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Leukodystrophy, hypomyelinating, 14(HLD14)

MedGen UID:
1635255
Concept ID:
C4693535
Disease or Syndrome
Synonyms: HLD14; LEUKODYSTROPHY, HYPOMYELINATING, 14
 
Gene (location): UFM1 (13q13.3)
 
Monarch Initiative: MONDO:0033486
OMIM®: 617899

Definition

Hypomyelinating leukodystrophy-14 is an autosomal recessive neurodevelopmental disorder characterized by hypotonia, almost complete lack of motor or cognitive skills, and absent language development. Additional features include spasticity and intractable seizures; many patients also have perceptive hearing loss and/or blindness. Most patients require tube feeding or ventilatory support, and most die in the first years of life. Brain imaging shows hypomyelination, small caudate and putamen, and cerebral and cerebellar atrophy (summary by Hamilton et al., 2017). 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.
Hearing impairment
MedGen UID:
235586
Concept ID:
C1384666
Disease or Syndrome
A decreased magnitude of the sensory perception of sound.
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.
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.
Cerebral atrophy
MedGen UID:
116012
Concept ID:
C0235946
Disease or Syndrome
Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.
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
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.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Respiratory insufficiency
MedGen UID:
11197
Concept ID:
C0035229
Pathologic Function
Impairment of gas exchange within the lungs secondary to a disease process, neoplasm, or trauma, possibly resulting in hypoxia, hypercarbia, or both, but not requiring intubation or mechanical ventilation. Patients are normally managed with pharmaceutical therapy, supplemental oxygen, or both.
Blindness
MedGen UID:
99138
Concept ID:
C0456909
Disease or Syndrome
Blindness is the condition of lacking visual perception defined as a profound reduction in visual perception. On the 6m visual acuity scale, blindness is defined as less than 3/60. On the 20ft visual acuity scale, blindness is defined as less than 20/400. On the decimal visual acuity scale, blindness is defined as less than 0.05. Blindness is typically characterized by a visual field of no greater than 10 degrees in radius around central fixation.

Recent clinical studies

Etiology

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
Kraoua I, Karkar A, Drissi C, Benrhouma H, Klaa H, Samaan S, Renaldo F, Elmaleh M, Ben Hamouda M, Abdelhak S, Boespflug-Tanguy O, Ben Youssef-Turki I, Dorboz I
Mol Genet Genomic Med 2019 Sep;7(9):e914. Epub 2019 Jul 31 doi: 10.1002/mgg3.914. PMID: 31368241Free PMC Article
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
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
Daoud H, Tétreault M, Gibson W, Guerrero K, Cohen A, Gburek-Augustat J, Synofzik M, Brais B, Stevens CA, Sanchez-Carpintero R, Goizet C, Naidu S, Vanderver A, Bernard G
J Med Genet 2013 Mar;50(3):194-7. Epub 2013 Jan 25 doi: 10.1136/jmedgenet-2012-101357. PMID: 23355746

Diagnosis

Ünalp A, Köse M, Karaoğlu P, Güzin Y, Yılmaz Ü
Turk J Pediatr 2022;64(4):747-753. doi: 10.24953/turkjped.2021.1662. PMID: 36082649
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
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
Schiffmann R, Boespflüg-Tanguy O
Curr Opin Neurol 2001 Dec;14(6):789-94. doi: 10.1097/00019052-200112000-00018. PMID: 11723390

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

Prognosis

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
Kraoua I, Karkar A, Drissi C, Benrhouma H, Klaa H, Samaan S, Renaldo F, Elmaleh M, Ben Hamouda M, Abdelhak S, Boespflug-Tanguy O, Ben Youssef-Turki I, Dorboz I
Mol Genet Genomic Med 2019 Sep;7(9):e914. Epub 2019 Jul 31 doi: 10.1002/mgg3.914. PMID: 31368241Free PMC Article
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
Bernard G, Chouery E, Putorti ML, Tétreault M, Takanohashi A, Carosso G, Clément I, Boespflug-Tanguy O, Rodriguez D, Delague V, Abou Ghoch J, Jalkh N, Dorboz I, Fribourg S, Teichmann M, Megarbane A, Schiffmann R, Vanderver A, Brais B
Am J Hum Genet 2011 Sep 9;89(3):415-23. doi: 10.1016/j.ajhg.2011.07.014. PMID: 21855841Free PMC Article

Clinical prediction guides

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
Kraoua I, Karkar A, Drissi C, Benrhouma H, Klaa H, Samaan S, Renaldo F, Elmaleh M, Ben Hamouda M, Abdelhak S, Boespflug-Tanguy O, Ben Youssef-Turki I, Dorboz I
Mol Genet Genomic Med 2019 Sep;7(9):e914. Epub 2019 Jul 31 doi: 10.1002/mgg3.914. PMID: 31368241Free PMC Article
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
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
Bernard G, Chouery E, Putorti ML, Tétreault M, Takanohashi A, Carosso G, Clément I, Boespflug-Tanguy O, Rodriguez D, Delague V, Abou Ghoch J, Jalkh N, Dorboz I, Fribourg S, Teichmann M, Megarbane A, Schiffmann R, Vanderver A, Brais B
Am J Hum Genet 2011 Sep 9;89(3):415-23. doi: 10.1016/j.ajhg.2011.07.014. PMID: 21855841Free PMC Article

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