I-cell Disease

What is I-cell disease?

Autosomal Recessive lysosomal storage disorder.

Abnormalities give rise to connective tissue that is called inclusion bodies which is where the disease gets its name I = inclusion bodies.

Normally the cell will tag (mark) lysosomal enzymes with mannose-6-phosphate to direct them to the lysosomes. It is like the cell gives the enzyme a map to the find the lysosomes. In I-cell disease there is a defect in the addition of mannose-6-phosphate. This causes the lysosomal enzymes to get lost and they get released into the extracellular space and because they never find the lysosomes the lysosomes are empty and lack the important enzymes they need to break things down. 

Features of I-cell disease:

Coarse facial features like thick gums (gingiva hyperplasia like a side effect of phenytoin) and a large tongue (glossitis) 

Skeletal abnormalities like congenital dislocation of the hip or clubbing of the feet Psychomotor retardation or immobility of extremities. Failure to thrive.

The boards can test this concept in a couple of ways:

They can ask where does the lysosomal enzymes get released in I-cell disease. 

Answer = ECM

They can also ask about the defect of I-cell disease. 

Answer = phosphorylation of mannose = defect in the addition of mannose-6- phosphate moiety to the lysosomal enzymes. 

Finally they can ask about features of the lysosomes in I-cell disease. 

Answer = they are empty = defective.

In every question they will give hints by describing the features of the patient with the above abnormalities, often the patient is an infant as I-cell presents at birth

Finally = the absolute details:

Deficient enzyme = UDP-N-acetylglucosamine-1-phosphotransferase due to a mutation of the GNPTA gene.

The accumulation = the misguided lysosomal enzymes

I-cell is said to be similar to Hurler syndrome but more severe.

So we have Hunter's syndrome (X-linked , Hunters aim for the X) which is a like milder form of Hurlers's and now I-cell disease which = more severe than Hurler's.

Hunters:

Deficient enzyme = Iduronate Sulfatase. Accumulates Heparan Sulfate and dermatan sulfate. Features = Milde Hurler's plus aggressive behavior and no corneal clouding

Hurler's 

Deficient enzyme = alpha-L-iduronidase. Accumulation is Heparan Sulfate and Dermatan Sulfate. Features = Developmental Delay, gargoylism, corneal clouding.

Last but not least, when I think of I-cell disease I also remember Chediak-Higashi because this disease has some common themes with I-cell:

Chediak-Higashi:

Autosomal Recessive

Microtubule defect which messes up lysosomal emptying of phagocytic enzymes.

Presents:

Recurrent pyogenic infections by Staph and Strep, partial albinism, and peripheral neuropathy.

I-cell has empty lysosomes because the enzymes were misguided and got released into the ECM rather than being put in the lysosomes,  so the Lysosomes do not work properly. Chediak-Higashi = lysosomes have defective emptying so the lysosomes do not work properly. Both = autosomal recessive.