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Hypomyelinating leukodystrophy 11(HLD11)

MedGen UID:
897960
Concept ID:
C4225305
Disease or Syndrome
Synonyms: 4H LEUKODYSTROPHY 3; HLD11; LEUKODYSTROPHY, HYPOMYELINATING, 11
 
Gene (location): POLR1C (6p21.1)
 
Monarch Initiative: MONDO:0014666
OMIM®: 616494

Disease characteristics

Excerpted from the GeneReview: POLR3-Related Leukodystrophy
POLR3-related leukodystrophy, a hypomyelinating leukodystrophy with specific features on brain MRI, is characterized by varying combinations of four major clinical findings: Neurologic dysfunction, typically predominated by motor dysfunction (progressive cerebellar dysfunction, and to a lesser extent extrapyramidal [i.e., dystonia], pyramidal [i.e., spasticity] and cognitive dysfunctions). Abnormal dentition (delayed dentition, hypodontia, oligodontia, and abnormally placed or shaped teeth). Endocrine abnormalities such as short stature (in ~50% of individuals) with or without growth hormone deficiency, and more commonly, hypogonadotropic hypogonadism manifesting as delayed, arrested, or absent puberty. Ocular abnormality in the form of myopia, typically progressing over several years and becoming severe. POLR3-related leukodystrophy and 4H leukodystrophy are the two recognized terms for five previously described overlapping clinical phenotypes (initially described as distinct entities before their molecular basis was known). These include: Hypomyelination, hypodontia, hypogonadotropic hypogonadism (4H syndrome); Ataxia, delayed dentition, and hypomyelination (ADDH); Tremor-ataxia with central hypomyelination (TACH); Leukodystrophy with oligodontia (LO); Hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum (HCAHC). Age of onset is typically in early childhood but later-onset cases have also been reported. An infant with Wiedemann-Rautenstrauch syndrome (neonatal progeroid syndrome) was recently reported to have pathogenic variants in POLR3A on exome sequencing. Confirmation of this as a very severe form of POLR3-related leukodystrophy awaits replication in other individuals with a clinical diagnosis of Wiedemann-Rautenstrauch syndrome. [from GeneReviews]
Authors:
Geneviève Bernard  |  Adeline Vanderver   view full author information

Additional description

From OMIM
Hypomyelinating leukodystrophy-11 (HLD11) is an autosomal recessive neurologic disorder characterized by delayed psychomotor development and other neurologic features associated with hypomyelination on brain imaging. Some patients may have additional nonneurologic features, particularly dental abnormalities and possibly hypogonadotropic hypogonadism (summary by Thiffault et al., 2015). For a general phenotypic description and a discussion of genetic heterogeneity of HLD, see 312080.  http://www.omim.org/entry/616494

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.
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).
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.
Myoclonus
MedGen UID:
10234
Concept ID:
C0027066
Finding
Very brief, involuntary random muscular contractions occurring at rest, in response to sensory stimuli, or accompanying voluntary movements.
Tremor
MedGen UID:
21635
Concept ID:
C0040822
Sign or Symptom
An unintentional, oscillating to-and-fro muscle movement about a joint axis.
Delayed ability to walk
MedGen UID:
66034
Concept ID:
C0241726
Finding
A failure to achieve the ability to walk at an appropriate developmental stage. Most children learn to walk in a series of stages, and learn to walk short distances independently between 12 and 15 months.
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.
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.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
CNS hypomyelination
MedGen UID:
892446
Concept ID:
C4025616
Finding
Reduced amount of myelin in the central nervous system resulting from defective myelinogenesis.
Abnormality of the dentition
MedGen UID:
78084
Concept ID:
C0262444
Finding
Any abnormality of the teeth.
Myopia
MedGen UID:
44558
Concept ID:
C0027092
Disease or Syndrome
Nearsightedness, also known as myopia, is an eye condition that causes blurry distance vision. People who are nearsighted have more trouble seeing things that are far away (such as when driving) than things that are close up (such as when reading or using a computer). If it is not treated with corrective lenses or surgery, nearsightedness can lead to squinting, eyestrain, headaches, and significant visual impairment.\n\nNearsightedness usually begins in childhood or adolescence. It tends to worsen with age until adulthood, when it may stop getting worse (stabilize). In some people, nearsightedness improves in later adulthood.\n\nFor normal vision, light passes through the clear cornea at the front of the eye and is focused by the lens onto the surface of the retina, which is the lining of the back of the eye that contains light-sensing cells. People who are nearsighted typically have eyeballs that are too long from front to back. As a result, light entering the eye is focused too far forward, in front of the retina instead of on its surface. It is this change that causes distant objects to appear blurry. The longer the eyeball is, the farther forward light rays will be focused and the more severely nearsighted a person will be.\n\nNearsightedness is measured by how powerful a lens must be to correct it. The standard unit of lens power is called a diopter. Negative (minus) powered lenses are used to correct nearsightedness. The more severe a person's nearsightedness, the larger the number of diopters required for correction. In an individual with nearsightedness, one eye may be more nearsighted than the other.\n\nEye doctors often refer to nearsightedness less than -5 or -6 diopters as "common myopia." Nearsightedness of -6 diopters or more is commonly called "high myopia." This distinction is important because high myopia increases a person's risk of developing other eye problems that can lead to permanent vision loss or blindness. These problems include tearing and detachment of the retina, clouding of the lens (cataract), and an eye disease called glaucoma that is usually related to increased pressure within the eye. The risk of these other eye problems increases with the severity of the nearsightedness. The term "pathological myopia" is used to describe cases in which high myopia leads to tissue damage within the eye.

Recent clinical studies

Etiology

Biglari S, Vahidnezhad H, Tabatabaiefar MA, Khorram Khorshid HR, Esmaeilzadeh E
Mol Genet Genomic Med 2024 Apr;12(4):e2435. doi: 10.1002/mgg3.2435. PMID: 38618971Free PMC Article
Ashrafi M, Kameli R, Hosseinpour S, Razmara E, Zamani Z, Rezaei Z, Mashayekhi R, Pak N, Barzegar M, Azizimalamiri R, Kashani MR, Khosroshahi N, Rasulinezhad M, Heidari M, Amanat M, Abdi A, Mohammadi B, Mohammadi M, Zamani GR, Badv RS, Omrani A, Nikbakht S, Bereshneh AH, Movahedinia M, Moghaddam HF, Ardakani HS, Akbari MG, Tousi MB, Shahi MV, Hosseini F, Amouzadeh MH, Hosseini SA, Nikkhah A, Khajeh A, Alizadeh H, Yarali B, Rohani M, Karimi P, Elahi HML, Hosseiny SMM, Sadeghzadeh MS, Mohebbi H, Moghadam MH, Aryan H, Vahidnezhad H, Soveizi M, Rabbani B, Rabbani A, Mahdieh N, Garshasbi M, Tavasoli AR
Neurogenetics 2023 Oct;24(4):279-289. Epub 2023 Aug 19 doi: 10.1007/s10048-023-00730-y. PMID: 37597066
Yan H, Yang S, Hou Y, Ali S, Escobar A, Gao K, Duan R, Kubisiak T, Wang J, Zhang Y, Xiao J, Jiang Y, Zhang T, Wu Y, Burmeister M, Wang Q, Cuajungco MP, Wang J
Cells 2022 Apr 9;11(8) doi: 10.3390/cells11081285. PMID: 35455965Free 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
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

Ashrafi M, Kameli R, Hosseinpour S, Razmara E, Zamani Z, Rezaei Z, Mashayekhi R, Pak N, Barzegar M, Azizimalamiri R, Kashani MR, Khosroshahi N, Rasulinezhad M, Heidari M, Amanat M, Abdi A, Mohammadi B, Mohammadi M, Zamani GR, Badv RS, Omrani A, Nikbakht S, Bereshneh AH, Movahedinia M, Moghaddam HF, Ardakani HS, Akbari MG, Tousi MB, Shahi MV, Hosseini F, Amouzadeh MH, Hosseini SA, Nikkhah A, Khajeh A, Alizadeh H, Yarali B, Rohani M, Karimi P, Elahi HML, Hosseiny SMM, Sadeghzadeh MS, Mohebbi H, Moghadam MH, Aryan H, Vahidnezhad H, Soveizi M, Rabbani B, Rabbani A, Mahdieh N, Garshasbi M, Tavasoli AR
Neurogenetics 2023 Oct;24(4):279-289. Epub 2023 Aug 19 doi: 10.1007/s10048-023-00730-y. PMID: 37597066
Helman G, Zerem A, Almad A, Hacker JL, Woidill S, Sase S, LeFevre AN, Ekstein J, Johansson MM, Stutterd CA, Taft RJ, Simons C, Grinspan JB, Pizzino A, Schmidt JL, Harding B, Hirsch Y, Viaene AN, Fattal-Valevski A, Vanderver A
Pediatr Neurol 2021 Aug;121:11-19. Epub 2021 May 14 doi: 10.1016/j.pediatrneurol.2021.04.014. PMID: 34111619Free 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
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
Kumar S, Mattan NS, de Vellis J
Ment Retard Dev Disabil Res Rev 2006;12(2):157-65. doi: 10.1002/mrdd.20108. PMID: 16807907

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
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

Riedhammer KM, Stockler S, Ploski R, Wenzel M, Adis-Dutschmann B, Ahting U, Alhaddad B, Blaschek A, Haack TB, Kopajtich R, Lee J, Murcia Pienkowski V, Pollak A, Szymanska K, Tarailo-Graovac M, van der Lee R, van Karnebeek CD, Meitinger T, Krägeloh-Mann I, Vill K
Brain 2021 Mar 3;144(2):411-419. doi: 10.1093/brain/awaa410. PMID: 33313762Free PMC Article
Remerand G, Boespflug-Tanguy O, Tonduti D, Touraine R, Rodriguez D, Curie A, Perreton N, Des Portes V, Sarret C; RMLX/AHDS Study Group
Dev Med Child Neurol 2019 Dec;61(12):1439-1447. Epub 2019 Aug 13 doi: 10.1111/dmcn.14332. PMID: 31410843
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
Zaki MS, Bhat G, Sultan T, Issa M, Jung HJ, Dikoglu E, Selim L, G Mahmoud I, Abdel-Hamid MS, Abdel-Salam G, Marin-Valencia I, Gleeson JG
Ann Neurol 2016 Jul;80(1):59-70. Epub 2016 Jun 1 doi: 10.1002/ana.24678. PMID: 27130255Free PMC Article
Numata Y, Gotoh L, Iwaki A, Kurosawa K, Takanashi J, Deguchi K, Yamamoto T, Osaka H, Inoue K
J Neurol 2014 Apr;261(4):752-8. Epub 2014 Feb 16 doi: 10.1007/s00415-014-7263-5. PMID: 24532200

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
Yan H, Yang S, Hou Y, Ali S, Escobar A, Gao K, Duan R, Kubisiak T, Wang J, Zhang Y, Xiao J, Jiang Y, Zhang T, Wu Y, Burmeister M, Wang Q, Cuajungco MP, Wang J
Cells 2022 Apr 9;11(8) doi: 10.3390/cells11081285. PMID: 35455965Free PMC Article
Riedhammer KM, Stockler S, Ploski R, Wenzel M, Adis-Dutschmann B, Ahting U, Alhaddad B, Blaschek A, Haack TB, Kopajtich R, Lee J, Murcia Pienkowski V, Pollak A, Szymanska K, Tarailo-Graovac M, van der Lee R, van Karnebeek CD, Meitinger T, Krägeloh-Mann I, Vill K
Brain 2021 Mar 3;144(2):411-419. doi: 10.1093/brain/awaa410. PMID: 33313762Free PMC Article
Zaki MS, Bhat G, Sultan T, Issa M, Jung HJ, Dikoglu E, Selim L, G Mahmoud I, Abdel-Hamid MS, Abdel-Salam G, Marin-Valencia I, Gleeson JG
Ann Neurol 2016 Jul;80(1):59-70. Epub 2016 Jun 1 doi: 10.1002/ana.24678. PMID: 27130255Free PMC Article
Numata Y, Gotoh L, Iwaki A, Kurosawa K, Takanashi J, Deguchi K, Yamamoto T, Osaka H, Inoue K
J Neurol 2014 Apr;261(4):752-8. Epub 2014 Feb 16 doi: 10.1007/s00415-014-7263-5. PMID: 24532200

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