Open Access

Chronic granulomatous disease, the McLeod phenotype and the contiguous gene deletion syndrome-a review

  • Casey E Watkins1,
  • John Litchfield2,
  • Eunkyung Song3,
  • Gayatri B Jaishankar3,
  • Niva Misra1,
  • Nikhil Holla2,
  • Michelle Duffourc4 and
  • Guha Krishnaswamy5Email author
Clinical and Molecular Allergy20119:13

https://doi.org/10.1186/1476-7961-9-13

Received: 29 October 2011

Accepted: 23 November 2011

Published: 23 November 2011

Abstract

Chronic Granulomatous Disease (CGD), a disorder of the NADPH oxidase system, results in phagocyte functional defects and subsequent infections with bacterial and fungal pathogens (such as Aspergillus species and Candida albicans). Deletions and missense, frameshift, or nonsense mutations in the gp91phox gene (also termed CYBB), located in the Xp21.1 region of the X chromosome, are associated with the most common form of CGD. When larger X-chromosomal deletions occur, including the XK gene deletion, a so-called "Contiguous Gene Deletion Syndrome" may result. The contiguous gene deletion syndrome is known to associate the Kell phenotype/McLeod syndrome with diseases such as X-linked chronic granulomatous disease, Duchenne muscular dystrophy, and X-linked retinitis pigmentosa. These patients are often complicated and management requires special attention to the various facets of the syndrome.

Keywords

Granulomatous Disease Chronic gene deletion XK Kell blood group precursor (McLeod phenotype) human KX antigen human anemia hemolytic

Introduction

Primary immune deficiencies can involve defects in phagocyte function, resulting in Chronic granulomatous disease (CGD) [1, 2]. CGD is characterized by repeated infections with bacterial and fungal pathogens, as well as the formation of granulomas [14]. In this disease, the NADPH oxidase system is dysfunctional due to specific gene mutations, culminating in an inability of the phagocyte to eliminate pathogenic organisms. Typically, this defect in phagocyte function leads to serious infections including Staphylococcus aureus, Pseudomonas species, Nocardia species, fungi such as Aspergillus species, and Candida albicans. Significant morbidity and mortality may result.

The genetic defect in CGD can be transmitted in either an X-linked or autosomal recessive manner [1, 57]. Genes regulating NADPH assembly and function are most commonly affected. When X-linked disease occurs, deletion of the contiguous genes that border the gene on the X chromosome that regulates NADPH function can result in the "contiguous X-chromosome gene deletion syndrome" [812]. Mutations extending into these surrounding genes may result in Duchenne muscular dystrophy (DMD) or Retinitis pigmentosa [13, 14]. Other conditions, such as the McLeod syndrome, may also result in such patients [1518]. In some selected situations, mutations in other innate immune system genes such as the complement pathway genes (especially mannose binding lectin) may further complicate disease severity and management [19].

CGD and the Contiguous Gene Deletion Syndrome

X-linked CGD is responsible for the majority (> 60%) of the CGD cases seen in the United States [2, 20]. The X-linked type is caused by a mutation in the gp91phox gene, which is also referred to as the cytochrome b-245 beta polypeptide (CYBB) gene. Autosomal recessive CGD is seen in the remaining 35% of cases and arises due to mutations of the other components of the NADPH oxidase system [1, 2, 57]. These mutations include p22phox , p67phox, and p47phox . Of these, the dominant mutation observed is in the p22phox gene which accounts for almost 25% of the autosomal recessive cases. The associated phenotypes are also referred to as the A22/A47/A67 CGD. The phenotype of the gp91phox gene mutation is referred to as X-CGD. Mutations of other nearby genes, p40phox and Rac, have yet to be associated with any CGD phenotype [2, 20]. Gene location and associated disease state are described in Table 1.
Table 1

Gene and Chromosomal localization

Condition

Gene

Chromosome

Comments

Clinical

X-linked CGD

CYBB

XP21

Deletion or missense, nonsense and/or frameshift mutations may occur

Opportunistic infection

Autoimmunity

Organ dysfunction

McLeod syndrome

XK

XP21

Absent Kx antigen and weak expression of Kell on RBC surface

XK is linked to Kell blood group antigen

Kell locus mutations can also lead to the syndrome

Acanthocytosis

Elevated CPK

Huntington's chorea-like disease

Muscle weakness and atrophy

Cardiomyopathy

Psychiatric disease Cognitive impairment

The CYBB gene spans a 30 kb region in the Xp21.1 region of the X chromosome (Figure 1A). Deletions and frameshift, missense, nonsense, or splice site mutations of the CYBB gene can contribute to defects seen in CGD. On occasion, larger X-chromosomal deletions may occur. The Kell locus or XK gene, which encodes an essential glycoprotein for Kell antigen expression, may be involved in such cases. These larger deletions that extend across multiple genes will result in manifestations of the "Contiguous gene deletion syndrome" (Figure 1B)[8, 9]. As stated earlier, this syndrome (Figure 2) encompasses the McLeod syndrome in association with X-linked Chronic granulomatous disease, Duchenne muscular dystrophy, and/or X-linked Retinitis pigmentosa [10, 14, 15].
Figure 1

XK and CYBB are neighboring genes. A. Idiogram of human chromosome X at 550 banding resolution. The bar indicates the location XK and CYBB genes and is expanded below to show the genomic region. B. Genomic context of Xp21.1. The region of chromosome X from 37,500 to 37,700 K is shown. Arrows indicate the location of the XK and CYBB genes. Numbering is based upon GenBank accession number NC_000023.10.

Figure 2

Complicating conditions often seen in the Contiguous gene deletion syndrome associated with chronic granulomatous disease.

The Kell blood group and Kell antigens

The Kell blood group system was first identified by Coombs in 1946 when ABO and Rhesus incompatibility were excluded in a mother, Mrs. Kelleher, who had delivered a baby with hemolytic anemia. It is now considered the third most important blood group system based on immunological potency. The antigens of the Kell system are numerous and complex [17, 2125]. The K antigen may be the most significant antigen of the Kell system with regards to development of disease and transfusion-related complications.

The Kell antigens, which are encoded for by the KEL gene, are carried by the transmembrane Kell glycoprotein (XK) (Figure 3). The KEL gene is found on chromosome 7 (7q33). It is highly polymorphic [26, 27] and encodes the numerous Kell antigens. There appear to be two major co-dominant alleles referred to as k (Cellano) and K (Kell) that differ by a single amino acid change; the latter is considered the more potent immunogen.
Figure 3

Structure of the XK and Kell proteins.

Although there have been 25 Kell antigens identified, the "k" antigen is the most common. The phenotype K-k+ is seen in a majority of Caucasians and African Americans, while a smaller number (9%) of Caucasians may be K+k+. When the Kell antigens are absent on red blood cells, this is referred to as the rare K null phenotype (K0). Individuals with this phenotype produce anti-Ku antibodies that target RBCs expressing Kell antigens, but are otherwise healthy. Anti-Ku antibodies may result in the development of moderate to severe transfusion reactions following transfusion from a donor who is Kell+. For this reason, patients with the K0 phenotype should only be transfused with K0 blood products. Anti-Ku antibodies are also involved in fetomaternal immunization. Pregnant females with the K0 phenotype produce anti-Ku antibodies which target Kell antigens located on the surface of fetal RBCs. These antibodies are responsible for the third most common cause of hemolytic anemia in the newborn. The McLeod phenotype is seen with a severe reduction in Kell antigens; this can be associated with CGD [2325].

The McLeod Syndrome

The McLeod syndrome is characterized by an absence of the Kx antigen on red blood cells. This is associated with weak expression of Kell antigens. Kell antigens are covalently bound to the RBC transmembrane XK protein. When XK is absent on RBC membranes, McLeod syndrome develops. In this syndrome, the Kell antigens are weakly expressed which leads to the appearance of abnormally shaped RBCs (referred to as acanthocytes) [28]. Characteristics of the Kell and XK proteins are shown in Table 2. The McLeod syndrome manifests either as a hemolytic anemia following transfusion of Kell(+) RBC to a Kell(-) recipient or as a delayed onset (usually in the 4th decade or later) of neuropsychological or cardiovascular impairment in patients with CGD.
Table 2

Characteristics of the Kell system

Kell protein

93 kDa type II membrane glycoprotein

Short N-terminal intracellular segment with one cysteine residue

Single transmembrane section

Large extracellular domain (665 amino acids with 15 cysteine residues)

One cysteine residue (Cys72) in extracellular domain binds XK protein

Homology to certain zinc endoproteases

Demonstrates endothelin-3 converting enzymatic activity

Encoded by the KEL gene (7q33)

K0 (null) RBC lack Kell antigens but have enhance XK activity

KEL gene is inherited autosomally

XK protein

Molecular weight of 50.9 kDa

10 transmembrane segments

Short N-terminal domain (intracellular)

Large C-terminal domain (intracellular)

A large hydrophilic loop (Figure 3)

Single cysteine residue that binds covalently to Cys72 on Kell

Loss of XK leads to McLeod syndrome that has X-linked inheritance

As reviewed by Jung et al., this disorder may be discovered accidentally by routine screening of apparently healthy blood donors [29]. Affected individuals may be detected by elevated creatinine kinase levels and acanthocytosis [29]. In addition to extravascular hemolytic anemia, patients manifesting the McLeod syndrome may develop multisystem disease, including splenomegaly and neurological problems late in life [30]. With time, neurological complications and manifestations of Huntington's disease-like disorder may become evident. The neurological symptoms may appear between the 2nd and 6th decades of life. Besides Huntington's chorea-like disease and cardiomyopathy, patients develop muscle weakness and atrophy, psychiatric disease, and cognitive impairment [16, 17, 2934]. In some cases, the disorder that develops may be indistinguishable from neuroacanthocytosis with chorea, orofacial dyskinesia, dysarthria, and dementia [35]. It is therefore essential to evaluate these more complex patients for the conditions listed in Table 3 including generalized seizures and cardiomyopathy which may culminate in ventricular and atrial arrhythmia.
Table 3

Contiguous Gene Syndrome (including McLeod Syndrome) complicating CGD

Clinical component

Evaluation (selected)

Myopathy

CPK level (serum)

 

EMG/NCS

Hemolytic Anemia

Reticulocyte cell count

 

Low haptoglobin

 

Acanthocytosis

Late-onset neurological syndrome

 

   Cerebral atrophy

CT/MRI

   Neuropathy

EMG/NCS

   Huntington's chorea-like disease

CT/MRI

   Neuropsychological and cognitive impairment

Neuropsychological testing

   Myopathy/DMD

EMG/NCS

 

Muscle biopsy*

   Seizures

EEG

Glomerulopathy with renal failure

Serum creatinine level

 

24 hour urine analysis

 

Renal imaging

 

+/- kidney biopsy

Cardiovascular disease

 

   Cardiomyopathy

ECHO

   Arrythmia

EPS

CPK = creatine phosphokinase; EMG/NCS = electromyography and nerve conduction study

CT = computed tomography; MRI = magnetic resonance imaging; EEG = electroencephalography

ECHO = echocardiography (transthoracic or transesophageal); EPS = electrophysiological studies

DMD = Duchenne muscular dystrophy; * = typical muscle histology of DMD and absent muscle dystrophin

Duchenne Muscular Dystrophy

DMD is an X-linked progressive myopathy that can occasionally complicate a contiguous gene deletion syndrome involving X-linked CGD [13, 34]. In the case reported by Kang et al., the DMD manifestations developed several years after the successful treatment of CGD by allogeneic stem cell transplantation [13]. This male child had a large scale deletion spanning the region between CYBB and DMD on the X chromosome. No dystrophin was expressed in the muscle, and a muscle biopsy demonstrated the typical histological changes of DMD. Dystrophin is located on the short arm of the X chromosome at the locus p21. Deletion of the dystrophin gene is commonly seen in DMD-especially when complicating CGD and the contiguous gene deletion syndrome. In other cases, point mutations and/or microdeletions may occur. Western blotting or immunocytochemistry for dystrophin protein expression can also be used diagnostically. The disease manifests as clumsy gait, development of the typical "Gower's maneuver" (the child has to place one hand on the knee in order to stand upright while rising from a seated position) and calf muscle changes (characterized by pseudo-hypertrophy). The child develops progressive muscular weakness that results in frequent falls, inability to climb and, eventually, culminates in the child becoming wheelchair bound. Cardiomyopathy and respiratory failure may result in severe morbidity and mortality. Treatment may involve physiotherapy, application of a brace, and surgery where indicated. Attempts are being made to develop pharmacological approaches (such as the use of glucocorticoids, not without adverse effects, or more muscle-specific therapies) and gene therapy to reverse the disease process.

Retinitis Pigmentosa

This is a condition that leads to progressive visual loss due to loss of the photoreceptors. There are several reports of Retinitis pigmentosa complicating CGD and the Contiguous gene deletion syndrome [14, 34, 3638]. Ophthalmic examination reveals fairly typical findings including pigment loss, waxy pallor of the optic nerve head, and attenuation of the retinal arterioles. There are several genetic variants of Retinitis pigmentosa. The X-linked type, involving mutations of the RPGR gene, is seen in the Contiguous gene deletion syndrome. Clinically, there is progressive loss of visual acuity and night blindness followed by a rapid decline in vision and blindness by the 4th decade.

Conclusion

CGD is a chronic disease caused by a mutation in a gene encoding essential components of NADPH oxidase function. As a result, increased susceptibility for infections occurs. The more common form of CGD involves the gene regulating NADPH function that is located on the X-chromosome. A deletion that results in X-linked CGD can also involve contiguous genes. This results in the "contiguous X-chromosome gene deletion syndrome" with manifestations of the McLeod syndrome, Duchenne muscular dystrophy and X-linked retinitis pigmentosa that further complicate disease severity and management.

List of Abbreviations

CGD: 

chronic granulomatous disease

CGS: 

contiguous gene syndrome

RBC: 

red blood cell

CYBB: 

cytochrome b-245 beta polypeptide.

Declarations

Acknowledgements

We would like to thank Dr. David Adler of the Department of Pathology, University of Washington for the use of his idiogram of the X-chromosome depicted in Figure 1.

Authors’ Affiliations

(1)
Quillen College of Medicine, East Tennessee State University
(2)
Department of Medicine, Quillen College of Medicine, East Tennessee State University
(3)
Department of Pediatrics, Quillen College of Medicine, East Tennessee State University
(4)
Department of Pharmacology, Quillen College of Medicine, East Tennessee State University
(5)
Division of Allergy, Asthma and Clinical Immunology, Department of Medicine, Quillen College of Medicine, East Tennessee State University

References

  1. Song E, Jaishankar GB, Saleh H, Jithpratuck W, Sahni R, Krishnaswamy G: Chronic granulomatous disease: a review of the infectious and inflammatory complications. Clin Mol Allergy. 2011, 9: 10. 10.1186/1476-7961-9-10PubMed CentralView ArticlePubMedGoogle Scholar
  2. Curnutte JT: Chronic granulomatous disease: the solving of a clinical riddle at the molecular level. Clin Immunol Immunopathol. 1993, 67: S2-15. 10.1006/clin.1993.1078View ArticlePubMedGoogle Scholar
  3. Biggar WD, Buron S, Holmes B: Chronic granulomatous disease in an adult male: A proposed X-linked defect. J Pediatr. 1976, 88: 63-70. 10.1016/S0022-3476(76)80728-7View ArticlePubMedGoogle Scholar
  4. Bylund J, Goldblatt D, Speert DP: Chronic granulomatous disease: from genetic defect to clinical presentation. Adv Exp Med Biol. 2005, 568: 67-87. 10.1007/0-387-25342-4_5View ArticlePubMedGoogle Scholar
  5. Casimir CM, Bu-Ghanim HN, Rodaway AR, Bentley DL, Rowe P, Segal AW: Autosomal recessive chronic granulomatous disease caused by deletion at a dinucleotide repeat. Proc Natl Acad Sci USA. 1991, 88: 2753-2757. 10.1073/pnas.88.7.2753PubMed CentralView ArticlePubMedGoogle Scholar
  6. de BM, Hilarius-Stokman PM, Hossle JP, Verhoeven AJ, Graf N, Kenney RT: Autosomal recessive chronic granulomatous disease with absence of the 67-kD cytosolic NADPH oxidase component: identification of mutation and detection of carriers. Blood. 1994, 83: 531-536.Google Scholar
  7. Heyworth PG, Cross AR, Curnutte JT: Chronic granulomatous disease. Curr Opin Immunol. 2003, 15: 578-584. 10.1016/S0952-7915(03)00109-2View ArticlePubMedGoogle Scholar
  8. Arai T, Zhao M, Kanegane H, van Zelm MC, Futatani T, Yamada M: Genetic analysis of contiguous X-chromosome deletion syndrome encompassing the BTK and TIMM8A genes. J Hum Genet. 2011, 56: 577-582. 10.1038/jhg.2011.61View ArticlePubMedGoogle Scholar
  9. Engelstad H, Carney G, S'aulis D, Rise J, Sanger WG, Rudd MK: Large contiguous gene deletions in Sjogren-Larsson syndrome. Mol Genet Metab. 2011, 104: 356-361. 10.1016/j.ymgme.2011.05.015PubMed CentralView ArticlePubMedGoogle Scholar
  10. Bertelson CJ, Pogo AO, Chaudhuri A, Marsh WL, Redman CM, Banerjee D: Localization of the McLeod locus (XK) within Xp21 by deletion analysis. Am J Hum Genet. 1988, 42: 703-711.PubMed CentralPubMedGoogle Scholar
  11. Densen P, Wilkinson S, Mandell GL, Sullivan G, Oyen R, Marsh WL: Chronic granulomatous disease, Kx negative neutrophils and linkage with Xg. Adv Exp Med Biol. 1982, 141: 655-658.View ArticlePubMedGoogle Scholar
  12. Densen P, Wilkinson-Kroovand S, Mandell GL, Sullivan G, Oyen R, Marsh WL: Kx: its relationship to chronic granulomatous disease and genetic linkage with Xg. Blood. 1981, 58: 34-37.PubMedGoogle Scholar
  13. Kang PB, Lidov HG, White AJ, Mitchell M, Balasubramanian A, Estrella E: Inefficient dystrophin expression after cord blood transplantation in Duchenne muscular dystrophy. Muscle Nerve. 2010, 41: 746-750. 10.1002/mus.21702PubMed CentralView ArticlePubMedGoogle Scholar
  14. Brown J, Dry KL, Edgar AJ, Pryde FE, Hardwick LJ, Aldred MA: Analysis of three deletion breakpoints in Xp21.1 and the further localization of RP3. Genomics. 1996, 37: 200-210. 10.1006/geno.1996.0543View ArticlePubMedGoogle Scholar
  15. Russo DC, Oyen R, Powell VI, Perry S, Hitchcock J, Redman CM: First example of anti-Kx in a person with the McLeod phenotype and without chronic granulomatous disease. Transfusion. 2000, 40: 1371-1375. 10.1046/j.1537-2995.2000.40111371.xView ArticlePubMedGoogle Scholar
  16. Uchida K, Nakajima K, Shima H, Ichiba K: The first example of the McLeod phenotype in a Japanese baby with chronic granulomatous disease. Transfusion. 1992, 32: 691.View ArticlePubMedGoogle Scholar
  17. Ho MF, Monaco AP, Blonden LA, van Ommen GJ, Affara NA, Ferguson-Smith MA: Fine mapping of the McLeod locus (XK) to a 150-380-kb region in Xp21. Am J Hum Genet. 1992, 50: 317-330.PubMed CentralPubMedGoogle Scholar
  18. Bertelson CJ, Pogo AO, Chaudhuri A, Marsh WL, Redman CM, Banerjee D: Localization of the McLeod locus (XK) within Xp21 by deletion analysis. Am J Hum Genet. 1988, 42: 703-711.PubMed CentralPubMedGoogle Scholar
  19. Miller C, Wilgenbusch S, Michaels M, Chi DS, Youngberg G, Krishnaswamy G: Molecular defects in the mannose binding lectin pathway in dermatological disease: Case report and literature review. Clin Mol Allergy. 2010, 8: 6. 10.1186/1476-7961-8-6PubMed CentralView ArticlePubMedGoogle Scholar
  20. Baehner RL: Chronic granulomatous disease of childhood: clinical, pathological, biochemical, molecular, and genetic aspects of the disease. Pediatr Pathol. 1990, 10: 143-153. 10.3109/15513819009067103View ArticlePubMedGoogle Scholar
  21. Sasaki M, Watanabe N: Kell blood group system and antibodies. Nippon Rinsho. 2005, 63 (Suppl 7): 687-689.PubMedGoogle Scholar
  22. Marsh WL: Chronic granulomatous disease, Kx antigen and the Kell blood groups. Prog Clin Biol Res. 1978, 21: 493-511.PubMedGoogle Scholar
  23. Marsh WL: Chronic granulomatous disease, the McLeod syndrome, and the Kell blood groups. Birth Defects Orig Artic Ser. 1978, 14: 9-25.PubMedGoogle Scholar
  24. Marsh WL: The Kell blood group, Kx antigen, and chronic granulomatous disease. Mayo Clin Proc. 1977, 52: 150-152.PubMedGoogle Scholar
  25. Taswell HF, Lewis JC, Marsh WL, Wimer BM, Pineda AA, Brzica SM Jr: Erythrocyte morphology in genetic defects of the Rh and Kell blood group systems. Mayo Clin Proc. 1977, 52: 157-159.PubMedGoogle Scholar
  26. Daniels G: The molecular genetics of blood group polymorphism. Hum Genet. 2009, 126: 729-742. 10.1007/s00439-009-0738-2View ArticlePubMedGoogle Scholar
  27. Lee S: The value of DNA analysis for antigens of the Kell and Kx blood group systems. Transfusion. 2007, 47: 32S-39S. 10.1111/j.1537-2995.2007.01308.xView ArticlePubMedGoogle Scholar
  28. Witt TN, Danek A, Reiter M, Heim MU, Dirschinger J, Olsen EG: McLeod syndrome: a distinct form of neuroacanthocytosis. Report of two cases and literature review with emphasis on neuromuscular manifestations. J Neurol. 1992, 239: 302-306. 10.1007/BF00867584View ArticlePubMedGoogle Scholar
  29. Jung HH, Danek A, Frey BM: McLeod syndrome: a neurohaematological disorder. Vox Sang. 2007, 93: 112-121. 10.1111/j.1423-0410.2007.00949.xView ArticlePubMedGoogle Scholar
  30. Hoger P, Seger R, Schenker T, Daniels GL, Irle U: Acanthocytosis in chronic septic granulomatosis: the McLeod syndrome. Monatsschr Kinderheilkd. 1985, 133: 296-299.PubMedGoogle Scholar
  31. Frey D, Machler M, Seger R, Schmid W, Orkin SH: Gene deletion in a patient with chronic granulomatous disease and McLeod syndrome: fine mapping of the Xk gene locus. Blood. 1988, 71: 252-255.PubMedGoogle Scholar
  32. Curnutte JT, Babior BM: Chronic granulomatous disease. Adv Hum Genet. 1987, 16: 229-297.View ArticlePubMedGoogle Scholar
  33. Branch DR, Gaidulis L, Lazar GS: Human granulocytes lack red cell Kx antigen. Br J Haematol. 1986, 62: 747-755. 10.1111/j.1365-2141.1986.tb04098.xView ArticlePubMedGoogle Scholar
  34. Francke U, Ochs HD, de MB, Giacalone J, Lindgren V, Disteche C: Minor Xp21 chromosome deletion in a male associated with expression of Duchenne muscular dystrophy, chronic granulomatous disease, retinitis pigmentosa, and McLeod syndrome. Am J Hum Genet. 1985, 37: 250-267.PubMed CentralPubMedGoogle Scholar
  35. Stevenson VL, Hardie RJ: Acanthocytosis and neurological disorders. J Neurol. 2001, 248: 87-94. 10.1007/s004150170241View ArticlePubMedGoogle Scholar
  36. Coman D, Yaplito-Lee J, La P, Nasioulas S, Bruno D, Slater HR: Three Mendelian disorders (chronic granulomatous disease, retinitis pigmentosa, ornithine transcarbamylase deficiency) in a young woman with an X chromosome deletion, del(X)(p11.4p21.1). Mol Genet Metab. 2010, 99: 329. 10.1016/j.ymgme.2009.11.006View ArticlePubMedGoogle Scholar
  37. de Saint-Basile G, Bohler MC, Fischer A, Cartron J, Dufier JL, Griscelli C: Xp21 DNA microdeletion in a patient with chronic granulomatous disease, retinitis pigmentosa, and McLeod phenotype. Hum Genet. 1988, 80: 85-89. 10.1007/BF00451463View ArticlePubMedGoogle Scholar
  38. Deardorff MA, Gaddipati H, Kaplan P, Sanchez-Lara PA, Sondheimer N, Spinner NB: Complex management of a patient with a contiguous Xp11.4 gene deletion involving ornithine transcarbamylase: a role for detailed molecular analysis in complex presentations of classical diseases. Mol Genet Metab. 2008, 94: 498-502. 10.1016/j.ymgme.2008.04.011PubMed CentralView ArticlePubMedGoogle Scholar

Copyright

© Watkins et al; licensee BioMed Central Ltd. 2011

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Advertisement