I-cell Disease

Inclusion-cell disease (I-cell disease, mucolipidosis II, or ML II) is caused by a defect in uridine diphosphate (UDP)-N-acetylgucosamine-1-phosphotransferase, an enzyme that transfers phosphate to mannose residues on specific proteins. Lysosomes must have this protein, since it is responsible for the breakdown of oligosaccharides, lipids, and glycosaminoglycans. A deficiency in this enzyme results in the accumulation of these chemicals in the body, causing “inclusion cells.” Patients present within the 1st year of life with failure to thrive Failure to Thrive Failure to thrive (FTT), or faltering growth, describes suboptimal weight gain and growth in children. The majority of cases are due to inadequate caloric intake; however, genetic, infectious, and oncological etiologies are also common. Failure to Thrive and developmental delay. Blood testing for enzyme activity and the presence of inclusion bodies are diagnostic. Treatment is aimed at reducing symptoms, as there is no cure for I-cell disease. Complications of disease include heart failure and infection, with death occurring in the 1st decade of life.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Definition

I-cell disease is a rare lysosomal storage disorder that presents in early childhood with severe skeletal abnormalities and failure to thrive Failure to Thrive Failure to thrive (FTT), or faltering growth, describes suboptimal weight gain and growth in children. The majority of cases are due to inadequate caloric intake; however, genetic, infectious, and oncological etiologies are also common. Failure to Thrive. A mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in the GNPTA gene causes a deficiency in the enzyme uridine diphosphate (UDP)-N-acetylglucosamine-1-phosphotransferase.

Epidemiology

  • Autosomal recessive
  • Prevalence: approximately 1 in 100,000–400,000 live births
  • Male = female
  • Disease most common in Japan

Etiology

  • Mutation of GNPTA gene: located on long arm Arm The arm, or "upper arm" in common usage, is the region of the upper limb that extends from the shoulder to the elbow joint and connects inferiorly to the forearm through the cubital fossa. It is divided into 2 fascial compartments (anterior and posterior). Arm of chromosome 4 (4q21-q23)
  • Phosphodiesterase deficiency: rare

Pathophysiology

  • GNPTA mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations causes UDP-N-acetylglucosamine-1-phosphotransferase deficiency.
  • Causes lysosomal targeting disfunction → lysosomal enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes are erroneously transported to extracellular matrix 
  • These enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes do not function outside of acidic lysosomes.
  • Lysosomes lack requisite enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes for metabolism of absorbed cellular debris → debris accumulates within the cell, forming inclusion bodies:
    • Fatty substances: mucolipids
    • Complex carbohydrates Carbohydrates Carbohydrates are one of the 3 macronutrients, along with fats and proteins, serving as a source of energy to the body. These biomolecules store energy in the form of glycogen and starch, and play a role in defining the cellular structure (e.g., cellulose). Basics of Carbohydrates: mucopolysaccharides
  • Symptoms result from accumulation of mucolipids and mucopolysaccharides.

Clinical Presentation

Clinical features evident by 6 months of age:

  • Coarse facial features (often present at birth)
  • Craniofacial abnormalities (often present at birth)
  • Restricted joint movement
  • Hypotonia

Patients present in 1st year of life with:

  • Severe psychomotor retardation
  • Congenital hip dislocation 
  • Inguinal hernias
  • Gingival hypertrophy
  • Skeletal manifestations (kyphoscoliosis, lumbar gibbus)
  • Hepatomegaly
  • Splenomegaly Splenomegaly Splenomegaly is pathologic enlargement of the spleen that is attributable to numerous causes, including infections, hemoglobinopathies, infiltrative processes, and outflow obstruction of the portal vein. Splenomegaly

Progressive, severe psychomotor impairment leads to death in early childhood.

Child with i-cell disease

Facial features seen in I-cell disease:
Characteristic coarse facial features are distinctive of patients with mucolipidosis II. These features become more evident with time and can present a challenge for intubation during surgery.

Image: “Patient at the end of surgery before extubation” by Al Nahdha Hospital, Muscat, Sultanate of Oman. License: CC BY 2.0
Radiographs of 21-month-old korean girl with ml ii

Skeletal abnormalities in patients with I-cell disease:
Patients with mucolipidosis II often present with skeletal abnormalities. Commonly seen defects are restriction of the joints. These X-rays X-rays X-rays are high-energy particles of electromagnetic radiation used in the medical field for the generation of anatomical images. X-rays are projected through the body of a patient and onto a film, and this technique is called conventional or projectional radiography. X-rays show broad, undermodeled proximal phalanges and proximal pointing of metacarpals (a) and hip dysplasia (b).

Image: “Radiographs of 21-month-old Korean girl with ML II” by Mina Yang et al. License: CC BY 4.0, cropped by Lecturio.

Diagnosis

Prenatal diagnosis:

  • Amniocentesis or chorionic villus sampling
  • Low levels of UDP-N-acetylglucosamine-1-phosphotransferase enzyme activity is diagnostic.

Diagnostic tests Diagnostic tests Diagnostic tests are important aspects in making a diagnosis. Some of the most important epidemiological values of diagnostic tests include sensitivity and specificity, false positives and false negatives, positive and negative predictive values, likelihood ratios, and pre-test and post-test probabilities. Epidemiological Values of Diagnostic Tests performed after delivery:

  • Elevated plasma lysosomal enzyme concentration and low level of lysosomal enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes in cultured fibroblasts
  • Inclusion bodies visible in peripheral blood lymphocytes Lymphocytes Lymphocytes are heterogeneous WBCs involved in immune response. Lymphocytes develop from the bone marrow, starting from hematopoietic stem cells (HSCs) and progressing to common lymphoid progenitors (CLPs). B and T lymphocytes and natural killer (NK) cells arise from the lineage. Lymphocytes
  • Low levels of UDP-N-acetylglucosamine-1-phosphotransferase enzyme activity

Management

No curative treatment is available for I-cell disease. Management is symptomatic and supportive:

  • Nutritional supplements are recommended: iron and vitamin B12
  • Physical therapy to slow degeneration of motor function
  • Speech therapy
  • Hip replacement and other orthopedic surgeries may be recommended to maintain mobility. 
  • Hearing aids

Bone marrow transplantation may be helpful as a remedy for neurologic degeneration (currently under investigation).

Genetic counseling should be offered to families considering having additional children.

Differential Diagnosis

  • Hurler syndrome (mucopolysaccharidosis type I): rare lysosomal storage disease Lysosomal storage disease Lysosomal storage diseases are a group of metabolic disorders caused by genetic mutations in the enzymes responsible for normal lysosomal function. The dysfunction of enzymatic processes causes an accumulation of undigested metabolites, resulting in cellular death. The main groups include sphingolipidoses, oligosaccharidoses, and mucolipidoses. Overview of Lysosomal Storage Diseases caused by deficiency in enzyme alpha-L-iduronidase, which causes accumulation of mucopolysaccharides in various body tissues. Infants appear normal at birth, but they develop symptoms within the 1st year of life. These symptoms include skeletal abnormalities, abdominal and inguinal hernias, coarse facial features, severe intellectual disability, and loss of developmental milestones Developmental milestones Developmental milestones are the skills or abilities that most children are able to perform when they reach a certain age. Understanding the appropriate milestones and at what age they are reached helps clinicians identify symptoms of delayed development. Developmental milestones are divided into 5 important domains: gross motor, fine motor, language, social, and cognitive. Developmental Milestones and Normal Growth. As the patient ages, further symptoms become evident, including joint contractures, vision/hearing deficits, and cardiac dysfunction. The condition is fatal; 5 years is the average age at death. 
  • Sialidosis (mucolipidosis I): very rare autosomal recessive lysosomal storage disease Lysosomal storage disease Lysosomal storage diseases are a group of metabolic disorders caused by genetic mutations in the enzymes responsible for normal lysosomal function. The dysfunction of enzymatic processes causes an accumulation of undigested metabolites, resulting in cellular death. The main groups include sphingolipidoses, oligosaccharidoses, and mucolipidoses. Overview of Lysosomal Storage Diseases caused by deficiency in enzyme alpha-neuraminidase leading to pathologic accumulation of oligosaccharides. There are 2 forms of sialidosis. Type 1 presents later in life with involuntary muscle contractions and cherry-red macules in the retina. Type 2 presents during infancy with skeletal dysplasia, intellectual disability, and hepatosplenomegaly. Treatment is supportive.
  • Pseudo-Hurler polydystrophy (mucolipidosis III): autosomal recessive lysosomal storage disease Lysosomal storage disease Lysosomal storage diseases are a group of metabolic disorders caused by genetic mutations in the enzymes responsible for normal lysosomal function. The dysfunction of enzymatic processes causes an accumulation of undigested metabolites, resulting in cellular death. The main groups include sphingolipidoses, oligosaccharidoses, and mucolipidoses. Overview of Lysosomal Storage Diseases caused by a defect in UDP-N-acetylglucosamine-1-phosphotransferase and leading to accumulation of mucopolysaccharides and mucolipids. Symptoms are similar to, but less severe than, those of I-cell disease and include progressive stiffness, hip dysfunction, growth delay, intellectual disability, and mildly coarse facies. Treatment is supportive and similar to that for I-cell disease.

References

  1. Edmiston, R., Wilkinson, S., Jones, S., Tylee, K., Broomfield, A., Bruce, I. A. (2019). I-cell disease (mucolipidosis II): a case series from a tertiary paediatric centre reviewing the airway and respiratory consequences of the disease. JIMD Rep 45:1–8.
  2. Khan, S. A., Tomatsu, S. C. (2020). Mucolipidoses overview: past, present, and future. Int J Mol Sci 21:6812.
  3. National Organization for Rare Disorders. I cell disease. Retrieved April 28, 2021, from https://rarediseases.org/rare-diseases/i-cell-disease/
  4. Beck, M., Barone, R., et al. (1995). Inter- and intrafamilial variability in mucolipidosis II (I-cell disease). Clin Genet. https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1399-0004.1995.tb03958.x

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