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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
Vrije Universiteit Medical Center
Amsterdam, The Netherlands
, PhD
Vrije Universiteit Medical Center
Amsterdam, The Netherlands

Initial Posting: ; Last Update: February 12, 2015.

Summary

Clinical 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) in most patients. 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. Neonatal or early-infantile onset patients have a severe disease course and may die, whereas late-infantile and early-childhood onset is associated with early wheelchair dependency.

Diagnosis/testing.

The diagnosis of LBSL can be made with confidence in persons with characteristic abnormalities observed on brain and spinal cord MRI and identification of biallelic pathogenic variants 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 pathogenic variants have been identified in the family.

Diagnosis

Suggestive Findings

Diagnosis of leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL) should be suspected in individuals with characteristic abnormalities observed on brain and spinal cord MRI [van der Knaap et al 2003, Scheper et al 2007, Steenweg et al 2012].

MRI Criteria for LBSL 1, 2

Major criteria. Signal abnormalities 3 in the:

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

Supportive criteria. Signal abnormalities 3 in the:

  • Splenium of the corpus callosum
  • Posterior limb of the internal capsule
  • Superior cerebellar peduncles
  • Inferior cerebellar peduncles
  • Intraparenchymal part of the trigeminal nerve
  • Mesencephalic trigeminal tracts
  • Anterior spinocerebellar tracts in the medulla
  • Cerebellar white matter

Notes:

1.

Steenweg et al [2012]

2.

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

3.

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

Note: 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, Távora et al 2007]. Lactate elevation in proton magnetic resonance spectroscopy of abnormal white matter has been mentioned as a diagnostic criterion but has a low distinguishing value. If the MRI meets the criteria for LBSL, this diagnosis should be considered, whether lactate is elevated or not. If the MRI does not meet the criteria for LBSL, elevated lactate may be a general indicator of a mitochondrial leukoencephalopathy, but not specifically LBSL.

Establishing the Diagnosis

The diagnosis of LBSL is established in a proband with the identification of biallelic pathogenic variants in DARS2 (see Table 1).

Molecular testing approaches can include:

  • Single-gene testing. Sequence analysis of DARS2 is performed first followed by deletion/duplication analysis and/ or mRNA if only one or no pathogenic variant is found.
  • Use of a multi-gene panel that includes DARS2 and other genes of interest (see Differential Diagnosis). Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time.
  • Genomic testing. If single gene testing (and/or use of a multi-gene panel) has not confirmed a diagnosis in an individual with features of LBSL, genomic testing may be considered. Such testing may include whole-exome sequencing (WES), whole-genome sequencing (WGS), and whole mitochondrial sequencing (WMitoSeq).

    Notes regarding WES and WGS. (1) False negative rates vary by genomic region; therefore, genomic testing may not be as accurate as targeted single gene testing or multi-gene molecular genetic testing panels; (2) most laboratories confirm positive results using a second, well-established method; (3) nucleotide repeat expansions and epigenetic alterations cannot be detected; (4) deletions/duplications larger than eight to ten nucleotides are not detected effectively [Biesecker & Green 2014].

    Notes regarding WMitoSeq. (1) Pathogenic mtDNA variants present at low levels of heteroplasmy in blood may not be detected in DNA extracted from blood and may require DNA extracted from skeletal muscle; (2) mtDNA deletions/duplications may not be detected effectively.

Table 1.

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

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method
DARS2Sequence analysis 2~90% 3, 4
Deletion/duplication analysis 5None reported
1.

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene.

2.

Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

3.

Affected individuals are almost invariably compound heterozygous for two pathogenic variants in DARS2. In a few individuals it has not been possible to determine both pathogenic variants (see footnote 4). A few individuals with homozygous pathogenic variants have been identified.

4.

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].

5.

Testing that identifies exonic or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

Clinical Characteristics

Clinical Description

Variable severity. The disease spectrum ranges from neonatal-onset severe forms with death before age two years [Steenweg et al 2012] to adult-onset slow forms with only mild impairment [van Berge at al 2014]. Childhood onset is most common [van Berge et al 2014]. With the exception of the early-onset variant, the disease is slowly progressive. Most individuals with childhood onset become partially or fully wheelchair-dependent in their teens, twenties or later, while patients with adult-onset disease are not known to become wheelchair dependent [van Berge at al 2014]. By contrast, neonatal or early-infantile onset patients have a severe disease course and may die, while late-infantile and early childhood onset is associated with early wheelchair dependency.

Motor skills. In most affected individuals, initial development is normal. Deterioration of motor skills usually starts in childhood or adolescence [van der Knaap et al 2003, Linnankivi et al 2004, Serkov et al 2004, Távora et al 2007, Uluc et al 2008, van Berge et al 2014] and occasionally in infancy [Steenweg et al 2012] or adulthood [Petzold et al 2006, Labauge et al 2007, van Berge et al 2014].

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.

Evidence of an axonal neuropathy is found in some but not all affected individuals, leading to decreased or absent tendon reflexes and distal weakness and sensory loss [van der Knaap et al 2003, Távora et al 2007, Uluc et al 2008, Isohanni et al 2010].

Speech. Dysarthria develops over time.

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

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

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

Routine laboratory tests, including CSF analysis, are usually normal. In a few individuals mild and inconsistent mild elevation of lactate concentration has been noted in blood or CSF or both. No published information is available.

Neuropathologic findings have been described in two siblings with a severe variant of LBSL [Yamashita et al 2013]. Electron microscopy revealed vacuolar changes and myelin splitting in the affected white matter [Yamashita et al 2013]. Quantitative MR parameters are in line with these findings [Steenweg et al 2011].

Genotype-Phenotype Correlations

The study of genotype-phenotype correlations is hampered by the very high number of different pathogenic variants observed in individuals with LBSL. The numbers of patients sharing the same genotype are low. An overview study of 66 affected individuals revealed preliminary evidence in support of a genotype-phenotype correlation [van Berge et al 2014].

Prevalence

LBSL is rare.

Carrier rate in the general population is low, with the exception of Finland, where a carrier rate of 1:95 has been reported [Isohanni et al 2010]. So far, only one family with parental consanguinity has been observed [Miyake et al 2011]. Almost all affected individuals are compound heterozygous for two pathogenic variants. Only four patients from two families have been described with homozygous mutations [Miyake et al 2011, Synofzik et al 2011]. Strikingly, no cases of homozygosity have been seen among Finnish persons with LBSL [van Berge et al 2014].

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].

Hypomyelination with brain stem and spinal cord involvement and leg spasticity (HBSL), caused by mutations in DARS, shares part of the selective vulnerability of brain stem and spinal cord structures [Taft et al 2013].

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs 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
  • Medical genetics consultation

Treatment of Manifestations

Supportive therapy includes the following:

  • 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 in most cases. Annual clinical evaluations suffice. In case of rapid worsening more frequent evaluations are appropriate. Follow-up MRI can be performed once every few years. Only in severe, early-onset cases are more frequent evaluations necessary.

Evaluation of Relatives at Risk

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

Pregnancy Management

The authors are aware of several affected mothers who have had children. There do not appear to be specific risks for the mother or fetus other than the risk of recurrence of LBSL in the fetus (see Genetic Counseling).

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 DARS2 pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier of a DARS2 pathogenic variant is 2/3.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with LBSL are obligate heterozygotes (carriers) for a pathogenic variant in DARS2.

Other family members of a proband. Each sib of the proband’s parents is at a 50% risk of being a carrier of a DARS2 pathogenic variant.

Carrier Detection

Carrier testing for at-risk family members requires prior identification of the DARS2 pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

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

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

Prenatal Testing

If the DARS2 pathogenic variants have been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the pathogenic variants 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)
    224 North Second Street
    Suite 2
    DeKalb IL 60115
    Phone: 800-728-5483 (toll-free); 815-748-3211
    Fax: 815-748-0844
    Email: office@ulf.org
  • Children Living with Inherited Metabolic Diseases (CLIMB)
    United Kingdom
    Phone: 0800-652-3181
    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 from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein 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

Gene structure. The genomic copy of the gene comprises 33,725 bases; it contains 17 exons. The cDNA has 3348 base pairs. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. In almost all affected individuals one pathogenic variant 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 ten or 11 C-residues that lies ten nucleotides upstream of exon 3 [Scheper et al 2007].

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

Table 2.

Selected DARS2 Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.228-20_-21delTTinsCp.Arg76SerfsTer5NM_108122​.4
NP_060592​.2
c.492+2T>Cp.Met134_Lys165del
c.455G>Tp.Cys152Phe

Note on variant classification: Variants listed in the table have been provided by the authors. 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. On 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 homodimers [Delarue et al 1994].

Abnormal gene product. The majority of affected individuals have a pathogenic variant 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 pathogenic variants upstream of exon 3 diminish but do not completely abolish correct splicing. As a result, a low amount of wild-type protein is produced in the cells of an affected individual. A total lack of mtAspRS activity is thought to be incompatible with life.

Another common pathogenic variant, c.492+2T>C (p.Met134_Lys165del) leads to a deletion of part of the protein. Though not fully understood, this deletion 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

Literature Cited

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Chapter Notes

Author History

Gajja S Salomons, PhD (2015-present)
Gert C Scheper, PhD; Vrije Universiteit Medical Center, Amsterdam (2010-2015)
Marjo S van der Knaap, MD, PhD (2010-present)

Revision History

  • 12 February 2015 (me) Comprehensive update posted live
  • 25 May 2010 (me) Review posted live
  • 22 February 2010 (mvdk) Original submission
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