Lysosomal storage disorders: Pathology review

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Case study0:00–1:05

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.

Pathology1:05–1:49

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 disease1:49–4:52

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.
Diagnosis of Gaucher disease relies on measuring glucocerebrosidase enzyme activity in white blood cells, as well as genetic testing, to look for mutations in the GBA gene.
A high yield fact is that, on a tissue biopsy, Gaucher cells have a characteristic lipid-laden, or “fatty” appearance, similar to “crumpled tissue-paper.”Treatment depends on the severity of the condition.
Symptoms can be managed with supportive therapy. In addition, some individuals can get enzyme replacement therapy with a synthetic form of glucocerebrosidase, as well as substrate reduction therapy designed to block the production of glucocerebroside.
Another high yield sphingolipidosis is Tay-Sachs disease or TSD for short, which is an autosomal recessive disorder, caused by a mutation in the HEX-A gene.

Tay-Sachs disease4:52–6:32

This results in hexosaminidase A, or HEX-A deficiency, which normally breaks down a GM2 ganglioside. GM2 is found mainly in neurons, so when it builds up inside lysosomes, it results in progressive neurodegeneration.
For your exams, keep in mind that Tay-Sachs disease is also more common in those of Ashkenazi Jewish heritage. Symptoms typically begin between 2 and 6 months of age and include progressive loss of motor and cognitive skills, along with hypotonia or decreased muscle tone, hyperreflexia, or abnormally increased reflexes, seizures, hyperacusis, or increased sensitivity to normal sounds, as well as feeding problems and vision loss.
What’s extremely important to remember is that GM2 can also build up in the retinal cells around the central macular area, causing a “cherry red spot” in the macula of the eye that can be seen with fundoscopy during an ophthalmologic examination.
Diagnosis of TSD is done by determining the activity of HEX-A in serum, leukocytes, tears, or any other body tissue, as well as genetic testing to look for mutations in the HEX-A gene.
On histologic exam, neurons are distended with cytoplasmic vacuoles due to lysosomes filled with GM2, which give a characteristic onion skin appearance.
Treatment involves supportive care to manage symptoms. Moving on to Fabry disease, this is caused by a mutation in the GLA gene that codes for alpha galactosidase A.

Fabry disease6:32–8:58

For your exams, remember that this is an X-linked recessive disorder, which means that all carrier males develop the disease because they have only one X chromosome and thus one GLA gene available.
On the other hand, females have two X chromosomes, so even if they have a defective GLA gene on one chromosome, they still have another functional one.
Now, alpha galactosidase A normally breaks down a sphingolipid called ceramide trihexoside, otherwise known as globotriaosylceramide or GL3 for short.
Without alpha galactosidase A, GL3 builds up in the lysosomes of endothelial cells lining blood vessels, as well as cells of the peripheral nervous systems, kidney, and heart cells.
Symptoms start in childhood and include a classic triad of peripheral neuropathy, hypohidrosis, and angiokeratomas. Peripheral neuropathy typically manifests as burning, tingling, prickling, and pain in the hands and feet, and is frequently triggered by exercise, fatigue, stress, or illness.
Hypohidrosis means there’s a gradual decrease of sweating, which may progress to anhidrosis or an entire lack of sweating.
And angiokeratomas are small reddish-purple rashes that usually appear around the lower abdomen and “bathing trunk” region of the body.
In addition to this classic triad, individuals may present gastrointestinal symptoms like cramping, frequent bowel movements, constipation, or diarrhea.
A slit lamp eye exam might also reveal a whorl-like pattern of brown or gray corneal opacities, called cornea verticillata, which results from GL3 buildup in the cornea, but remember that it doesn’t typically affect vision.
Later on, individuals with Fabry disease can develop complications, such as kidney disease with progressive renal failure, cardiomyopathy with heart enlargement, and an increased risk of stroke.
Diagnosis of Fabry disease starts with blood tests showing low alpha galactosidase A levels, and is confirmed via genetic testing of the GLA gene.
Treatment options include enzyme replacement therapy with a synthetic alpha galactosidase A, or chaperone therapy with migalastat to help enhance residual enzyme activity.
Another sphingolipidoses is Krabbe disease, which originates from a mutation in the GALC gene, resulting in a deficiency of the enzyme galactocerebrosidase, also known as galactosylceramidase.

Krabbe disease8:58–10:41

Normally, galactocerebrosidase breaks down galactosylceramides, such as galactocerebroside and galactosylsphingosine, also known as psychosine.
As a result, these molecules build up in the glial cells in the central and peripheral nervous system, resulting in demyelination and impaired nerve impulse transmission.
The most important thing to remember for your exams is that demyelination occurs both in the central as well as the peripheral nervous system.
Galactosylceramides can also accumulate inside macrophages, which become these gigantic, multinucleated macrophages called globoid cells that move in to clear out the damaged glial cells.
And these globoid cells are a classic finding in Krabbe disease. Symptoms typically begin before 6 months of age.
Common symptoms of central nervous system demyelination include muscle stiffness, seizures, optic atrophy with visual disturbances, and developmental delay with difficulty in speaking, walking, or swallowing; while symptoms of peripheral nervous system demyelination may include loss of sensation in the extremities, along with hyporeflexia or diminished deep tendon reflexes.
Unfortunately, most infants die by the age of two. Diagnosis is based on measuring the activity of galactocerebroside in leukocytes, along with genetic testing to look for mutations in the GALC gene.
There’s no cure for Krabbe disease, so treatment is mainly supportive.Next is metachromatic leukodystrophy or MLD, which is an autosomal recessive disorder caused by a mutation in the ARSA gene, which codes for arylsulfatase A.
This enzyme normally breaks down cerebroside sulfate, so without it, sulfatide accumulates in neurons and myelin-producing cells of the central and peripheral nervous system, resulting in demyelination.

Metachromatic leukodystrophy (MLD)10:41–12:18

What’s important to remember here is that symptoms vary by the age of onset. So, there’s a late infantile form, where symptoms develop within the first three years of life, and include severe muscle weakness, difficulty walking, irritability, and developmental delay, meaning a delay in reaching certain developmental milestones.
In the juvenile form, symptoms usually develop between the age of 4 and adolescence, which is around 12 and 14 years of age, and include behavioral changes and decreased ability in school.
In the adult form, symptoms usually develop after the age of 16 and include memory loss and psychosis. As the symptoms progress, all forms of MLD can result in blindness, paralysis, unresponsiveness, dementia, and psychosis.
Diagnosis is based on measuring arylsulfatase A enzyme activity in white blood cells, measuring the sulfatide levels in the urine, as well as genetic testing to confirm the ARSA gene mutation.
A brain MRI might also show areas of hyperintensity in the white matter regions, which indicate the loss of myelin. And again, there’s no cure, so treatment involves supportive care to manage symptoms.
Okay, the last sphingolipidoses is Niemann-Pick disease, which is an autosomal recessive disorder, more common in those of Ashkenazi Jewish descent.
There are three types of Niemann-Pick disease. So, in types A and B, there’s a mutation in the SMPD1 gene that causes a defect in the production of sphingomyelinase.
This leads to an inability to break down sphingomyelin, which ends up accumulating in the lysosomes. In contrast, Niemann-Pick disease type C, or NPC, is caused by mutations in either the NPC1 or NPC2 genes.

Niemann-Pick disease12:18–15:00

Normally, cholesterol is processed by lysosomes, then carried up to the lysosomal membrane by the NPC2 protein, and finally transported out of the lysosome and into the cytoplasm with the help of NPC1 protein, so that it can be incorporated into the cell membrane.
So with NPC1 or NPC2 mutations, intracellular cholesterol transport is impaired, and instead, cholesterol ends up accumulating inside lysosomes.
Now, the accumulated sphingomyelin and cholesterol can affect many different kinds of cells, causing a variety of symptoms.
The most common ones are progressive neurologic symptoms, but remember that these typically only appear in types A and C and can include a delay in reaching developmental motor milestones, like lifting the head or crawling, as well as a developmental regression, meaning that a child may lose certain developmental skills that they had previously acquired.
In all three types, ophthalmologic examination may show a “cherry red spot” in the macula of the eye, resulting from the buildup of material in the retinal cells around the central macular area.
Another high-yield symptom is hepatosplenomegaly, which is often accompanied by jaundice and thrombocytopenia, which causes easy bruising and bleeding issues.
In a test question, you should compare Niemann-Pick disease to Tay-Sachs, which also has that cherry red macular spot and is more common in Ashkenazi Jews, but a key difference is that Tay-Sachs doesn’t cause hepatosplenomegaly.
Diagnosis of Niemann-Pick disease includes measuring sphingomyelinase activity in white blood cells for types A and B, while for type C, a skin sample can be taken to look for the accumulated cholesterol in fibroblasts.
If a biopsy is performed, what’s important to remember is that macrophages develop a characteristic lipid-laden appearance, due to the buildup of sphingomyelin or cholesterol, and are called “foam cells”.
Finally, diagnosis can be confirmed via genetic testing to evaluate the SMPD1, NPC1, and NPC2 genes. Treatment mainly involves supportive therapy.Okay, let’s switch gears and discuss the two most classic mucopolysaccharidoses, Hurler and Hunter syndrome.
Hurler syndrome is an autosomal recessive disorder, caused by a mutation in the IDUA gene, which results in alpha-L-iduronidase deficiency.
In contrast, Hunter syndrome is an X-linked recessive disorder, caused by a mutation in the IDS gene, which results in a deficiency in iduronate sulfatase.
Now, since the polysaccharides heparan sulfate and dermatan sulfate need both alpha-L-iduronidase and iduronate sulfatase to be broken down, both syndromes cause them to build up in various tissues.

Hurler & Hunter syndrome15:00–17:17

Common symptoms include distinctive facial features, like a prominent forehead, a flat nose bridge, and enlarged lips, tongue, and gums, which is described as gargoylism.
Skeletal malformations like short stature, kyphosis, hip dysplasia, and joint disease are also common, as well as other complications like developmental delay, hernias, respiratory problems, cardiomyopathy, and thickened heart valves.
However, all these features are typically milder in Hunter syndrome. What’s even more important to set these two apart though is that Hurler syndrome is also classically associated with corneal clouding, where the cornea turns opaque, leading to visual problems and even blindness.
On the other hand, Hunter syndrome doesn’t cause corneal clouding but can affect the central nervous system, causing aggressive behavior, as well as hyperactivity, symptoms of ADHD, autism, or OCD.
So remember that “ A good hunter needs to see and be aggressive.” Diagnosis of Hurler and Hunter syndromes starts by measuring glycosaminoglycans in urine, or measuring enzyme levels of alpha-L-iduronidase and iduronate sulfatase in blood.
In many countries, these tests are performed as a uniform newborn screening. Diagnosis can be confirmed through genetic testing, looking for mutations in the IDUA and IDS genes.
Treatment can involve enzyme replacement therapy or bone marrow transplantation, depending on the severity of the symptoms.Finally, let’s discuss the highest yield mucolipidosis, which is I-cell disease, or inclusion cell disease, which is an autosomal recessive disorder caused by a deficiency in N-acetylglucosamine-1-phosphotransferase.
This enzyme is responsible for labeling glycoproteins in the Golgi apparatus by adding a phosphate group to their mannose residues.
Without this mannose-6-phosphate signal, those glycoproteins can’t get delivered into the lysosomes, and instead get secreted to the extracellular space.
Now, the problem is that these glycoproteins actually serve as lysosomal enzymes, so without them, lysosomes can’t break down a variety of substances, including sphingolipids and mucopolysaccharides, which end up accumulating inside lysosomes.

I-cell disease17:17–19:20

And that’s why this disorder shares characteristics of both sphingolipidoses and mucopolysaccharidoses! Symptoms include a flat face with epicanthal folds, flat nasal bridge, prominent mouth, long philtrum and gingival hypertrophy, which are usually apparent soon after birth.
At the same time, there’s often failure to thrive, hepatosplenomegaly, as well as abnormal bone growth with claw hand deformity, kyphoscoliosis, and a restricted movement of joints.
In addition, individuals typically have cardiomegaly with congestive heart failure and recurrent respiratory infections.
And that’s why they frequently die during childhood. Now, an ophthalmological examination reveals a cloudy cornea.
And remember that makes it very similar to Hurler syndrome! But what will help you set these two apart is that I-cell disease has no glycosaminoglycans in the urine.
Now, diagnosis is mainly based on the elevated blood levels of lysosomal enzymes. If a biopsy is done, you’ll find the accumulated substances forming characteristic inclusion bodies within white blood cells, which is why these cells are also known as inclusion cells or I-cells.
Treatment is once again only symptomatic. Alright, as a quick recap, sphingolipidoses include Gaucher disease, which is caused by glucocerebrosidase deficiency leading to the accumulation of glucocerebroside in macrophages, which are called Gaucher cells.
Symptoms include anemia, leukopenia and thrombocytopenia, painful bone crises, avascular necrosis of the femur, osteoporosis, and hepatosplenomegaly.
Tay-Sachs disease is caused by hexosaminidase A deficiency, leading to the accumulation of GM2 ganglioside, and manifests early with neurodegeneration, hypotonia, seizures, hyperacusis, a cherry red macular spot, and neurons with onion skin appearance on histology.
Fabry disease is caused by alpha galactosidase A deficiency, leading to the accumulation of ceramide trihexoside. This can manifest early on with peripheral neuropathy, hypohidrosis, and angiokeratomas, while later on, complications can include kidney disease, cardiomyopathy, and stroke.
Krabbe disease and metachromatic leukodystrophy both result in central and peripheral nervous system demyelination. Krabbe disease is caused by galactocerebrosidase deficiency that leads to galactosylceramides buildup in glial cells and macrophages, which become multinucleated globoid cells.

Review19:20–23:03

Symptoms include developmental delay and optic atrophy, and death by the age of 2. Metachromatic leukodystrophy is caused by arylsulfatase A deficiency leading to the buildup of cerebroside sulfate, and can result in blindness, paralysis, unresponsiveness, dementia, and psychosis.
Niemann-Pick disease types A and B are caused by a deficiency of sphingomyelinase, leading to the accumulation of sphingomyelin, while type C is caused by a deficiency in NPC1 or NPC2 proteins, which impairs intracellular cholesterol transport.
Types A and C have progressive neurologic symptoms, while all types have hepatosplenomegaly, a cherry red macular spot, and lipid laden macrophages called foam cells.
Now, mucopolysaccharidoses include Hurler syndrome, caused by alpha-L-iduronidase deficiency, and Hunter syndrome, caused by iduronate sulfatase deficiency.
Both result in the accumulation of heparan sulfate and dermatan sulfate, and can present with distinctive facial features, developmental delay, skeletal malformations, respiratory and cardiac problems.
Hurler syndrome is typically more severe and has corneal clouding, while Hunter syndrome is milder, has no corneal clouding, and is associated with aggressive behavior.
Finally, mucolipidoses include I-cell disease, which is caused by a deficiency in N-acetylglucosamine-1-phosphotransferase, ultimately resulting in the accumulation of both sphingolipids and mucopolysaccharides.
Ophthalmological examination reveals a cloudy cornea, while a biopsy shows inclusion bodies within white blood cells, which are called inclusion cells or I-cells.
Regarding inheritance, remember that all these are autosomal recessive, except for Fabry disease and Hunter syndrome which are X-linked recessive.
A final thing to note is that Gaucher, Tay-Sachs and Niemann-Pick are all more common in people of Ashkenazi Jewish descent.Okay, back to our cases.
Abigail is a 5-month-old girl with recurring episodes of seizures, hyperacusis, hypotonia and hyperreflexia. These findings, along with the cherry red spot on her maculae, her Ashkenazi Jewish descent, make us suspect Tay-Sachs disease; while the absence of hepatosplenomegaly allows us to rule out Niemann-Pick disease.
Diagnosis of Tay-Sachs disease was confirmed by finding a decreased activity of HEX-A in leukocytes along with genetic testing, revealing a mutation in the HEX-A gene.
On the other hand, Harry, the 2-year-old boy, came in with developmental regression and distinctive facial features, which are characteristic for mucopolysaccharidoses.
The hyperactivity and aggressive behavior, combined with the absence of corneal clouding, helps rule out Hurler syndrome, and makes Hunter syndrome more likely.
Urinalysis was ordered, revealing increased levels of glycosaminoglycans. Diagnosis was confirmed with genetic testing, showing a defect in the IDS gene, so Harry was started on enzyme replacement therapy with iduronate sulfatase.
Ashkenazi Jewish descent. Okay, finally back to our cases.

Summary23:03–24:12

Abigail is a 5 month old girl with recurrent episodes of seizures hyperacusis hypotonia and hyperreflexia along with the cherry red spot on her Maca life and her Ashkenazi Jewish descent make us suspect a sex disease while the absence of hepatosplenomegaly allows us to rule out niemann-pick disease.
Diagnosis of Tay-Sachs disease. Was confirmed by finding a decreased activity of hex, a and leukocytes.
Along with genetic testing revealing a mutation in the hex aging on the other hand, Harry the two year old boy came in with developmental regression and distinctive facial features, which are characteristic from mucopolysaccharidosis, the hyperactivity and aggressive behavior combined with the absence of corneal clouding helps rule out hurler syndrome and makes Hunter syndrome more.
Likely your analysis was ordered revealing increase levels of glycosaminoglycans. Diagnosis was confirmed with genetic testing showing a defect in the IDS Gene.
So Harry was started on enzyme replacement therapy with I