• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation

Synonyms: LBSL, Mitochondrial Aspartyl-tRNA Synthetase Deficiency

, MD, PhD and , PhD.

Author Information
, MD, PhD
VU University Medical Center
Amsterdam, The Netherlands
, PhD
VU University Medical Center
Amsterdam, The Netherlands

Initial Posting: .

Summary

Disease characteristics. Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL) is characterized by slowly progressive cerebellar ataxia and spasticity with dorsal column dysfunction (decreased position and vibration sense). The neurologic dysfunction involves the legs more than the arms. The tendon reflexes are retained. Deterioration of motor skills usually starts in childhood or adolescence, but occasionally not until adulthood. Dysarthria develops over time. Occasional findings include epilepsy; learning problems; cognitive decline; and reduced consciousness, neurologic deterioration, and fever following minor head trauma. Many affected individuals become wheelchair dependent in their teens or twenties.

Diagnosis/testing. The diagnosis of LBSL can be made with confidence in persons with characteristic abnormalities observed on brain and spinal cord MRI and two alleles with identifiable mutations in DARS2, encoding mitochondrial aspartyl tRNA synthase.

Management. Treatment of manifestations: Supportive therapy includes physical therapy and rehabilitation to improve motor function, and the following as needed: antiepileptic drugs (AED), special education, speech therapy.

Prevention of secondary complications: Rehabilitation and physical therapy are helpful in the prevention of secondary complications, such as contractures and scoliosis.

Genetic counseling. LBSL 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 family members and prenatal testing for pregnancies at increased risk are possible if the disease-causing mutations have been identified in the family.

Diagnosis

Clinical Diagnosis

The diagnosis of leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL) can be made with confidence in persons with characteristic abnormalities observed on brain and spinal cord MRI [Van der Knaap et al 2003] and identifiable mutations in the causative gene DARS2, encoding mitochondrial aspartyl tRNA synthetase [Scheper et al 2007].

MRI criteria for LBSL [Scheper et al 2007]

Major criteria 1. Signal abnormalities 2 in the:

  • Cerebral white matter, which is either nonhomogeneous and spotty or homogeneous and confluent, with relative sparing of the U-fibers
  • Dorsal columns and lateral corticospinal tracts of the spinal cord (Visualization of such abnormalities in the cervical spinal cord suffices.)
  • Pyramids in the medulla oblongata

Supportive criteria

  • Signal abnormalities 2 in the
    • Splenium of the corpus callosum
    • Posterior limb of the internal capsule
    • Medial lemniscus in the brain stem
    • Superior cerebellar peduncles
    • Inferior cerebellar peduncles
    • Intraparenchymal part of the trigeminal nerve
    • Mesencephalic trigeminal tracts
    • Anterior spinocerebellar tracts in the medulla
    • Cerebellar white matter with subcortical preponderance
  • Elevated lactate in the abnormal cerebral white matter, as measured by proton magnetic resonance spectroscopy (MRS) 3

1. For an MRI-based diagnosis, all major criteria and at least one supportive criterion should be fulfilled.

2. ‘Signal abnormalities’ refer to abnormally low signal on T1-weighted images and abnormally high signal on T2-weighted images.

3. Lactate is elevated within the abnormal cerebral white matter in most but not all affected individuals [van der Knaap et al 2003, Petzold et al 2006, Labauge et al 2007, Tavora et al 2007].

White matter lactate [Van der Knaap et al 2003]:

— Affected individuals: range = 0.5-4.1 mmol/L (SD = 1.1 mmol/L; mean = 2.4 mmol/L)

— Controls: mean = 0.2 mmol/L; SD = 0.3 mmol/L

Testing

Routine laboratory tests, including CSF analysis, are usually normal. In a few individuals mild and inconsistent elevation of lactate concentration has been noted in blood or CSF or both. No published information is available. Normal values for CSF lactate vary per laboratory, but are typically below 1.5 mmol/L. In LBSL CSF lactate is usually normal, but values between 2 and 3 mmol/L may be seen occasionally [Author, personal observation].

Neuropathologic findings have not been reported.

Molecular Genetic Testing

Gene. DARS2 is the only gene known to be associated with LBSL.

Clinical testing

  • Sequence analysis of the coding exons and surrounding intronic regions is performed to detect DARS2 genomic DNA (gDNA) mutations in individuals fulfilling the MRI criteria for LBSL. Affected individuals are invariably compound heterozygous for two mutations in DARS2. In a few individuals it has not been possible to determine both pathogenic mutations at the genomic level. No individuals with homozygous mutations have been identified.
  • Sequence analysis of complementary DNA (cDNA), if available, can be performed to:
    • Detect aberrant splice products that occur as a result of mutations outside the regions that are included in the standard analysis of exons and surrounding intronic regions;
    • Determine the effect of mutations close to but not within the acceptor or donor sites, including the c.228-20_-21delTTinsC (p.Arg76Serfs*5) mutation that occurs in the majority of affected individuals. Theoretically, this change would not be predicted to affect splicing; however, cDNA analysis reveals partial skipping of exon 3, leading to a frame shift and a premature stop codon.

Table 1. Summary of Molecular Genetic Testing Used in Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation

Gene SymbolTest MethodMutation Detection Frequency by This Method 1
DARS2Sequence analysis~90% 2

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

2. In four of 43 families the second pathogenic mutation could not be found in gDNA; in two of three the second mutation was detected using cDNA; cells of the fourth individual were not available for isolation of mRNA for cDNA synthesis. In one person fulfilling the MRI criteria for LBSL, no mutations in DARS2 were detected in either gDNA or cDNA [Scheper et al 2007; Scheper & van der Knaap, personal communication].

Interpretation of test results

  • For issues to consider in interpretation of sequence analysis results, click here.
  • Finding two-disease causing mutations in DARS2 confirms the diagnosis of LBSL, but absence of DARS2 mutations does not exclude the diagnosis when the clinical and MRI findings are characteristic.

Testing Strategy

To confirm/establish the diagnosis in a proband. Because the clinical picture of LBSL is consistent with a spinocerebellar ataxia of any type, it is the MRI findings that raise the suspicion of LBSL. In some instances affected individuals have minimal neurologic signs but MRI abnormalities typical of LBSL.

  • If the MRI fulfills the criteria for LBSL, molecular genetic testing of DARS2 should be performed.
  • If the MRI is suggestive of LBSL, but the MRI criteria are not fully met, molecular genetic testing of DARS2 should still be considered.
  • If the MRI fulfills the criteria for LBSL and molecular genetic testing of DARS2 does not identify disease-causing mutations, LBSL is not excluded.
  • If the clinical picture is consistent with a spinocerebellar ataxia and MRI of the brain and spinal cord is normal or shows abnormalities that are not compatible with LBSL, molecular genetic testing of DARS2 is not warranted.

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.

Clinical Description

Natural History

Initial development is normal in most affected children. In some children, independent walking is late and unstable from the beginning. Deterioration of motor skills usually starts in childhood or adolescence [Van der Knaap et al 2003, Linnankivi et al 2004, Serkov et al 2004, Tavora et al 2007, Uluc et al 2008] and occasionally in adulthood [Petzold et al 2006, Labauge et al 2007]. The clinical picture of LBSL consists of slowly progressive cerebellar ataxia, spasticity, and dorsal column dysfunction, involving the legs more than the arms. Tendon reflexes are retained. Most affected individuals have decreased position and vibration sense of the legs more than the arms, leading to increased difficulty walking in the dark.

Manual dexterity becomes impaired to a variable degree.

Dysarthria develops over time.

Some affected individuals develop epilepsy. Seizures are infrequent and easily controlled with medication [Van der Knaap et al 2003].

Some have learning problems from early on, but most have normal intellectual capacities. Cognitive decline may occur and is usually mild [Van der Knaap et al 2003, Serkov et al 2004].

Some affected individuals experience lowered consciousness, neurologic deterioration, and fever following minor head trauma [Serkov et al 2004]. Recovery is only partial.

Evidence of an axonal neuropathy is found in some but not in all affected individuals [Van der Knaap et al 2003, Tavora et al 2007, Uluc et al 2008, Isohanni et al 2010].

The disease is slowly progressive. Most affected individuals become wheelchair-dependent in their teens or twenties; however, disease severity varies. Some affected individuals become wheelchair dependent before age ten and are totally incapacitated in their twenties, whereas others have the first signs of the disease in their twenties and still walk in their forties.

Genotype-Phenotype Correlations

No genotype-phenotype correlation has been described, but the subject has not been investigated systematically. So far, no major intrafamilial variation has been observed.

Prevalence

LBSL is rare.

The carrier rate in the general population is low. So far, no parental consanguinity has been observed. All affected individuals are compound heterozygous for two mutations.

Differential Diagnosis

The clinical picture of LBSL consists of slowly progressive cerebellar ataxia, spasticity, and dorsal column dysfunction, involving the legs more than the arms. The tendon reflexes are retained. Based on these findings alone, many disorders can be considered [Finsterer 2009a]; however, the MRI findings distinguish LBSL from other spinocerebellar ataxias [Van der Knaap et al 2003].

The clinical findings of a spinocerebellar ataxia in combination with MRI abnormalities of the dorsal columns, lateral corticospinal tracts, and cerebral white matter would be compatible with vitamin B12 deficiency (combined cord degeneration) [Locatelli et al 1999]. The brain stem abnormalities typically seen in LBSL do not occur in vitamin B12 deficiency. In vitamin B12 deficiency the cervical spinal cord is mainly affected [Locatelli et al 1999], whereas in LBSL the entire spinal cord is affected [Van der Knaap et al 2003].

Elevated lactate in MRS or body fluids or both in combination with clinical findings of a spinocerebellar ataxia or white matter abnormalities on MRI or both should lead to the consideration of mitochondrial disorders [Finsterer 2009b]. Although the brain stem and spinal cord are frequently affected in mitochondrial disorders, the selective involvement of specific brain stem and spinal cord tracts is unique for LBSL [Van der Knaap & Valk 2005].

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with LBSL, the following evaluations are recommended:

  • Neurologic examination
  • Brain and spinal cord MRI
  • If possible, proton MRS of abnormal cerebral white matter
  • Physical therapy/occupational therapy assessment

Treatment of Manifestations

Supportive therapy includes:

  • Physical therapy and rehabilitation to improve motor function
  • The following as needed:
    • Antiepileptic drugs (AED) if epileptic seizures are present
    • Special education
    • Speech therapy

Prevention of Secondary Complications

Rehabilitation and physical therapy are helpful in the prevention of secondary complications, such as contractures and scoliosis.

Surveillance

LBSL is very slowly progressive. Annual evaluations suffice. In case of rapid worsening more frequent evaluations are appropriate.

Evaluation of Relatives at Risk

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

Therapies Under Investigation

Search Clinical Trials.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.

Other

Studies of muscle biopsies, fibroblasts, and lymphoblasts show no evidence of mitochondrial dysfunction; therefore, there is no rationale for the “mitochondrial cocktail” of vitamins and cofactors, often given to persons with mitochondrial dysfunction.

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

Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child 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 LBSL are obligate heterozygotes (carriers) for a disease-causing mutation in the DARS2 gene.

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 if the disease-causing mutations have been identified in the family.

Related Genetic Counseling Issues

Family planning. The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.

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

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. Both disease-causing alleles of an affected family member must be identified or linkage established in the family before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

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.

  • European Leukodystrophy Association (ELA)
    2, rue Mi-les-Vignes
    B.P. 61024
    Laxou Cedex 54521
    France
    Phone: 03833093 34
    Fax: 03833000 68
    Email: ela@ela-asso.com
  • United Leukodystrophy Foundation (ULF)
    2304 Highland Drive
    Sycamore IL 60178
    Phone: 800-728-5483 (toll-free)
    Fax: 815-895-2432
    Email: office@ulf.org
  • Children Living with Inherited Metabolic Diseases (CLIMB)
    Climb Building
    176 Nantwich Road
    Crewe CW2 6BG
    United Kingdom
    Phone: 0800-652-3181 (toll free); 0845-241-2172
    Fax: 0845-241-2174
    Email: info.svcs@climb.org.uk
  • Myelin Disorders Bioregistry Project
    Email: myelindisorders@cnmc.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. Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation: Genes and Databases

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 Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation (View All in OMIM)

610956ASPARTYL-tRNA SYNTHETASE 2; DARS2
611105LEUKOENCEPHALOPATHY WITH BRAINSTEM AND SPINAL CORD INVOLVEMENT AND LACTATE ELEVATION; LBSL

Normal allelic variants. The genomic copy of the gene comprises 33,725 bases; it contains 17 exons. The cDNA has 3348 base pairs. Two variants in the dbSNP database have frequency data that indicate their role as normal variants. Only one of those, rs35515638 (c.587A>G), has frequency data with an average heterozygosity of 0.07. Another nonsynonymous SNP, c.1013G>A was observed in 12 out of 360 control chromosomes (Scheper and van der Knaap, personal communication).

Pathologic allelic variants. In almost all affected individuals one mutation is present upstream of exon 3. The c.228-20_-21delTTinsC is most often observed. In other affected individuals nucleotide changes are seen in the same region, within a stretch of 10 or 11 C-residues that lies 10 nucleotides upstream of exon 3 [Scheper et al 2007].

Several individuals share haplotypes involving five or six microsatellite markers on chromosome 1p25. The mutations c.492+2T>C and c.455G>T are correlated with two of these haplotypes and are often seen in affected individuals of North-East European origin [Scheper et al 2007, Isohanni et al 2010].

Table 2. Selected DARS2 Allelic Variants

Class of
Variant Allele
DNA Nucleotide ChangeProtein Amino Acid ChangeReference
Sequences
Normalc.587A>Gp.Lys196ArgNM_108122​.4
NP_060592​.2
c.1013G>Ap.Gly338Glu
Pathologicc.228-20_-21delTTinsCp.Arg76Serfs*5
c.492+2T>Cp.Met134_Lys165del
c.455G>Tp.Cys152Phe

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. The protein length is 645 amino acids; its predicted molecular weight is 74 kd. It is a mitochondrial aspartyl-tRNA synthetase (mtAspRS), which charges tRNAAsp in mitochondria. Upon entry into mitochondria, the predicted N-terminal mitochondrial targeting sequence of 47 amino acids is removed. The functional protein contains 598 amino acids with a predicted molecular weight of 68 kd. Multiple alignment with related enzymes reveals 36−43% identity of the full-length sequence with bacterial sequences, 32% with the mitochondrial sequence from the lower eukaryote S. cerevisiae, and below 23% with enzymes from archæa and cytosol of eukaryotes, including human cytosolic aspartyl-tRNA synthetase. Alignment also shows that human mt-AspRS possesses strictly conserved residues found in all known AspRS sequences, including those for ATP binding and tRNA binding. Residues involved in amino acid binding include those typical for class II aaRSs and those specific for aspartic acid recognition [Bonnefond et al 2005]. Based on the homology to its bacterial counterparts, mtAspRS is thought to form homo-dimers [Delarue et al 1994].

Abnormal gene product. The majority of affected individuals have a mutation that affects splicing of exon 3. Incorrect splicing of this exon results in a frame shift in the reading frame and nonsense-mediated decay of the wrongly-spliced mRNA. It should be noted that these mutations upstream of exon 3 diminish but not completely abolish correct splicing. As a consequence, in patient cells a low amount of wild type protein is produced. A total lack of mtAspRS activity is thought to be incompatible with life.

Another common mutation, c.492+2T>C (p.Met134_Lys165del) leads to a deletion of part of the protein. The effect of this deletion is unclear but is likely to have a severe effect on the function of the protein.

Several missense mutations have been shown to severely reduce the amino acylation function in assays with purified bacterially-expressed recombinant proteins [Scheper et al 2007].

References

  1. Bonnefond L, Fender A, Rudinger-Thirion J, Giegé R, Florentz C, Sissler M. Toward the full set of human mitochondrial aminoacyl-tRNA synthetases: characterization of AspRS and TyrRS. Biochemistry. 2005;44:4805–4816. [PubMed: 15779907]
  2. Delarue M, Poterszman A, Nikonov S, Garber M, Moras D, Thierry JC. Crystal structure of a prokaryotic aspartyl tRNA-synthetase. EMBO J. 1994;13:3219–3229. [PMC free article: PMC395218] [PubMed: 8045252]
  3. Finsterer J. Ataxias with autosomal, X-chromosomal or maternal inheritance. Can J Neurol Sci. 2009a;36:409–428. [PubMed: 19650351]
  4. Finsterer J. Mitochondrial ataxias. Can J Neurol Sci. 2009b;36:543–553. [PubMed: 19831121]
  5. Isohanni P, Linnankivi T, Buzkova J, Lonnqvist T, Pihko H, Valanne L, Tienari PJ, Elovaara I, Pirttila T, Reunanen M, Koivisto K, Marjavaara S, Suomalainen A. DARS2 mutations in mitochondrial leukoencephalopathy and multiple sclerosis. J Med Genet. 2010;47:66–70. [PubMed: 19592391]
  6. Labauge P, Roullet E, Boespflug-Tanguy O, Nicoli F, Le Fur Y, Cozzone PJ, Ducreux D, Rodriguez D. Familial, adult onset form of leukoencephalopathy with brain stem and spinal cord involvement: inconstant high brain lactate and very slow disease progression. Eur Neurol. 2007;58:59–61. [PubMed: 17483590]
  7. Linnankivi T, Lundbom N, Autti T, Hakkinen AM, Koillinen H, Kuusi T, Lonnqvist T, Sainio K, Valanne L, Aarimaa T, Pihko H. Five new cases of a recently described leukoencephalopathy with high brain lactate. Neurology. 2004;63:688–692. [PubMed: 15326244]
  8. Locatelli ER, Laureno R, Ballard P, Mark AS. MRI in vitamin B12 deficiency myelopathy. Can J Neurol Sci. 1999;26:60–63. [PubMed: 10068811]
  9. Petzold GC, Bohner G, Klingebiel R, Amberger N, van der Knaap MS, Zschenderlein R. Adult onset leucoencephalopathy with brain stem and spinal cord involvement and normal lactate. J Neurol Neurosurg Psychiatry. 2006;77:889–891. [PMC free article: PMC2117479] [PubMed: 16788019]
  10. Scheper GC, van der Klok T, van Andel RJ, van Berkel CG, Sissler M, Smet J, Muravina TI, Serkov SV, Uziel G, Bugiani M, Schiffmann R, Krageloh-Mann I, Smeitink JA, Florentz C, Van CR, Pronk JC, van der Knaap MS. Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation. Nat Genet. 2007;39:534–539. [PubMed: 17384640]
  11. Serkov SV, Pronin IN, Bykova OV, Maslova OI, Arutyunov NV, Muravina TI, Kornienko VN, Fadeeva LM, Marks H, Bonnemann C, Schiffmann R, van der Knaap MS. Five patients with a recently described novel leukoencephalopathy with brainstem and spinal cord involvement and elevated lactate. Neuropediatrics. 2004;35:1–5. [PubMed: 15002045]
  12. Tavora DG, Nakayama M, Gama RL, Alvim TC, Portugal D, Comerlato EA. Leukoencephalopathy with brainstem and spinal cord involvement and high brain lactate: report of three Brazilian patients. Arq Neuropsiquiatr. 2007;65:506–511. [PubMed: 17665025]
  13. Uluc K, Baskan O, Yildirim KA, Ozsahin S, Koseoglu M, Isak B, Scheper GC, Gunal DI, van der Knaap MS. Leukoencephalopathy with brain stem and spinal cord involvement and high lactate: a genetically proven case with distinct MRI findings. J Neurol Sci. 2008;273:118–122. [PubMed: 18619624]
  14. Van der Knaap MS, van der Voorn P, Barkhof F, van Coster R, Krageloh-Mann I, Feigenbaum A, Blaser S, Vles JS, Rieckmann P, Pouwels PJ. A new leukoencephalopathy with brainstem and spinal cord involvement and high lactate. Ann Neurol. 2003;53:252–258. [PubMed: 12557294]
  15. Van der Knaap MS, Valk J. Magnetic Resonance of Myelin Myelination and Myelin Disorders. 3 ed. Berlin, Heidelberg, New York: Springer; 2005.

Chapter Notes

Revision History

  • 25 May 2010 (me) Review posted live
  • 22 February 2010 (mvdk) Original submission
Copyright © 1993-2014, University of Washington, Seattle. All rights reserved.

For more information, see the GeneReviews Copyright Notice and Usage Disclaimer.

For questions regarding permissions: ude.wu@tssamda.

Bookshelf ID: NBK43417PMID: 20506600
PubReader format: click here to try

Views

  • PubReader
  • Print View
  • Cite this Page
  • Disable Glossary Links

Tests in GTR by Gene

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to pubmed
  • Gene
    Gene records cited in chapters on the NCBI bookshelf. Links are provided by the authors or the NCBI Bookshelf staff.

Related citations in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...