Lysosomal Storage Diseases

Alroy, Joseph; Lyons, Jeremiah A.

doi:10.1177/2326409813517663

Joseph Alroy Joseph Alroy, DVM, DACVP, Department of Biomedical Sciences, Cummings School of Veterinary Medicine, Tufts University, 200 Westboro Road, North Grafton, MA 01536, USA.Email: joseph.alroy@tufts.edu

Department of Pathology, Tufts University School of Medicine¹, Boston, MA, USA

Tufts Medical Center, Boston, MA, USA

Department of Biomedical Sciences, Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA, USA

Jeremiah A. Lyons

Department of Biomedical Sciences, Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA, USA

Joseph Alroy, DVM, DACVP, Department of Biomedical Sciences, Cummings School of Veterinary Medicine, Tufts University, 200 Westboro Road, North Grafton, MA 01536, USA.Email: joseph.alroy@tufts.edu

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures (15)
Tables (2)

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Figure 1
Schematic illustration of synthesis and targeting of lysosomal hydrolases to lysosomes, the mechanisms for transferring substrates to lysosomes for degradation, and the efflux of cystinosin and sialin. Nascent lysosomal hydrolases, secretory, and membrane proteins are glycosylated in the rough endoplasmic reticulum (RER) by transference of preformed oligosaccharides from dolichol-P-P-oligosaccharides. These glycosylated glycoproteins are translocated to the Golgi apparatus, where secretory and membrane glycoproteins are further modified and oligosaccharides of lysosomal hydrolases are phosphorylated (P). All but 2 lysosomal enzymes bind to the M-P receptors and are transported to a prelysosome compartment, where the enzymes are released and the receptor shuttles back to the Golgi apparatus. In the primary lysosome, the prohydrolases are cleaved. The secondary lysosome is formed by fusion of a phagosome with the primary lysosome via lysosomal-associated membrane protein 2 (LAMP-2). The catabolic products exit via transporter proteins such as sialin and cysteine (*).

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Figure 2
Blood smear of a patient with multiple sulfatase deficiency showing a lymphocyte and neutrophil stained with Wright-Giemsa. The cytoplasm of both cells contains metachromatic granules.

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Figure 3
Photomicrographs of a cow cerebrum with α-mannosidosis illustrating (A) enlarged neurons with vacuolated cytoplasm, hematoxylin and eosin (H&E). B, Staining with Con A demonstrating the storage of oligosaccharides with terminal α-mannosyl residues.

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Figure 4
Photomicrograph of frozen section of spinal cord of a 1½-year-old Australian Blue Heeler dog with neuronal ceroid lipofuscinosis in spinal cord stained with Sudan black revealing the storage of ceroid lipofuscin within the neurons.

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Figure 5
Paraffin section of the brain of a 7-month-old English Springer Spaniel dog stained with Luxol Fast Blue demonstrating the storage of G_M1-gangliosides.

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Figure 6
Photomicrograph of the cerebellum of New Zealand sheep with neuronal ceroid lipofuscinosis revealing the presence of autofluorescent neurons.

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Figure 7
Electron micrographs of the cerebellum from a 5½-month-old Portuguese water dog. A, Low magnification illustrating on the left neuronal cytoplasm packed with enlarged secondary lysosomes, at the center is a section through an endothelial cell, and on the right is an axon. B, High magnification reveals lysosomes packed with gangliosides. C, Close-up view of the endothelial cell that has enlarged electron-lucent lysosomes containing oligosaccharides. D, On the right, there is high magnification of an axon packed with spheroids.

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Figure 8
Low (A) and high magnification (B) of a brain from a rhesus monkey with Krabbe disease demonstrating globoid cells (*) that have cleft-like storage material.

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Figure 9
Electron micrograph of glomerular mesangial cell of a Siamese cat with mucopolysaccharidosis (MPS)-IV revealing secondary lysosomes that contains a mixture of lamellated membrane structures and fine fibrillar material.

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Figure 10
Low-magnification electron micrograph of myocardial cells from a 2-year-old Australian Blue Heeler dog with neuronal lipofuscinosis that contain secondary lysososmes. Inset: Higher magnification of a lysosome that is packed with curvilinear material.

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Figure 11
Electron micrograph of the corneal stroma from cats with mucopolysaccharidosis (MPS)-I (A), MPS-VI (B), both with cloudy cornea, and a normal control cat (C). There is an increase in fibril spacing and more irregular packing of fibrils (*) in the affected corneas but not in the control. The collagen fibrils from affected cats are larger and more varied in diameter size. Bar 100 nm.¹⁶16 Alroy, J, Haskins, M, Birk, DE. Altered corneal stromal matrix organization is associated with mucopolysaccharidosis I, III and VI. Exp Eye Res. 1999;68(5):523–530.

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Figure
Photograph of lumbar vertebrae from a 3-month-old normal Portuguese water dog (A) and his brother with G_M1-gangliosidosis (B). In (B) the vertebrae are shorter and the intervertebral disks are irregular and wide.

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Figure 13
Longitudinal section of part of a lumbar vertebra of a 2-month-old normal Portuguese water dog and his affected sex- and age-matched brother. B, In the normal puppy (A), the ossification is advanced and the primary spongiosa are well developed. In the affected puppy (B), the ossification is retarded, the primary spongiosis is poorly developed and there is metaphysical osteoporosis. Safranin-O.¹²12 Alroy, J, Knowles, K, Schelling, SH, Kaye, EM, Rosenberg, AE. Retarded bone formation in GM1 gangliosidosis: A study of the infantile form and canine models. Virchows Archive. 1995;426(2):141–148.

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Figure 14
A, T2-weighted magnetic resonance imaging (MRI) of a 9-month-old normal control English Springer Spaniel, illustrating a normal ratio between gray and white matter. B, Corresponding coronal section from the hemisected fixed brain demonstrating prominent gray and white matter. C, MRI of an affected 9-month-old littermate illustrating increased volume of gray matter and poor development of low signal intensity of the white matter. D, Corresponding coronal section revealed increased gray matter and reduced white matter, in particular in the corona radiate.¹¹11 Kaye, EM, Alroy, J, Raghavan, SS. Dysmyelinogenesis in animal model for GM1-gangliosidosis: Radiological, morphological and biochemical studies. Pediat Neurol. 1992;8(4):255–261,

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Figure 15
A, Electron micrograph of the corpus callosum from a 2-month-old normal Portuguese water dog (PWD) puppy, illustrating an oligodendrocyte (oligo) and normal myelinated axons. Corresponding electron micrograph from an age-matched affected PWD litter mate demonstrating erythrocyte (RBC), vacuolated endothelial cells, and only few myelinated axons. Inset: Higher magnification of the square revealing normal appearing unmyelinated axons.¹¹11 Kaye, EM, Alroy, J, Raghavan, SS. Dysmyelinogenesis in animal model for GM1-gangliosidosis: Radiological, morphological and biochemical studies. Pediat Neurol. 1992;8(4):255–261,

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Table 1
Lysosomal Storage Diseases.

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Table 2
Classification of Mechanism of Lysosomal Storage Disorders

Disease		Deficient Hydrolases		Primary Storage Products		Major Organs Involved		Corresponding Disease in Animals
MPS
	MPS-I Hurler, Scheie	α-L-Iduronidase		Dermatan sulfate,		CNS, connective tissue,		DSH cats, Plott hounds
	syndrome				heparan sulfate		heart, skeleton,
							cornea
	MPS-II Hunter syndrome	Iduronate sulfatase		Dermatan sulfate,		CNS, connective tissue,		Labrador Retriever dogs
	MPS-III Sanfilippo syndrome				heparan sulfate		heart, skeleton
	Subtype A	Sulfaminidase		Heparan sulfate		CNS		Wire-haired Dachshund, New
									Zealand Huntaway dogs
	Subtype B	α-N-Acetylglucosaminidase		Heparan sulfate		CNS		Emus, Schipperke dogs
	Subtype C	Acetyl Co A α-		Heparan sulfate		CNS
			glucosaminide
			acetyltransferase
	Subtype D	N-acetylglucosamine 6-		Heparan sulfate		CNS		Nubian goats
	MPS-IV Morquio syndrome		sulfatase
	Type A	Galactose 6-sulfatase		Chondroitin-4 sulfate,		Cartilage, skeleton,
					keratan sulfate		cornea, heart
	Type B	β-Galactosidase		Keratan sulfate		Cartilage, bone, cornea
	MPS-VI Maroteaux-Lamy	Arylsulfatase β-N-		Dermatan sulfate		Skeleton, cornea, heart		DSH Siamese Cats, rats,
	syndrome		acetylgalactosamine 4-						schnauzers, miniature
			sulfatase						pinschers, and Welsh Corgi dogs
	MPS-VII Sly syndrome	β-Glucuronidase		Dermatan sulfate,		CNS, connective tissue,		Dogs, DSH Cats, Gus mice
					heparan sulfate,		skeleton, heart
					chondroitin 4-8-
					sulfate
	MPS-IX hyaluronidase	Hyaluronidase		Hyaluronan		Periarticular soft tissue
	deficiency
Sphingolipidoses (lipid storage diseases)
	Glucocerebrosidosis
	(Gaucher disease)
	Infantile type 2	β-Glucocerebrosidase		Glucosylceramide		CNS, spleen, liver,		Silky Terrier dogs, Sheep, pigs
							bone marrow
	Juvenile type 3						CNS, spleen, liver,
							bone marrow
	Adult type 1						Spleen, liver, bone
							marrow
	Fabry disease	α-Galactosidase		Trihexosylceramide		Blood vessels of skin,
							kidney, and brain
	Schindler disease (type I)	α-N-acetylgalactosaminidase		Sialylated and		CNS, PNS
					asialopeptides and
					oligosaccharides
	Type II	α-N-acetylgalactosaminidase		Sialylated and		CNS, PNS
					asialopeptides and
					oligosaccharides
	Metachromatic leukodystrophy
	Late infantile form	Arylsulfatase A		Galactosylsulfatide		CNS, liver, kidney,		Hawaiian geese
							gallbladder
	Late-onset form	Arylsulfatase A
	Multiple sulfatase	At least 7 lysosomal				CNS, visceral organs,
	deficiency		sulfatases and a				and skeleton
			microsomal sulfatase
	Niemann-Pick disease
	Type A	Sphingomyelinase		Sphingomyelin		CNS, liver, spleen,		Poodles, boxers, Balinese, DSH,
							bone marrow		and Siamese cats
	Type B
	Type C (NPC-1 and	Proteins required for lipid		Unesterified		CNS, liver, spleen		Flight model mice, DSH cats,
	NPC-2)		transport through late		cholesterol and				boxers
			endosome		spingolipids
	G_M1-gangliosidosis	β-galactosidase		G_M1-ganglioside,		CNS, skeleton, viscera		DSH, Korat and Siamese cats,
					oligosaccharides,				English Springer Spaniels,
					keratan sulfate				Portuguese water dogs,
									Shebas, Alaskan Huskies,
									Beagle dogs, Friesian cattle,
									Coopworth-Romney, Suffolk
									cross-bred sheep, and Ameri-
									can black bears
	G_M2-gangliosidosis
	Tay-Sachs disease,	β-hexosaminidase A		G_M2-ganglioside		CNS		Muntjac deer, flamingos,
	A variant								Yorkshire pigs, Jacob sheep,
									raccoons
	Sandhoff disease	β-hexosaminidases A and B		G_M2-ganglioside,		CNS		DSH, European Burmese,
					oligosaccharides				Japanese domestic and Korat
									cats, German Short-hair Poin-
									ters, Golden retriever dogs,
									and Yorkshire pigs
	AB variant	Deficiency of G_M2 -activator		G_M2-ganglioside		CNS		Japanese Spaniel, DSH, emu
			protein
	Galactosialidosis	Protective protein/		Glycolipids and		CNS, spleen, liver,		Suffolk cross-breed sheep,
			cathepsin A, resulting in		oligosaccharides		skeleton		Schipperke
			deficiency of β-
			galactosidase and a-
			neuraminidase
	Globoid cell	Galactosylcerebroside, β-		Galactosylsphingosine		CNS		Cairn and West Highland
	leukodystrophy		galactosidase						terriers, poodles, beagles, blue
	(Krabbe disease)								tick hound dogs, Pomeranians,
									Irish Setters, Twitcher mice,
									Polled Dorset sheep, DSH
									Cats, rhesus monkeys
Farber granulomatosis		Ceramidase		Ceramide		Subcutaneous nodules,
							joints, larynx, liver, lung, heart
	Wolman disease	Acid lipase/cholesterol		Triglycerides,		Liver, spleen, adrenal		Sheel Parakeets, Donryu rats,
			esterase		cholesteryl esters				Fox terriers
Disorders of glycoprotein degradation
	Aspartylglucosaminuria	Aspartylglucosaminidase		Fragments of		CNS, connective tissue,
					glycoprotein,		bone marrow
					aspartyl-2-deoxyl-2-
					acetamide glycosyla-
					mine, N-linked
					oligosaccharides
	α-Mannosidosis	α-Mannosidase		N-linked		CNS, skeleton, liver,		Angus, Shorthorn cattles,
					oligosaccharides		spleen		Simmentals, Galloways,
									Murray Grey cattle, DSH,
									DLH, and Persian cats
	β-Mannosidosis	β-mannosidase		N-linked		CNS, skeleton, liver,		Anglo-Nubian goats, Saler cattle
					oligosaccharides		spleen
	Fucosidosis	α-fucosidase		Oligosaccharides and		CNS, spleen, liver		English Springer Spaniels, English
					Glycolipids				Pointer dogs
	Sialidosis (mucolipidosis-		Neuraminidase	Fragments of		CNS, spleen, liver,		DSH cats
	I)				glycoprotein		skeleton
Neuronal ceroid lipofuscinosis (NCL)
	Infantile NCL (CLN-1)	Palmitoyl protein		Protein, saposins A and		CNS, Heart,		Swedish sheep, ferrets
			thioesterase		D		endothelial Cells,
							retina
	Congenital NCL	Cathepsin D (CTSD)		Protein		CNS, Liver		American Bulldogs, White
	(CLN-10)								Swedish Landrace sheep
	Classic late infantile	Pepstatin-sensitive pro-		Mitochondrial subunit		CNS, retina		Australian cattle dogs, blue
	NCL (CLN-2)		tease, tripeptydyl-		C of ATPase				heelers, and border collies,
			peptidase		synthase				Dachshund dogs
	Late infantile (Indian	Endoplasmic reticulum		Mitochondrial subunit		CNS, heart, endothelial		Merino, Rambouillet, South
	Variant) NCL (CLN-6)		transmembrane protein		C of ATPase		cells		Hampshire sheep, English
					synthase				Setter and blue heeler dogs,
									Devon cattle, DSH cats
	Late infantile (Turkish	Protein		Mitochondrial subunit		CNS
	variant) NCL (CLN-7)				C of ATPase
					synthase
	Late infantile (Finnish	Transmembrane protein		Mitochondrial subunit		CNS, heart, endothelial		Borderdale sheep, Devon cattle
	variant) NCL (CLN-5)				C of ATPase		cells
					synthase
	Juvenile NCL (CLN-3)	(Battenin) Lysosomal		Mitochondrial subunit		CNS, heart, endothelial		Chihuahua, Cocker Spaniel,
			transmembrane protein		C of ATPase		cells, retina		Dachshund, Dalmatian, English
					synthase				Setter, Saluki, Tibetian terrier,
									Yugoslavian shepherd dogs,
									Siamese cat, South Hampshire
									and Swedish sheep.
	Adult NCL (CLN-4)	Unknown		Mitochondrial subunit		CNS, heart, endothelial		American Staffordshire terriers
					C of ATPase		cells
					synthase
	Progressive epilepsy with	Transmembrane protein		Mitochondrial subunit		CNS		English Setter dogs
	mental retardation,				C of ATPase
	Northern epilepsy				synthase
	(CLN-8)
	Juvenile variant (CLN-9)	Unknown				CNS
Glycogen storage disease
	Pompe disease, type II
	Early onset	α-Glucosidase (acid		Glycogen		CNS, muscle, heart		Brahman and shorthorn cattle,
			maltase)						Lapland dog, cat, Corriedale
									sheep, and Japanese Quail
	Late onset	α-Glucosidase (acid		Glycogen		CNS, muscle, heart
			maltase)
Disorders of protein degradation
	Pycnodysostosin	Cathepsin K		Collagen		Osteochondrodysplasia
	Experimental dilated	Cathepsin L		Sarcomeric protein		Heart		Mice L^-1
	cardiomyopathy
	Papillon-Lefevre	Cathepsin C		Proteins		Periodontal disease and		Mice^-1B^-1
	syndrome						palmoplantar
							keratosis
	Neuronal loss and	Cathepsins B and L		Proteins		CNS
	brain atrophy
Abnormal lysosomal membrane transport
	Mucolipidosis-II (I-cell	N-acetylglucosaminyl-		Mucopolysaccharides,		CNS, connective tissue,		DSH cats
	disease)		phosphotransferase		lipids, glycoproteins		skeleton, heart,
			resulting in multiple				kidney
			enzyme deficiencies
	Mucolipidosis-III	N-acetylglucosaminyl-		Mucopolysaccharides,		Joint and connective
	(pseudo-Hurler		phosphotransferase		lipids, glycoproteins		tissue predominantly
	polydystrophy)		resulting in multiple
			enzyme deficiencies
	Mucolipidosis-IV	TRPML-I		Lipids		CNS, connective tissue
	Danon disease	Deficiency of LAMP-2		Glycogen		CNS, muscle, heart
	Infantile osteopetrosis	OSTMI Chloride Channel 7		Glycoproteins and		CNS, skeleton
	and neuronal				glycolipids
Disorders of lysosomal efflux
	Cystinosis	Cysteine efflux mediator		Cysteine		Kidney
	Salla disease	Sialic acid efflux mediator		Free sialic acid		CNS
	Infantile dialiuria	Sialic acid efflux mediator		Free sialic acid		CNS, kidney, liver
Other
	Acid phosphatases	Acid phosphatase				CNS, skeleton

Mechanisms		Examples
Disorders in which no immunologically detectable enzyme is		Infantile forms of glycoprotein, glycolipid, glycogen, or liquid storage
	synthesized; include conditions with grossly abnormal structural genes		diseases and mucopolysaccharides
Disorders in which a catalytically inactive polypeptide is synthesized; the		Juvenile or adult forms of glycoproteins, glycolipids, glycogen, or lipid
	mutation may also affect the stability or transport of the polypeptide		storage diseases and mucopolysaccharides
Disorders in which a catalytically active enzyme is synthesized, but the		I-cell disease, pseudo-Hurler polydystrophy
	enzyme is not segregated into lysosomes
Disorders in which a catalytically active enzyme is synthesized; however,		Galactosialidosis
	the enzyme is unstable in prelysosomal or lysosomal compartments
Disorders in which activator proteins (saposins) of liquid-degrading		AB variant of GM₂-gangliosidosis, variants of Gaucher and Farber
	hydrolases are missing		diseases, juvenile variant of meta-chromatic leukodystrophy
Disorders in which the structural gene of the hydrolase is normal, but		Multiple sulfatase deficiencies
	there is a mutation of the genes that codes for posttranslational
	modification of the hydrolase
Disorders due to abnormal transport to the lysosomes		Mucolipidosis-IV, NPC-1, and NPC-2. Infantile osteopetrosis with
			neuronal storage
Disorder due to lack of fusion between endosome and lysosome due to		Danon disease
	mutation of the gene that codes for lysosomal membrane protein 2
	(LAMP-2)
Disorders due to a decrease in transport of degradation end products		Salla disease, infantile sialidosis, and cystinosis
	(ie, free cysteine) out of the lysosomes
Disorders due to oversupply of substrate		Some cases of chronic myelocytic leukemia, sickle-cell anemia, tha-
			lassemia that are associated with Gaucher-like cells, that is, sea-
			blue histiocytes
Disorders in which deficiencies in lysosomal enzyme activities result		Cationic amphophilic drugs (ie, amiodarone, chloroquine,
	from intoxication with neutral or synthetic inhibitors of lysosomal		swainsonine)
	enzymes

[1] Joseph Alroy, DVM, DACVP, Department of Biomedical Sciences, Cummings School of Veterinary Medicine, Tufts University, 200 Westboro Road, North Grafton, MA 01536, USA.Email: joseph.alroy@tufts.edu

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Lysosomal Storage Diseases

Abstract