I-cell disease stands for inclusion cell disease. It
is a genetically inherited lysosomal storage disease clinically similar to
Hurler syndrome (without mucopolysaccharides) and originally characterized by
the presence of intracytoplasmic inclusions in fibroblasts (“inclusion
cells” or “I cells”).
GNPTA Deficiency; Inclusion Cell Disease; Leroy Disease;
Mucolipidosis II (ML II); N-Acetylglucosaminyl-1-Phosphotransferase
Genetic disorder involving abnormal trafficking of
lysosomal enzymes. The disease was classified as mucolipidosis type II
because it had clinical characteristics of both the mucopolysaccharidoses
and the sphingolipidoses.
1:640,000 live births in the Netherlands. In the French
Canadian population of Saguenay Lac Saint-Jean of the province of Quebec,
the estimated prevalence at birth is 1:6184, giving a carrier frequency of
1/39. No ethnic or sexual predilection. Life expectancy is reduced (first
decade); patients usually die of pneumonia or congestive heart failure.
Autosomal recessive. Caused by a deficiency of
the enzyme N-acetylglucosaminyl-1-phosphotransferase, which is produced by
the GNPTA gene located at chromosome band 4q21-q23.
The disease results from abnormal enzyme
transport. The deficiency is N-acetylglucosamine-1-phosphotransferase, a
membrane enzyme that catalyzes the formation of mannose-6-phosphate
(Man-6-P) on nascent lysosomal enzymes (by ribosomes). This Man-6-P
component is recognized by Man-6-P receptors, which direct the transfer of
lysosomal enzymes into lysosomes. This failed internalization results in
release of lysosome enzymes into the extracellular medium instead. Although
all cells are deficient in phosphotransferase activity, not all cells are
deficient in lysosomal enzyme content, indicating that some cells have
Man-6-P-independent pathways. The functional deficiency of lysosomal
enzymes results in abnormal cell architecture (vacuolization and formation
of inclusions) in cells of mesenchymal origin, which involves several
tissues of the body: skeletal system (abnormal trabeculation of bone and
cartilage), heart valves (vacuolization leading to thickening of the
valves), renal glomerules, and liver fibroblasts of the periportal spaces.
Clinical history and physical findings. Elevated levels
of lysosomal enzymes (e.g., arylsulfatase A) in serum and body fluids.
Deficient enzymes can be demonstrated in cultured fibroblasts. Microscopy of
fibroblasts shows numerous “inclusion bodies” for which the disease is
I-cell disease has many clinical and radiographic
features similar to Hurler syndrome, but with earlier presentation and
without mucopolysaccharides. Striking gingival hyperplasia can distinguish
this disease from Hurler syndrome. Other features include kyphoscoliosis,
wedging of vertebral bodies, craniofacial abnormalities, and restricted
joint movements. Repeated upper respiratory infections (bronchitis and
pneumonia) are frequent. Severe mucosal thickening of the epiglottis,
larynx, and trachea increases with age. Macroglossia is often present.
Hepatomegaly is prominent with hernias. Severe psychomotor retardation,
developmental delay, myelopathy, and neonatal hypotonia are important
neurologic characteristics. Mental status is variable but can present with
severe progressive psychomotor retardation. The cardiovascular anomalies
include hypertrophic cardiopathy, cardiomegaly, and aortic insufficiency.
Death within the first decade is usually from bronchopneumonia or congestive
heart failure. No specific treatment is available. Physical therapy may
delay progression of joint immobility. Nasal continuous positive airway
pressure has been shown to reduce respiratory infections. Successful ...