Clinical characteristics.

Myopathy with deficiency of ISCU, a mitochondrial myopathy, is classically characterized by lifelong exercise intolerance in which minor exertion causes tachycardia, shortness of breath, fatigue, and pain of active muscles; episodes of more profound exercise intolerance associated with rhabdomyolysis, myoglobinuria, and weakness that may be severe; and typically full recovery of muscle strength between episodes of rhabdomyolysis. Affected individuals usually have near-normal strength; they can have large calves.

Diagnosis/testing.

The diagnosis of myopathy with deficiency of ISCU is established in a proband by the identification of biallelic pathogenic variants in ISCU by molecular genetic testing or, if molecular genetic testing is uninformative, by characteristic histochemical and biochemical findings on muscle biopsy.

Management.

Prevention of primary manifestations: Anecdotal evidence suggests that episodes of rhabdomyolysis and myoglobinuria may be prevented by avoiding sustained fatiguing physical exertion.

Prevention of secondary complications: The 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.

Agents/circumstances to avoid: Sustained fatiguing physical exertion.

Genetic counseling.

Myopathy with deficiency of ISCU is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased are possible if the pathogenic variants in the family have been identified.

Suggestive Findings

Myopathy with deficiency of ISCU (i.e., iron-sulfur cluster assembly enzyme ISCU), a mitochondrial myopathy, should be suspected in individuals with the following clinical and suggestive laboratory findings:

Clinical features

• Lifelong exercise intolerance in which minor exertion causes tachycardia, shortness of breath, 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 calves

Suggestive laboratory findings

• Elevated blood lactate concentration (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.
• Decreased peak levels of oxygen utilization, typically one third or less than that of healthy persons. Reported values in affected persons are 10-12 mL O₂ kg^-1 min^-1.

Establishing the Diagnosis

The diagnosis of myopathy with deficiency of ISCU is established in a proband by the identification of biallelic pathogenic variants in ISCU by molecular genetic testing (see Table 1) or, if molecular genetic testing is uninformative, by characteristic histochemical and biochemical findings on muscle biopsy.

Molecular testing approaches can include single-gene testing, use of a multi-gene panel, and more comprehensive genomic testing.

• Single-gene testing
  • Sequence analysis of ISCU is performed first, followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.
  • Targeted analysis for the pathogenic variant c.418+382G>C can be performed first in individuals of Swedish ancestry.
• A multi-gene panel that includes ISCU and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time. (2) Some multi-gene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multi-gene panel provides the best opportunity to identify the genetic cause of the condition at the most reasonable cost.
• More comprehensive genomic testing (when available) including exome sequencing, genome sequencing, and mitochondrial sequencing may be considered if single-gene testing (and/or use of a multi-gene panel) fails to confirm a diagnosis in an individual with features of myopathy with deficiency of ISCU. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene that results in a similar clinical presentation). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Muscle biopsy. Diagnosis classically has required histochemical and biochemical assessment of a muscle biopsy, most commonly the quadriceps, gastrocnemius, biceps, or deltoid muscle to identify a characteristic deficiency of proteins containing iron-sulfur clusters. However, molecular genetic testing has superseded muscle biopsy in most cases. Characteristic findings on muscle biopsy include the following:

• 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
  • Respiratory chain complexes which contain iron-sulfur clusters (i.e., complex I and III) [Haller et al 1991, Hall et al 1993].

Clinical Description

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 [Larsson et al 1964, Linderholm et al 1969].

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 pathogenic variant and a novel pathogenic missense variant. They had early-onset severe muscle weakness and cardiomyopathy, features not reported in individuals homozygous for the common intronic variant.

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.

For further information on the Pathophysiology of this condition, see Molecular Genetic Pathogenesis.

Genotype-Phenotype Correlations

Homozygosity for the common pathogenic splice site variant results in a mitochondrial disorder restricted to skeletal muscle with characteristic features of severe exercise intolerance. Although data are limited, reported individuals who are compound heterozygotes for the common pathogenic splice site variant and a novel pathogenic missense variant have had a more severe muscle phenotype with weakness and cardiomyopathy [Kollberg et al 2009].

Prevalence

Originally myopathy with deficiency of ISCU was described primarily in individuals of northern Swedish ancestry. Three non-Swedish individuals have been reported: one individual of Norwegian ancestry who was homozygous for the common intronic g.7044G>C pathogenic variant [Sanaker et al 2010] and two Finnish brothers who were compound heterozygotes for the common intronic pathogenic variant and a novel c.149G>A missense pathogenic variant in exon 3 [Kollberg et al 2009].

The carrier rate in northern Sweden has been estimated at 1:188 [Mochel et al 2008].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with myopathy with deficiency of ISCU, the following evaluations are recommended:

• Consideration of cardiac evaluation in an affected individual who has at least one pathogenic variant that is not the common Swedish pathogenic splice site variant
• No special evaluations in an affected individual who is homozygous for the common Swedish pathogenic splice site variant
• Clinical genetics consultation

Treatment of Manifestations

No specific therapy currently exists for this disorder.

Prevention of Primary Manifestations

The 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 Complications

The 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 Avoid

Avoid sustained fatiguing physical exertion.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Antisense oligonucleotides that induce skipping of the aberrant splice site produced by the pathogenic variant 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.

Mode of Inheritance

Myopathy with deficiency of ISCU is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The unaffected parents of an individual with myopathy with deficiency of ISCU are obligate heterozygotes (i.e., carriers of one mutated allele).
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. Unless an individual with myopathy with deficiency of ISCU has children with an affected individual or a carrier, his/her offspring will be obligate heterozygotes (carriers) for a pathogenic variant in ISCU.

Other family members. Each sib of the proband’s unaffected parents is at a 50% risk of being a carrier.

Carrier (Heterozygote) Detection

Carrier testing for at-risk family members is possible once the pathogenic variants have been identified in the family.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the ISCU pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for Cantú syndrome are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although decisions about prenatal testing are the choice of the parents, discussion of these issues is appropriate.

Molecular Genetic Pathogenesis

The pathophysiology of exercise in affected individuals was described in the classic papers of Linderholm and colleagues [1969]. It consists of low muscle oxidative capacity in which the muscle mitochondrial defect limits the extraction of available O₂ from blood and is associated with a hyperkinetic circulatory response in which O₂ delivery greatly exceeds O₂ utilization. Similarly, exercise ventilation is greatly exaggerated relative to metabolic rate, accounting for the prominence of exertional dyspnea [Heinicke et al 2011]. 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]. Fibroblast growth factor 21 (FGF21) expression and protein levels in muscle and plasma are greatly increased in affected individuals in keeping with the observation that plasma FGF21 may be increased in muscle-manifesting mitochondrial disease [Suomalainen et al 2011].

Selective skeletal muscle involvement in affected individuals with the common splice site variant relates to several factors. First, ISCU messenger RNA and protein are low in skeletal muscle compared to other tissues [Sanaker et al 2010, Crooks et al 2012]. In affected individuals, levels of misspliced ISCU RNA are much higher and levels of ISCU protein lower in skeletal muscle than in other tissues [Sanaker et al 2010, Nordin et al 2011, Crooks et al 2012]. Accordingly, succinate dehydrogenase, aconitase, and related iron-sulfur proteins that are severely deficient in skeletal muscle are relatively preserved in other tissues, and iron deposition, which is present in skeletal muscle mitochondria, is not detected in other tissues [Nordin et al 2012]. The incorrect splicing of ISCU in muscle may be driven by specific splicing factors [Nordin et al 2012]. Differential expression of these factors in a tissue-specific manner could underlie the severity of the phenotype in the skeletal muscle of individuals with ISCU. Additionally ISCU protein is further decreased by oxidative stress that is likely promoted by physical activity, mitochondrial dysfunction, and mitochondrial iron deposition [Crooks et al 2012]. Remarkably, two months after an episode of rhabdomyolysis, an individual homozygous for the common Swedish pathogenic variant had higher muscle levels of normally spliced ISCU RNA and ISCU protein and normal levels of histochemically assessed succinate dehydrogenase in regenerating muscle [Kollberg et al 2011]. This observation suggests that increased levels of misspliced ISCU and decreased levels of ISCU protein that accompany muscle maturation and physical activity-related oxidative stress may play important roles in the development of the classic biochemical phenotype [Crooks et al 2012].

Gene structure. 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.

Pathogenic variants. The common pathogenic variant c.418+382G>C is a homozygous splice variant in intron 4 of ISCU (Table 2), originating from a founder haplotype in northern Sweden [Mochel et al 2008, Olsson et al 2008]. This variant 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 variant and a missense c.149G>A variant in exon 3 converting a highly conserved glycine to glutamate [Kollberg et al 2009].

Normal gene product. The iron-sulfur cluster assembly enzyme ISCU, or iron-sulfur cluster scaffold protein, is a highly conserved protein [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, Maio & Rouault 2015].

Abnormal gene product. The pathogenic splice variant 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 and account for a variable reduction of cytochrome c oxidase (which does not contain Fe-S subunits) in some affected individuals [Kollberg et al 2009].

The missense pathogenic variant 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.

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Suggested Reading

• Raulfs EC, O'Carroll IP, Dos Santos PC, Unciuleac MC, Dean DR. In vivo iron-sulfur cluster formation. Proc Natl Acad Sci U S A. 2008;105:8591–6. [PMC free article: PMC2438426] [PubMed: 18562278]
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• Ye H, Rouault TA. Human iron-sulfur cluster assembly, cellular iron homeostasis, and disease. Biochemistry. 2010;49:4945–56. [PMC free article: PMC2885827] [PubMed: 20481466]

Acknowledgments

Supported by National Institute of Arthritis and Musculoskeletal and Skin Diseases (RO1 AR050597)

Revision History

• 3 March 2016 (ma) Comprehensive update posted live
• 1 September 2011 (me) Comprehensive update posted live
• 11 August 2009 (cd) Revision: sequence analysis and prenatal testing available clinically
• 31 March 2009 (me) Review posted live
• 18 December 2008 (fm) Original submission