Lysosomal storage disorders: Pathology review

At the pediatric clinic, Abigail, a 5-month-old girl of Ashkenazi Jewish descent, is brought in by her parents because of recurring episodes of seizures, which started about a month ago. Her parents have also noticed that Abigail startles easily at loud noises. Physical examination reveals a low muscle tone with exaggerated reflexes. Upon palpation of the abdomen, the liver and spleen are of normal size. On ophthalmologic examination, a cherry red spot is found on the maculae of both eyes. Next in the clinic, there’s 2-year-old Harry. According to his mother, he recently stopped walking and speaking in sentences, and instead started crawling and babbling again. On further questioning, his mother mentions that Harry seems to have a hard time sitting still and often shows aggressive behavior. Physical examination reveals a prominent forehead, a nose with a flattened bridge and flared nostrils, an enlarged tongue, and thickened lips. On ophthalmologic examination, no corneal clouding is observed.

Based on the initial presentation, both Abigail and Harry seem to have some form of lysosomal storage disorder. These are a group of inherited metabolic disorders that result in the inability to break down certain substances in lysosomes, causing them to build up, and ultimately leading to cell damage and death. Lysosomal storage disorders include sphingolipidoses, caused by the accumulation of a certain type of lipids called sphingolipids. Mucopolysaccharidoses are caused by the accumulation of a type of complex sugars called mucopolysaccharides or glycosaminoglycans. Finally, there’s also mucolipidoses, which are caused by the accumulation of both sphingolipids and mucopolysaccharides.

Okay, let’s start with sphingolipidoses! Gaucher disease is the most common lysosomal storage disorder. It is caused by a mutation in the GBA gene, which codes for the enzyme glucocerebrosidase, also known as beta-glucosidase. For your exams, remember that Gaucher disease is autosomal recessive, meaning that an individual needs to inherit two copies of the mutated gene, one from each parent, to develop the condition. Another thing to note is that Gaucher disease is more common in those of Ashkenazi Jewish heritage.

Now, glucocerebroside is a glycolipid that's included in the membrane of many different cells. When these cells become old or damaged, they are often engulfed by macrophages, and digested in their lysosomes. That’s where glucocerebrosidase breaks down glucocerebroside. In Gaucher disease, glucocerebroside can’t be broken down, so it accumulates inside the lysosomes of macrophages. These macrophages are called Gaucher cells and can build up in multiple organs and tissues, including the bone marrow, liver, and spleen. And that’s a high yield fact! Signs and symptoms vary depending on the tissue affected. So, if that's the bone marrow, there can be anemia with fatigue, and leukopenia with increased susceptibility to infections. Bone infarctions can also be caused by reduced blood flow to part of the bone, and can manifest as a painful “bone crisis” or result in physical deformity and avascular necrosis, or death of bone tissue, mostly involving the femur. These individuals may also be more susceptible to fractures due to osteoporosis. For your exams, another extremely high yield finding is hepatosplenomegaly, meaning that both the liver and spleen can become enlarged. And when platelets are sequestered, or trapped, within the enlarged spleen, this can cause thrombocytopenia or low platelet count, leading to bleeding and easy bruising. If glucocerebroside builds up in the brain, neurological symptoms can also appear, including loss of motor skills, hypotonia or decreased muscle tone, muscle spasms, seizures, and dysphagia or trouble swallowing. 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.