory chain. Kollberg et al. (2009) reported 2 brothers with myopathy and lactic acidosis born of a Finnish mother. The boys had a more severe phenotype than other reported patients: both had progressive and severe muscle weakness and muscle wasting beginning at age 2 years. They also showed evidence of cardiac involvement, with EKG changes and mild cardiac hypertrophy without dilatation. Kollberg et al. (2009) noted that the boys did not complain of exercise intolerance, and suggested that they were too weak to even elicit symptoms such as tachycardia, palpitations, or shortness of breath.
Within a common region of homozygosity on chromosome 12q24.1, Mochel et al. (2008) identified an intronic G-to-C transversion (7044G-C; 611911.0001) in the ISCU gene in 3 patients with myopathy with lactic acidosis. This homozygous mutation strengthened a weak ... Within a common region of homozygosity on chromosome 12q24.1, Mochel et al. (2008) identified an intronic G-to-C transversion (7044G-C; 611911.0001) in the ISCU gene in 3 patients with myopathy with lactic acidosis. This homozygous mutation strengthened a weak splice acceptor site and resulted in reduced levels of ISCU mRNA and protein, leading to adverse effects on iron-sulfur proteins and intracellular iron homeostasis. In 15 affected members from 9 families reported by Larsson et al. (1964) and Linderholm et al. (1969, 1990), Olsson et al. (2008) independently identified homozygosity for the G-to-C transversion in intron 5 of the ISCU gene. In 2 brothers with myopathy and lactic acidosis, Kollberg et al. (2009) identified compound heterozygosity for the common intronic mutation (7044G-C) and a missense mutation (611911.0002) in the ISCU gene. Western blot analysis of skeletal muscle mitochondria showed only slightly reduced levels of ISCU protein in the 2 brothers, suggesting that the missense mutation gives rise to a nonfunctional protein.
The diagnosis of myopathy with deficiency of ISCU (i.e., iron-sulfur cluster assembly enzyme ISCU), a mitochondrial myopathy, is based on clinical history and characteristic findings of muscle histochemistry and biochemistry. ...
DiagnosisClinical DiagnosisThe diagnosis of myopathy with deficiency of ISCU (i.e., iron-sulfur cluster assembly enzyme ISCU), a mitochondrial myopathy, is based on clinical history and characteristic findings of muscle histochemistry and biochemistry. Myopathy with deficiency of ISCU is characterized by the following:Lifelong exercise intolerance in which minor exertion causes tachycardia, shortness of breath, and fatigue and pain of active muscles Episodes of more profound exercise intolerance associated with rhabdomyolysis, myoglobinuria, and weakness that may be severe Typically, full recovery of muscle strength between episodes of rhabdomyolysis and usually near-normal strength In some individuals, large calvesTesting The pathophysiology of exercise in severe muscle oxidative defects was first identified in studies of this mitochondrial myopathy. Impaired muscle oxidative phosphorylation blocks the extraction of O2 from blood and results in exaggerated O2 delivery by the circulation. During exercise, O2 levels in effluent venous blood are abnormally high; peak systemic arteriovenous O2 difference (a-v O2 diff) remains near resting levels in contrast to the threefold increase in a-v O2 diff from rest to exercise observed in healthy persons; the circulation is 'hyperkinetic,' with the increase in cardiac output in relation to oxygen utilization 4-6 times that of healthy individuals [Larsson et al 1964, Linderholm et al 1969, Haller et al 1991]. Impaired oxygen utilization by working muscle combined with exaggerated oxygen delivery by the circulation are now recognized to be a feature of all severe muscle mitochondrial defects [Taivassalo et al 2003].Peak levels of oxygen utilization are one third or less that of healthy persons. Reported values in affected persons are 10-12 mL O2 kg-1 min-1. Blood lactate concentration may be elevated (i.e., >2 mmol/L) at rest. Blood lactate and pyruvate concentrations increase steeply at low levels of exercise with increases in pyruvate higher and peak lactate to pyruvate concentrations lower than in persons with mitochondrial defects restricted to the respiratory chain. This finding is presumably attributable to impaired tricarboxylic acid cycle flux as a result of deficiency of succinate dehydrogenase and aconitase.Muscle biopsy. Diagnosis requires histochemical and biochemical assessment of a muscle biopsy, most commonly the quadriceps, gastrocnemius, biceps, or deltoid muscle.Succinate dehydrogenase (SDH) histochemistry is distinctive, showing generalized, severe deficiency of SDH enzyme activity [Linderholm et al 1990, Haller et al 1991]. Iron stains show punctate deposition of iron, consistent with mitochondrial iron accumulation in many SDH-deficient muscle fibers as demonstrated by electron microscopy [Haller et al 1991, Mochel et al 2008]. Biochemical testing shows deficiency of multiple iron-sulfur cluster-containing proteins including the tricarboxylic acid cycle enzymes succinate dehydrogenase (complex II) and mitochondrial aconitase, and deficiency of respiratory chain complexes which contain iron-sulfur clusters (i.e., complex I and III) [Haller et al 1991, Hall et al 1993]. Molecular Genetic Testing Gene. ISCU, encoding the iron-sulfur cluster assembly enzyme ISCU, is the only gene in which mutation is known to cause myopathy with deficiency of ISCU [Mochel et al 2008, Olsson et al 2008].Clinical testingSequence analysis. Most affected individuals tested to date are homozygous for a splice mutation in intron 4, originating from a founder haplotype in northern Sweden (see Tables 1 and 2). However, two brothers were recently described as compound heterozygous for the common Swedish splice mutation and a c.149G>A missense mutation in exon 3 [Kollberg et al 2009].Targeted mutation analysis identifies the g.7044G>C mutation.Table 1. Summary of Molecular Genetic Testing Used in Myopathy with Deficiency of ISCUView in own windowGene Symbol Test MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityISCUSequence analysisSequence variants 2 including splice mutation in intron 4100%ClinicalTargeted mutation analysisg.7044G>C1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.Testing Strategy To confirm/establish the diagnosis in a probandHistory of muscle fatigue and shortness of breath brought on by minor exertion and, in some cases, episodes of myoglobinuria Cycle or treadmill exercise testing to identify the presence of severely limited oxidative capacity Muscle biopsy demonstrating on histochemistry severe deficiency of succinate dehydrogenase and on biochemical testing deficiency of succinate dehydrogenase and other iron-sulfur cluster-containing enzymes (aconitase, respiratory chain complexes I and III)Molecular genetic testing of ISCU either by sequence analysis or by targeted mutation analysis for the g.7044G>C mutation followed by sequence analysis if neither or only one mutation in ISCU is identifiedCarrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) Disorders To date, no other phenotypes are known to be associated with mutations in ISCU.
Symptoms of exercise intolerance in myopathy with deficiency of ISCU are typically present from childhood. Episodes of rhabdomyolysis and myoglobinuria usually occur during or after the second decade of life and are usually triggered by sustained or recurrent physical activity. Episodes of rhabdomyolysis with myoglobinuria may result in renal failure and associated metabolic crises that in some instances have been fatal....
Natural History Symptoms of exercise intolerance in myopathy with deficiency of ISCU are typically present from childhood. Episodes of rhabdomyolysis and myoglobinuria usually occur during or after the second decade of life and are usually triggered by sustained or recurrent physical activity. Episodes of rhabdomyolysis with myoglobinuria may result in renal failure and associated metabolic crises that in some instances have been fatal.Affected individuals are generally able to minimize or avoid episodes of rhabdomyolysis by moderating physical activity.Kollberg et al [2009] reported two Finnish brothers who harbored the common Swedish mutation and a novel missense mutation. They had severe muscle weakness and features of cardiomyopathy, features not reported in individuals homozygous for the common intronic mutation. Life span. Available evidence suggests that the disease is compatible with a relatively normal life span and that symptoms of exercise intolerance remain relatively stable.Pathophysiology. The pathophysiology of this disorder was first described by Larsson et al [1964] and Linderholm et al [1969].
The clinical features of lifelong exercise intolerance, low oxidative capacity with impaired mitochondrial extraction of available oxygen from blood, and a hyperkinetic circulation in exercise are mimicked by other mitochondrial myopathies [Taivassalo et al 2003]. Differentiation from other mitochondrial myopathies requires muscle biopsy to identify histochemical deficiency of SDH and deficiency of SDH, aconitase, and other iron-sulfur cluster-containing proteins as determined biochemically (see Mitochondrial Disorders Overview)....
Differential DiagnosisThe clinical features of lifelong exercise intolerance, low oxidative capacity with impaired mitochondrial extraction of available oxygen from blood, and a hyperkinetic circulation in exercise are mimicked by other mitochondrial myopathies [Taivassalo et al 2003]. Differentiation from other mitochondrial myopathies requires muscle biopsy to identify histochemical deficiency of SDH and deficiency of SDH, aconitase, and other iron-sulfur cluster-containing proteins as determined biochemically (see Mitochondrial Disorders Overview).Elevated blood lactate concentration at rest and marked increases in blood lactate concentration relative to workload are also typical of other mitochondrial myopathies. Episodes of myoglobinuria also have been described in other mitochondrial myopathies although less commonly than in myopathy with deficiency of ISCU. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
No special evaluations are recommended to establish the extent of disease in an individual diagnosed with myopathy with deficiency of ISCU because the evaluations needed to establish the diagnosis provide this information....
ManagementEvaluations Following Initial Diagnosis No special evaluations are recommended to establish the extent of disease in an individual diagnosed with myopathy with deficiency of ISCU because the evaluations needed to establish the diagnosis provide this information.Treatment of ManifestationsNo specific therapy currently exists for this disorder.Prevention of Primary ManifestationsThe major management goal is to prevent episodes of rhabdomyolysis and myoglobinuria. Anecdotal evidence suggests that this goal may be achieved by avoiding sustained, fatiguing physical exertion.Prevention of Secondary ComplicationsThe major secondary complications are those attributable to rhabdomyolysis and myoglobinuria, including renal failure and hyperkalemia. Management is similar to that for other causes of rhabdomyolysis including monitoring of renal and electrolyte status, maintenance of intravascular volume and urinary output, urine alkalinization, and institution of dialysis when needed [Malinoski et al 2004].Agents/Circumstances to AvoidAvoid sustained fatiguing physical exertion.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationAntisense oligonucleotides that induce skipping of the aberrant splice site produced by the mutation have restored normal mRNA splicing in fibroblasts from affected individuals [Kollberg & Holme 2009], suggesting a potential role for this type of therapy.Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Myopathy with Deficiency of ISCU: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDISCU12q23.3Iron-sulfur cluster assembly enzyme ISCU, mitochondrialISCU homepage - Leiden Muscular Dystrophy pagesISCUData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Myopathy with Deficiency of ISCU (View All in OMIM) View in own window 255125MYOPATHY WITH LACTIC ACIDOSIS, HEREDITARY; HML 611911IRON-SULFUR CLUSTER SCAFFOLD, E. COLI, HOMOLOG OF; ISCUNormal allelic variants. ISCU (isoform ISCU2) comprises five exons. Two ISCU splice variants have been identified to date: ISCU1 and ISCU2 type [Tong & Rouault 2000, Tong et al 2003]. The two variants share the same transcription initiation site but differ in the presence (ISCU1) or absence (ISCU2) of exon 1B. ISCU1 (NM_014301.3, NP_055116.1) encodes a deduced 142-amino acid protein with 13 unique N-terminal residues, and ISCU2 (NM_213595.2, NP_998760.1) encodes a deduced 167-amino acid protein with 38 unique N-terminal residues, including a mitochondrial targeting signal.Pathologic allelic variants. The common mutation is a homozygous splice mutation in intron 4 of ISCU (Table 2), originating from a founder haplotype in northern Sweden [Mochel et al 2008, Olsson et al 2008]. The g.7044G>C mutation leads to the inclusion of an additional exon 4A that is predicted to result in a premature stop codon [Mochel et al 2008]. Two brothers were heterozygous for the common splice mutation and a missense c.149G>A mutation in exon 3 converting a highly conserved glycine to glutamate [Kollberg et al 2009].Note: The information in Table 2 is provided by the authors of this GeneReview; it has not been reviewed by GeneReviews staff.Table 2. Selected ISCU Pathologic Allelic Variants View in own windowDNA Nucleotide Change Protein Amino Acid Change Reference Sequenceg.7044G>C--EU334585c.149G>Aglycine>glutamateSee Quick Reference for an explanation of nomenclature. Normal gene product. The iron-sulfur cluster assembly enzyme ISCU, or iron-sulfur cluster scaffold protein, is a highly conserved protein comprising 167 amino acids [Liu et al 2005]. Iron-sulfur clusters are prosthetic groups composed of iron and sulfur and usually ligated to proteins via the sulfhydryl side chains of cysteine. Iron-sulfur clusters often function as electron acceptors or donors; they are important for function of the mitochondrial respiratory chain, which contains 12 iron-sulfur clusters in respiratory complexes I-III. In humans, the citric acid cycle enzymes succinate dehydrogenase and aconitase are iron-sulfur proteins. In addition to their importance in electron transfer, iron-sulfur clusters can ligate substrate in enzymes such as aconitase, which converts citrate to isocitrate; iron-sulfur proteins can also have important structural and sensing roles. In mammalian iron sulfur-cluster assembly, a cysteine desulfurase known as ISCS, encoded by NFS1, provides sulfur, and assembly of nascent iron-sulfur clusters takes place on ISCU, which functions as a scaffold on which the cluster is assembled [Rouault & Tong 2008]. ISCU has also been reported to interact with the Friedreich ataxia gene product frataxin in iron-sulfur cluster biosynthesis; this interaction is thought to facilitate delivery of iron from frataxin to nascent iron-sulfur clusters on ISCU [Shan et al 2007].Abnormal gene product. The splice mutation detected in persons from northern Sweden results in aberrant splicing, with the increased retention of an additional exon (exon 4A) and the introduction of a premature stop codon in the penultimate exon; this ultimately alters the C terminus of the protein and decreases levels of ISCU protein [Mochel et al 2008]. Impaired iron-sulfur synthesis results in deficiency of multiple Fe-S-containing mitochondrial enzymes including succinate dehydrogenase (complex II), aconitase, and respiratory chain complexes I and III. The iron-sulfur protein, ferrochelatase, which catalyzes the terminal step in heme biosynthesis, is also deficient [Crooks et al 2010]. This may impair cytochrome synthesis to account for a variable reduction of cytochrome c oxidase (which does not contain Fe-S subunits) in some affected individuals [Kollberg et al 2009]. Although the common intronic mutation causing aberrant mRNA splicing is generalized, the symptoms are restricted to skeletal muscle. This apparently relates to the fact that mature muscle contains high levels of aberrantly spliced ISCU mRNA whereas higher levels of normally spliced mRNA are found in fibroblasts [Sanaker et al 2010], heart, liver, and kidney [Nordin et al 2011] to normalize ISCU protein levels and preserve Fe-S-containing proteins in these tissues. The missense mutation in exon 3 changes a glycine residue to a glutamate at amino acid position 50 [Kollberg et al 2009]. This amino acid residue is totally conserved among species from bacteria to mammals.