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Leukodystrophy, hypomyelinating, 18(HLD18)

MedGen UID:
1680067
Concept ID:
C5193078
Disease or Syndrome
Synonyms: HLD18; LEUKODYSTROPHY, HYPOMYELINATING, 18
 
Gene (location): DEGS1 (1q42.11)
 
Monarch Initiative: MONDO:0032730
OMIM®: 618404

Definition

Hypomyelinating leukodystrophy-18 (HLD18) is an autosomal recessive neurologic disorder characterized by onset of global developmental delay usually in early infancy. Affected individuals have very poor psychomotor development, including inability to sit or walk independently in the more severe cases, as well as poor or absent speech, dystonia, and spasticity. A subset of patients may develop seizures. Brain imaging shows hypomyelinating leukodystrophy affecting various brain regions; some patients may also have progressive atrophy of the corpus callosum, thalami, and cerebellum (summary by Pant et al., 2019). For a general phenotypic description and a discussion of genetic heterogeneity of hypomyelinating leukodystrophy, see 312080. [from OMIM]

Clinical features

From HPO
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
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.
Gastrostomy tube feeding in infancy
MedGen UID:
892362
Concept ID:
C4023342
Finding
Feeding problem necessitating gastrostomy tube feeding.
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.
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
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.
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.
Demyelinating peripheral neuropathy
MedGen UID:
82859
Concept ID:
C0270922
Disease or Syndrome
Demyelinating neuropathy is characterized by slow nerve conduction velocities with reduced amplitudes of sensory/motor nerve conduction and prolonged distal latencies.
Spastic tetraplegia
MedGen UID:
98433
Concept ID:
C0426970
Disease or Syndrome
Spastic paralysis affecting all four limbs.
Delayed speech and language development
MedGen UID:
105318
Concept ID:
C0454644
Finding
A degree of language development that is significantly below the norm for a child of a specified age.
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.
Cerebellar atrophy
MedGen UID:
196624
Concept ID:
C0740279
Disease or Syndrome
Cerebellar atrophy is defined as a cerebellum with initially normal structures, in a posterior fossa with normal size, which displays enlarged fissures (interfolial spaces) in comparison to the foliae secondary to loss of tissue. Cerebellar atrophy implies irreversible loss of tissue and result from an ongoing progressive disease until a final stage is reached or a single injury, e.g. an intoxication or infectious event.
Severe global developmental delay
MedGen UID:
332436
Concept ID:
C1837397
Finding
A severe delay in the achievement of motor or mental milestones in the domains of development of a child.
Absent speech
MedGen UID:
340737
Concept ID:
C1854882
Finding
Complete lack of development of speech and language abilities.
Decreased nerve conduction velocity
MedGen UID:
347509
Concept ID:
C1857640
Finding
A reduction in the speed at which electrical signals propagate along the axon of a neuron.
Progressive spasticity
MedGen UID:
347171
Concept ID:
C1859520
Finding
Spasticity that increases in degree with time.
Abnormal periventricular white matter morphology
MedGen UID:
435926
Concept ID:
C2673431
Finding
A structural abnormality of the myelinated axons (white matter) located near the cerebral ventricles.
Abnormal motor nerve conduction velocity
MedGen UID:
866684
Concept ID:
C4021031
Anatomical Abnormality
Atrophy/Degeneration affecting the brainstem
MedGen UID:
870454
Concept ID:
C4024900
Disease or Syndrome
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
Flexion contracture
MedGen UID:
83069
Concept ID:
C0333068
Anatomical Abnormality
A flexion contracture is a bent (flexed) joint that cannot be straightened actively or passively. It is thus a chronic loss of joint motion due to structural changes in muscle, tendons, ligaments, or skin that prevents normal movement of joints.
Secondary microcephaly
MedGen UID:
608952
Concept ID:
C0431352
Finding
Head circumference which falls below 2 standard deviations below the mean for age and gender because of insufficient head growth after birth.
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.

Recent clinical studies

Etiology

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
Yoon Han J, Gon Cho Y, Park J, Jang W
Clin Chim Acta 2022 Aug 1;533:15-21. Epub 2022 Jun 9 doi: 10.1016/j.cca.2022.06.007. PMID: 35691411
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
Shahrour MA, Ashhab M, Edvardson S, Gur M, Abu-Libdeh B, Elpeleg O
Neurogenetics 2017 Jul;18(3):135-139. Epub 2017 May 10 doi: 10.1007/s10048-017-0515-7. PMID: 28493104
Baskin JM, Wu X, Christiano R, Oh MS, Schauder CM, Gazzerro E, Messa M, Baldassari S, Assereto S, Biancheri R, Zara F, Minetti C, Raimondi A, Simons M, Walther TC, Reinisch KM, De Camilli P
Nat Cell Biol 2016 Jan;18(1):132-8. Epub 2015 Nov 16 doi: 10.1038/ncb3271. PMID: 26571211Free PMC Article

Diagnosis

Potic A, Perrier S, Radovic T, Gavrilovic S, Ostojic J, Tran LT, Thiffault I, Pastinen T, Schiffmann R, Bernard G
Orphanet J Rare Dis 2023 Jul 13;18(1):187. doi: 10.1186/s13023-023-02802-6. PMID: 37443037Free PMC Article
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
Dinov D, Vorona G, Harper A
Neurology 2021 Nov 2;97(18):875-878. Epub 2021 Jun 29 doi: 10.1212/WNL.0000000000012445. PMID: 34187860
Harting I, Al-Saady M, Krägeloh-Mann I, Bley A, Hempel M, Bierhals T, Karch S, Moog U, Bernard G, Huntsman R, van Spaendonk RML, Vreeburg M, Rodríguez-Palmero A, Pujol A, van der Knaap MS, Pouwels PJW, Wolf NI
Neurogenetics 2020 Apr;21(2):121-133. Epub 2020 Jan 15 doi: 10.1007/s10048-019-00602-4. PMID: 31940116Free PMC Article
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

Potic A, Perrier S, Radovic T, Gavrilovic S, Ostojic J, Tran LT, Thiffault I, Pastinen T, Schiffmann R, Bernard G
Orphanet J Rare Dis 2023 Jul 13;18(1):187. doi: 10.1186/s13023-023-02802-6. PMID: 37443037Free PMC Article

Prognosis

Hülsmeier AJ, Toelle SP, Bellstedt P, Wentzel C, Bahr A, Kolokotronis K, Hornemann T
J Lipid Res 2023 Dec;64(12):100464. Epub 2023 Oct 27 doi: 10.1016/j.jlr.2023.100464. PMID: 37890668Free PMC Article
Potic A, Perrier S, Radovic T, Gavrilovic S, Ostojic J, Tran LT, Thiffault I, Pastinen T, Schiffmann R, Bernard G
Orphanet J Rare Dis 2023 Jul 13;18(1):187. doi: 10.1186/s13023-023-02802-6. PMID: 37443037Free PMC Article
Dinov D, Vorona G, Harper A
Neurology 2021 Nov 2;97(18):875-878. Epub 2021 Jun 29 doi: 10.1212/WNL.0000000000012445. PMID: 34187860
Miyake N, Wolf NI, Cayami FK, Crawford J, Bley A, Bulas D, Conant A, Bent SJ, Gripp KW, Hahn A, Humphray S, Kimura-Ohba S, Kingsbury Z, Lajoie BR, Lal D, Micha D, Pizzino A, Sinke RJ, Sival D, Stolte-Dijkstra I, Superti-Furga A, Ulrick N, Taft RJ, Ogata T, Ozono K, Matsumoto N, Neubauer BA, Simons C, Vanderver A
Neurogenetics 2017 Dec;18(4):185-194. Epub 2017 Aug 26 doi: 10.1007/s10048-017-0520-x. PMID: 28842795Free PMC Article
Shahrour MA, Ashhab M, Edvardson S, Gur M, Abu-Libdeh B, Elpeleg O
Neurogenetics 2017 Jul;18(3):135-139. Epub 2017 May 10 doi: 10.1007/s10048-017-0515-7. PMID: 28493104

Clinical prediction guides

Hülsmeier AJ, Toelle SP, Bellstedt P, Wentzel C, Bahr A, Kolokotronis K, Hornemann T
J Lipid Res 2023 Dec;64(12):100464. Epub 2023 Oct 27 doi: 10.1016/j.jlr.2023.100464. PMID: 37890668Free PMC Article
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
Di Donato I, Gallo A, Ricca I, Fini N, Silvestri G, Gurrieri F, Cirillo M, Cerase A, Natale G, Matrone F, Riso V, Melone MAB, Tessa A, De Michele G, Federico A, Filla A, Dotti MT, Santorelli FM
Neurol Sci 2022 Feb;43(2):1071-1077. Epub 2021 Jul 23 doi: 10.1007/s10072-021-05462-1. PMID: 34296356Free PMC Article
Miyake N, Wolf NI, Cayami FK, Crawford J, Bley A, Bulas D, Conant A, Bent SJ, Gripp KW, Hahn A, Humphray S, Kimura-Ohba S, Kingsbury Z, Lajoie BR, Lal D, Micha D, Pizzino A, Sinke RJ, Sival D, Stolte-Dijkstra I, Superti-Furga A, Ulrick N, Taft RJ, Ogata T, Ozono K, Matsumoto N, Neubauer BA, Simons C, Vanderver A
Neurogenetics 2017 Dec;18(4):185-194. Epub 2017 Aug 26 doi: 10.1007/s10048-017-0520-x. PMID: 28842795Free PMC Article
Shahrour MA, Ashhab M, Edvardson S, Gur M, Abu-Libdeh B, Elpeleg O
Neurogenetics 2017 Jul;18(3):135-139. Epub 2017 May 10 doi: 10.1007/s10048-017-0515-7. PMID: 28493104

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