Lysosomal storage diseases

Abstract

Lysosomes are cytoplasmic organelles that contain a variety of different hydrolases. A genetic deficiency in the enzymatic activity of one of these hydrolases will lead to the accumulation of the material meant for lysosomal degradation. Examples include glycogen in the case of Pompe disease, glycosaminoglycans in the case of the mucopolysaccharidoses, glycoproteins in the cases of the oligosaccharidoses, and sphingolipids in the cases of Niemann-Pick disease types A and B, Gaucher disease, Tay-Sachs disease, Krabbe disease, and metachromatic leukodystrophy. Sometimes, the lysosomal storage can be caused not by the enzymatic deficiency of one of the hydrolases, but by the deficiency of an activator protein, as occurs in the AB variant of GM2 gangliosidosis. Still other times, the accumulated lysosomal material results from failed egress of a small molecule as a consequence of a deficient transporter, as in cystinosis or Salla disease. In the last couple of decades, enzyme replacement therapy has become available for a number of lysosomal storage diseases. Examples include imiglucerase, taliglucerase and velaglucerase for Gaucher disease, laronidase for Hurler disease, idursulfase for Hunter disease, elosulfase for Morquio disease, galsulfase for Maroteaux-Lamy disease, alglucosidase alfa for Pompe disease, and agalsidase alfa and beta for Fabry disease. In addition, substrate reduction therapy has been approved for certain disorders, such as eliglustat for Gaucher disease. The advent of treatment options for some of these disorders has led to newborn screening pilot studies, and ultimately to the addition of Pompe disease and Hurler disease to the Recommended Uniform Screening Panel (RUSP) in 2015 and 2016, respectively.

Keywords: Fabry disease; Farber disease; GM1 gangliosidosis; Gaucher disease; Krabbe disease; Lysosomal storage diseases; Niemann-Pick disease; Sandhoff disease; Schindler disease; Tay-Sachs disease; cystinosis; free sialic acid storage disease; metachromatic leukodystrophy; mucolipidosis IV; newborn screening.

Fig.1

Receptor-mediated and lysosome formation. (Courtesy of Dr. Eberhard Passarge and Thieme Medical Publishers.).

Fig.2

Structure of sphingolipids. Sphingosine (top) plus a fatty acid forms ceramide (middle). Ceramide attached to a single sugar forms a glucocerebroside (bottom). If ceramide is combined with a polysaccharide (complex sugar) with one or more terminal N-acetylneuraminic acids, the result is a ganglioside.

Fig.3

Metabolic disorders characterized by sphingolipid storage and their enzyme deficiencies. Notice accumulation of glucocerebroside in Gaucher disease, sphingomyelin in Niemann-Pick disease, galactocerebroside in Krabbe disease, sulfatide in metachromatic leukodystrophy, globotriaosylceramide in Fabry disease, and GM2 ganglioside in Tay-Sachs disease. In addition to GM2 ganglioside, patients with Sandhoff disease also accumulate globosides. GM1 ganglioside is stored in generalized β-galactosidase deficiency, while the H antigen accumulates in fucosidosis.

Fig.4

Niemann-Pick disease. (A) A sea-blue histiocyte is present in the marrow. These cells are predominantly seen in types C and F. (B) A histiocyte in the bone marrow has a “soap-bubble” appearance and measures 60 to 80 μm in diameter.

Fig.5

Niemann-Pick disease. Vacuolated storage cells are present in Kupffer cells within the sinusoids of the liver.

Figs. 6–8

Niemann-Pick disease. The splenic sinusoids are filled with distended vacuolated histiocytes; (7) Niemann-Pick disease. The alveoli of the lungs are filled with storage cells; (8) Niemann-Pick disease. The ganglion cells of the myenteric plexus of the gastrointestinal tract are distended with storage material (Luxol fast blue stain).

Figs. 9–11

Niemann-Pick disease. Ganglion cells of the myenteric plexus stain strongly for lipid with Sudan black B stain; (10) Niemann-Pick disease. Electron micrograph of a storage cell in the spleen contains pleomorphic lipid profiles; (11) Niemann-Pick disease. Electron micrograph of a cultured fibroblast contains pleomorphic lipid profiles and electron-dense deposits.

Figs. 12–14

Niemann-Pick disease. The brain is large during the first years of life due to the accumulation of storage material; (13) Niemann-Pick disease. Electron micrograph of a neuron shows membranous concentric bodies of gangliosides; (14) Niemann-Pick disease. Microscopic section of the brain shows large distended neurons.

Fig.15

Niemann-Pick disease. A child 2 years of age. The brain is atrophic with enlargement of the ventricles.

Fig.16

(A) The pathophysiology of Gaucher disease. It should be noted that this macrophage-centric view of the disease has recently been called into question, since it does not explain certain aspects of the disease such as the predisposition to malignancy, osteoporosis or Parkinson disease (108). (B) The enzymatic defect in Gaucher disease. (From Gaucher Disease Diagnosis Evaluation and Treatment, Genzyme Therapeutics, Parsipanny, NJ; with permission.)

Figs. 17,18

Gaucher disease type I. A child 10 years of age showing marked distension of the abdomen due to massive splenomegaly. The spleen was surgically removed and weighed 10 kg; (18) Gaucher disease. Radiograph of lower extremities showing Erlenmeyer flask deformity of the distal ends of the femur.

Fig.19

Gaucher disease. (A) Microscopic section of the spleen. The sinusoids are filled with large distended storage cells. (B) The bone marrow contains a large Gaucher cell with cytoplasmic striations with typical “crinkled tissue paper” appearance.

Fig.20

Gaucher disease. Electron micrograph of a Gaucher cell. (A). Branching tubular profiles are present in a lysosome. (B) High magnification of tubule with clockwise spiral in Gaucher disease lysosome.

Fig.21

Krabbe disease. (A) Coronal section of the brain stained with oil red O. Only a few myelinated areas stain. The remainder of the white matter does not stain, indicating loss of myelin. (B) Microscopic section of brain with globoid cells in white matter. The brain does not store the substrate, galactosylceramide, but it stimulates infiltration of macrophages which transform to globoid cells. The increased levels of psychosine that occur have cytotoxic effects.

Fig.22

Krabbe disease. Electron micrograph of brain. (A) A globoid cell containing tubules with electron-dense deposits. (B) High magnification of the twisted tubule with a counterclockwise spiral.

Fig.23

Farber disease. (A) Child with multiple skin nodules. (B) Large nodules on the wrist and (C) on the ankle. (Courtesy of Dr. Steven Qualman.).

Figs.24, 25

Farber disease. The opened abdominal cavity at autopsy shows a greatly enlarged liver that has a yellow appearance. (Courtesy of Dr. Steven Qualman.); (25) Farber disease. Microscopic section of the liver. The hepatocytes are distended with lipid. (Courtesy of Dr. Steven Qualman.).

Figs. 26–28

Farber disease. Microscopic section of a lymph node showing PAS-positive storage histiocytes. (Courtesy of Dr. Steven Qualman.); (27) Farber disease. Electron micrograph of Farber’s lipogranulomatosis. Typical curvilinear bodies (arrowheads) are shown. (Courtesy of Dr. James Phillips.); (28) Farber disease. Dense white nodules removed from the larynx. (Courtesy of Dr. Steven Qualman.).

Figs. 29–31

Farber disease. Section of larynx greatly narrowed by infiltration of storage histiocytes (right) compared with normal larynx (left). (Courtesy of Dr. Steven Qualman.); (30) Farber disease. Microscopic section of larynx showing large distended vacuolated histiocytes. (Courtesy of Dr. Steven Qualman.); (31) Farber disease. Microscopic section of the joint synovium with infiltration by storage histiocytes.

Figs. 32–34

Farber disease. The heart shows epicardial nodules. (Courtesy of Dr. Steven Qualman.); (33) Farber disease. Microscopic section of heart showing epicardial infiltration by storage histiocytes. PAS stain. (Courtesy of Dr. Steven Qualman.); (34) Farber disease. Microscopic section of the lung showing infiltration by storage histiocytes.

Figs. 35,36

Farber disease. Microscopic section of the cerebral cortex of the brain. The neurons are distended with storage material; (36) Farber disease. Microscopic section of spinal cord. The anterior horn cells are distended with storage material. (Courtesy of Dr. Steven Qualman.).

Fig.37

Fabry Disease. (A) Corneal whorls, representing storage of trihexosylceramide. (B) Angiokeratomata of umbilicus. (C) Tortuous vessels in bulbar conjunctiva.

Fig.38

Fabry disease. (A) Microscopic section of the myenteric plexus showing large distended ganglion cells that are PAS-positive. (B) Microscopic section of a blood vessel showing thickening of the vessel wall by accumulation of glycosphingolipid (PAS stain).

Fig.39

Fabry disease: kidney. (A) Gross appearance of end-stage disease with scarring and cyst formation. External view (left), cut surface (right). (B) Microscopic section of kidney glomerulus. Foamy glomerular epithelial cells are present. (C) Electron micrograph of kidney. Glomerular epithelial cells contain myelin-like figures. (D) Glomerular parietal epithelial cells show pleomorphic lipid inclusions.

Fig.40

Fabry disease. (A) Large distended ganglion cells in gasserian ganglion. Hematoxylin and eosin stain (left); Luxol fast blue stain (right). (B) Electron micrograph shows concentric parallel lamellae of the lipid storage substance.

Fig.41

The terminal residue of blood group antigen B is metabolized by α-galactosidase A–deficient in patients with Fabry disease-while antigen A is cleaved by α-galactosidase B–deficient in patients with Schindler’s disease.

Figs. 42,43

GM₁ gangliosidosis type I: brain. The cortical neurons are distended with ganglioside; (43) GM₁ gangliosidosis type I: liver. Some hepatocytes are swollen and contain storage material.

Figs. 44,45

GM₁ gangliosidosis type I: kidney. The glomerular epithelial cells are vacuolated; (45) GM₁ gangliosidosis type I. Electron micrograph in conjunctival biopsy showing typical membranous concentric bodies (MCBs) of gangliosides. MCBs are the morphologic expression of gangliosides seen in all the gangliosidoses including Tay-Sachs disease.

Figs. 46,47

GM₁ gangliosidosis type II. Facial appearance at autopsy. Mild anomalies of the ear and a prominent philtrum are present; (47) GM₁ gangliosidosis type II. Appearance of oral cavity at autopsy. Note marked gingival hypertrophy.

Figs. 48,49

GM₁ gangliosidosis type II. Postmortem X-ray. (A) Changes of dysostosis multiplex in skull. (B) Lateral projection of vertebrae that shows mild generalized platyspondyly of cervical vertebrae and tear-drop deformity of vertebrae; (49) GM₁ gangliosidosis type II. Gross appearance of heart opened through the left ventricle. The mitral valve leaflets are markedly deformed and thickended.

Figs. 50–52

GM₁ gangliosidosis type II. Microscopic section of mitral valve showing vacuolated histiocytes and intense staining of collagen. Alcian blue stain; (51) GM₁ gangliosidosis type II. Gross appearance of brain showing atrophy of cerebral hemisphere, particularly the frontal and occipital lobes; (52) GM₁ gangliosidosis type II. Microscopic section of cerebellar cortex showing large distended Purkinje cells. PAS stain.

Figs. 53–55

GM₁ gangliosidosis type II. Microscopic section of spinal cord showing large vacuolated anterior motor neurons. PAS stain; (54) GM₁ gangliosidosis type II. Electron micrograph of cerebral cortical neuron. Membranous cytoplasmic bodies (MCB) in neuronal perikaryon; (55) GM₁ gangliosidosis type II. Electron micrograph of cerebral cortical neuron. The cytoplasm is filled with pleomorphic lipid bodies (PLB).

Figs. 56,57

GM₁ gangliosidosis type II. Electron micrograph of glial cell containing cytoplasmic inclusion displaying unusual lamellar pattern; (57) GM₁ gangliosidosis type II. Electron micrographs of tubular inclusions (T) in cytoplasm of splenic macrophage. Mosaic-like pattern of membrane bounded compartments filled with tubules.

Figs. 58–60

GM₁ gangliosidosis type II. Electron micrograph of tubular inclusions in cytoplasm of splenic macrophage with curved tubules at higher magnification and cut obliquely; (59) GM₁ gangliosidosis type II. Microscopic section of marrow with large histiocytes containing PAS positive material. PAS stain; (60) GM₁ gangliosidosis type II. Microscopic section of liver showing Kupffer cells distended with storage material.

Figs. 61,62

GM₁ gangliosidosis type II. Microscopic section of kidney showing enlarged visceral glomerular epithelial cells containing granules; (62) GM₁ gangliosidosis type II. Microscopic section of gastrointestinal tract showing ganglion cells in the myenteric plexus. One ganglion cell contains granular deposits stained deeply with Luxol fast blue.

Fig.63

GM₂ gangliosidosis type I (Tay-Sachs disease). The retina shows a cherry-red spot in the macula.

Fig.64

GM₂ gangliosidosis type I (Tay-Sachs disease). (A) Microscopic section of the brain shows large swollen neurons due to accumulation of ganglioside. (B) Electron micrograph showing characteristic membranous concentric bodies.

Fig.65

GM₂ gangliosidosis type II (Sandhoff disease). (A) The brain shows atrophy of gyri. (B) On cross section, both gray and white matter are atrophic.

Figs. 66,67

GM₂ gangliosidosis type II (Sandhoff disease). A coronal section of the brain, normal brain (top) compared with severe cortical atrophy (bottom); (67) GM₂ gangliosidosis type II (Sandhoff disease). A normal spinal cord (top) is compared with atrophy in Sandhoff disease (bottom).

Fig.68

GM₂ gangliosidosis type II (Sandhoff disease). Electron micrograph of (A) cerebral cortex showing inclusions of electron-dense profiles with concentric laminations, and (B) liver containing intracellular concentric laminations within hepatocytes.

Fig.69

Metachromatic leukodystrophy. Urinary spot test showing metachromasia due to the presence of sulfatide (right) compared to normal (left).

Fig.70

Metachromatic leukodystrophy. (A) The white matter in the cerebellum shows brown metachromasia after staining with cresyl violet. (B) Microscopic section of cerebellum showing brown metachromasia. (C) Dense metachromasia in the spinal cord.

Figs. 71,72

Metachromatic leukodystrophy. (A) The neurons of the cerebral cortex show metachromatic staining with cresyl violet. (B) Anterior horn cell of spinal cord shows metachromasia with cresyl violet; (72) Metachromatic leukodystrophy. Vacuolated storage histiocyte cells are present in the lamina propria of the gallbladder.

Fig.73

Metachromatic leukodystrophy. Autofluorescence of storage cells.

Figs. 74,75

Metachromatic leukodystrophy. Microscopic section of the kidney shows brown metochromasia of the renal tubular epithelial cells; (75) Metachromatic leukodystrophy. A sural nerve biopsy show metachromatic substance within the nerve fibers.

Figs. 76,77

Metachromatic leukodystrophy. Section of the pancreas shows brown metachromasia in the acinar cells; (77) Metachromatic leukodystrophy. Electron micrograph of a neuron of the white matter shows pleomorphic and parallel crystalline lipid profiles. Inset, crystalline arrays at high magnification.

Figs. 78,79

Light micrograph under birefringent light showing cystine crystals of various shapes. Aequeous fixative has smoothed the hexagonal and rectangular edges; (79) Slit lamp examination of cornea of a child with cystinosis showing a multitude of crystals.