Hypomyelination with brainstem and spinal cord involvement and leg spasticity

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Hypomyelination with brainstem and spinal cord involvement and leg spasticity
Other namesAspartyl-tRNA synthetase deficiency, HBSL
Autosomal recessive - en.svg
HBSL is inherited in Autosomal recessive fashion.
Symptoms Regression of the motor milestones, epilepsy, intellectual disability, ataxia, nystagmus, and spasticity.
Causes Mutations in a gene DARS1
Deaths1

Hypomyelination with brainstem and spinal cord involvement and leg spasticity (HBSL) is a rare autosomal recessive disorder which is caused by a mutation in a gene DARS1. [1] HBSL usually begins at the age of 3-36 months, and the main signs of this disorder are: Regression of the motor milestones, epilepsy, intellectual disability, ataxia, nystagmus, and spasticity. [2] [3]

Contents

Approximately 19 cases had been reported as of 2023. [4]

Symptoms

In case of infantile-onset HBSL, patients experience regression of the motor development/developmental delay, also some patients experience tethered cord syndrome, triangular head shape, Chiari malformation, and vertebral anomalies. [3] [5] In case of older-onset HBSL, it begins with spasticity. [6]

Almost all of the patients experience hypertonia, positive Babinski sign, and hyper-reflexia, also nystagmus is a common finding for this disorder. [2] In much rarer cases patients also have diminished muscle tone of the trunk musculature, seizures, intellectual disability, and headaches. [5] [3] [6] Upper limbs are also involved in a severe forms of HBSL. [2]

Patients with HBSL have either diplegic gait or in-toeing gait. [3] [6]

Diagnosis

HBSL doesn't have exact MRI criteria, but some of the features can be observed in MRI, such as: [6] [3] [2]

Also, most of the patients had this signs: [2]

Cause

HBSL is caused by a mutation in a gene DARS1, which encodes protein aspartyl-tRNA synthetase, cytoplasmic. [7]

Pathophysiology

According to studies, the hypomorphic variant of DARS1 causes decreased levels of the myelin proteins (such as PLP1, MBP, and CNP), which might be the cause of the symptoms. [8] [9] Also, one of mutations (D367Y to be exact) slightly increases activity of enzyme, which reduces specificity for the aspartate's tRNA, and enzyme mischarges other amino acid's tRNA with aspartate. Incorrectly charged tRNA causes accumulation of misfolded proteins, which is harmful for the cell. [9]

Treatment

HBSL doesn't have a cure, although it can be managed (by using steroids, immunoglobulins, physiotherapy etc). [4]

Prognosis

Because of the rarity of HBSL, exact prognosis is unknown, although if HBSL begins early, then prognosis would be worse. [4]

History

HBSL was first described by Taft and colleagues in 2013. [3]

Culture

MacPac Foundation is a non-profit organisation which is dedicated to raise awareness about HBSL, also raising funds for the scientist and affected families. [10]

References

  1. ↑ "Entry - #615281 - HYPOMYELINATION WITH BRAINSTEM AND SPINAL CORD INVOLVEMENT AND LEG SPASTICITY; HBSL - OMIM". www.omim.org. Retrieved 2025-05-18.
  2. 1 2 3 4 5 Muthiah, Annapoorani; Housley, Gary D.; Klugmann, Matthias; Fröhlich, Dominik (2021-01-26). "The Leukodystrophies HBSL and LBSL—Correlates and Distinctions". Frontiers in Cellular Neuroscience. 14. Creative Commons by small.svg  This article incorporates textfrom this source, which is available under the CC BY 4.0 license.. doi: 10.3389/fncel.2020.626610 . ISSN   1662-5102. PMC   7870476 . PMID   33574740.
  3. 1 2 3 4 5 6 Taft, Ryan J.; Vanderver, Adeline; Leventer, Richard J.; Damiani, Stephen A.; Simons, Cas; Grimmond, Sean M.; Miller, David; Schmidt, Johanna; Lockhart, Paul J.; Pope, Kate; Ru, Kelin; Crawford, Joanna; Rosser, Tena; de Coo, Irenaeus F. M.; Juneja, Monica (2013-05-02). "Mutations in DARS Cause Hypomyelination with Brain Stem and Spinal Cord Involvement and Leg Spasticity". The American Journal of Human Genetics. 92 (5): 774–780. doi:10.1016/j.ajhg.2013.04.006. hdl: 1871.1/8eeab4b7-6d75-4184-b6f6-2fd306fd4437 . ISSN   0002-9297. PMC   3644624 . PMID   23643384.
  4. 1 2 3 Zhu, Jingyi; Guo, Xiaomin; Ran, Ningjing; Liang, Jingtao; Liu, Fuyou; Liu, Junyan; Wang, Rongyu; Jiang, Lianyan; Yang, Dongdong; Liu, Meijun (2023-01-12). "Leukoencephalopathy hypomyelination with brainstem and spinal cord involvement and leg spasticity caused by DARS1 mutations". Frontiers in Genetics. 13. doi: 10.3389/fgene.2022.1009230 . ISSN   1664-8021. PMC   9878823 . PMID   36712860.
  5. 1 2 "Genotype–phenotype variability of DARS mutation—case reports of a trio of siblings" (PDF). www.ejmanager.com.{{cite web}}: CS1 maint: url-status (link)
  6. 1 2 3 4 Wolf, Nicole I.; Toro, Camilo; Kister, Ilya; Latif, Kartikasalwah Abd; Leventer, Richard; Pizzino, Amy; Simons, Cas; Abbink, Truus E.M.; Taft, Ryan J.; van der Knaap, Marjo S.; Vanderver, Adeline (2015-01-20). "DARS-associated leukoencephalopathy can mimic a steroid-responsive neuroinflammatory disorder". Neurology. 84 (3): 226–230. doi:10.1212/WNL.0000000000001157. PMC   4335995 . PMID   25527264.
  7. ↑ "UniProt". UniProt. Retrieved 2025-05-18.
  8. ↑ Klugmann, Matthias; Kalotay, Elizabeth; Delerue, Fabien; Ittner, Lars M.; Bongers, Andre; Yu, Josephine; Morris, Margaret J.; Housley, Gary D.; Fröhlich, Dominik (2022-07-01). "Developmental delay and late onset HBSL pathology in hypomorphic Dars1M256L mice". Neurochemical Research. 47 (7): 1972–1984. doi:10.1007/s11064-022-03582-4. ISSN   1573-6903. PMC   9217827 . PMID   35357600.
  9. 1 2 Fröhlich, Dominik; Mendes, Marisa I.; Kueh, Andrew J.; Bongers, Andre; Herold, Marco J.; Salomons, Gajja S.; Housley, Gary D.; Klugmann, Matthias (2021-01-20). "A Hypomorphic Dars1D367Y Model Recapitulates Key Aspects of the Leukodystrophy HBSL". Frontiers in Cellular Neuroscience. 14. doi: 10.3389/fncel.2020.625879 . hdl: 11343/273041 . ISSN   1662-5102. PMC   7855723 . PMID   33551752.
  10. ↑ "Our Vision". macpacfoundation. Retrieved 2025-05-18.
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