Leukoencephalopathy With Brain Stem And Spinal Cord Involvement And Lactate Elevation
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 and followed by deletion/duplication analysis and/ or mRNA if only one or no pathogenic variant is found.
- Use of a multigene panel that includes DARS2 and other genes of interest (see Differential Diagnosis). Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
- More comprehensive genomic testing. If single-gene testing (and/or use of a multigene panel) has not confirmed a diagnosis in an individual with features of LBSL, more comprehensive genomic testing (when available) may be considered. Such testing may include exome sequencing, genome sequencing, and mitochondrial sequencing. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant Detectable by Method |
|---|---|---|
| DARS2 | Sequence analysis 2 | ~90% 3, 4 |
| Deletion/duplication analysis 5 | None 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. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 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 variant could not be found in gDNA; in two of three the second pathogenic variant 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 pathogenic variants in DARS2 were detected in either gDNA or cDNA [Scheper et al 2007; Scheper & van der Knaap, personal communication].
- 5.
Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include 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 sibs 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 pathogenic variants [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 pathogenic variants 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
- Clinical 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 ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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.