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Hypomyelinating leukodystrophy 13(HLD13)

MedGen UID:
896545
Concept ID:
C4225170
Disease or Syndrome
Synonyms: HLD13; LEUKODYSTROPHY, HYPOMYELINATING, 13
 
Gene (location): HIKESHI (11q14.2)
 
Monarch Initiative: MONDO:0014813
OMIM®: 616881

Definition

Hypomyelinating leukodystrophy-13 is an autosomal recessive neurodegenerative disorder characterized by infantile onset of delayed psychomotor development, axial hypotonia, and spasticity associated with delayed myelination and periventricular white matter abnormalities on brain imaging. More variable neurologic deficits, such as visual impairment, may also occur. Some patients may experience cardiac failure during acute illness (summary by Edvardson et al., 2016). For a general phenotypic description and a discussion of genetic heterogeneity of HLD, 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.
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).
Clonus
MedGen UID:
40341
Concept ID:
C0009024
Sign or Symptom
A series of rhythmic and involuntary muscle contractions (at a frequency of about 5 to 7 Hz) that occur in response to an abruptly applied and sustained stretch.
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.
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.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
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.
Delayed myelination
MedGen UID:
224820
Concept ID:
C1277241
Finding
Delayed myelination.
Absent speech
MedGen UID:
340737
Concept ID:
C1854882
Finding
Complete lack of development of speech and language abilities.
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.
Hypertonia
MedGen UID:
10132
Concept ID:
C0026826
Finding
A condition in which there is increased muscle tone so that arms or legs, for example, are stiff and difficult to move.
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.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
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 atrophy
MedGen UID:
18180
Concept ID:
C0029124
Disease or Syndrome
Atrophy of the optic nerve. Optic atrophy results from the death of the retinal ganglion cell axons that comprise the optic nerve and manifesting as a pale optic nerve on fundoscopy.
Visual impairment
MedGen UID:
777085
Concept ID:
C3665347
Finding
Visual impairment (or vision impairment) is vision loss (of a person) to such a degree as to qualify as an additional support need through a significant limitation of visual capability resulting from either disease, trauma, or congenital or degenerative conditions that cannot be corrected by conventional means, such as refractive correction, medication, or surgery.

Recent clinical studies

Etiology

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
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
Yan H, Ji H, Kubisiak T, Wu Y, Xiao J, Gu Q, Yang Y, Xie H, Ji T, Gao K, Li D, Xiong H, Shi Z, Li M, Zhang Y, Duan R, Bao X, Jiang Y, Burmeister M, Wang J
J Hum Genet 2021 Aug;66(8):761-768. Epub 2021 Feb 18 doi: 10.1038/s10038-020-00896-5. PMID: 33597727Free PMC Article
Pelletier F, Perrier S, Cayami FK, Mirchi A, Saikali S, Tran LT, Ulrick N, Guerrero K, Rampakakis E, van Spaendonk RML, Naidu S, Pohl D, Gibson WT, Demos M, Goizet C, Tejera-Martin I, Potic A, Fogel BL, Brais B, Sylvain M, Sébire G, Lourenço CM, Bonkowsky JL, Catsman-Berrevoets C, Pinto PS, Tirupathi S, Strømme P, de Grauw T, Gieruszczak-Bialek D, Krägeloh-Mann I, Mierzewska H, Philippi H, Rankin J, Atik T, Banwell B, Benko WS, Blaschek A, Bley A, Boltshauser E, Bratkovic D, Brozova K, Cimas I, Clough C, Corenblum B, Dinopoulos A, Dolan G, Faletra F, Fernandez R, Fletcher J, Garcia Garcia ME, Gasparini P, Gburek-Augustat J, Gonzalez Moron D, Hamati A, Harting I, Hertzberg C, Hill A, Hobson GM, Innes AM, Kauffman M, Kirwin SM, Kluger G, Kolditz P, Kotzaeridou U, La Piana R, Liston E, McClintock W, McEntagart M, McKenzie F, Melançon S, Misbahuddin A, Suri M, Monton FI, Moutton S, Murphy RPJ, Nickel M, Onay H, Orcesi S, Özkınay F, Patzer S, Pedro H, Pekic S, Pineda Marfa M, Pizzino A, Plecko B, Poll-The BT, Popovic V, Rating D, Rioux MF, Rodriguez Espinosa N, Ronan A, Ostergaard JR, Rossignol E, Sanchez-Carpintero R, Schossig A, Senbil N, Sønderberg Roos LK, Stevens CA, Synofzik M, Sztriha L, Tibussek D, Timmann D, Tonduti D, van de Warrenburg BP, Vázquez-López M, Venkateswaran S, Wasling P, Wassmer E, Webster RI, Wiegand G, Yoon G, Rotteveel J, Schiffmann R, van der Knaap MS, Vanderver A, Martos-Moreno GÁ, Polychronakos C, Wolf NI, Bernard G
J Clin Endocrinol Metab 2021 Jan 23;106(2):e660-e674. doi: 10.1210/clinem/dgaa700. PMID: 33005949Free 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

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
Yan H, Ji H, Kubisiak T, Wu Y, Xiao J, Gu Q, Yang Y, Xie H, Ji T, Gao K, Li D, Xiong H, Shi Z, Li M, Zhang Y, Duan R, Bao X, Jiang Y, Burmeister M, Wang J
J Hum Genet 2021 Aug;66(8):761-768. Epub 2021 Feb 18 doi: 10.1038/s10038-020-00896-5. PMID: 33597727Free PMC Article
Cömert C, Brick L, Ang D, Palmfeldt J, Meaney BF, Kozenko M, Georgopoulos C, Fernandez-Guerra P, Bross P
Cold Spring Harb Mol Case Stud 2020 Jun;6(3) Epub 2020 Jun 12 doi: 10.1101/mcs.a004879. PMID: 32532876Free 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
Mierzewska H, Jamroz E, Mazurczak T, Hoffman-Zacharska D, Szczepanik E
Folia Neuropathol 2016;54(1):59-65. doi: 10.5114/fn.2016.58916. PMID: 27179222

Therapy

Kristjánsdóttir R, Uvebrant P, Hagberg B, Kyllerman M, Wiklund LM, Blennow G, Flodmark O, Gustavsson L, Ekholm S, Månsson JE
Neuropediatrics 1996 Dec;27(6):295-8. doi: 10.1055/s-2007-973797. PMID: 9050046

Prognosis

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
Mierzewska H, Jamroz E, Mazurczak T, Hoffman-Zacharska D, Szczepanik E
Folia Neuropathol 2016;54(1):59-65. doi: 10.5114/fn.2016.58916. PMID: 27179222
Kristjánsdóttir R, Uvebrant P, Hagberg B, Kyllerman M, Wiklund LM, Blennow G, Flodmark O, Gustavsson L, Ekholm S, Månsson JE
Neuropediatrics 1996 Dec;27(6):295-8. doi: 10.1055/s-2007-973797. PMID: 9050046

Clinical prediction guides

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
Choquet K, Yang S, Moir RD, Forget D, Larivière R, Bouchard A, Poitras C, Sgarioto N, Dicaire MJ, Noohi F, Kennedy TE, Rochford J, Bernard G, Teichmann M, Coulombe B, Willis IM, Kleinman CL, Brais B
Mol Brain 2017 Apr 13;10(1):13. doi: 10.1186/s13041-017-0294-y. PMID: 28407788Free PMC Article
Marteyn A, Sarrazin N, Yan J, Bachelin C, Deboux C, Santin MD, Gressens P, Zujovic V, Baron-Van Evercooren A
Stem Cells 2016 Apr;34(4):984-96. Epub 2015 Dec 31 doi: 10.1002/stem.2263. PMID: 26676415
La Piana R, Tonduti D, Gordish Dressman H, Schmidt JL, Murnick J, Brais B, Bernard G, Vanderver A
J Child Neurol 2014 Feb;29(2):214-20. Epub 2013 Oct 7 doi: 10.1177/0883073813503902. PMID: 24105487
Mochel F, Engelke UF, Barritault J, Yang B, McNeill NH, Thompson JN, Vanderver A, Wolf NI, Willemsen MA, Verheijen FW, Seguin F, Wevers RA, Schiffmann R
Neurology 2010 Jan 26;74(4):302-5. doi: 10.1212/WNL.0b013e3181cbcdc4. PMID: 20101035Free PMC Article

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