Lysosomal storage diseases


Lysosomal storage diseases are a group of inherited metabolic disorders caused by a deficiency of specific enzymes. This causes an accumulation of abnormal substances that are usually degraded within lysosomes, resulting in cell damage and death. These substances include specific lipids and glycoproteins such as sphingolipids, glycosaminoglycans, and gangliosides, among others. Lysosomal storage diseases have a progressive course and, depending on the exact disease and subtype, can also be fatal in early childhood.


Gaucher disease

Krabbe disease

  • Etiology: autosomal recessive inherited disease
  • Pathophysiology: : lack of or reduced activity of the lysosomal enzyme galactocerebrosidase (GALC) → accumulation of psychosine, galactocerebroside (toxic myelin degradation products) + formation of globoid cellsdemyelination + destruction of oligodendrocytes up to decerebration
  • Clinical features
    • Major mental and motor deficits
      • Developmental delay
      • Peripheral neuropathy
      • Limb stiffness
      • Opisthotonic posture
    • Loss of vision (atrophy of the optical nerve)
  • Diagnosis
    • Globoid cell: A large multinucleated cell of mesodermal origin that is found clustered in the brain tissue
  • Treatment
    • Before symptom onset, stem cell transplantation may improve outcome.
    • Only supportive treatment is possible after symptom onset.

Tay-Sachs disease

  • Etiology: autosomal recessive inherited disease
  • Epidemiology: : more common in the Ashkenazi Jewish population
  • Pathophysiology: hexosaminidase A deficiency → intracellular accumulation of GM2 ganglioside → progressive neurodegeneration
  • Clinical features
    • Developmental delay
    • Rapid reduction of physical and mental ability beginning at 6 months of age; patients typically die around the age of 4
    • “Cherry-red” spot on macula
    • Hypotonia
    • Seizures
    • Hearing impairment
    • Note: no hepatomegaly (compared to Niemann-Pick disease)
  • Diagnostics: lysosomes with “onion skin” appearance
  • Treatment: supportive

Fabry disease

  • Etiology: x-linked recessive inherited disease
  • Epidemiology
    • Typical onset is during childhood but may also appear in 60–80-year-old adults
    • Mainly affects boys
  • Pathophysiology: α-galactosidase A deficiency → accumulation of ceramide trihexoside in the endothelium of vessels, in the epithelium of many organs, and in smooth muscle cells → disorder affecting many organ systems
  • Clinical features
    • Early symptoms
      • Periodically occurring dysesthesia in the hands and feet, which presents as burning pain (Fabry crises)
      • Anhidrosis or hypohidrosis
      • Nonspecific gastrointestinal disturbances
      • Angiokeratomas
      • Corneal clouding
      • Cataract
    • Late symptoms
  • Treatment: enzyme replacement therapy with α-galactosidase A

Metachromatic leukodystrophy

  • Etiology: autosomal recessive inherited disease
  • Pathophysiology: : arylsulfatase A deficiency → cerebroside sulfate accumulation in neural and non-neural tissue → central and peripheral nervous system demyelination
  • Clinical features:
  • Treatment: supportive

Niemann-Pick disease

  • Etiology: autosomal recessive inherited disease
  • Epidemiology: : more common in the Ashkenazi Jewish population
  • Pathophysiology
    • Type A and B: genetic deficiency of sphingomyelinase → accumulation of sphingomyelin
    • Type C: defective NPC proteins (mainly NPC1)
  • Clinical features
    • Progressive neurodegeneration (type A and C)
    • “Cherry-red” spot in the macula
    • Hepatosplenomegaly
  • Diagnostics
  • Treatment: mainly conservative

No MAN PICKs (Niemann-Pick) his nose with his SPHINGer (sphingomyelinase).



Mucopolysaccharidoses are a group of metabolic disorders that result in the impaired breakdown of glycosaminoglycans due to mutations in lysosomal enzymes. At least nine different types of mucopolysaccharidosis are recognized. The two classic conditions are Hurler syndrome and Hunter syndrome.

Hurler syndrome (mucopolysaccharidosis type I) Hunter syndrome (mucopolysaccharidosis type II)
  • Deficiency of α-L-iduronidase
  • Deficiency of Iduronate-2-sulfatase
  • Accumulation of heparan sulfate and dermatan sulfate
Clinical features
  • Increased urinary levels of dermatan sulfate (DS) and heparan sulfate (HS)
  • Enzyme assay to confirm specific enzyme deficiency (definitive test)


I-cell disease

  • Definition: An autosomal recessive inherited disease in which impaired N-acetylglucosaminyl-1-phosphotransferase activity leads to defective targeting of glycoproteins in the Golgi apparatus.
  • Pathophysiology
    • Defective N-acetylglucosaminyl-1-phosphotransferase → impaired phosphorylation of mannose residues of glycoproteins in the Golgi apparatus that should be transported to lysosomes (glycoproteins do not have mannose-6-phosphate) → extracellular secretion of these glycoproteins instead of delivery to lysosomes → inability to degrade lysosomal content → accumulation of abnormal lysosomal substances
  • Clinical features
    • Coarse facial features
    • Corneal clouding → progresses to blindness
    • Gingival hyperplasia
    • Claw hand deformity
    • Kyphoscoliosis
    • Abnormal bone growth and restricted joint movements
    • Failure to thrive (growth failure by age 2 years)
    • Developmental delay
  • Diagnosis
  • Treatment
    • No cure available
    • Only symptomatic treatment
      • Nutritional support
      • Physical therapy for musculoskeletal problems
  • Complications
  • Prognosis: most patients die in childhood from cardiopulmonary complications


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  • 2. Kaback MM, Desnick RJ, Adam MP, et al. Hexosaminidase A Deficiency. url: Accessed January 24, 2018.
  • 3. Pastores GM, Hughes DA, Adam MP, et al. Gaucher Disease. url: Accessed January 24, 2018.
  • 4. Mehta A, Hughes DA, Adam MP, et al. Fabry Disease. url: Accessed January 24, 2018.
  • 5. Wasserstein MP, Schuchman EH, Adam MP, et al. Acid Sphingomyelinase Deficiency. url: Accessed January 24, 2018.
  • 6. Patterson M, Adam MP, Ardinger HH, et al. Niemann-Pick Disease Type C. url: Accessed January 24, 2018.
  • 7. Gomez-Ospina N, Adam MP, Ardinger HH, et al. Arylsulfatase A Deficiency. url: Accessed January 24, 2018.
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  • 10. White KK. Orthopaedic aspects of mucopolysaccharidoses. Rheumatology (Oxford). 2011; 50(Suppl 5): pp. v26–v33. doi: 10.1093/rheumatology/ker393.
  • 11. Le T, Bhushan V,‎ Sochat M, Chavda Y, Zureick A. First Aid for the USMLE Step 1 2018. New York, NY: McGraw-Hill Medical; 2017.
  • 12. Roth KS. Inclusion-Cell (I-Cell) Disease (Mucolipidosis Type II). In: Rohena LO. Inclusion-Cell (I-Cell) Disease (Mucolipidosis Type II). New York, NY: WebMD. Updated August 8, 2017. Accessed June 28, 2018.
  • Genetics Home Reference. Krabbe disease. Updated January 23, 2018. Accessed January 24, 2018.
  • Kaplan. USMLE Step 1 Lecture Notes 2018: Biochemistry and Medical Genetics. New York, NY: Kaplan; 2017.
last updated 04/16/2019
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