Lysosomal storage diseases

Summary

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.

Overview

Lysosomal storage diseases

Disease Inheritance Pathophysiology Main findings
Sphingolipidoses

Gaucher disease

Krabbe disease

  • Galactocerebrosidase↑ galactocerebroside

Tay-Sachs disease

  • Progressive neurodegeneration
  • Cherry-red spot on macula
  • “Onion-skin” lysosomes

Fabry disease

  • ↓ α-Galactosidase Aceramide trihexoside
Metachromatic leukodystrophy
  • Arylsulfatase A↑ cerebroside sulfate
Niemann-Pick disease
  • sphingomyelinasesphingomyelin
  • Progressive neurodegeneration
  • Cherry-red spot on macula
  • Hepatosplenomegaly
  • Foam cells
Mucopolysaccharidoses
Hurler syndrome
  • α-L-iduronidase↑ heparan sulfate and dermatan sulfate
  • Developmental delay
  • Facial dysmorphism
  • Airway obstruction
  • Hepatosplenomegaly
  • Corneal clouding
Hunter syndrome
  • Iduronate-2-sulfatase↑ heparan sulfate and dermatan sulfate
  • Aggressive behavior
Mucolipidoses
I-cell disease
  • N-acetylglucosaminyl-1-phosphotransferase↑ abnormal lysosomal substances
  • Coarse facial features
  • Corneal clouding
  • Gingival hyperplasia
  • Claw hand deformity
  • Kyphoscoliosis
Adrenoleukodystrophy
  • X-linked

Sphingolipidoses

Sphingolipidoses are a group of lysosomal storage diseases caused by genetic deficiencies of lysosomal enzymes which lead to alteration of sphingolipid catabolism. There are three main classes, which include: [1]

  • Sphingomyelin: derived from a ceramide with phosphorylcholine as a hydrophilic group
  • Cerebrosides: derived from a ceramide with a single sugar residue (galactose or glucose)
  • Gangliosides: derived from a ceramide with an oligosaccharide chain and one or more sialic acids linked to the chain

Gaucher disease

Girl Has A Pen in a crumpled tissue paper (= Glucocerebrosidase, Hepatosplenomegaly, Avascular necrosis of the femur, Pancytopenia, in a macrophage).

Krabbe disease

  • Etiology: autosomal recessive inherited disease [3]
  • 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 [4]
  • 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)
  • Diagnosis: lysosomes with “onion-skin” appearance
  • Treatment: supportive

Fabry disease

  • Etiology: x-linked recessive inherited disease [5]
  • Epidemiology
    • Typical onset is during childhood but may also appear in 60- to 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

Think of Fabry as a FABRYC: Foam cells, α-galactosidase A deficiency/Angiokeratomas, Burning pain in hands and feet, Renal failure, YX genotype (male), Cardio-Cerebrovascular disease/Ceramide trihexoside accumulation.

Metachromatic leukodystrophy

  • Etiology: autosomal recessive inherited disease [6]
  • 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 [7][8]
  • 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 PHINGer (sphingomyelinase).

Mucopolysaccharidoses

Mucopolysaccharidoses are a group of metabolic disorders that result in the impaired breakdown of glycosaminoglycans (previously known as mucopolysaccharides), 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. [9][10]

Hurler syndrome (mucopolysaccharidosis type I) Hunter syndrome (mucopolysaccharidosis type II)
Inheritance
Pathophysiology
  • Deficiency of α-L-iduronidase
  • Deficiency of Iduronate-2-sulfatase
  • Accumulation of glycosaminoglycans, i.e., heparan sulfate (HS) and dermatan sulfate (DS)
Clinical features
  • Occur in both conditions (typically milder in Hunter syndrome):
    • Developmental delay
    • Facial dysmorphism: frontal bossing, elongated skull , flattened nasal bridge, broad nasal tip, thickened gingiva, anteverted nostrils, constant nasal discharge, spaced and protruded eyes.
    • Airway obstruction
Diagnosis
  • Increased urinary levels of dermatan sulfate (DS) and heparan sulfate (HS)
  • Enzyme assay to confirm specific enzyme deficiency (definitive test)
Treatment

Hunters have great eyesight (no corneal clouding) and they aggressively (aggressive behavior) and actively (hyperactivity) try to catch the target X (X-linked recessive).

Mucolipidosis

Mucolipids are complex lipid polymers that contain sialic acid or a related substance. Mucolipidoses were originally phenotypically confused with the mucopolysaccharidoses. However, the storage material in tissues includes not only mucopolysaccharides but also lipids. Additionally, glycosaminoglycans are not present in the urine of patients with mucolipidosis, while patients affected by mucopolysaccharidoses may have mucopolysacchariduria.

The four main types of mucolipidosis include:

I-cell disease

  • 1. Kaplan. USMLE Step 1 Lecture Notes 2018: Biochemistry and Medical Genetics. New York, NY: Kaplan; 2017.
  • 2. Pastores GM, Hughes DA, Adam MP, et al. Gaucher Disease. url: https://www.ncbi.nlm.nih.gov/pubmed/20301446 Accessed January 24, 2018.
  • 3. Genetics Home Reference. Krabbe disease. https://ghr.nlm.nih.gov/condition/krabbe-disease. Updated January 23, 2018. Accessed January 24, 2018.
  • 4. Kaback MM, Desnick RJ, Adam MP, et al. Hexosaminidase A Deficiency. url: https://www.ncbi.nlm.nih.gov/pubmed/20301397 Accessed January 24, 2018.
  • 5. Mehta A, Hughes DA, Adam MP, et al. Fabry Disease. url: https://www.ncbi.nlm.nih.gov/pubmed/20301469 Accessed January 24, 2018.
  • 6. Gomez-Ospina N, Adam MP, Ardinger HH, et al. Arylsulfatase A Deficiency. url: https://www.ncbi.nlm.nih.gov/pubmed/20301309 Accessed January 24, 2018.
  • 7. Wasserstein MP, Schuchman EH, Adam MP, et al. Acid Sphingomyelinase Deficiency. url: https://www.ncbi.nlm.nih.gov/pubmed/20301544 Accessed January 24, 2018.
  • 8. Patterson M, Adam MP, Ardinger HH, et al. Niemann-Pick Disease Type C. url: https://www.ncbi.nlm.nih.gov/pubmed/20301473 Accessed January 24, 2018.
  • 9. Kliegman R, Stanton B, St. Geme J, Schor N. Nelson Textbook of Pediatrics. Elsevier; 2015.
  • 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. https://emedicine.medscape.com/article/945460-overview. Updated August 8, 2017. Accessed June 28, 2018.
  • Le T, Bhushan V, Sochat M, Chavda Y. First Aid for the USMLE Step 1 2017. McGraw-Hill Education; 2017.
  • Kaplan Medical Staff. USMLE Step 1 Lecture Notes 2017: 7-Book Set. Kaplan Publishing; 2017.
last updated 09/23/2019
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