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Hypomyelinating leukodystrophy 4(HLD4)

MedGen UID:
383026
Concept ID:
C2677109
Disease or Syndrome
Synonyms: MITCHAP60 DISEASE; MITOCHONDRIAL HSP60 CHAPERONOPATHY
SNOMED CT: Pelizaeus Merzbacher like disease due to HSPD1 mutation (870284000)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): HSPD1 (2q33.1)
 
Monarch Initiative: MONDO:0012824
OMIM®: 612233
Orphanet: ORPHA280288

Definition

Any leukodystrophy in which the cause of the disease is a mutation in the HSPD1 gene. [from MONDO]

Clinical features

From HPO
Ethylmalonic aciduria
MedGen UID:
355967
Concept ID:
C1865353
Finding
The concentration of ethylmalonic acid in the urine, normalized for urine concentration, is above the upper limit of normal.
Feeding difficulties in infancy
MedGen UID:
436211
Concept ID:
C2674608
Finding
Impaired feeding performance of an infant as manifested by difficulties such as weak and ineffective sucking, brief bursts of sucking, and falling asleep during sucking. There may be difficulties with chewing or maintaining attention.
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.
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.
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.
Spastic paraplegia
MedGen UID:
20882
Concept ID:
C0037772
Disease or Syndrome
Spasticity and weakness of the leg and hip muscles.
Choreoathetosis
MedGen UID:
39313
Concept ID:
C0085583
Disease or Syndrome
Involuntary movements characterized by both athetosis (inability to sustain muscles in a fixed position) and chorea (widespread jerky arrhythmic movements).
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.
Head titubation
MedGen UID:
299071
Concept ID:
C1608410
Sign or Symptom
A head tremor of moderate speed (3 to 4 Hz) in the anterior-posterior direction.
Progressive spasticity
MedGen UID:
347171
Concept ID:
C1859520
Finding
Spasticity that increases in degree with time.
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.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
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.
Secondary microcephaly
MedGen UID:
608952
Concept ID:
C0431352
Finding
Head circumference which falls below 2 standard deviations below the mean for age and gender because of insufficient head growth after birth.
Poor head control
MedGen UID:
322809
Concept ID:
C1836038
Finding
Difficulty to maintain correct position of the head while standing or sitting.
Apnea
MedGen UID:
2009
Concept ID:
C0003578
Sign or Symptom
Lack of breathing with no movement of the respiratory muscles and no exchange of air in the lungs. This term refers to a disposition to have recurrent episodes of apnea rather than to a single event.
Increased circulating lactate concentration
MedGen UID:
332209
Concept ID:
C1836440
Finding
Abnormally increased level of blood lactate (2-hydroxypropanoic acid). Lactate is produced from pyruvate by lactate dehydrogenase during normal metabolism. The terms lactate and lactic acid are often used interchangeably but lactate (the component measured in blood) is strictly a weak base whereas lactic acid is the corresponding acid. Lactic acidosis is often used clinically to describe elevated lactate but should be reserved for cases where there is a corresponding acidosis (pH below 7.35).
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.
Strabismus
MedGen UID:
21337
Concept ID:
C0038379
Disease or Syndrome
A misalignment of the eyes so that the visual axes deviate from bifoveal fixation. The classification of strabismus may be based on a number of features including the relative position of the eyes, whether the deviation is latent or manifest, intermittent or constant, concomitant or otherwise and according to the age of onset and the relevance of any associated refractive error.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVHypomyelinating leukodystrophy 4
Follow this link to review classifications for Hypomyelinating leukodystrophy 4 in Orphanet.

Recent clinical studies

Etiology

Verdura E, Rodríguez-Palmero A, Vélez-Santamaria V, Planas-Serra L, de la Calle I, Raspall-Chaure M, Roubertie A, Benkirane M, Saettini F, Pavinato L, Mandrile G, O'Leary M, O'Heir E, Barredo E, Chacón A, Michaud V, Goizet C, Ruiz M, Schlüter A, Rouvet I, Sala-Coromina J, Fossati C, Iascone M, Canonico F, Marcé-Grau A, de Souza P, Adams DR, Casasnovas C, Rehm HL, Mefford HC, González Gutierrez-Solana L, Brusco A, Koenig M, Macaya A, Pujol A
Brain 2021 Oct 22;144(9):2659-2669. doi: 10.1093/brain/awab124. PMID: 34415322Free PMC Article
Salter CG, Cai Y, Lo B, Helman G, Taylor H, McCartney A, Leslie JS, Accogli A, Zara F, Traverso M, Fasham J, Lees JA, Ferla MP, Chioza BA, Wenger O, Scott E, Cross HE, Crawford J, Warshawsky I, Keisling M, Agamanolis D, Ward Melver C, Cox H, Elawad M, Marton T, Wakeling MN, Holzinger D, Tippelt S, Munteanu M, Valcheva D, Deal C, Van Meerbeke S, Walsh Vockley C, Butte MJ, Acar U, van der Knaap MS, Korenke GC, Kotzaeridou U, Balla T, Simons C, Uhlig HH, Crosby AH, De Camilli P, Wolf NI, Baple EL
Brain 2021 Dec 31;144(12):3597-3610. doi: 10.1093/brain/awab313. PMID: 34415310Free 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
Barañano KW
Semin Neurol 2016 Aug;36(4):362-6. Epub 2016 Sep 19 doi: 10.1055/s-0036-1585455. PMID: 27643905
Wolf NI, Vanderver A, van Spaendonk RM, Schiffmann R, Brais B, Bugiani M, Sistermans E, Catsman-Berrevoets C, Kros JM, Pinto PS, Pohl D, Tirupathi S, Strømme P, de Grauw T, Fribourg S, Demos M, Pizzino A, Naidu S, Guerrero K, van der Knaap MS, Bernard G; 4H Research Group
Neurology 2014 Nov 18;83(21):1898-905. Epub 2014 Oct 22 doi: 10.1212/WNL.0000000000001002. PMID: 25339210Free PMC Article

Diagnosis

Harting I, Al-Saady M, Krägeloh-Mann I, Bley A, Hempel M, Bierhals T, Karch S, Moog U, Bernard G, Huntsman R, van Spaendonk RML, Vreeburg M, Rodríguez-Palmero A, Pujol A, van der Knaap MS, Pouwels PJW, Wolf NI
Neurogenetics 2020 Apr;21(2):121-133. Epub 2020 Jan 15 doi: 10.1007/s10048-019-00602-4. PMID: 31940116Free 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
Cayami FK, Bugiani M, Pouwels PJW, Bernard G, van der Knaap MS, Wolf NI
Neuropediatrics 2018 Apr;49(2):112-117. Epub 2017 Nov 27 doi: 10.1055/s-0037-1608780. PMID: 29179231
Barañano KW
Semin Neurol 2016 Aug;36(4):362-6. Epub 2016 Sep 19 doi: 10.1055/s-0036-1585455. PMID: 27643905
Wolf NI, Vanderver A, van Spaendonk RM, Schiffmann R, Brais B, Bugiani M, Sistermans E, Catsman-Berrevoets C, Kros JM, Pinto PS, Pohl D, Tirupathi S, Strømme P, de Grauw T, Fribourg S, Demos M, Pizzino A, Naidu S, Guerrero K, van der Knaap MS, Bernard G; 4H Research Group
Neurology 2014 Nov 18;83(21):1898-905. Epub 2014 Oct 22 doi: 10.1212/WNL.0000000000001002. PMID: 25339210Free PMC Article

Therapy

Li H, Okada H, Suzuki S, Sakai K, Izumi H, Matsushima Y, Ichinohe N, Goto YI, Okada T, Inoue K
JCI Insight 2019 May 16;4(10) doi: 10.1172/jci.insight.125052. PMID: 31092737Free 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
Gupta N, Henry RG, Strober J, Kang SM, Lim DA, Bucci M, Caverzasi E, Gaetano L, Mandelli ML, Ryan T, Perry R, Farrell J, Jeremy RJ, Ulman M, Huhn SL, Barkovich AJ, Rowitch DH
Sci Transl Med 2012 Oct 10;4(155):155ra137. doi: 10.1126/scitranslmed.3004373. PMID: 23052294Free PMC Article

Prognosis

Edgerley K, Barnicoat A, Offiah AC, Calder AD, Mankad K, Thomas NS, Bunyan DJ, Williams M, Buxton C, Majumdar A, Vijayakumar K, Hilliard T, Turner J, Burren CP, Monsell F, Smithson SF
Am J Med Genet A 2021 Apr;185(4):1228-1235. Epub 2021 Jan 13 doi: 10.1002/ajmg.a.62072. PMID: 33439541
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
Lossos A, Elazar N, Lerer I, Schueler-Furman O, Fellig Y, Glick B, Zimmerman BE, Azulay H, Dotan S, Goldberg S, Gomori JM, Ponger P, Newman JP, Marreed H, Steck AJ, Schaeren-Wiemers N, Mor N, Harel M, Geiger T, Eshed-Eisenbach Y, Meiner V, Peles E
Brain 2015 Sep;138(Pt 9):2521-36. Epub 2015 Jul 15 doi: 10.1093/brain/awv204. PMID: 26179919Free PMC Article
Wolf NI, Vanderver A, van Spaendonk RM, Schiffmann R, Brais B, Bugiani M, Sistermans E, Catsman-Berrevoets C, Kros JM, Pinto PS, Pohl D, Tirupathi S, Strømme P, de Grauw T, Fribourg S, Demos M, Pizzino A, Naidu S, Guerrero K, van der Knaap MS, Bernard G; 4H Research Group
Neurology 2014 Nov 18;83(21):1898-905. Epub 2014 Oct 22 doi: 10.1212/WNL.0000000000001002. PMID: 25339210Free 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

Owczarek-Lipska M, Mulahasanovic L, Obermaier CD, Hörtnagel K, Neubauer BA, Korenke GC, Biskup S, Neidhardt J
Mol Biol Rep 2019 Aug;46(4):4507-4516. Epub 2019 Jul 3 doi: 10.1007/s11033-019-04906-4. PMID: 31270756
Sarret C, Lemaire JJ, Sontheimer A, Coste J, Savy N, Pereira B, Roche B, Boespflug-Tanguy O
Dev Neurosci 2018;40(4):301-311. Epub 2018 Sep 27 doi: 10.1159/000492218. PMID: 30261498
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
Wolf NI, Vanderver A, van Spaendonk RM, Schiffmann R, Brais B, Bugiani M, Sistermans E, Catsman-Berrevoets C, Kros JM, Pinto PS, Pohl D, Tirupathi S, Strømme P, de Grauw T, Fribourg S, Demos M, Pizzino A, Naidu S, Guerrero K, van der Knaap MS, Bernard G; 4H Research Group
Neurology 2014 Nov 18;83(21):1898-905. Epub 2014 Oct 22 doi: 10.1212/WNL.0000000000001002. PMID: 25339210Free 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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