Thyroid gland
Congenital anomalies
Lysosomal storage diseases

Authors: Andrey Bychkov, M.D., PhD (see Authors page)

Revised: 23 February 2017, last major update May 2016

Copyright: (c) 2017,, Inc.

PubMed search: Lysosomal storage diseases thyroid
Cite this page: Lysosomal storage diseases. website. Accessed February 26th, 2017.
Definition / General
  • Lysosomal storage disease (LSD) is a subgroup of inherited metabolic disorders, caused by mutations in genes encoding lysosomal enzymes, which results in cell damage due to excessive storage of undegraded substrates
  • Main target organ / systems are nervous, muscular, reticuloendothelial and liver
  • Thyroid involvement is uncommon
  • Major LSDs were first described in the late 19th (Tay-Sachs, Gaucher and Fabry diseases) and early 20th centuries (Niemann-Pick and Pompe diseases); however the lysosomal concept was developed only in the 1960s (Pediatr Endocrinol Rev 2013;11 Suppl 1:59)
  • Synonyms: lysosomal storage disease / disorder, lysosomal disease, thesaurismosis, storage disease
  • Broader category of inherited metabolic disorders is equivalent to metabolic storage disorder, or inborn errors of metabolism (Ann Endocrinol (Paris) 2009;70:14)
  • Approximately 50 diseases are included in the LSD group, similar to the number of different enzymes within a lysosome
  • Almost all names are eponymous
  • Classification is based on the nature of the primary accumulated material:
    • Lipid storage diseases, including sphingolipidoses (Fabry, Gaucher, Niemann-Pick) and gangliosidosis (Tay-Sachs)
    • Mucopolysacharidoses (Hunter, Hurler, Morquio)
    • Glycoproteinoses
    • Mucolipidoses
    • Glycogen storage disease (Pompe)
    • Cystinosis
  • Although individual LSDs are rare, the aggregate prevalence is 1:5,000 births, which is comparable to that of the most common genetic diseases (Nat Rev Neurol 2013;9:583)
  • LSDs are the second most common group of inborn errors of metabolism (1:1,500 births) after small molecule diseases, e.g. phenylketonuria and galactosemia (Pediatrics 2000;105:e10)
  • Some LSDs have ethnic or geographical predilections (Madame Curie Bioscience Database):
    • Ashkenazi Jews: Tay-Sachs and Gaucher disease
    • French Canadian: Tay-Sachs
    • Finnish: aspartylglucosaminuria and Salla disease
    • Russian: Hurler syndrome
  • Distribution of affected organs in LSDs is dependent on the nature of the substrates that accumulate and their specific cellular distribution, as well as the cell turnover rate in each tissue (Nat Rev Neurol 2013;9:583):
    • Sphingolipids: brain and nerves
    • Mucopolysaccharides: cardiovascular system and connective tissue, including bones
    • Glycogen: muscles
    • Cystine: kidney
Pathophysiology / Etiology
  • LSDs are caused by mutations in genes encoding soluble acidic hydrolases, activator proteins, transporter proteins, integral membrane proteins or nonlysosomal proteins that are necessary for lysosomal function (Annu Rev Med 2015;66:471)
  • Main genes in LSDs: glucosylceramidase beta / GBA (Gaucher), galactosidase alpha / GLA (Fabry), sphingomyelin phosphodiesterase 1 / SMPD1 (Niemann-Pick), hexosaminidase subunit alpha / HEXA (Tay-Sachs), iduronate 2-sulfatase / IDS (Hunter), glucosidase alpha, acid / GAA (Pompe), cystinosin, lysosomal cystine transporter / CTNS (cystinosis)
  • As a result, metabolic machinery of the cell is impaired by defects in degradative and synthetic enzymes, lysosomal membrane defects, disorders of lysosome biogenesis and endosome-lysosome traffic
  • Pathogenetic cascade leads to intralysosomal accumulation of undegraded substrates in multiple tissues and organs
  • Excessive storage of a substrate triggers cell damage via several mechanisms: activation of apoptosis, alterations of plasma membrane lipid content (affect receptor responses and downstream signaling), prolonged inflammation, calcium imbalance, dysregulation of autophagy, etc. (Nat Rev Neurol 2013;9:583)
  • All LSDs are inherited in an autosomal recessive manner, except X linked recessive Fabry, Hunter and Danon diseases
  • Severity and age of onset in LSDs depend on a range of factors: residual enzyme activity (20% is still enough for normal function), mutant protein size, location of the mutation with respect to catalytic site, distribution of tissue specific and cell specific substrates, cell turnover rate, defective protein expression and other mechanisms that influence the life span of the affected cells (Nat Rev Neurol 2013;9:583)
Diagrams / Tables

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Lysosomal storage diseases at a glance


Cell morphology

Clinical Features
  • In LSDs, buildup of material may begin in utero; disease progressively evolves over time, often becoming evident during the newborn period (i.e. infantile form)
  • Up to 15% of nonimmune hydrops fetalis are due to LSD (Stocker and Dehner's Pediatric Pathology, 3rd ed, 2010)
  • Presence of residual enzyme activity can result in mild and late onset forms, i.e. juvenile and adult variants (Madame Curie Bioscience Database)
  • Involvement of multiple organs and systems is typical, with variable association of visceral, ocular, hematological, skeletal and neurological manifestations, and there is partial phenotypic overlap among different disorders (Nat Rev Neurol 2013;9:583)
  • About two thirds of patients with LSDs display a significant neurological component, which ranges from progressive neurodegeneration and severe cognitive impairment to epileptic, behavioral and psychiatric disorders (Annu Rev Med 2015;66:471)
  • Abnormal thyroid function is mainly represented by primary hypothyroidism (Orphanet J Rare Dis 2012;7:11):
  • Current guidelines recommend that diagnosis must be established by specific enzyme assays and by mutational analysis (Genet Med 2011;13:457)
  • Early detection of LSDs via genetic screening programs, prenatal diagnosis and screening of newborns in at risk families has major impact for the long term course and outcome of the disease (National Organization for Rare Disorders)
Prognostic Factors
  • Most early onset (diagnosed in infants) LSDs have a rather predictable clinical course, when neurologic deterioration continues until the death of the child within 5 - 10 years, usually by infection
  • Predicting the clinical course in later onset patients, especially adolescents and adults, is nearly impossible (Arch Neurol 2003;60:322)
Case Reports
  • There is no cure for most LSDs; symptomatic treatment is usually provided by a multidisciplinary team (neurologic, orthopedic, cardiologic, etc.)
  • Early diagnosis with prompt initiation of presymptomatic therapy for defective soluble enzymes in the neonatal period, or as early as possible, can improve outcome (Nat Rev Neurol 2013;9:583)
  • Cystinosis is treated with cysteamine, which reduces intracellular cystine
  • Enzyme replacement therapy is a promising treatment; normal enzyme can be provided by intravenous injection, or as a precursor secreted into the circulation by engineered cells from the patient or by an allograft of transplanted cells (Annu Rev Med 2015;66:471)
  • Other advanced treatment strategies: stem cell therapies, substrate reduction and chaperone mediated delivery (Nat Rev Neurol 2013;9:583)
Clinical Images

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Cystinosis: Cystine crystals in cornea

Skeletal deformities in mucopolysaccharidoses

Gross Description
Micro Description
  • LSDs are characterized by progressive intracellular (rarely extracellular, e.g. mucopolysacharidoses) accumulation of a substrate
  • The most prominent thyroid abnormalities are observed in cystinosis (Am J Med 1970;48:678, J Pediatr 1977;91:204):
    • Destruction and infiltration of thyroid epithelial cells by cystine crystals
    • Focal areas of papillary hyperplasia with dilated follicles and focal acute inflammation
    • Follicular atrophy with fibrosis and decreased amounts of colloid
    • Frozen sections show abundance of birefringent crystals within follicular cells and macrophages, but these are usually lost in fixed tissue sections; to preserve crystals, specimens should be fixed in absolute alcohol, not formalin, otherwise cystine may dissolve
  • Minor changes represented by intracellular deposits are found in thyroid in other LSDs:
Micro Images

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Liver biopsy in Gaucher disease (H&E, PAS)

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Gaucher disease (spleen)

Hepatic glycogenosis (H&E, PAS, Masson)

Niemann-Pick disease (hepatic steatosis)

Niemann-Pick disease (spleen)

Virtual Slides

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Gaucher disease (spleen)

Niemann-Pick disease (liver biopsy)

Niemann-Pick disease in children #1, #2
Hurler disease (lung)
Cytology Images

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Cystine crystals in bone marrow macrophages

Gaucher cell in bone marrow

Peripheral Smear Description
Positive Stains
Negative Stains
  • CD107b helps to differentiate cardiomyopathy due to Danon disease
Electron Microscopy Description
Electron Microscopy Images

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Crystalline profiles in cystinosis

Lamellated "zebra" bodies in Fabry disease (fig 10)

Lamellar bodies in gangliosidosis

Leukocyte in mannosidosis

Myocyte in Pompe disease


Video #1: Histopathology of glycogen storage disease (heart, liver)
Video #2: A primer in inherited metabolic disorders (2013)
Video #3: Mechanism of LSDs (2014)

Video #1: Newborn screening for LSDs (2012)
Video #2, #3: Lecture series on LSDs by The Excellence In Pediatrics Institute (2014-2016)