Easy Way to Remember Lysosomal Storage Diseases

Lysosomal storage diseases

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April 27, 2022

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

Sphingolipidoses

Gaucher disease

• Etiology: autosomal recessive inherited disease ^[1]
• Epidemiology
• Pathophysiology: deficiency of β-glucocerebrosidase → accumulation of glucocerebroside (sphingolipid found in cell membranes that can accumulate in the lysosome of macrophages) in the brain, liver, spleen, and bone marrow
• Clinical features
  • Vary according to the exact subtype of Gaucher disease
    • Type I: non-neuronopathic Gaucher disease
    • Type II: acute neuronopathic Gaucher disease
    • Type III: chronic neuronopathic Gaucher disease
  • All types
    • Hepatosplenomegaly
    • Bone: bone crises , osteoporosis , avascular necrosis of the femur
    • Blood abnormalities: anemia , thrombocytopenia, pancytopenia
    • Pulmonary manifestations
    • Growth delays
  • Type II
    • Congenital ichthyosis (collodion baby), acute neurodegeneration
    • Death within the first years of life ^[3]
  • Type III
    • Gradual onset of symptoms
    • Neurodegeneration
• Diagnostics
  • Reduced glucocerebrosidase activity in leukocytes or fibroblasts
  • Accumulation of glucocerebroside in leukocytes or fibroblasts
  • Gaucher cell : lipid-rich macrophages with an enlarged cytoplasm with inclusions that resemble crumpled tissue paper on microscopy
• Treatment: recombinant glucocerebrosidase

"The Girl HaS Painted A Bone Meticulously on a Crumpled Tissue Paper:" Glucocerebrosidase, H epato S plenomegaly, Pancytopenia, Avascular necrosis of the femur, Bone crises, Macrophage inclusions that resemble crumpled tissue paper.

Krabbe disease

• Etiology: autosomal recessive inherited disease ^[4]
• Pathophysiology: lack of or reduced activity of the lysosomal enzyme galactocerebrosidase ( GALC; also called galactosylceramidase ) → accumulation of galactocerebroside and psychosine (toxic myelin degradation products) and formation of globoid cells → demyelination and 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)
• Diagnostics: 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 ^[5]
• Epidemiology : : more common in the Ashkenazi Jewish population ^[6]
• Pathophysiology: hexosaminidase A deficiency → intracellular accumulation of GM₂ ganglioside → progressive neurodegeneration
• Clinical features: Rapid reduction of physical and mental abilities begins around the age of 3–6 months ^[5]
  • Developmental delay
  • Macula showing a " cherry-red " spot
  • Hypotonia
  • Seizures, hyperreflexia
  • Hyperacusis
  • Note: no hepatomegaly (unlike in Niemann-Pick disease)
  • Affected individuals typically die around the age of 2–3 years ^[5]
• Diagnostics: lysosomes with onion-skin appearance
• Treatment: supportive

"After they Hexed Tay's Sax, his playing became deficient."

Fabry disease

• Etiology: X-linked recessive inherited disease ^[7]
• Epidemiology
• Pathophysiology: α-Galactosidase A deficiency → accumulation of ceramide trihexoside (also known as globotriaosylceramide; a glycolipid found in multiple body tissues) 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 manifest as a typical triad, consisting of
    • Periodically occurring dysesthesia ; in the hands and feet caused by small fiber neuropathy , which manifests as burning pain (Fabry crises)
    • Anhidrosis or hypohidrosis
    • Angiokeratomas
  • Other early symptoms include:
  • Late symptoms
    • Cardiomyopathy
    • Cerebrovascular lesions (TIA and stroke)
    • Fabry nephropathy , causing progressive renal failure
• Treatment: enzyme replacement therapy with α-galactosidase A

FABRYC: Foamy urine (Fabry nephropathy), α-galactosidase A deficiency/ A ngiokeratomas, Burning pain in hands and feet, Really sweaty/dry, YX genotype (male), Cardio-Cerebrovascular disease/Ceramide trihexoside accumulation.

Metachromatic leukodystrophy

• Etiology: autosomal recessive inherited disease ^[8]
• Pathophysiology: arylsulfatase A deficiency → cerebroside sulfate accumulation in neural and non-neural tissue → progressive demyelination of the central and peripheral nervous system
• Clinical features
  • Infantile onset
    • Motor regression and developmental delay
    • Impaired memory
    • Ataxia
    • Hypotonia and hyporeflexia
    • Optic nerve atrophy → loss of vision
    • Flaccid paralysis followed by spastic paralysis
  • Childhood and juvenile onset
    • Ataxia
    • Neurocognitive and behavioral changes (e.g., worsening school performance)
    • Peripheral neuropathy
• Treatment: supportive

Niemann-Pick disease

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 have been identified. The two most common conditions are Hurler syndrome and Hunter syndrome. ^{[13] [14]}

Overview of the most common mucopolysaccharidoses
	Hurler syndrome (mucopolysaccharidosis type I)	Hunter syndrome ( mucopolysaccharidosis type II )
Inheritance	Autosomal recessive	X-linked recessive
Pathophysiology	Deficiency of α-L-iduronidase (enzyme responsible for the hydrolysis of glycosaminoglycans)	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 Hepatosplenomegaly
	Corneal clouding Failure to thrive Dysostosis multiplex Inguinal hernia	Aggressive behavior Hyperactivity No corneal clouding Pearly papules Carpal tunnel syndrome
Diagnostics	Increased urinary levels of dermatan sulfate (DS) and heparan sulfate (HS) Enzyme assay to confirm specific enzyme deficiency (definitive test)
Treatment	Symptomatic and palliative treatment Enzyme replacement therapy Bone marrow transplantation

"Hunters with good eyesight will catch the aggressive chupacabra active in TeXas:" Hunter syndrome (no corneal clouding, aggressive behavior, carpal tunnel syndrome, hyper activity , and X -linked recessive inheritance).

Mucolipidosis

I-cell disease

References

1. Krabbe disease. https://ghr.nlm.nih.gov/condition/krabbe-disease. Updated: January 23, 2018. Accessed: January 24, 2018.
2. Hexosaminidase A Deficiency.
3. Gross SJ, Pletcher BA, Monaghan KG, Professional Practice and Guidelines Committee.. Carrier screening in individuals of Ashkenazi Jewish descent.. Genet Med. 2008; 10 (1): p.54-6. doi: 10.1097/GIM.0b013e31815f247c . | Open in Read by QxMD
4. Fabry Disease.
5. Arylsulfatase A Deficiency.
6. Acid Sphingomyelinase Deficiency.
7. Niemann-Pick Disease Type C.
8. Levran O, Desnick RJ, Schuchman EH. Niemann-Pick disease: a frequent missense mutation in the acid sphingomyelinase gene of Ashkenazi Jewish type A and B patients.. Proc Natl Acad Sci U S A. 1991; 88 (9): p.3748-52. doi: 10.1073/pnas.88.9.3748 . | Open in Read by QxMD
9. Schuchman EH, Desnick RJ. Types A and B Niemann-Pick disease.. Mol Genet Metab. 2016; 120 (1-2): p.27-33. doi: 10.1016/j.ymgme.2016.12.008 . | Open in Read by QxMD
10. Matalon R, Matalon KM. The Mucolipidoses. Elsevier ; 2015 : p. 365-368
11. Kliegman R, Stanton B, St. Geme J, Schor N. Nelson Textbook of Pediatrics. Elsevier ; 2015
12. White KK. Orthopaedic aspects of mucopolysaccharidoses. Rheumatology (Oxford). 2011; 50 (Suppl 5): p.v26-v33. doi: 10.1093/rheumatology/ker393 . | Open in Read by QxMD
13. Cathey SS, Leroy JG, Wood T, et al. Phenotype and genotype in mucolipidoses II and III alpha/beta: a study of 61 probands.. J Med Genet. 2010; 47 (1): p.38-48. doi: 10.1136/jmg.2009.067736 . | Open in Read by QxMD
14. Gaucher Disease.
15. Balwani M, Fuerstman L, Kornreich R, Edelmann L, Desnick RJ. Type 1 Gaucher disease: significant disease manifestations in "asymptomatic" homozygotes.. Arch Intern Med. 2010; 170 (16): p.1463-9. doi: 10.1001/archinternmed.2010.302 . | Open in Read by QxMD
16. Weiss K, Gonzalez A, Lopez G, Pedoeim L, Groden C, Sidransky E. The clinical management of Type 2 Gaucher disease.. Mol Genet Metab. 2015; 114 (2): p.110-122. doi: 10.1016/j.ymgme.2014.11.008 . | Open in Read by QxMD
17. Le T, Bhushan V, Sochat M, Chavda Y. First Aid for the USMLE Step 1 2017. McGraw-Hill Education ; 2017
18. Kaplan Medical Staff. USMLE Step 1 Lecture Notes 2017: 7-Book Set. Kaplan Publishing ; 2017

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