mucolipidosis type 2
Friday 17 February 2006
Definition: Mucolipidosis II is a Hurler-like condition with severe clinical and radiologic features, peculiar fibroblast inclusions, and no excessive mucopolysacchariduria. It is an autosomal recessive metabolic disease caused by mutation in the GNPTAB gene (MIM.607840).
UDP-N-acetylglucosamine:lysosomal-enzyme N-acetylglucosamine-1-phosphotransferase (GNPTAB) (GlcNAc-phosphotransferase) (EC 18.104.22.168) catalyzes the initial step in the synthesis of the mannose 6-phosphate determinant required for efficient intracellular targeting of newly synthesized lysosomal hydrolases to the lysosome. GlcNAc-phosphotransferase is an alpha-2/beta-2/gamma-2 hexameric complex.
Congenital dislocation of the hip, thoracic deformities, hernia, and hyperplastic gums are evident soon after birth. Retarded psychomotor development, clear corneas, and restricted joint mobility are other features.
- birth length less than normal
- deceleration of linear growth during first year
- birth weight less than normal
- progressive failure to thrive
- Hurler-like body configuration
- marked growth retardation
- death in childhood
- death often secondary to pneumonia or congestive heart failure
- high, narrow forehead
- long philtrum
- coarse facial features
- recurrent episodes of otitis media
- thick, firm earlobes
- thin eyebrows
- puffy eyelids
- epicanthal folds
- clear to faintly hazy corneas
- increased corneal diameter
- corneal opacities on slit-lamp exam
- low nasal bridge
- progressive alveolar ridge hypertropy
- congestive heart failure
- hypertrophic cardiomyopathy
- cardiac murmur
- aortic insufficiency
- recurrent bronchitis
- recurrent pneumonia
widely spaced nipples
- scapular hypoplasia
- broad, spatulate-appearing ribs
- moderate joint limitation
- osteopenia in early infancy
- pathologic fractures
- thickened cranium
- normal enlarged sella turcica
- dorsolumbar kyphosis
- atlantoaxial dislocation
- ovoid vertebral bodies
- narrowness of interpediculate distances in lower thoracic
- hypoplastic odontoid process
- beaking of vertebral bodies T12-L3
- lumbar gibbus
- flared iliac wings
- horizontal acetabular roofs
- supra-acetabular constriction
- hip dislocation
- irregular contours of pubis and ischium
- cortical bone erosion (especially proximal femora)
- long bone shortening
- widened metaphyses
- varus deformity of humeral neck
- tilted distal ends of radius and ulna
- broadening of wrist
- hypoplasia of carpal bones
- conical bullet-shaped distal ends of phalanges
- claw-hand deformities
- talipes equinovarus
- thick, relatively tight skin
devere psychomotor retardation
inclusion bodies (membrane-bound vacuoles) in fibroblasts
Normal to mildly increased mucopolysacchariduria
Increased serum beta-hexosaminidase (10-20x)
Increased serum iduronate sulfatase (10-20x)
Increased serum arylsulfatase A (10-20x)
Deficiency of N-acetylglucosamine-1-phosphotransferase
mucolipidosis II is caused by mutation in the GNPTAB gene (MIM.607840)
Mucolipidosis type II is the prototypical genetic disorder affecting the machinery of protein sorting. This syndrome is characterized by the leakage of multiple lysosomal hydrolases from cells, which leads to abnormally low cellular concentrations of these enzymes and to the lysosomal accumulation of undegraded macromolecules.
The major clinical consequences include multiple skeletal abnormalities (e.g., congenital hip dislocation and dwarfism), hepatosplenomegaly, and retarded psychomotor development.
The lysosomal deposits probably interfere with cellular physiology in multiple organ systems through direct toxic effects or by mechanical disturbance.
The molecular defect of inclusion-cell disease was recognized as a lack of the mannose-6-phosphate modification of the glycans present on the lysosomal hydrolases.
This modification functions as a recognition tag for the mannose-6-phosphate receptors that capture lysosomal enzymes from the Golgi apparatus and the cell surface and direct them to vesicles destined for transport to endosomes and lysosomes.
In patients, the activity of the Golgi enzyme N-acetylglucosamine-1-phosphotransferase (GNPTAB), one of the two enzymes responsible for synthesizing the mannose-6-phosphate tag, is missing.
UDP-N-acetylglucosamine:lysosomal-enzyme N-acetylglucosamine-1-phosphotransferase (GNPTAB) (GlcNAc-phosphotransferase) (EC 22.214.171.124) catalyzes the initial step in the synthesis of the mannose 6-phosphate determinant required for efficient intracellular targeting of newly synthesized lysosomal hydrolases to the lysosome.
A related defect with milder symptoms, pseudo-Hurler polydystrophy, is caused by a less drastic impairment in the activity of the same glycan-modifying enzyme.
Olkkonen VM, Ikonen E. Genetic defects of intracellular-membrane transport. N Engl J Med. 2000 Oct 12;343(15):1095-104. PMID: #11027745#