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Hypomyelinating leukodystrophy 9(HLD9)

MedGen UID:
863760
Concept ID:
C4015323
Disease or Syndrome
Synonyms: HLD9; LEUKODYSTROPHY, HYPOMYELINATING, 9
SNOMED CT: Arginyl-tRNA synthetase 1-related autosomal recessive hypomyelinating leukodystrophy (1220600004); RARS-related autosomal recessive hypomyelinating leukodystrophy (1220600004)
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): RARS1 (5q34)
 
Monarch Initiative: MONDO:0014506
OMIM®: 616140
Orphanet: ORPHA438114

Definition

Hypomyelinating leukodystrophy-9 (HLD9) is an autosomal recessive neurologic disorder characterized by onset of delayed psychomotor development, spasticity, and nystagmus in the first year of life. Additional neurologic features such as ataxia and abnormal movements may also occur. Brain imaging shows diffuse hypomyelination affecting all regions of the brain (summary by Wolf et al., 2014). For a general phenotypic description and a discussion of genetic heterogeneity of HLD, see 312080. [from OMIM]

Clinical features

From HPO
Feeding difficulties
MedGen UID:
65429
Concept ID:
C0232466
Finding
Impaired ability to eat related to problems gathering food and getting ready to suck, chew, or swallow it.
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.
Dystonic disorder
MedGen UID:
3940
Concept ID:
C0013421
Sign or Symptom
An abnormally increased muscular tone that causes fixed abnormal postures. There is a slow, intermittent twisting motion that leads to exaggerated turning and posture of the extremities and trunk.
Leukodystrophy
MedGen UID:
6070
Concept ID:
C0023520
Disease or Syndrome
Leukodystrophy refers to deterioration of white matter of the brain resulting from degeneration of myelin sheaths in the CNS. Their basic defect is directly related to the synthesis and maintenance of myelin membranes. Symmetric white matter involvement at MRI is a typical finding in patients with leukodystrophies.
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.
Pseudobulbar paralysis
MedGen UID:
10989
Concept ID:
C0033790
Disease or Syndrome
Bilateral impairment of the function of the cranial nerves 9-12, which control musculature involved in eating, swallowing, and speech. Pseudobulbar paralysis is characterized clinically by dysarthria, dysphonia, and dysphagia with bifacial paralysis, and may be accompanied by Pseudobulbar behavioral symptoms such as enforced crying and laughing.
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.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
Abnormality of extrapyramidal motor function
MedGen UID:
115941
Concept ID:
C0234133
Sign or Symptom
A neurological condition related to lesions of the basal ganglia leading to typical abnormalities including akinesia (inability to initiate changes in activity and perform volitional movements rapidly and easily), muscular rigidity (continuous contraction of muscles with constant resistance to passive movement), chorea (widespread arrhythmic movements of a forcible, rapid, jerky, and restless nature), athetosis (inability to sustain the muscles of the fingers, toes, or other group of muscles in a fixed position), and akathisia (inability to remain motionless).
Dysmetria
MedGen UID:
68583
Concept ID:
C0234162
Finding
A type of ataxia characterized by the inability to carry out movements with the correct range and motion across the plane of more than one joint related to incorrect estimation of the distances required for targeted movements.
Cerebral atrophy
MedGen UID:
116012
Concept ID:
C0235946
Disease or Syndrome
Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.
Hypoplasia of the corpus callosum
MedGen UID:
138005
Concept ID:
C0344482
Congenital Abnormality
Underdevelopment of the corpus callosum.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
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.
Lower limb hyperreflexia
MedGen UID:
322973
Concept ID:
C1836696
Finding
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Intention tremor
MedGen UID:
1642960
Concept ID:
C4551520
Sign or Symptom
A type of kinetic tremor that occurs during target directed movement is called intention tremor. That is, an oscillatory cerebellar ataxia that tends to be absent when the limbs are inactive and during the first part of voluntary movement but worsening as the movement continues and greater precision is required (e.g., in touching a target such as the patient's nose or a physician's finger).
Poor head control
MedGen UID:
322809
Concept ID:
C1836038
Finding
Difficulty to maintain correct position of the head while standing or sitting. Infant head lag is observed when the head seems to flop around or lags posteriorly behind the trunk. Several articles have maintained that head lag should be absent by age 3 to 4 months.
Axial hypotonia
MedGen UID:
342959
Concept ID:
C1853743
Finding
Muscular hypotonia (abnormally low muscle tone) affecting the musculature of the trunk.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
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.
Rotary nystagmus
MedGen UID:
116106
Concept ID:
C0240595
Disease or Syndrome
A form of nystagmus in which the eyeball makes rotary motions around the axis.
Pendular nystagmus
MedGen UID:
78770
Concept ID:
C0271388
Disease or Syndrome
Rhythmic, involuntary sinusoidal oscillations of one or both eyes. The waveform of pendular nystagmus may occur in any direction.
Absent smooth pursuit
MedGen UID:
870481
Concept ID:
C4024928
Finding
A complete lack of the ability to track objects with the ocular smooth pursuit system, a class of rather slow eye movements that minimizes retinal target motion.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVHypomyelinating leukodystrophy 9

Professional guidelines

PubMed

Fogli A, Schiffmann R, Bertini E, Ughetto S, Combes P, Eymard-Pierre E, Kaneski CR, Pineda M, Troncoso M, Uziel G, Surtees R, Pugin D, Chaunu MP, Rodriguez D, Boespflug-Tanguy O
Neurology 2004 May 11;62(9):1509-17. doi: 10.1212/01.wnl.0000123259.67815.db. PMID: 15136673

Recent clinical studies

Etiology

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Eur J Paediatr Neurol 2020 Jul;27:9-24. Epub 2020 Apr 22 doi: 10.1016/j.ejpn.2020.04.007. PMID: 32418752
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
Ji H, Li D, Wu Y, Zhang Q, Gu Q, Xie H, Ji T, Wang H, Zhao L, Zhao H, Yang Y, Feng H, Xiong H, Ji J, Yang Z, Kou L, Li M, Bao X, Chang X, Zhang Y, Li L, Li H, Niu Z, Wu X, Xiao J, Jiang Y, Wang J
PLoS One 2018;13(2):e0188869. Epub 2018 Feb 16 doi: 10.1371/journal.pone.0188869. PMID: 29451896Free PMC Article

Diagnosis

Wu C, Wang M, Wang X, Li W, Li S, Chen B, Niu S, Tai H, Pan H, Zhang Z
Brain 2023 Jun 1;146(6):2364-2376. doi: 10.1093/brain/awac426. PMID: 36380532Free PMC Article
Ando M, Higuchi Y, Yuan JH, Yoshimura A, Kitao R, Morimoto T, Taniguchi T, Takeuchi M, Takei J, Hiramatsu Y, Sakiyama Y, Hashiguchi A, Okamoto Y, Mitsui J, Ishiura H, Tsuji S, Takashima H
Ann Clin Transl Neurol 2022 May;9(5):747-755. Epub 2022 Apr 28 doi: 10.1002/acn3.51555. PMID: 35482004Free PMC Article
Malik P, Muthusamy K, Mankad K, Shroff M, Sudhakar S
Eur J Paediatr Neurol 2020 Jul;27:9-24. Epub 2020 Apr 22 doi: 10.1016/j.ejpn.2020.04.007. PMID: 32418752
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
Ji H, Li D, Wu Y, Zhang Q, Gu Q, Xie H, Ji T, Wang H, Zhao L, Zhao H, Yang Y, Feng H, Xiong H, Ji J, Yang Z, Kou L, Li M, Bao X, Chang X, Zhang Y, Li L, Li H, Niu Z, Wu X, Xiao J, Jiang Y, Wang J
PLoS One 2018;13(2):e0188869. Epub 2018 Feb 16 doi: 10.1371/journal.pone.0188869. PMID: 29451896Free PMC Article

Therapy

Gupta N, Henry RG, Strober J, Kang SM, Lim DA, Bucci M, Caverzasi E, Gaetano L, Mandelli ML, Ryan T, Perry R, Farrell J, Jeremy RJ, Ulman M, Huhn SL, Barkovich AJ, Rowitch DH
Sci Transl Med 2012 Oct 10;4(155):155ra137. doi: 10.1126/scitranslmed.3004373. PMID: 23052294Free PMC Article

Prognosis

Szűcs Z, Fitala R, Nyuzó ÁR, Fodor K, Czemmel É, Vrancsik N, Bessenyei M, Szabó T, Szakszon K, Balogh I
Genes (Basel) 2021 Aug 27;12(9) doi: 10.3390/genes12091331. PMID: 34573312Free PMC Article
Battini R, Milone R, Aiello C, Astrea G, Sferra A, Pasquariello R, Cioni G, Bertini E
Brain Dev 2021 Oct;43(9):939-944. Epub 2021 Jun 13 doi: 10.1016/j.braindev.2021.05.015. PMID: 34134906
Kraoua I, Karkar A, Drissi C, Benrhouma H, Klaa H, Samaan S, Renaldo F, Elmaleh M, Ben Hamouda M, Abdelhak S, Boespflug-Tanguy O, Ben Youssef-Turki I, Dorboz I
Mol Genet Genomic Med 2019 Sep;7(9):e914. Epub 2019 Jul 31 doi: 10.1002/mgg3.914. PMID: 31368241Free PMC Article
Duignan S, Wright S, Rossor T, Cazabon J, Gilmour K, Ciccarelli O, Wassmer E, Lim M, Hemingway C, Hacohen Y
Dev Med Child Neurol 2018 Sep;60(9):958-962. Epub 2018 Feb 22 doi: 10.1111/dmcn.13703. PMID: 29468668
Lossos A, Elazar N, Lerer I, Schueler-Furman O, Fellig Y, Glick B, Zimmerman BE, Azulay H, Dotan S, Goldberg S, Gomori JM, Ponger P, Newman JP, Marreed H, Steck AJ, Schaeren-Wiemers N, Mor N, Harel M, Geiger T, Eshed-Eisenbach Y, Meiner V, Peles E
Brain 2015 Sep;138(Pt 9):2521-36. Epub 2015 Jul 15 doi: 10.1093/brain/awv204. PMID: 26179919Free PMC Article

Clinical prediction guides

Yang H, Wu Z, Li X, Huang Y, Li J, He F, Feng L, Xiao B, Tang W
Neurol Sci 2023 Sep;44(9):3363-3368. Epub 2023 Mar 29 doi: 10.1007/s10072-023-06767-z. PMID: 36988728
Choquet K, Pinard M, Yang S, Moir RD, Poitras C, Dicaire MJ, Sgarioto N, Larivière R, Kleinman CL, Willis IM, Gauthier MS, Coulombe B, Brais B
Mol Brain 2019 Jun 20;12(1):59. doi: 10.1186/s13041-019-0479-7. PMID: 31221184Free PMC Article
Minnerop M, Kurzwelly D, Wagner H, Soehn AS, Reichbauer J, Tao F, Rattay TW, Peitz M, Rehbach K, Giorgetti A, Pyle A, Thiele H, Altmüller J, Timmann D, Karaca I, Lennarz M, Baets J, Hengel H, Synofzik M, Atasu B, Feely S, Kennerson M, Stendel C, Lindig T, Gonzalez MA, Stirnberg R, Sturm M, Roeske S, Jung J, Bauer P, Lohmann E, Herms S, Heilmann-Heimbach S, Nicholson G, Mahanjah M, Sharkia R, Carloni P, Brüstle O, Klopstock T, Mathews KD, Shy ME, de Jonghe P, Chinnery PF, Horvath R, Kohlhase J, Schmitt I, Wolf M, Greschus S, Amunts K, Maier W, Schöls L, Nürnberg P, Zuchner S, Klockgether T, Ramirez A, Schüle R
Brain 2017 Jun 1;140(6):1561-1578. doi: 10.1093/brain/awx095. PMID: 28459997Free PMC Article
Lossos A, Elazar N, Lerer I, Schueler-Furman O, Fellig Y, Glick B, Zimmerman BE, Azulay H, Dotan S, Goldberg S, Gomori JM, Ponger P, Newman JP, Marreed H, Steck AJ, Schaeren-Wiemers N, Mor N, Harel M, Geiger T, Eshed-Eisenbach Y, Meiner V, Peles E
Brain 2015 Sep;138(Pt 9):2521-36. Epub 2015 Jul 15 doi: 10.1093/brain/awv204. PMID: 26179919Free PMC Article
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J Child Neurol 2014 Feb;29(2):214-20. Epub 2013 Oct 7 doi: 10.1177/0883073813503902. PMID: 24105487

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