Question

Imagine that you are part of a research team that specializes in diagnosing disorders associated with malfunctioning cellular organelles and structures.Medical doctors consult your group to help diagnose particularly difficult cases.  Read the patient history, physical examination and lab results to provide a cellular explanation for the case below. In the answer box type the tell the malfunctioning organelle (4 points) AND Rationale for Diagnosis (6 points) (explanation of how history, physical examination and laboratory results suggest diagnosis). Be sure to give all details as rationale counts majority of points.

Patient History:    

• 2-day old male, Low birth-weight (4pds. 5 ounces), Difficulty suckling/swallowing, Seizures, Gastrointestinal bleeding

Physical Examination

• Enlarged liver, Low muscle tone/inability to move, Glaucoma, Facial deformities, Impaired hearing
• Jaundiced skin

Laboratory Results

• High levels of hydrogen peroxide in cells
• High levels of fats and amino acids in cells

Answer 1

Malfunctioning organelle= Peroxisomes

Peroxisomes are membrane bound organelles present in cytoplasm that carry out break down of very long chain fatty acids. They contain more than 50 enzymes that help in energy metabolism. Lipid biosynthesis of plasmalogens also occurs in peroxisome along with production of bile acids. One of the major products from fatty acid oxidation formed in peroxisomes is hydrogen peroxide. As levels of H202 are increased in the patient, malfunctioning organelle should be peroxisomes.

Rationale: The patient is suffering from Zellweger syndrome, where is there is reduced or absent functioning peroxisomes. It is inherited in autosomal recessive manner and can be caused by mutation in any of 12 genes. It is most common in infants, which show facial deformities, such as a flattened face, high forehead, abnormally small jaw, palate etc. Sensorineural hearing loss is seen in these patients due to effects on cochlea or vestibular apparatus. Gastrointestinal bleeding is caused by decreased clotting factors in blood, which are formed in liver. Liver contains large amount of peroxisomes, occupying around 2% of the liver volume. Due to increased number of peroxisome in ZS, there is enlarged liver observed. Liver also produces excess bilirubin, leading to jaundice (yellowing of skin). The patient shows increase hydrogen peroxide production. Normally hydrogen peroxide produced in peroxisomes is converted to water and oxygen. However, as the peroxisomes are less functional, H202 levels increase.

Glaucoma is caused by increased pressure in eyes due to damage to optic nerve. Mutation in cryptic signaling site of a protein can cause its mislocalization to the eye causing glaucoma. Eye changes may occur due to nerve impairment, effects on retina, optic atrophy, and defects on eye movements. There is lack of muscle tone, leading to hypotonia. Difficulty in suckling/swallowing may be due to facial deformities and muscle defects. Due to defective fatty acid oxidation, fats will increase. Similarly, amino acids are not converted to glucose. This leads to increased amino acid levels.