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I cell disease

MedGen UID:
435914
Concept ID:
C2673377
Disease or Syndrome
Synonyms: GNPTAB-Related Mucolipidoses; Inclusion cell disease; Leroy Disease; ML 2; ML disorder type 2; ML II ALPHA/BETA; Mucolipidosis 2; Mucolipidosis II; Mucolipidosis III Alpha/Beta; N-acetylglucosamine 1phosphotransferase deficiency
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)
 
Gene (location): GNPTAB (12q23.2)
OMIM®: 252500
Orphanet: ORPHA576

Disease characteristics

Excerpted from the GeneReview: Mucolipidosis II
Mucolipidosis II (ML II, I-cell disease) is a slowly progressive inborn error of metabolism with clinical onset at birth and fatal outcome most often in early childhood. Postnatal growth is limited and often ceases in the second year of life; contractures develop in all large joints. The skin is thickened, facial features are coarse, and gingiva are hypertrophic. Orthopedic abnormalities present at birth may include thoracic deformity, kyphosis, clubfeet, deformed long bones, and/or dislocation of the hip(s). Already in infancy skeletal radiographs reveal dysostosis multiplex. All children appear to have cardiac involvement, most commonly thickening and insufficiency of the mitral valve and, less frequently, the aortic valve. Progressive mucosal thickening narrows the airways and gradual stiffening of the thoracic cage contributes to respiratory insufficiency, the most common cause of death. [from GeneReviews]
Authors:
Jules G Leroy  |  Sara Cathey  |  Michael J Friez   view full author information

Additional descriptions

From OMIM
Mucolipidosis type II 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 more severe than the allelic disorder mucolipidosis type III alpha/beta (summary by Paik et al., 2005).  http://www.omim.org/entry/252500
From GHR
Mucolipidosis II alpha/beta (also known as I-cell disease) is a progressively debilitating disorder that affects many parts of the body. Most affected individuals do not survive past early childhood.At birth, children with mucolipidosis II alpha/beta are small and have weak muscle tone (hypotonia) and a weak cry. Affected individuals grow slowly after birth and usually stop growing during the second year of life. Development is delayed, particularly the development of speech and motor skills such as sitting and standing.Children with mucolipidosis II alpha/beta typically have several bone abnormalities, many of which are present at birth. Affected individuals may have an abnormally rounded upper back (kyphosis), feet that are abnormally rotated (clubfeet), dislocated hips, unusually shaped long bones, and short hands and fingers. People with this condition also have joint deformities (contractures) that significantly affect mobility. Most children with mucolipidosis II alpha/beta do not develop the ability to walk independently. Affected individuals have dysostosis multiplex, which refers to multiple skeletal abnormalities seen on x-ray.Other features of mucolipidosis II alpha/beta include a soft out-pouching around the belly-button (umbilical hernia) or lower abdomen (inguinal hernia), heart valve abnormalities, distinctive-looking facial features that are described as "coarse," and overgrowth of the gums (gingival hypertrophy). Vocal cords can stiffen, resulting in a hoarse voice. The airway is narrow, which can contribute to prolonged or recurrent respiratory infections. Affected individuals may also have recurrent ear infections, which can lead to hearing loss.  https://ghr.nlm.nih.gov/condition/mucolipidosis-ii-alpha-beta

Clinical features

Congestive heart failure
MedGen UID:
9169
Concept ID:
C0018802
Disease or Syndrome
The presence of an abnormality of cardiac function that is responsible for the failure of the heart to pump blood at a rate that is commensurate with the needs of the tissues or a state in which abnormally elevated filling pressures are required for the heart to do so. Heart failure is frequently related to a defect in myocardial contraction.
Heart murmur
MedGen UID:
9171
Concept ID:
C0018808
Finding
A periodic humming or blowing sound heard on auscultation of the heart that can indicate the presence of cardiac disease; murmurs are the result of vibrations caused by the turbulent flow of blood in the heart or great vessels. Murmurs are characterized according to the area of generation (mitral, aortic, tricuspid, or pulmonary) and according to the period of the cycle (systolic or diastolic).
Cavernous hemangioma
MedGen UID:
9184
Concept ID:
C0018920
Neoplastic Process
The presence of a cavernous hemangioma. A hemangioma characterized by large endothelial spaces (caverns) is called a cavernous hemangioma.
Talipes equinovarus
MedGen UID:
3130
Concept ID:
C0009081
Congenital Abnormality
Clubfoot is a congenital limb deformity defined as fixation of the foot in cavus, adductus, varus, and equinus (i.e., inclined inwards, axially rotated outwards, and pointing downwards) with concomitant soft tissue abnormalities (Cardy et al., 2007). Clubfoot may occur in isolation or as part of a syndrome (e.g., diastrophic dysplasia, 222600). Clubfoot has been reported with deficiency of long bones and mirror-image polydactyly (Gurnett et al., 2008; Klopocki et al., 2012).
Hip dislocation
MedGen UID:
42455
Concept ID:
C0019554
Injury or Poisoning
Displacement of the femur from its normal location in the hip joint.
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.
Flat acetabular roof
MedGen UID:
373340
Concept ID:
C1837485
Finding
Flattening of the superior part of the acetabulum, which is a cup-shaped cavity at the base of the hipbone into which the ball-shaped head of the femur fits. The acetabular roof thereby appears horizontal rather than arched, as it normally does.
Varus deformity of humeral neck
MedGen UID:
340755
Concept ID:
C1854948
Finding
Carpal bone hypoplasia
MedGen UID:
355049
Concept ID:
C1863749
Finding
Underdevelopment of one or more carpal bones.
Failure to thrive
MedGen UID:
115900
Concept ID:
C0231246
Finding
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Sign or Symptom
Enlargement of the liver.
Inguinal hernia
MedGen UID:
6817
Concept ID:
C0019294
Finding
An abdominal hernia with an external bulge in the GROIN region. It can be classified by the location of herniation. Indirect inguinal hernias occur through the internal inguinal ring. Direct inguinal hernias occur through defects in the ABDOMINAL WALL (transversalis fascia) in Hesselbach's triangle. The former type is commonly seen in children and young adults; the latter in adults.
Umbilical hernia
MedGen UID:
9232
Concept ID:
C0019322
Anatomical Abnormality
Protrusion of abdominal contents through a defect in the abdominal wall musculature around the umbilicus. Skin and subcutaneous tissue overlie the defect.
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Enlargement of the spleen.
Diastasis recti
MedGen UID:
113171
Concept ID:
C0221766
Anatomical Abnormality
A separation of the rectus abdominis muscle into right and left halves (which are normally joined at the midline at the linea alba).
Recurrent infections of the middle ear
MedGen UID:
155436
Concept ID:
C0747085
Disease or Syndrome
Increased susceptibility to otitis media, as manifested by recurrent episodes of otitis media.
Macroglossia
MedGen UID:
44236
Concept ID:
C0024421
Disease or Syndrome
Increased length and width of the tongue.
Diastasis recti
MedGen UID:
113171
Concept ID:
C0221766
Anatomical Abnormality
A separation of the rectus abdominis muscle into right and left halves (which are normally joined at the midline at the linea alba).
Neonatal hypotonia
MedGen UID:
412209
Concept ID:
C2267233
Disease or Syndrome
Muscular hypotonia (abnormally low muscle tone) manifesting in the neonatal period.
Recurrent bronchitis
MedGen UID:
148159
Concept ID:
C0741796
Disease or Syndrome
An increased susceptibility to bronchitis as manifested by a history of recurrent bronchitis.
Recurrent infections of the middle ear
MedGen UID:
155436
Concept ID:
C0747085
Disease or Syndrome
Increased susceptibility to otitis media, as manifested by recurrent episodes of otitis media.
Increased serum iduronate sulfatase activity
MedGen UID:
340747
Concept ID:
C1854916
Finding
An increased rate of iduronate-2-sulfatase activity in the blood.
Increased serum beta-hexosaminidase
MedGen UID:
435911
Concept ID:
C2673361
Finding
Hoarse voice
MedGen UID:
5602
Concept ID:
C0019825
Sign or Symptom
Hoarseness refers to a change in the pitch or quality of the voice, with the voice sounding weak, very breathy, scratchy, or husky.
Pathologic fracture
MedGen UID:
42095
Concept ID:
C0016663
Pathologic Function
Fractures occurring as a result of disease of a bone or from some undiscoverable cause, and not due to trauma. (Dorland, 27th ed)
Hip dislocation
MedGen UID:
42455
Concept ID:
C0019554
Injury or Poisoning
Displacement of the femur from its normal location in the hip joint.
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.
Flat acetabular roof
MedGen UID:
373340
Concept ID:
C1837485
Finding
Flattening of the superior part of the acetabulum, which is a cup-shaped cavity at the base of the hipbone into which the ball-shaped head of the femur fits. The acetabular roof thereby appears horizontal rather than arched, as it normally does.
Odontoid hypoplasia
MedGen UID:
339524
Concept ID:
C1846439
Finding
The odontoid process, or dens, is a bony projection from the axis (C2) upward into the ring of the atlas (C1) at the top of the spine. During embryogenesis, the body of the odontoid derives from the centrum of the atlas and separates from the atlas, fusing with the superior portion of the axis. If the odontoid is hypoplastic or absent, the attachments for the apical and alar ligaments are missing, allowing for excessive rotation of the atlas, craniocervical instability, and possibly cord compression (summary by Stevens et al., 2009).
short long bones
MedGen UID:
344385
Concept ID:
C1854912
Finding
One or more abnormally short long bone.
Varus deformity of humeral neck
MedGen UID:
340755
Concept ID:
C1854948
Finding
Flared iliac wings
MedGen UID:
356097
Concept ID:
C1865841
Finding
Widening of the ilium ala, that is of the wing of the ilium, combined with external rotation, leading to a flared appearance of the iliac wing.
Large sella turcica
MedGen UID:
334811
Concept ID:
C1843677
Finding
An abnormal enlargement of the sella turcica.
Thickened calvaria
MedGen UID:
346823
Concept ID:
C1858452
Finding
The presence of an abnormally thick calvaria.
Inguinal hernia
MedGen UID:
6817
Concept ID:
C0019294
Finding
An abdominal hernia with an external bulge in the GROIN region. It can be classified by the location of herniation. Indirect inguinal hernias occur through the internal inguinal ring. Direct inguinal hernias occur through defects in the ABDOMINAL WALL (transversalis fascia) in Hesselbach's triangle. The former type is commonly seen in children and young adults; the latter in adults.
Umbilical hernia
MedGen UID:
9232
Concept ID:
C0019322
Anatomical Abnormality
Protrusion of abdominal contents through a defect in the abdominal wall musculature around the umbilicus. Skin and subcutaneous tissue overlie the defect.
Wide intermamillary distance
MedGen UID:
473489
Concept ID:
C1827524
Finding
A larger than usual distance between the left and right nipple.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for I cell disease in Orphanet.

Recent clinical studies

Etiology

Lin MH, Pitukcheewanont P
J Pediatr Endocrinol Metab 2012;25(1-2):191-5. doi: 10.1515/jpem-2011-0429. PMID: 22570975
Yuksel A, Kayserili H, Gungor F
Fetal Diagn Ther 2007;22(3):198-202. Epub 2007 Jan 17 doi: 10.1159/000098717. PMID: 17228159
Kudo M, Brem MS, Canfield WM
Am J Hum Genet 2006 Mar;78(3):451-63. Epub 2006 Jan 24 doi: 10.1086/500849. PMID: 16465621Free PMC Article
Kabra M, Gulati S, Kaur M, Sharma J, Singh A, Chopra V, Menon PS, Kalra V
Indian J Pediatr 2000 Sep;67(9):683-7. PMID: 11028124
Breningstall GN, Tubman DE
Clin Neurol Neurosurg 1994 May;96(2):161-3. PMID: 7924082

Diagnosis

Mallen J, Highstein M, Smith L, Cheng J
Int J Pediatr Otorhinolaryngol 2015 May;79(5):760-2. Epub 2015 Mar 7 doi: 10.1016/j.ijporl.2015.02.034. PMID: 25818347
Lin MH, Pitukcheewanont P
J Pediatr Endocrinol Metab 2012;25(1-2):191-5. doi: 10.1515/jpem-2011-0429. PMID: 22570975
Takanashi J, Hayashi M, Yuasa S, Satoh H, Terada H
Brain Dev 2012 Oct;34(9):780-3. Epub 2012 Jan 24 doi: 10.1016/j.braindev.2011.12.013. PMID: 22269149
Yuksel A, Kayserili H, Gungor F
Fetal Diagn Ther 2007;22(3):198-202. Epub 2007 Jan 17 doi: 10.1159/000098717. PMID: 17228159
Bocca G, Monnens LA
Pediatr Nephrol 2003 Aug;18(8):830-2. Epub 2003 Jun 13 doi: 10.1007/s00467-003-1213-2. PMID: 12811655

Therapy

Lee W, O'Donnell D
Int J Paediatr Dent 2003 Jan;13(1):41-5. PMID: 12542623
Hochman JA, Treem WR, Dougherty F, Bentley RC
J Inherit Metab Dis 2001 Oct;24(5):603-4. PMID: 11757590
Ylikangas PK, Mononen IT
Clin Chem 1998 Dec;44(12):2543-4. PMID: 9882166
Tylki-Szymańska A, Maciejko D, Kidawa M, Jabłońska-Budaj U, Czartoryska B
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van Dongen JM, Willemsen R, Ginns EI, Sips HJ, Tager JM, Barranger JA, Reuser AJ
Eur J Cell Biol 1985 Nov;39(1):179-89. PMID: 2935398

Prognosis

Saul RA, Proud V, Taylor HA, Leroy JG, Spranger J
Am J Med Genet A 2005 Jun 15;135(3):328-32. doi: 10.1002/ajmg.a.30716. PMID: 15887289
Kabra M, Gulati S, Kaur M, Sharma J, Singh A, Chopra V, Menon PS, Kalra V
Indian J Pediatr 2000 Sep;67(9):683-7. PMID: 11028124
Güngör N, Coşkun T, Akçören Z, Cağlar M
Turk J Pediatr 1994 Apr-Jun;36(2):145-52. PMID: 8016916
Breningstall GN, Tubman DE
Clin Neurol Neurosurg 1994 May;96(2):161-3. PMID: 7924082
Matsuda I, Arashima S, Mitsuyama T, Oka Y, Ikeuchi T, Kaneko Y, Ishikawa M
Humangenetik 1975 Oct 20;30(1):69-73. PMID: 171215

Clinical prediction guides

Tardy C, Autefage H, Garcia V, Levade T, Andrieu-Abadie N
J Biol Chem 2004 Dec 17;279(51):52914-23. Epub 2004 Sep 27 doi: 10.1074/jbc.M408261200. PMID: 15452110
Mazrier H, Van Hoeven M, Wang P, Knox VW, Aguirre GD, Holt E, Wiemelt SP, Sleeper MM, Hubler M, Haskins ME, Giger U
J Hered 2003 Sep-Oct;94(5):363-73. PMID: 14557388
Nishimura F, Naruishi H, Naruishi K, Yamada T, Sasaki J, Peters C, Uchiyama Y, Murayama Y
Am J Pathol 2002 Dec;161(6):2047-52. doi: 10.1016/S0002-9440(10)64483-5. PMID: 12466121Free PMC Article
van der Meer W, Jakobs BS, Bocca G, Smeitink JA, Schuurmans Steckhoven JH, de Keijzer MH
J Clin Pathol 2001 Sep;54(9):724-6. PMID: 11533084Free PMC Article
Sheikh S, Madiraju K, Qazi Q, Rao M
Pediatr Pulmonol 1998 Feb;25(2):128-9. PMID: 9516097

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