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Pseudo-Hurler polydystrophy(ML3)

MedGen UID:
10988
Concept ID:
C0033788
Disease or Syndrome
Synonyms: GNPTAB-Related Mucolipidoses; ML 3 A; ML III; ML III ALPHA/BETA; ML IIIA; ML3; Mucolipidosis II; Mucolipidosis III Alpha/Beta; Mucolipidosis type 3A; Type III Mucolipidosis
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM, 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 homozygotes. In the context of medical genetics, autosomal recessive disorders manifest in homozygotes (with two copies of the mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal recessive inheritance (HPO, OMIM, Orphanet)
SNOMED CT: Pseudo-Hurler polydystrophy (65764006); Mucolipidosis III (65764006); Pseudo-Hurler disease (65764006); Pseudo-Hurler's disease (65764006)
 
Gene (location): GNPTAB (12q23.2)
OMIM®: 252600
Orphanet: ORPHA423461

Disease characteristics

Excerpted from the GeneReview: Mucolipidosis III Alpha/Beta
Mucolipidosis alpha/beta (ML III alpha/beta; pseudo-Hurler polydystrophy), a slowly progressive disorder with clinical onset at approximately age three years, is characterized by slow growth rate and subnormal stature; radiographic evidence of mild to moderate dysostosis multiplex; joint stiffness and pain initially in the shoulders, hips, and fingers; gradual mild coarsening of facial features; and normal to mildly impaired cognitive development. If present, organomegaly is mild. Pain from osteoporosis that is clinically and radiologically apparent in childhood becomes more severe from adolescence. Cardiorespiratory complications (restrictive lung disease, thickening and insufficiency of the mitral and aortic valves, left and/or right ventricular hypertrophy) are common causes of death, typically in early to middle adulthood. [from GeneReviews]
Authors:
Jules G Leroy  |  Sara S Cathey  |  Michael J Friez   view full author information

Additional descriptions

From OMIM
Mucolipidosis type III alpha/beta is an autosomal recessive disorder characterized clinically by short stature, skeletal abnormalities, cardiomegaly, and developmental delay. The disorder is caused by a defect in proper lysosomal enzyme phosphorylation and localization, which results in accumulation of lysosomal substrates. It is phenotypically less severe than the allelic disorder mucolipidosis type II alpha/beta (summary by Paik et al., 2005).  http://www.omim.org/entry/252600
From GHR
Mucolipidosis III alpha/beta is a slowly progressive disorder that affects many parts of the body. Signs and symptoms of this condition typically appear around age 3.Individuals with mucolipidosis III alpha/beta grow slowly and have short stature. They also have stiff joints and dysostosis multiplex, which refers to multiple skeletal abnormalities seen on x-ray. Many affected individuals develop low bone mineral density (osteoporosis), which weakens the bones and makes them prone to fracture. Osteoporosis and progressive joint problems also cause bone pain that becomes more severe over time in people with mucolipidosis III alpha/beta.People with mucolipidosis III alpha/beta often have heart valve abnormalities and mild clouding of the clear covering of the eye (cornea). Their facial features become slightly thickened or "coarse" over time. Affected individuals may also develop frequent ear and respiratory infections. About half of people with this condition have mild intellectual disability or learning problems. Individuals with mucolipidosis III alpha/beta generally survive into adulthood, but they may have a shortened lifespan.  https://ghr.nlm.nih.gov/condition/mucolipidosis-iii-alpha-beta

Clinical features

Retinal degeneration
MedGen UID:
48432
Concept ID:
C0035304
Finding
A retrogressive pathological change in the retina, focal or generalized, caused by genetic defects, inflammation, trauma, vascular disease, or aging. Degeneration affecting predominantly the macula lutea of the retina is MACULAR DEGENERATION. (Newell, Ophthalmology: Principles and Concepts, 7th ed, p304)
Opacification of the corneal stroma
MedGen UID:
602191
Concept ID:
C0423250
Finding
Reduced transparency of the stroma of cornea.
Hyperopic astigmatism
MedGen UID:
376146
Concept ID:
C1847524
Disease or Syndrome
A form of astigmatism in which one meridian is hyperopic while the one at a right angle to it has no refractive error.
Mucopolysacchariduria
MedGen UID:
870284
Concept ID:
C4024726
Finding
Excessive amounts of mucopolysaccharide in the urine.
Split hand
MedGen UID:
67457
Concept ID:
C0221373
Anatomical Abnormality
A condition in which middle parts of the hand (fingers and metacarpals) are missing giving a cleft appearance. The severity is very variable ranging from slightly hypoplastic middle fingers over absent middel fingers as far as oligo- or monodactyl hands.
Soft tissue swelling of interphalangeal joints
MedGen UID:
340744
Concept ID:
C1854913
Finding
Carpal bone hypoplasia
MedGen UID:
355049
Concept ID:
C1863749
Finding
Underdevelopment of one or more carpal bones.
Irregular carpal bones
MedGen UID:
428046
Concept ID:
CN003743
Finding
Carpal bones with irregular or fragmented margins.
Aortic regurgitation
MedGen UID:
504897
Concept ID:
CN001510
Finding
An insufficiency of the aortic valve, leading to regurgitation (backward flow) of blood from the aorta into the left ventricle.
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
Height greater than two standard deviations below the mean of the appropriate reference population for the age and sex of the individual.
Intellectual disability
MedGen UID:
334384
Concept ID:
C1843367
Finding
Specific learning disability
MedGen UID:
504802
Concept ID:
CN001216
Finding
Impairment of certain skills such as reading or writing, coordination, self-control, or attention that interfere with the ability to learn. The impairment is not related to a global deficiency of intelligence.
Increased serum beta-hexosaminidase
MedGen UID:
435911
Concept ID:
C2673361
Finding
Mucopolysacchariduria
MedGen UID:
870284
Concept ID:
C4024726
Finding
Excessive amounts of mucopolysaccharide in the urine.
Increased serum iduronate sulfatase activity
MedGen UID:
892439
Concept ID:
C4025599
Finding
Deficiency of N-acetylglucosamine-1-phosphotransferase
MedGen UID:
505502
Concept ID:
CN002947
Finding
Hurler syndrome
MedGen UID:
39698
Concept ID:
C0086795
Disease or Syndrome
Mucopolysaccharidosis type I (MPS I) is a progressive multisystem disorder with features ranging over a continuum of severity. While affected individuals have traditionally been classified as having one of three MPS I syndromes (Hurler syndrome, Hurler-Scheie syndrome, or Scheie syndrome), no easily measurable biochemical differences have been identified and the clinical findings overlap; thus, affected individuals are best described as having either severe or attenuated MPS I, a distinction that influences therapeutic options. Severe MPS I. Infants appear normal at birth. Typical early manifestations are nonspecific (e.g., umbilical or inguinal hernia, frequent upper respiratory-tract infections before age 1 year). Coarsening of the facial features may not become apparent until after age one year. Gibbus deformity of the lower spine is common and often noted within the first year. Progressive skeletal dysplasia (dysostosis multiplex) involving all bones is universal. By age three years, linear growth decreases. Intellectual disability is progressive and profound. Hearing loss is common. Death, typically caused by cardiorespiratory failure, usually occurs within the first ten years of life. Attenuated MPS I. The severity and rate of disease progression range from serious life-threatening complications leading to death in the second to third decades to a normal life span complicated by significant disability from progressive joint manifestations and cardiorespiratory disease. While some individuals have no neurologic involvement and psychomotor development may be normal in early childhood, learning disabilities can be present. Clinical onset is usually between ages three and ten years. Hearing loss and cardiac valvular disease are common.
Split hand
MedGen UID:
67457
Concept ID:
C0221373
Anatomical Abnormality
A condition in which middle parts of the hand (fingers and metacarpals) are missing giving a cleft appearance. The severity is very variable ranging from slightly hypoplastic middle fingers over absent middel fingers as far as oligo- or monodactyl hands.
Mandibular prognathia
MedGen UID:
98316
Concept ID:
C0399526
Finding
Abnormal prominence of the chin related to increased length of the mandible.
Scoliosis
MedGen UID:
195976
Concept ID:
C0700208
Finding
The presence of an abnormal lateral curvature of the spine.
Broad ribs
MedGen UID:
336390
Concept ID:
C1848654
Finding
Increased width of ribs
J-shaped sella turcica
MedGen UID:
381480
Concept ID:
C1854718
Finding
A deformity of the sella turcica whereby the sella extends further anterior than normal such that the anterior clinoid process appears to overhang it, giving the appearance of the letter J on imaging of the skull.
short long bones
MedGen UID:
344385
Concept ID:
C1854912
Finding
One or more abnormally short long bone.
Soft tissue swelling of interphalangeal joints
MedGen UID:
340744
Concept ID:
C1854913
Finding
Carpal bone hypoplasia
MedGen UID:
355049
Concept ID:
C1863749
Finding
Underdevelopment of one or more carpal bones.
Craniosynostosis
MedGen UID:
504814
Concept ID:
CN001249
Finding
Craniosynostosis refers to the premature closure of the cranial sutures. Primary craniosynostosis refers to the closure of one or more sutures due to abnormalities in skull development, and secondary craniosynostosis results from failure of brain growth.
Irregular carpal bones
MedGen UID:
428046
Concept ID:
CN003743
Finding
Carpal bones with irregular or fragmented margins.
Mandibular prognathia
MedGen UID:
98316
Concept ID:
C0399526
Finding
Abnormal prominence of the chin related to increased length of the mandible.
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.
J-shaped sella turcica
MedGen UID:
381480
Concept ID:
C1854718
Finding
A deformity of the sella turcica whereby the sella extends further anterior than normal such that the anterior clinoid process appears to overhang it, giving the appearance of the letter J on imaging of the skull.
Craniosynostosis
MedGen UID:
504814
Concept ID:
CN001249
Finding
Craniosynostosis refers to the premature closure of the cranial sutures. Primary craniosynostosis refers to the closure of one or more sutures due to abnormalities in skull development, and secondary craniosynostosis results from failure of brain growth.
Thickened skin
MedGen UID:
90736
Concept ID:
C0334008
Finding
Laminar thickening of skin.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVPseudo-Hurler polydystrophy

Recent clinical studies

Etiology

Ben-Yoseph Y, Potier M, Mitchell DA, Pack BA, Melançon SB, Nadler HL
Biochem J 1987 Dec 15;248(3):697-701. PMID: 2829837Free PMC Article
Ben-Yoseph Y, Pack BA, Mitchell DA, Elwell DG, Potier M, Melançon SB, Nadler HL
Enzyme 1986;35(2):106-16. PMID: 3017692
Mueller OT, Little LE, Miller AL, Lozzio CB, Shows TB
Clin Chim Acta 1985 Aug 30;150(3):175-83. PMID: 2998644
Varki AP, Reitman ML, Kornfeld S
Proc Natl Acad Sci U S A 1981 Dec;78(12):7773-7. PMID: 6461005Free PMC Article
Reitman ML, Varki A, Kornfeld S
J Clin Invest 1981 May;67(5):1574-9. PMID: 6262380Free PMC Article

Diagnosis

Pourjavan S, Fryns JP, Van Hove JL, Poorthuis BJ, Casteels I
Bull Soc Belge Ophtalmol 2002;(286):19-24. PMID: 12564313
Umehara F, Matsumoto W, Kuriyama M, Sukegawa K, Gasa S, Osame M
J Neurol Sci 1997 Mar 10;146(2):167-72. PMID: 9077513
Varki AP, Reitman ML, Kornfeld S
Proc Natl Acad Sci U S A 1981 Dec;78(12):7773-7. PMID: 6461005Free PMC Article
Kelly TE, Thomas GH, Taylor HA Jr, McKusick VA, Sly WS, Glaser JH, Robinow M, Luzzatti L, Espiritu C, Feingold M, Bull MJ, Ashenhurst EM, Ives EJ
Johns Hopkins Med J 1975 Oct;137(4):156-75. PMID: 810612
Starreveld E, Ashenhurst EM
Neurology 1975 Mar;25(3):234-8. PMID: 803649

Prognosis

Tiede S, Cantz M, Spranger J, Braulke T
Hum Mutat 2006 Aug;27(8):830-1. doi: 10.1002/humu.9443. PMID: 16835905
Tylki-Szymańska A, Czartoryska B, Groener JE, Ługowska A
Am J Med Genet 2002 Mar 15;108(3):214-8. PMID: 11891688
Umehara F, Matsumoto W, Kuriyama M, Sukegawa K, Gasa S, Osame M
J Neurol Sci 1997 Mar 10;146(2):167-72. PMID: 9077513
Starreveld E, Ashenhurst EM
Neurology 1975 Mar;25(3):234-8. PMID: 803649
Leung LS, Weinstein GW, Hobson RR
Birth Defects Orig Artic Ser 1971 Mar;7(3):32-40. PMID: 5006141

Clinical prediction guides

Ranieri E, Paton B, Poulos A
Biochem J 1986 Feb 1;233(3):763-72. PMID: 3518703Free PMC Article
Honey NK, Mueller OT, Little LE, Miller AL, Shows TB
Proc Natl Acad Sci U S A 1982 Dec;79(23):7420-4. PMID: 6961420Free PMC Article
Varki A, Reitman ML, Vannier A, Kornfeld S, Grubb JH, Sly WS
Am J Hum Genet 1982 Sep;34(5):717-29. PMID: 6289658Free PMC Article
Reitman ML, Varki A, Kornfeld S
J Clin Invest 1981 May;67(5):1574-9. PMID: 6262380Free PMC Article
Taylor HA, Thomas GH, Miller CS, Kelly TE, Siggers D
Clin Genet 1973;4(5):388-97. PMID: 4201594

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