Content Reviewers:Antonella Melani, MD
8 month old Emmanuel is brought to the clinic due to repeated episodes of jerking movements and loss of consciousness over the past few months. His parents are also worried because he feels limp when they lift him up, and his head tends to flop backward or to the side. On physical examination, you notice he has a flat face with a broad nasal bridge, and upon palpation of the abdomen, the liver appears enlarged. Right after him, 17 year old Arletta comes in. She complains that, recently, she has started to have difficulties seeing clearly at night. She also noticed that her skin is unusually dry, and doesn’t seem to improve with moisturizing cream. On physical examination, there are rough scaly patches of skin all over her body. You also notice that both her fourth toes are shorter than normal, and she tells you that they’ve been like that since birth. Finally, you see 32 year old George, who comes in with a 6 month history of progressive fatigue and weight loss. His wife has also recently noticed that, on occasion, he has been slurring his speech. On further questioning, George reluctantly tells you that he has experienced difficulties maintaining an erection. Examination reveals a low blood pressure, along with increased skin pigmentation, mostly around the oral mucosa, palmar creases, and knuckles.
Based on the initial presentation, Emmanuel, Arletta,, and George all seem to have some form of peroxisomal disorder. But first a bit of physiology real quick. Peroxisomes are cellular organelles that neutralize free radicals, which are molecules with an unpaired electron that can damage the cells by oxidizing lipids, proteins, and even the DNA. When free radicals enter peroxisomes, they get converted by an enzyme called oxidase into hydrogen peroxide or H2O2. But since hydrogen peroxide is still dangerous, there’s another enzyme, called catalase, which safely converts it into water and oxygen. Another thing catalase can do is use that hydrogen peroxide to break down toxic substances like ethanol and formaldehyde. That’s why you would expect liver cells to have more peroxisomes than most other cells in the body.
Peroxisomes also play an important role in two types of fatty acid oxidation: beta oxidation, where linear fatty acids called very long chain fatty acids, or VLCFAs for short, and medium chain fatty acids, or MCFAs for short, are chopped down into progressively smaller chains; and alpha oxidation, where branched chain fatty acids are broken down into linear ones, which can then undergo beta oxidation. For your exams, what’s important to know is that alpha oxidation takes place exclusively within peroxisomes, while beta oxidation can also occur in the mitochondria. It’s important to remember that peroxisomes are responsible for the beta oxidation of very long chain fatty acids, while mitochondria can only work with medium chain fatty acids. Now, the thing is that one of the byproducts of both alpha and beta oxidation is hydrogen peroxide, so catalase is used once again to convert it into water and oxygen.
Finally, peroxisomes are also involved in the breakdown of amino acids and production of cholesterol, bile salts, and plasmalogen, which is a phospholipid found particularly in the cell membrane of neurons.
Okay, now the first peroxisomal disorder is Zellweger syndrome. This is caused by a mutation in the PEX genes, which code for peroxins. For your exams, remember that Zellweger syndrome is autosomal recessive, meaning that an individual needs to inherit two copies of the mutated gene, one from each parent, to develop the condition. Normally, peroxins are proteins required for the formation of peroxisomes. Now, in Zellweger syndrome, peroxisomes can’t assemble, so the cells can’t break down VLCFAs, branched chain fatty acids, amino acids, and toxic substances like ethanol and formaldehyde. As a result, these end up building up in multiple organs and tissues, including facial tissues, the liver, and the nervous system. And that’s a high yield fact! At the same time, plasmalogens cannot be synthesized, which can further impair the function of the nervous system.
Signs and symptoms vary depending on the tissue affected. So, if that’s the facial tissues, there can be a flat face with epicanthal folds, broad nasal bridge, and large anterior fontanelle. And these are usually apparent soon after birth. For your exams, another extremely high yield finding is hepatomegaly, meaning that the liver can become enlarged and sometimes cirrhotic or replaced by fibrous tissue. This can affect the liver’s ability to conjugate bilirubin, so the increased unconjugated bilirubin builds up in the blood, which leads to jaundice, or yellowing of the skin and sclera.
If the nervous system is affected, symptoms may include muscle weakness, seizures, vision or hearing loss, along with hypotonia or reduced muscle tone, and hyporeflexia or diminished deep tendon reflexes. In a test question, these babies are usually described as “floppy” or looking like rag dolls, meaning that they feel limp when they are picked up, and can’t control their head and neck muscles, so their heads will tilt forward, backward or to the side, while their arms and legs will hang down. Over time, this can progress to severe breathing and feeding difficulties, which, if left untreated, can progress to death within the first few years of life.
Diagnosis of Zellweger syndrome starts with blood tests showing elevated VLCFAs levels, and is confirmed via genetic testing of the PEX genes. Unfortunately, no cure for the disease is currently available.
Next is Refsum disease, which is an autosomal recessive disorder caused by a mutation in the PHYH gene coding for phytanoyl-CoA hydroxylase. This enzyme is normally involved in the alpha oxidation of a branched chain fatty acid called phytanic acid, which turns it into pristanic acid. So without this enzyme, phytanic acid accumulates primarily in the nervous system, the retina, the skin, and the bones. Now, common neurological symptoms include ataxia or difficulty with coordination and movement, as well as peripheral neuropathy, which can manifest as burning, tingling, prickling, and pain in the hands and feet. Damage to the olfactory nerve can also result in anosmia or loss of smell, while damage to the acoustic nerve can cause impaired hearing and tinnitus. As for the eyes, what you need to know is that Refsum disease is associated with cataracts, which refers to the clouding or opacification of the lens, as well as retinitis pigmentosa. This is named after the pattern of spicule-shaped dark spots and blotches that are visible around the macula of the retina on a fundoscopic exam. An extremely high-yield fact is that the earliest symptoms of retinitis pigmentosa is night blindness and peripheral vision loss and, in late stages, goes on to affect central vision.
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