What is the underlying enzyme deficiency that causes I-cell disease?

I-Cell Disease is Caused by GlcNAc Phosphotransferase Deficiency

I-cell disease (Mucolipidosis II) is caused by a deficiency of GlcNAc phosphotransferase (UDP-N-acetylglucosamine: lysosomal-enzyme-N-acetylglucosamine-1-phosphotransferase), which leads to defective targeting of lysosomal enzymes. 1

Pathophysiology of I-Cell Disease

• GlcNAc phosphotransferase is responsible for the first step in tagging lysosomal enzymes with mannose 6-phosphate (M6P) markers, which are essential for proper transport of these enzymes to lysosomes 1
• The deficiency of this enzyme results in failure of newly synthesized lysosomal enzymes to acquire their M6P targeting signal, leading to their inappropriate secretion outside of cells 2
• This results in multiple lysosomal enzyme deficiencies within the cells, while paradoxically causing increased levels of these enzymes in plasma and other extracellular fluids 3
• The term "I-cell" comes from the "inclusion cells" observed in patient fibroblasts, which contain abnormal lysosomes filled with undegraded substrates 4

Diagnostic Patterns in I-Cell Disease

• The diagnostic hallmark of I-cell disease is a specific pattern of enzyme distribution:
  • Deficient intracellular lysosomal enzyme activities in fibroblasts and leukocytes
  • Markedly elevated extracellular lysosomal enzyme activities (10-70 fold higher than normal) in plasma and culture media 3
• Multiple enzyme assays show this pattern, including:
  • β-hexosaminidase
  • N-acetyl-α-D-glucosaminidase
  • Iduronate-2-sulfatase
  • α-mannosidase
  • α-fucosidase
  • β-glucuronidase
  • β-galactosidase 2, 3

Clinical Manifestations

• Early onset of symptoms, typically before 6 months of age 4
• Coarse facial features similar to mucopolysaccharidoses 3
• Skeletal abnormalities (dysostosis multiplex) 1
• Severe gingival hyperplasia 5
• Developmental delay and regression 3
• Limited life expectancy, with death typically occurring before age 10 in severe cases 1

Differentiating from Similar Conditions

• I-cell disease must be distinguished from:
  • Mucopolysaccharidoses (MPS) - similar clinical features but without mucopolysacchariduria 4
  • Pseudo-Hurler polydystrophy (Mucolipidosis III) - a milder form caused by partial deficiency of the same enzyme 6
  • Multiple sulfatase deficiency - affects multiple sulfatase enzymes due to a defect in post-translational modification 2
  • Galactosialidosis - caused by deficiency of protective protein cathepsin A 2

Important Clinical Considerations

• Early diagnosis is critical for genetic counseling and potential prenatal diagnosis in subsequent pregnancies 4
• Enzyme testing in multiple tissues (leukocytes, fibroblasts, plasma) is essential for accurate diagnosis 3
• Currently, only supportive care is available for patients with I-cell disease 1
• The condition is inherited in an autosomal recessive pattern 6

In summary, I-cell disease results from GlcNAc phosphotransferase deficiency, leading to misrouting of lysosomal enzymes and subsequent cellular dysfunction. The diagnosis is confirmed by demonstrating decreased intracellular enzyme activities with paradoxically increased extracellular enzyme levels.