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Leukodystrophy, hypomyelinating, 20(HLD20)

MedGen UID:
1765130
Concept ID:
C5436730
Disease or Syndrome
Synonyms: HLD20; LEUKODYSTROPHY, HYPOMYELINATING, 20
 
Gene (location): CNP (17q21.2)
 
Monarch Initiative: MONDO:0033657
OMIM®: 619071

Definition

Hypomyelinating leukodystrophy-20 (HLD20) is an autosomal recessive neurodegenerative disorder characterized by the loss of developmental milestones at about 12 to 16 months of age after normal early development. Patients lose motor, language, and cognitive skills and show poor overall growth with microcephaly. The disorder is progressive, resulting in feeding difficulties and spastic quadriplegia. Some patients may have seizures. Brain imaging shows subcortical white matter abnormalities and a thin corpus callosum, suggesting a myelination defect. Death usually occurs in childhood (Al-Abdi et al., 2020). For 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.
Chronic constipation
MedGen UID:
98325
Concept ID:
C0401149
Sign or Symptom
Constipation for longer than three months with fewer than 3 bowel movements per week, straining, lumpy or hard stools, and a sensation of anorectal obstruction or incomplete defecation.
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.
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.
Torticollis
MedGen UID:
11859
Concept ID:
C0040485
Sign or Symptom
Torticollis is a twisted neck as a result of shortening of sternocleidomastoid muscle. This short and fibrotic muscle pulls the head laterally and rotates the chin and face to the opposite end. Facial asymmetry may be a manifestation (summary by Engin et al., 1997).
Hypoplasia of the corpus callosum
MedGen UID:
138005
Concept ID:
C0344482
Congenital Abnormality
Underdevelopment of the corpus callosum.
Spastic tetraplegia
MedGen UID:
98433
Concept ID:
C0426970
Disease or Syndrome
Spastic paralysis affecting all four limbs.
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.
Developmental regression
MedGen UID:
324613
Concept ID:
C1836830
Disease or Syndrome
Loss of developmental skills, as manifested by loss of developmental milestones.
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.
Punctate periventricular T2 hyperintense foci
MedGen UID:
868266
Concept ID:
C4022658
Finding
Multiple pointlike areas of high T2 signal observed upon magnetic resonance imaging of the periventricular cerebral white matter.
Reduced brain N-acetyl aspartate level by MRS
MedGen UID:
868367
Concept ID:
C4022761
Finding
A decrease in the level of N-acetyl aspartate in the brain identified by magnetic resonance spectroscopy (MRS).
Elevated brain choline level by MRS
MedGen UID:
868369
Concept ID:
C4022763
Finding
An increase in the level of choline-containing compounds in the brain identified by magnetic resonance spectroscopy (MRS).
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.
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
Progressive microcephaly
MedGen UID:
340542
Concept ID:
C1850456
Anatomical Abnormality
Progressive microcephaly is diagnosed when the head circumference falls progressively behind age- and gender-dependent norms.
Coarse facial features
MedGen UID:
335284
Concept ID:
C1845847
Finding
Absence of fine and sharp appearance of brows, nose, lips, mouth, and chin, usually because of rounded and heavy features or thickened skin with or without thickening of subcutaneous and bony tissues.
Hirsutism
MedGen UID:
42461
Concept ID:
C0019572
Disease or Syndrome
Abnormally increased hair growth referring to a male pattern of body hair (androgenic hair).
Ptosis
MedGen UID:
2287
Concept ID:
C0005745
Disease or Syndrome
The upper eyelid margin is positioned 3 mm or more lower than usual and covers the superior portion of the iris (objective); or, the upper lid margin obscures at least part of the pupil (subjective).

Recent clinical studies

Etiology

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
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
Chelban V, Alsagob M, Kloth K, Chirita-Emandi A, Vandrovcova J, Maroofian R, Davagnanam I, Bakhtiari S, AlSayed MD, Rahbeeni Z, AlZaidan H, Malintan NT, Johannsen J, Efthymiou S, Ghayoor Karimiani E, Mankad K, Al-Shahrani SA, Beiraghi Toosi M, AlShammari M, Groppa S, Haridy NA, AlQuait L, Qari A, Huma R, Salih MA, Almass R, Almutairi FB, Hamad MH, Alorainy IA, Ramzan K, Imtiaz F, Puiu M, Kruer MC, Bierhals T, Wood NW, Colak D, Houlden H, Kaya N
Eur J Neurol 2020 Feb;27(2):334-342. Epub 2019 Oct 17 doi: 10.1111/ene.14082. PMID: 31509304Free PMC Article
Tonduti D, Aiello C, Renaldo F, Dorboz I, Saaman S, Rodriguez D, Fettah H, Elmaleh M, Biancheri R, Barresi S, Boccone L, Orcesi S, Pichiecchio A, Zangaglia R, Maurey H, Rossi A, Boespflug-Tanguy O, Bertini E
Eur J Paediatr Neurol 2016 Mar;20(2):323-330. Epub 2015 Nov 28 doi: 10.1016/j.ejpn.2015.11.006. PMID: 26643067
Arai-Ichinoi N, Uematsu M, Sato R, Suzuki T, Kudo H, Kikuchi A, Hino-Fukuyo N, Matsumoto M, Igarashi K, Haginoya K, Kure S
Hum Genet 2016 Jan;135(1):89-98. Epub 2015 Nov 23 doi: 10.1007/s00439-015-1617-7. PMID: 26597493

Diagnosis

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
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
Chelban V, Alsagob M, Kloth K, Chirita-Emandi A, Vandrovcova J, Maroofian R, Davagnanam I, Bakhtiari S, AlSayed MD, Rahbeeni Z, AlZaidan H, Malintan NT, Johannsen J, Efthymiou S, Ghayoor Karimiani E, Mankad K, Al-Shahrani SA, Beiraghi Toosi M, AlShammari M, Groppa S, Haridy NA, AlQuait L, Qari A, Huma R, Salih MA, Almass R, Almutairi FB, Hamad MH, Alorainy IA, Ramzan K, Imtiaz F, Puiu M, Kruer MC, Bierhals T, Wood NW, Colak D, Houlden H, Kaya N
Eur J Neurol 2020 Feb;27(2):334-342. Epub 2019 Oct 17 doi: 10.1111/ene.14082. PMID: 31509304Free PMC Article
Lenk GM, Berry IR, Stutterd CA, Blyth M, Green L, Vadlamani G, Warren D, Craven I, Fanjul-Fernandez M, Rodriguez-Casero V, Lockhart PJ, Vanderver A, Simons C, Gibb S, Sadedin S; Broad Center for Mendelian Genomics, White SM, Christodoulou J, Skibina O, Ruddle J, Tan TY, Leventer RJ, Livingston JH, Meisler MH
Hum Mutat 2019 May;40(5):619-630. Epub 2019 Feb 28 doi: 10.1002/humu.23720. PMID: 30740813Free PMC Article
Arai-Ichinoi N, Uematsu M, Sato R, Suzuki T, Kudo H, Kikuchi A, Hino-Fukuyo N, Matsumoto M, Igarashi K, Haginoya K, Kure S
Hum Genet 2016 Jan;135(1):89-98. Epub 2015 Nov 23 doi: 10.1007/s00439-015-1617-7. PMID: 26597493

Therapy

Yamamoto A, Shimizu-Motohashi Y, Ishiyama A, Kurosawa K, Sasaki M, Sato N, Osaka H, Takanashi JI, Inoue K
Pediatr Neurol 2024 Feb;151:80-83. Epub 2023 Dec 1 doi: 10.1016/j.pediatrneurol.2023.11.014. PMID: 38134864
Tonduti D, Aiello C, Renaldo F, Dorboz I, Saaman S, Rodriguez D, Fettah H, Elmaleh M, Biancheri R, Barresi S, Boccone L, Orcesi S, Pichiecchio A, Zangaglia R, Maurey H, Rossi A, Boespflug-Tanguy O, Bertini E
Eur J Paediatr Neurol 2016 Mar;20(2):323-330. Epub 2015 Nov 28 doi: 10.1016/j.ejpn.2015.11.006. PMID: 26643067

Prognosis

Chapleau A, Mirchi A, Tran LT, Poulin C, Bernard G
Pediatr Neurol 2023 Nov;148:133-137. Epub 2023 Aug 19 doi: 10.1016/j.pediatrneurol.2023.08.013. PMID: 37713976
Chelban V, Alsagob M, Kloth K, Chirita-Emandi A, Vandrovcova J, Maroofian R, Davagnanam I, Bakhtiari S, AlSayed MD, Rahbeeni Z, AlZaidan H, Malintan NT, Johannsen J, Efthymiou S, Ghayoor Karimiani E, Mankad K, Al-Shahrani SA, Beiraghi Toosi M, AlShammari M, Groppa S, Haridy NA, AlQuait L, Qari A, Huma R, Salih MA, Almass R, Almutairi FB, Hamad MH, Alorainy IA, Ramzan K, Imtiaz F, Puiu M, Kruer MC, Bierhals T, Wood NW, Colak D, Houlden H, Kaya N
Eur J Neurol 2020 Feb;27(2):334-342. Epub 2019 Oct 17 doi: 10.1111/ene.14082. PMID: 31509304Free PMC Article
Kulhánek J, Brožová K, Hansíková H, Vondráčková A, Stránecký V, Šenkyřík J, Kmoch S, Zeman J, Honzík T, Tesařová M
Neurol Neurochir Pol 2019;53(5):369-376. Epub 2019 Oct 2 doi: 10.5603/PJNNS.a2019.0042. PMID: 31577365
Accogli A, Russell L, Sébire G, Rivière JB, St-Onge J, Addour-Boudrahem N, Laporte AD, Rouleau GA, Saint-Martin C, Srour M
Neurogenetics 2019 May;20(2):103-108. Epub 2019 Mar 28 doi: 10.1007/s10048-019-00572-7. PMID: 30924036
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

Clinical prediction guides

Yamamoto A, Shimizu-Motohashi Y, Ishiyama A, Kurosawa K, Sasaki M, Sato N, Osaka H, Takanashi JI, Inoue K
Pediatr Neurol 2024 Feb;151:80-83. Epub 2023 Dec 1 doi: 10.1016/j.pediatrneurol.2023.11.014. PMID: 38134864
Chapleau A, Mirchi A, Tran LT, Poulin C, Bernard G
Pediatr Neurol 2023 Nov;148:133-137. Epub 2023 Aug 19 doi: 10.1016/j.pediatrneurol.2023.08.013. PMID: 37713976
Lenk GM, Berry IR, Stutterd CA, Blyth M, Green L, Vadlamani G, Warren D, Craven I, Fanjul-Fernandez M, Rodriguez-Casero V, Lockhart PJ, Vanderver A, Simons C, Gibb S, Sadedin S; Broad Center for Mendelian Genomics, White SM, Christodoulou J, Skibina O, Ruddle J, Tan TY, Leventer RJ, Livingston JH, Meisler MH
Hum Mutat 2019 May;40(5):619-630. Epub 2019 Feb 28 doi: 10.1002/humu.23720. PMID: 30740813Free PMC Article
Tonduti D, Aiello C, Renaldo F, Dorboz I, Saaman S, Rodriguez D, Fettah H, Elmaleh M, Biancheri R, Barresi S, Boccone L, Orcesi S, Pichiecchio A, Zangaglia R, Maurey H, Rossi A, Boespflug-Tanguy O, Bertini E
Eur J Paediatr Neurol 2016 Mar;20(2):323-330. Epub 2015 Nov 28 doi: 10.1016/j.ejpn.2015.11.006. PMID: 26643067
Bassani R, Pareyson D, D'Incerti L, Di Bella D, Taroni F, Salsano E
J Clin Neurosci 2013 Oct;20(10):1443-5. Epub 2013 Jul 8 doi: 10.1016/j.jocn.2012.11.014. PMID: 23845262

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