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Hypomyelination with brain stem and spinal cord involvement and leg spasticity(HBSL)

MedGen UID:
1667792
Concept ID:
C4755254
Disease or Syndrome
Synonyms: ASPARTYL-tRNA SYNTHETASE DEFICIENCY; Hypomyelination with brainstem and spinal cord involvement and leg spasticity
SNOMED CT: HBSL - hypomyelination, brain stem, spinal cord, leg spasticity (777999008); Hypomyelination with brain stem and spinal cord involvement and leg spasticity (777999008)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): DARS1 (2q21.3)
 
Monarch Initiative: MONDO:0014115
OMIM®: 615281
Orphanet: ORPHA363412

Definition

Hypomyelination with brainstem and spinal cord involvement and leg spasticity is an autosomal recessive leukoencephalopathy characterized by onset in the first year of life of severe spasticity, mainly affecting the lower limbs and resulting in an inability to achieve independent ambulation. Affected individuals show delayed motor development and nystagmus; some may have mild mental retardation. Brain MRI shows hypomyelination and white matter lesions in the cerebrum, brainstem, cerebellum, and spinal cord (summary by Taft et al., 2013). [from OMIM]

Additional description

From MedlinePlus Genetics
Hypomyelination with brainstem and spinal cord involvement and leg spasticity (HBSL) is a condition that affects the brain and spinal cord (central nervous system). In particular, the condition affects nerves in specific regions (called tracts) within the spinal cord and the brainstem, which is the part of the brain that connects to the spinal cord. HBSL is a form of leukodystrophy, which is a group of conditions that involve abnormalities of the nervous system's white matter. The white matter consists of nerve fibers covered by a fatty substance, called myelin, that insulates the fibers and promotes the rapid transmission of nerve impulses. In HBSL, the nervous system has a reduced ability to form myelin (hypomyelination).

In HBSL, early development of motor skills (such as rolling over and sitting) may be normal, but movement problems typically begin within the infant's first year. However, in some individuals, these problems do not appear until adolescence. The characteristic feature of HBSL is muscle stiffness (spasticity) in the legs that worsens over time. Most people with HBSL are unable to walk independently. Other neurological problems in affected individuals can include abnormal side-to-side movements of the eyes (nystagmus), weak muscle tone (hypotonia) in the torso, and mild intellectual disability.

Distinct changes in the brains of people with HBSL can be seen using magnetic resonance imaging (MRI). These characteristic abnormalities typically involve specific regions (called tracts) within the brainstem and spinal cord, especially the pyramidal tract, lateral corticospinal tract, and the dorsal column.  https://medlineplus.gov/genetics/condition/hypomyelination-with-brainstem-and-spinal-cord-involvement-and-leg-spasticity

Clinical features

From HPO
Cherry red spot of the macula
MedGen UID:
786046
Concept ID:
C2216370
Finding
Pallor of the perifoveal macula of the retina with appearance of a small circular reddish choroid shape as seen through the fovea centralis due to relative transparency of the macula.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Dysarthria
MedGen UID:
8510
Concept ID:
C0013362
Mental or Behavioral Dysfunction
Dysarthric speech is a general description referring to a neurological speech disorder characterized by poor articulation. Depending on the involved neurological structures, dysarthria may be further classified as spastic, flaccid, ataxic, hyperkinetic and hypokinetic, or mixed.
Spastic diplegia
MedGen UID:
44181
Concept ID:
C0023882
Disease or Syndrome
Spasticity (neuromuscular hypertonia) primarily in the muscles of the legs, hips, and pelvis.
Intellectual disability, mild
MedGen UID:
10044
Concept ID:
C0026106
Mental or Behavioral Dysfunction
Mild intellectual disability is defined as an intelligence quotient (IQ) in the range of 50-69.
Babinski sign
MedGen UID:
19708
Concept ID:
C0034935
Finding
Upturning of the big toe (and sometimes fanning of the other toes) in response to stimulation of the sole of the foot. If the Babinski sign is present it can indicate damage to the corticospinal tract.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Spina bifida occulta
MedGen UID:
36380
Concept ID:
C0080174
Congenital Abnormality
The closed form of spina bifida with incomplete closure of a vertebral body with intact overlying skin.
Tethered cord
MedGen UID:
36387
Concept ID:
C0080218
Disease or Syndrome
During normal embryological development, the spinal cord first occupies the entire length of the vertebral column but goes on to assume a position at the level of L1 due to differential growth of the conus medullaris and the vertebral column. The filum terminale is a slender, threadlike structure that remains after the normal regression of the distal embryonic spinal cord and attaches the spinal cord to the coccyx. A tethered cord results if there is a thickened rope-like filum terminale which anchors the cord at the level of L2 or below, potentially causing neurologic signs owing to abnormal tension on the spinal cord.
Leukoencephalopathy
MedGen UID:
78722
Concept ID:
C0270612
Disease or Syndrome
This term describes abnormality of the white matter of the cerebrum resulting from damage to the myelin sheaths of nerve cells.
Hypoplasia of the corpus callosum
MedGen UID:
138005
Concept ID:
C0344482
Congenital Abnormality
Underdevelopment of the corpus callosum.
Lower limb spasticity
MedGen UID:
220865
Concept ID:
C1271100
Finding
Spasticity (velocity-dependent increase in tonic stretch reflexes with increased muscle tone and hyperexcitable tendon reflexes) in the muscles of the lower limbs, hips, and pelvis.
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Brisk reflexes
MedGen UID:
382164
Concept ID:
C2673700
Finding
Tendon reflexes that are noticeably more active than usual (conventionally denoted 3+ on clinical examination). Brisk reflexes may or may not indicate a neurological lesion. They are distinguished from hyperreflexia by the fact that hyerreflexia is characterized by hyperactive repeating (clonic) reflexes, which are considered to be always abnormal.
Irritability
MedGen UID:
397841
Concept ID:
C2700617
Mental Process
A proneness to anger, i.e., a tendency to become easily bothered or annoyed.
CNS hypomyelination
MedGen UID:
892446
Concept ID:
C4025616
Finding
Reduced amount of myelin in the central nervous system resulting from defective myelinogenesis.
Axial hypotonia
MedGen UID:
342959
Concept ID:
C1853743
Finding
Muscular hypotonia (abnormally low muscle tone) affecting the musculature of the trunk.
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Rhythmic, involuntary oscillations of one or both eyes related to abnormality in fixation, conjugate gaze, or vestibular mechanisms.
Optic disc pallor
MedGen UID:
108218
Concept ID:
C0554970
Finding
A pale yellow discoloration of the optic disc (the area of the optic nerve head in the retina). The optic disc normally has a pinkish hue with a central yellowish depression.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVHypomyelination with brain stem and spinal cord involvement and leg spasticity

Recent clinical studies

Etiology

Ashrafi MR, Amanat M, Garshasbi M, Kameli R, Nilipour Y, Heidari M, Rezaei Z, Tavasoli AR
Expert Rev Neurother 2020 Jan;20(1):65-84. Epub 2019 Dec 12 doi: 10.1080/14737175.2020.1699060. PMID: 31829048

Diagnosis

Ashrafi MR, Amanat M, Garshasbi M, Kameli R, Nilipour Y, Heidari M, Rezaei Z, Tavasoli AR
Expert Rev Neurother 2020 Jan;20(1):65-84. Epub 2019 Dec 12 doi: 10.1080/14737175.2020.1699060. PMID: 31829048
Taft RJ, Vanderver A, Leventer RJ, Damiani SA, Simons C, Grimmond SM, Miller D, Schmidt J, Lockhart PJ, Pope K, Ru K, Crawford J, Rosser T, de Coo IF, Juneja M, Verma IC, Prabhakar P, Blaser S, Raiman J, Pouwels PJ, Bevova MR, Abbink TE, van der Knaap MS, Wolf NI
Am J Hum Genet 2013 May 2;92(5):774-80. doi: 10.1016/j.ajhg.2013.04.006. PMID: 23643384Free PMC Article

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