Storage Disorders Flashcards
GM1 gangliosidosis type I:
- Enzyme deficiency and stored product?
- Species and breeds (4)
- Age at onset of clinical signs?
GM1 gangliosidosis type 1
- Enzyme deficiency = B-galactosidase
- stored product = ganglioside
- Beagle cross - 3m
- Portugese water dog 5m
- Domestic cat 2-3m
- Fresian cattle 1m
- English Springer Spaniel
Skeletal abnormalities and widened intervertebral disc spaces (English Springer Spaniels and PWD)
GM1 gangliositosis type 2:
Enzyme deficiency and stored product?
Species and breeds (4)
Age at onset of clinical signs?
Skeletal abnormalities?
GM1 gangliosidosis type 2:
B galactosidase enzyme deficiency
Siamese, Portugese water dog, Korat and domestic cat: 2-3m
Suffolk sheep 4m
Skeletal abnormalities and widened intervertebral disc spaces (English Springer Spaniels and PWD)
GM2 gangliosidosis (types 1, 2, 3)
Enzyme deficiency and stored product?
Species and breeds
Age at onset of clinical signs?
Glucocerebrosidosis:
Enzyme deficiency and stored product?
Species and breeds
Age at onset of clinical signs?
Glucocerebrodisosis
Enzyme deficiency = B-glucosidase
stored product = glucocerebroside
Breeds: Sydney silky and Abyssinian cat (6-8m)
Sphingomyelinosis:
Enzyme deficiency and stored product?
Species and breeds
Age at onset of clinical signs?
Pathologic lesions?
Sphingomyelinosis = Niemann Pick disease
enzyme deficiency = sphingomyelinase
stored product = sphingomyelin
Breeds: Siamese, Balinese, domestic cat (2-4m), Poodle 2-4m
Lesions: PNS affected
Globoid Cell Leukodystrophy
Enzyme deficiency and stored product?
Species and breeds
Age at onset of clinical signs?
Pathologic lesions?
globoid cell leukodystrophy
Enzyme deficiency: Galacrocerebrosidase (galactosylceramidase 1)
Stored product: Galactocerebroside (psychosine = galactosylsphingosine)
Breeds:
- Carin terrier 2-5m
- West Highland White Terrier, Beagle, Blue Tick Coonhound 4m
- Miniature Poodle 2y
- Basset Hound 1.5 - 2y
- Pomeranian dog 1.5y
- Domestic cat 5-6 weeks
- Polled Dorset Sheep 4-18m
Marked degeneration and loss of white matter in the cord and brain
Perivascular accumulation of globoid cells
PNS lesions common
Mucopolysaccharidosis
Enzyme deficiency and stored product?
Species and breeds
Age at onset of clinical signs?
Skeletal abnormalities?
Mucopolysaccharidosis
Enzyme deficiency: Arylsulfatase B and alpha-Iduronidase
Stored product: Mucopolysaccharide
Breeds:
- Siamese, domestic cat 4-7m
- Domestic cat 10m
- Plott Hound 3-6m
- Miniature Pinscher 6m
- Mixed-breed dog 4-6m
Craniofacial malformation, joint immobility
PL paresis secondary to bony vertebral growths that compress the spinal cord
Glycoproteinosis
Enzyme deficiency and stored product?
Species and breeds
Age at onset of clinical signs?
Glycoproteinosis
Enzyme deficiency and stored product = unknown
Breeds: Beagle, Basset hound, Poodle 5m - 9y
Mannosidosis (alpha and beta)
Enzyme deficiency and stored product?
Species and breeds
Age at onset of clinical signs?
Mannosidosis
Enzyme deficiency: alpha-mannosidase or beta mannosidase
Stored product: Mannoside (in both alpha ane beta)
Breeds:
- Alpha mannosidase: Domestic cat 7m, Persian cat 2m; Angus, Murray grey, Galloway and Holstein cattle (at birth); Horses and farm animals (at birth) ; Grazing species of Swainsona (at birth)
- Beta mannosidase: Nubian goat (Birth - 1y), Salers calf (at birth)
Glycogenosis
Enzyme deficiency and stored product?
Species and breeds
Age at onset of clinical signs?
Glycogenosis
Enzyme deficiency: alpha-glucosidase
Stored product: glucoside
Lapland dog (1.5y)
English springer spaniel (11y)
Domestic cat, Norwegian forest cat (5m)
Corriedale sheep (6m)
Short horn, Brahman cattle (3-9m)
Fucosidosis
Enzyme deficiency and stored product?
Species and breeds
Age at onset of clinical signs?
Clinical signs?
Pathology?
Fucosidosis
- Enzyme deficiency: alpha fucosidase
- Stored product: fucoside
- Springer Spaniel (2y) - older age is unique feature
- Forebrain dysfunction, progresses over 2-3 years to include signs of ataxia, dysphagia, vision and hearing loss, nystagmus, and dysphonia
- Enlargement of the ULNAR nerves is often palpable - edema and infiltration of the nerves with lipid filled phagocytes/Schwann cells
- Also ganglionic thickening
- Wide-spread vacuolation of neurons and glia throughout the brain
- PNS lesions common
Ceroid lipofuscinosis
Enzyme deficiency and stored product?
Species and breeds
Age at onset of clinical signs?
Autofluorescent pigment is stored in neurons and other cells of the body
Most common breeds: Pit Bull Terriers, Staffordshire Terriers, Irish Setters
In which lysosomal storage diseases are cerebellar dysfunction the initial clinical signs? (5)
In which diseases are forebrain signs the initial clinical signs? (
Cerebellar dysfunction:
- Mannosidosis
- Gangliosidosis
- Globoid cell leukodystrophy
- Glucocerebrosidosis
- Sphingomyelinosis
Forebrain dysfunction
- Neuronal glycoproteinosis (Lafora’s disease)
- Ceroid Lipofuscinosis
- Fucosidosis
(Dewey)
Which 2 lysosomal storage diseases are unique in their later onset in life?
Ceroid lipofuscinosis
- Behavior changes, visual deficits 1-2y old, progresses to seizures, ataxia, tremors, hypermetric gait
- A form of CL that selectively involves neurons in the cerebellum and thalamus of adult dogs has been described - progressive cerebellar dysfunction
Fucosidosis
- 12-18 mos of forebrain dysfunction progressive over 2-3y
- ataxia, dysphagia, vision and hearing loss, nystagmus, dysphonia
- Enlargement of the ULNAR nerves is often palpable (edema and infiltration of the nerves with lipid-filled phagocytes and Schwann cells)
(Dewey)
Storage disease that has later onset, clinical signs of:
- Behavior changes, visual deficits
- Progresses over 1-several years to include seizures, ataxia, tremors, hypermetric gait
- Gene mutations?
Ceroid lipofuscinosis
- Accumulation of autofluorescent lipofuscin pigment-like material (characteristic ultrastructural lamellar profiles) in NEURONS and other cells of the body –> degeneration
Gene mutations identified leading to neuronal Ceroid lipofuscinosis?
- TPP1 gene frameshift identified in Miniature Dachshunds (CLN 2 deficiency)
- CLN8 mutation in English Setters
- CLN5 deficiency in Border Collie
- Cathepsin D mutation in American Bulldog
- ATP13A2 mutation in Tibetan Terriers (late onset)
- Arylsulfatase G mutation –> sulfatase deficiency (lysosomal enzyme) in Staffordshire Terriers
- ** unclear if NCL is a lysosomal storage disease, may be a mitochondrial disease
(Vanvelde)
In american staffordshire terriers and crosses, NCL storage primarily affects _________ cells and certain __________ nuclei
Purkinje cells and thalamic nuclei –> thalamic and cerebellar atrophy
(Vanvelde)
Which 4 lysosomal storage diseases involve skeletal abnormalities
Craniofacial malformations, joint immobility
- Mannosidosis
- Mucopolysaccharidoses
- Mucolipidosis II
Mucopolysaccharidoses + mucolipidosis II - PL paresis often develops due to impingement of the spinal cord by bony vertebral growths
Skeletal abnormalities and widened intervertebral disc spaces
- Gangliosidosis of English Springer Spaniels and Portugese water dogs
- Dwarfism associated with gangliosidosis has been described in English Springer Spaniels
(Dewey)
Which storage diseases affect the PNS? (4)
- Fucosidosis
- Genes necessary for normal myelin assembly are down-regulated
- Globoid cell leukodystrophy
- Glycogenoses
- Myopathy
- Sphingomyelinosis (Niemann-Pick disease)
Dewey
In which LSD has generalized seizures, obtundation, tremors and weakness associated with hypoglycemia been reported?
Glycogenosis type Ia
Glucose-6 phosphate deficiency
Maltese
(Dewey)
In which LSD do cats have an increased risk for developing meningioma?
Mucopolysaccharidosis type I
alpha-L-iduronidase deficiency
(Dewey)
Ocular abnormalities with lysosomal storage disease
Corneal abnormalities? (3)
Retinal degeneration(2)
Cardiac abnormalities with lysosomal storage disease? (1)
Corneal abnormalities
- Gangliosidosis of cats
- Mannosidosis of cats
- Mucopolysaccharidosis type VII in dogs
Retinal degeneration
- Ceroid lipofuscinosis (Tibetan Terrier, Miniature Schnauzer, Cocker Spaniel)
- Cats with mucolipidosis II
Cardiac abnormalities - glycogenosis
Diagnosis of lysosomal storage disease?
- Tentative diagnosis based on progressive multifocal/diffuse encephalopathy in a young animal (especially susceptible breed)
- CSF analysis usually normal, may reveal increased protein with a normal cell count
- CT/MRI - ventriculomegaly, brain atrophy, abnormal brain tissue density
- GM1 with sequential brain MRI - diffuse cerebral white matter hyperintensity on T2 weighted and FLAIR images in addition to brain atrophy later in the disease course
- Definitive diagnosis is made by
- Identification of the storage product and/or demonstrating the presence of the defective gene responsible for the disease
- Whole blood leukocytes, tissue biopsy samples (liver), cultured fibroblasts can be used to demonstrate storage material and assay deficient lysosomal enzyme activity
- Mannosidosis, mucopolysaccharidosis, fucosidosis - accumulated storage product can be identified in urine using specific assays
(Dewey)
IV/intrathecal recombinant enzyme replacement therapy has been used to treat which lysosomal storage diseases?
Intrathecal or intraparenchmal therapy for lysosomal storage disease with viral vector has been done with which disease?
Oral treatment of which lysosomal storage disease has been successful?
IV/intrathecal recombinant enzyme replacement therapy
- Canine fucosidosis + Mucopolysaccharidosis I and IIIA
- Feline mucopolysaccharidosis type VI
Intrathecal or intraparenchmal therapy with viral vector
- Feline alpha-mannosidosis
- Canine mucopolysaccharidosis I and IIIB
Oral treatment - cats with Niemann-Pick disease type C with imino sugar called miglusat - delayed onset of neurologic signs, increased lifespan, decreased accumulation of gangliosides GM 2 in neurons and prolonged Purkinje survival
(Dewey)
