Myopathy With Deficiency Of Iscu
Summary
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.
Diagnosis
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 restBlood 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 Genetic Testing
Molecular testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing.
Single-gene testing
- Sequence analysis of ISCU is performed first and 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 multigene 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 are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
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 multigene 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.
Table 1.
Molecular Genetic Testing Used in Myopathy with Deficiency of ISCU
| Gene 1 | Method | Proportion of Probands with Pathogenic Variants 2 Detectable by Method |
|---|---|---|
| ISCU | Sequence analysis 3 | See footnote 4. |
| Targeted analysis for pathogenic variants 5 | ||
| Gene-targeted deletion/duplication analysis 6 | Unknown 7 | |
| Unknown | NA | |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Most affected individuals tested to date are homozygous for c.418+382G>C, a pathogenic splice variant in intron 4 originating from a founder haplotype in northern Sweden. However, two brothers were described as compound heterozygous for the common Swedish splice variant and a pathogenic c.149G>A missense variant in exon 3 [Kollberg et al 2009].
- 5.
Pathogenic variant c.418+382G>C [Mochel et al 2008]
- 6.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 7.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
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 Characteristics
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 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].
Differential Diagnosis
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 may be achieved by molecular genetic testing that includes evaluation of mitochondrial disease-causing genes. Muscle biopsy may be useful to identify histochemical 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. High levels of pyruvate relative to lactate may differentiate ISCU myopathy from other mitochondrial myopathies [Larsson et al 1964, Haller et al 1991].
Episodes of myoglobinuria also have been described in other mitochondrial myopathies, although less commonly than in myopathy with deficiency of ISCU.
Management
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
- Consultation with a clinical geneticist and/or genetic counselor
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.
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