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Pagon RA, Adam MP, Bird TD, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2013.

Bookshelf ID: NBK5299PMID: 20301757

Myopathy with Deficiency of ISCU

Synonyms: Iron-Sulfur Cluster Deficiency Myopathy; Myopathy with Deficiency of Succinate Dehydrogenase and Aconitase; Myopathy with Exercise Intolerance, Swedish Type

Fanny Mochel, MD, PhD and Ronald G Haller, MD.

Author Information

Initial Posting: March 31, 2009; Last Update: September 1, 2011.

Summary

Disease characteristics. Myopathy with deficiency of ISCU, a mitochondrial myopathy, is characterized by 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; 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. Diagnosis is based on clinical history and characteristic findings of muscle histochemistry and biochemistry. ISCU, encoding the iron-sulfur cluster assembly enzyme ISCU, is the only gene in which mutations are known to cause myopathy with deficiency of ISCU.

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 disease-causing mutations in the family have been identified.

Diagnosis

Clinical Diagnosis

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.

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 calves

Testing

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 testing

Sequence 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 ISCU

Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method ¹	Test Availability
ISCU	Sequence analysis	Sequence variants ² including splice mutation in intron 4	100%	Clinical
ISCU	Targeted mutation analysis	g.7044G>C	100%	Clinical

: 1. The ability of the test method used to detect a mutation that is present in the indicated gene
: 2. 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 proband

History 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 identified

Carrier 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.

Clinical Description

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].

Genotype-Phenotype Correlations

No genotype-phenotype correlations are known.

Prevalence

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

Management

Evaluations 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 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 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

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

Risk to Family Members

Parents of a proband

The parents of an individual with myopathy with deficiency of ISCU are obligate heterozygotes (i.e., carriers of one mutant allele).
Heterozygotes (carriers) are asymptomatic.

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.

Offspring of a proband. The offspring of an individual with myopathy with deficiency of ISCU are obligate heterozygotes (carriers) for a disease-causing mutation in ISCU.

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

Carrier Detection

Carrier testing for at-risk family members is possible once the mutations 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions such as myopathy with deficiency of ISCU are not common. 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.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Muscular Dystrophy Association - Canada
2345 Yonge Street
Suite 900
Toronto Ontario M4P 2E5
Canada
Phone: 866-687-2538 (toll-free); 416-488-0030
Fax: 416-488-7523
Email: info@muscle.ca
www.muscle.ca
Muscular Dystrophy Association - USA (MDA)
3300 East Sunrise Drive
Tucson AZ 85718
Phone: 800-572-1717
Email: mda@mdausa.org
www.mda.org
Muscular Dystrophy Campaign
61 Southwark Street
London SE1 0HL
United Kingdom
Phone: 0800 652 6352 (toll-free); +44 0 020 7803 4800
Email: info@muscular-dystrophy.org
www.muscular-dystrophy.org

Molecular Genetics

Information 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 Databases

Gene Symbol	Chromosomal Locus	Protein Name	Locus Specific	HGMD
ISCU	12q23.3	Iron-sulfur cluster assembly enzyme ISCU, mitochondrial	ISCU homepage - Leiden Muscular Dystrophy pages	ISCU

: Data 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)

255125	MYOPATHY WITH LACTIC ACIDOSIS, HEREDITARY; HML
611911	IRON-SULFUR CLUSTER SCAFFOLD, E. COLI, HOMOLOG OF; ISCU

Normal 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

DNA Nucleotide Change	Protein Amino Acid Change	Reference Sequence
g.7044G>C	--	EU334585
c.149G>A	glycine>glutamate

: See 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.

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page

Literature Cited

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Hall RE, Henriksson KG, Lewis SF, Haller RG, Kennaway NG. Mitochondrial myopathy with succinate dehydrogenase and aconitase deficiency. Abnormalities of several iron-sulfur proteins. J Clin Invest. 1993;92:2660–6. [PMC free article: PMC288463] [PubMed: 8254022]
Haller RG, Henriksson KG, Jorfeldt L, Hultman E, Wibom R, Sahlin K, Areskog NH, Gunder M, Ayyad K, Blomqvist CG, Hall RE, Thuillier P, Kennaway NG, Lewis SF. Deficiency of skeletal muscle succinate dehydrogenase and aconitase. Pathophysiology of exercise in a novel human muscle oxidative defect. J Clin Invest. 1991;88:1197–206. [PMC free article: PMC295585] [PubMed: 1918374]
Kollberg G, Tulinius M, Melberg A, Darin N, Andersen O, Holmgren D, Oldfors A, Holme E. Clinical manifestation and a new ISCU mutation in iron-sulphur cluster deficiency myopathy. Brain. 2009;132:2170–9. [PubMed: 19567699]
Kollberg G, Holme E. Antisense oligonucleotide therapeutics for iron-sulphur cluster deficiency myopathy. Neuromuscul Disord. 2009;19:833–6. [PubMed: 19846308]
Larsson LE, Linderholm H, Mueller R, Ringqvist T, Soernaes R. Hereditary metabolic myopathy with paroxysmal myoglobinuria due to abnormal glycolysis. J Neurol Neurosurg Psychiatry. 1964;27:361–80. [PMC free article: PMC495765] [PubMed: 14213465]
Linderholm H, Essén-Gustavsson B, Thornell LE. Low succinate dehydrogenase (SDH) activity in a patient with a hereditary myopathy with paroxysmal myoglobinuria. J Intern Med. 1990;228:43–52. [PubMed: 2384736]
Linderholm H, Müller R, Ringqvist T, Sörnäs R. Hereditary abnormal muscle metabolism with hyperkinetic circulation during exercise. Acta Med Scand. 1969;185:153–66. [PubMed: 5811159]
Liu J, Oganesyan N, Shin DH, Jancarik J, Yokota H, Kim R, Kim SH. Structural characterization of an iron-sulfur cluster assembly protein IscU in a zinc-bound form. Proteins. 2005;59:875–81. [PubMed: 15815978]
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Mochel F, Knight MA, Tong WH, Hernandez D, Ayyad K, Taivassalo T, Andersen PM, Singleton A, Rouault TA, Fischbeck KH, Haller RG. Splice mutation in the iron-sulfur cluster scaffold protein ISCU causes myopathy with exercise intolerance. Am J Hum Genet. 2008;82:652–60. [PMC free article: PMC2427212] [PubMed: 18304497]
Nordin A, Larsson E, Thornell L-E, Holmberg M. Tissue-specific splicing of ISCU results in a skeletal muscle phenotype in myopathy with lactic acidosis, while complete loss of ISCU results in early embryonic death in mice. Hum Genet. 2011;129:371–8. [PubMed: 21165651]
Olsson A, Lind L, Thornell LE, Holmberg M. Myopathy with lactic acidosis is linked to chromosome 12q23.3-24.11 and caused by an intron mutation in the ISCU gene resulting in a splicing defect. Hum Mol Genet. 2008;17:1666–72. [PubMed: 18296749]
Rouault TA, Tong WH. Iron-sulfur cluster biogenesis and human disease. Trends Genet. 2008;24:398–407. [PMC free article: PMC2574672] [PubMed: 18606475]
Sanaker PS, Toompuu M, Hogan VE, He L, Tzoulis C, Chrzanowska-Lightowlers ZM, Taylor RW, Bindoff LA. Differences in RNA processing underlie the tissue specific phenotype of ISCU myopathy. Biochim Biophys Acta. 2010;1802:539–44. [PubMed: 20206689]
Shan Y, Napoli E, Cortopassi G. Mitochondrial frataxin interacts with ISD11 of the NFS1/ISCU complex and multiple mitochondrial chaperones. Hum Mol Genet. 2007;16:929–41. [PubMed: 17331979]
Taivassalo T, Jensen TD, Kennaway N, DiMauro S, Vissing J, Haller RG. The spectrum of exercise tolerance in mitochondrial myopathies: a study of 40 patients. Brain. 2003;126:413–23. [PubMed: 12538407]
Tong WH, Jameson GN, Huynh BH, Rouault TA. Subcellular compartmentalization of human Nfu, an iron-sulfur cluster scaffold protein, and its ability to assemble a [4Fe-4S] cluster. Proc Natl Acad Sci U S A. 2003;100:9762–7. [PMC free article: PMC187839] [PubMed: 12886008]
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Chapter Notes

Acknowledgments

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

Revision History

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

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GeneReviews™ [Internet].

Pagon RA, Adam MP, Bird TD, et al., editors.

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