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Leukodystrophy, hypomyelinating, 17(HLD17)

MedGen UID:
1644557
Concept ID:
C4693912
Disease or Syndrome
Synonyms: HLD17; LEUKODYSTROPHY, HYPOMYELINATING, 17
 
Gene (location): AIMP2 (7p22.1)
 
Monarch Initiative: MONDO:0054817
OMIM®: 618006

Definition

Hypomyelinating leukodystrophy-17 is an autosomal recessive neurodevelopmental disorder characterized by poor, if any, development apparent from infancy. Affected individuals never learn to walk or speak, and have early-onset multifocal seizures, spasticity, poor overall growth, and microcephaly (up to -10 SD). Brain imaging shows multiple abnormalities, including cerebral and cerebellar atrophy, thin corpus callosum, abnormal signals in the basal ganglia, and features suggesting hypo- or demyelination. Some patients may die in childhood (summary by Shukla et al., 2018). For a general phenotypic description and a discussion of genetic heterogeneity of hypomyelinating leukodystrophy, see 312080. [from OMIM]

Clinical features

From HPO
Growth delay
MedGen UID:
99124
Concept ID:
C0456070
Pathologic Function
A deficiency or slowing down of growth pre- and postnatally.
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.
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.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterised by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
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.
Inability to walk
MedGen UID:
107860
Concept ID:
C0560046
Finding
Incapability to ambulate.
Hypsarrhythmia
MedGen UID:
195766
Concept ID:
C0684276
Finding
Hypsarrhythmia is abnormal interictal high amplitude waves and a background of irregular spikes. There is continuous (during wakefulness), high-amplitude (>200 Hz), generalized polymorphic slowing with no organized background and multifocal spikes demonstrated by electroencephalography (EEG).
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.
Absent speech
MedGen UID:
340737
Concept ID:
C1854882
Finding
Complete lack of development of speech and language abilities.
Intellectual disability, profound
MedGen UID:
892508
Concept ID:
C3161330
Mental or Behavioral Dysfunction
Profound mental retardation is defined as an intelligence quotient (IQ) below 20.
Profound global developmental delay
MedGen UID:
766364
Concept ID:
C3553450
Disease or Syndrome
A profound delay in the achievement of motor or mental milestones in the domains of development of a child.
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.
Kyphoscoliosis
MedGen UID:
154361
Concept ID:
C0575158
Anatomical Abnormality
An abnormal curvature of the spine in both a coronal (lateral) and sagittal (back-to-front) plane.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Gingival overgrowth
MedGen UID:
87712
Concept ID:
C0376480
Finding
Hyperplasia of the gingiva (that is, a thickening of the soft tissue overlying the alveolar ridge. The degree of thickening ranges from involvement of the interdental papillae alone to gingival overgrowth covering the entire tooth crown.
Mandibular prognathia
MedGen UID:
98316
Concept ID:
C0399526
Finding
Abnormal prominence of the chin related to increased length of the mandible.
Thick vermilion border
MedGen UID:
332232
Concept ID:
C1836543
Finding
Increased width of the skin of vermilion border region of upper lip.
Anteverted nares
MedGen UID:
326648
Concept ID:
C1840077
Finding
Anteriorly-facing nostrils viewed with the head in the Frankfurt horizontal and the eyes of the observer level with the eyes of the subject. This gives the appearance of an upturned nose (upturned nasal tip).
Widely spaced teeth
MedGen UID:
337093
Concept ID:
C1844813
Finding
Increased spaces (diastemata) between most of the teeth in the same dental arch.
Low hanging columella
MedGen UID:
344656
Concept ID:
C1856119
Finding
Columella extending inferior to the level of the nasal base, when viewed from the side.
Hirsutism
MedGen UID:
42461
Concept ID:
C0019572
Disease or Syndrome
Abnormally increased hair growth referring to a male pattern of body hair (androgenic hair).

Recent clinical studies

Etiology

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
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
Sumida K, Inoue K, Takanashi J, Sasaki M, Watanabe K, Suzuki M, Kurahashi H, Omata T, Tanaka M, Yokochi K, Iio J, Iyoda K, Kurokawa T, Matsuo M, Sato T, Iwaki A, Osaka H, Kurosawa K, Yamamoto T, Matsumoto N, Maikusa N, Matsuda H, Sato N
Brain Dev 2016 Jun;38(6):571-80. Epub 2016 Jan 13 doi: 10.1016/j.braindev.2015.12.007. PMID: 26774704
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
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

Diagnosis

Wolf NI, Ffrench-Constant C, van der Knaap MS
Nat Rev Neurol 2021 Feb;17(2):88-103. Epub 2020 Dec 15 doi: 10.1038/s41582-020-00432-1. PMID: 33324001
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
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
Schiffmann R, van der Knaap MS
Curr Opin Neurol 2004 Apr;17(2):187-92. doi: 10.1097/00019052-200404000-00017. PMID: 15021247
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

Therapy

Sumida K, Inoue K, Takanashi J, Sasaki M, Watanabe K, Suzuki M, Kurahashi H, Omata T, Tanaka M, Yokochi K, Iio J, Iyoda K, Kurokawa T, Matsuo M, Sato T, Iwaki A, Osaka H, Kurosawa K, Yamamoto T, Matsumoto N, Maikusa N, Matsuda H, Sato N
Brain Dev 2016 Jun;38(6):571-80. Epub 2016 Jan 13 doi: 10.1016/j.braindev.2015.12.007. PMID: 26774704
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

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
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
Sumida K, Inoue K, Takanashi J, Sasaki M, Watanabe K, Suzuki M, Kurahashi H, Omata T, Tanaka M, Yokochi K, Iio J, Iyoda K, Kurokawa T, Matsuo M, Sato T, Iwaki A, Osaka H, Kurosawa K, Yamamoto T, Matsumoto N, Maikusa N, Matsuda H, Sato N
Brain Dev 2016 Jun;38(6):571-80. Epub 2016 Jan 13 doi: 10.1016/j.braindev.2015.12.007. PMID: 26774704
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

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
Sumida K, Inoue K, Takanashi J, Sasaki M, Watanabe K, Suzuki M, Kurahashi H, Omata T, Tanaka M, Yokochi K, Iio J, Iyoda K, Kurokawa T, Matsuo M, Sato T, Iwaki A, Osaka H, Kurosawa K, Yamamoto T, Matsumoto N, Maikusa N, Matsuda H, Sato N
Brain Dev 2016 Jun;38(6):571-80. Epub 2016 Jan 13 doi: 10.1016/j.braindev.2015.12.007. PMID: 26774704

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