MNP - polyneuropathy Flashcards
Which protein is encoded by SCN9A? Which disease?
Sodium channel, voltage-gated, type 9, alpha subunit
Hereditary sensory and autonomic neuropathy (HSAN) = Congenital insensitivity to pain (CIP) in mixed breed
Which stain allows identification of mitochondria?
Nicotinamide adenine dinucleotide reductase reaction
How can you diagnose hyperoxaluria in cats?
Deficiency in enzyme D-glycerate dehydrogenese
-> oxalate crystals
-> can identify L-glyceric acid and/or oxalate in urine
What is the causative gene and the pathological hallmark in demyelinating motor and sensory neuropathy in Miniature Schnauzer ?
SBF2/MTMR13
Tomacula (presence of focally folded myelin sheaths)
Name 2 chemotherapy agents associated with development of neuropathy.
Vincristin
Cisplatin
Which type of botulism toxin affect dogs, cats, horses, and cattle?
Dogs – C and D
Cats – D (one case)
Horses – A, B and C
Cattle – C and D
What is the only described cause of neonatal tetanus in puppies?
Omphalitis
3–5 day old American Bully puppies from the same litter
What is the difference between tetanus and tetany?
Tetanus is sustained (continuous) contraction of muscle(s).
Tetany is variable, intermittent contraction of muscle(s).
What are the diagnostic criteria of immune mediated polyneuropathy in cats?
Progressive muscle weakness with relative symmetry in PL or 4 limbs.
Young age (juvenile or young adult)
History of previous episodes that resolved without treatment
Decreased or absent tendon reflexes in weak limbs
Absence of sensory deficit
Cranial nerve involvement, especially bilateral facial weakness
EDX consistent with motor axonal PN
Nerve biopsy consistent with nodo-paranodopathy
What tick species are implied in tick-paralysis?What is the mechanism of the toxin? EDX findings? Treatment? Outcome?
Tick species:
Australia: Ixodes holocyclus, Ixodes cornuatus
USA: Dermacentor andersoni, Dermatocentor variabilis
Toxin: prevents presynaptic release of ACh at NMJ (presynaptic disorder) -> clinical syndrome characterized by ascending flaccid paralysis.
EDX: mild decreased CMAP amplitude, normal MNCV, F-wave latencies, and F-wave ratio
Treatment: tick removal, hyperimmune serum and supportive care until clinical signs resolve.
Outcome: possible complete recovery, but mortality rates of 2–5% due to respiratory failure.
Explain the pathophysiology of the clinical disease called tetanus and the routes of transmission.
Tetanus is caused by an exotoxin (tetanospasmin) produced by the Gram-positive, rod-shaped, obligate anaerobic bacterium,Clostridium tetani.
Clostridial spores are found everywhere in the environment and enter the body most frequently through wound contamination, but can also enter the body via contaminated surgery and dental infection. Under anaerobic conditions, the spores germinate, colonize the tissues, and begin producing exotoxin.
The exotoxin enters motor nerve axons at peripheral neuromuscular junctions and is retrogradely transported to the central nervous system where it crosses synaptic membranes into inhibitory interneurons. Within interneurons, tetanospasmin destroys a vesicular synaptic membrane protein (VAMP, or synaptobrevin), a SNARE protein integral in the fusion of neurotransmitter vesicles to the pre-synaptic membrane. This prevents exocytosis of the inhibitory neurotransmitters glycine and GABA in the synaptic cleft. This lack of inhibition in turn leads to excessive excitation of motor neurons causing sustained muscle contraction (ie, tetanus).
Name 3 mutations responsible for polyneuropathy in Leonberg and give corresponding age of onset and type of transmission.
LPN 1: ARHGEF10 – 2-4 years (before 6 years) – autosomal recessive
LPN 2: GJA9 – 1-10 years (usually more than 6 years) – autosomal dominant
LPPN: CNTNAP1 – laryngeal Paralysis associated with Polyneuropathy
Which antibodies are sensitive and specific for IMPN in dogs and cats?
Anti-GM2
Dog: Se 65% - Sp 90%
Cats: Se 71% - Sp 78%
Anti-GalNAc-GD1a
Dog: Se 62% - Sp 89%
Cats: Se 71% - Sp 71%
Give 4 lysosomal storage diseases with involvement of PNS.
Fucosidosis
Globoid cell leukodystrophy
Glycogenosis
Sphingomyelinosis (Niemann-Pick)
Which factor was associated with significantly higher mortality in cats with tick-paralysis in Australia?
- Cases with body temperature <35%
- Not being clipped vs being clipped
- Not receiving TAS
- All of the above
4
Give 3 dog breeds affected by motor neuron disease.
Brittany Spaniel (SMA [AD])
Rottweiler (polyneuropathy, ocular abnormalities and neuronal vacuolation, POANV)
Swedish Lapland (Lysosomal, glycogen storage disease, type II, Pompe)
Collie, Doberman Pinscher, English Pointer, German Shepherd, Giant Breed crosses, Griffon Briquet/vendéen, Saluki
Name the disease that induce a dysfunction of the cutaneous distribution of the sympathetic nerve and its clinical signs.
Name: complex regional pain syndrome
Clinical signs:
Hyperesthesia
Allodynia
Hyper/hypothermia
Hyper/hypohidrosis
Oedema
Give the mutations associated with motor neuron disease in cats. How is characterized the survival time?
LIX1 & LNPEP (AR)
Rapid early progression, then stabilisation, and prolonged survival time
Dysautonomia in dogs and cats is usually associated with Horner: true or false?
False
Only mydriasis is described with delayed PLR. Some cats and dogs can present third eyelid protrusion.
examples of flaccid paresis or paralysi
Hypermagnesemia, botulism, tick paralysis
What are the 4 factors associated with good outcome in cats with IMPN?
Mononuclear infiltrate
Mild fiber loss in IM nerve branches
Younger cats
Sudden onset
Remyelination correlated with less favourable outcome.
Give 5 clinical signs associated with canine and feline dysautonomia
Mydriasis
Absent PLRs
Dry mucus membranes
Retching
Vomiting
Dysphagia
Prolapse of the third eyelid
Urinary incontinence
Faecal incontinence
Constipation
Diarrhoea
Bradycardia
What is the early clinical sign in magnesium toxicity during the tetanus treatment in dogs?
Loss of patellar reflex
What are the genes and breed-related implicated in the hereditary sensory and autonomic neuropathy in dogs?
RETREG 1 (reticulophagy regulator 1)
Border collies
Cross breed-related
GDNF (glial cells derived neutrophic factor)
French Spaniel
English Springer Spaniel
German Shorthaired Pointer
English Pointer
SCN9A (voltage gated sodium channel 9, subunit alpha)
Mixed breed
How demyelinating and hypomyelinating affections can be differenciated in nerve biopsy
Oinon bulb formation in demyelinating (repetitive attempts by Schwann cells to regenerate lost myelin).
HPN produces either no onion bulbs or atypical onion bulbs, the latter of which are composed of basement membraneand little or no Schwann cell processes
Most common clinical signs of dysautonomia in dog
ocular: dim PLR (70%), elev IIrd eyelid (65%), decrease tear prod (60%)
non ocul: vomit/regur (90%), diarrhea (40%)
response pilocarpine 82%
survival discharge 40%
most common ocular/non ocular abnomalities with dysautonomia in dog
- ocular:
diminushed pupillary light reflex 70%
elevation third eyelid 65%
decreased tear production 60%
80 % resp pilocarpine
- non ocular: 4
vomiting, regurgit 90%
diarrhea 40%
histo lesion of NM neosporosis
inflam myositis 60%
necrotizing myopathy 30%
neuropathy 55%
3 histo type of immunemed polyneuropathy in cat
- mononuclar infiltrate
- demyelination
- Wallerian degeneration
sex predisposition in cat immune-mediated polyneuropathy
male
affection of sensory nerve in immune med polyneuropathy in cat?
%relapse
clinical factor assoc with recovery
No, pure motor
30-35%
young age, sudden onset clinical signs
sensory neuropathies: breeds and mutation
- Border Collie, mixed FAM134B = RETREG1
- Pointer, English Springer Spaniel, and FrenchSpaniel GDNF
- Mixed breed SCN9A
- Jack Russel T, Miniature Pinscher, Long haired Dashund
- Golden mitochon tRNATyr (central + perif sens/mot )
sensory neuropathies: onset
1. Border Collie FAM134B
2-7m
2. Jack Russel T
6y
- Long haired Dashund
2-3m - Pointer GDNF
2-12m - French Spaniel GDNF
3-12m - Miniature Pinscher
6m
sensory neuropathies: clinical signs
- Border + mixed breed RETREG1
-
Long-haired Dachshund
maj pelvic limbs, self-mutilation, absent nociception in the distal portion of the limbs incontin, regurgit, muscle atrophy only in Border -
GNDF: Pointer, English Springer Spaniel, French Spaniel
and Miniature Pincher, FoxTerrier
loss of distal pain sensation, self mutil
in pinscher lumbar hyperestheisa -
Jack Russel
hypermetric prop deficit loss nocicep - Golden tRNA Tyr
ataxic, have postural reaction deficits and reduced or absent spinal reflexes
self mutil: Border, Long haired dashund, Pointer, min Pinscher
Electrodiag in sensory neuropathies
decrease to absent sensory nerve compond action pot
in Border FAM134B + decrease motor neur velocity
normal electrodiag in Pointer, French Spaniel
Histopath in sensory neuropathy
- Pointer
lack staining substance P - Mixed breed RETREG1
Wallerian degeneration with some dystrophic changes
neuronal necrosis and degeneration in dorsal root and autonomic ganglia
moderate infiltration of lymphocytes and plasma cells
mechanism sensory neuropathy
RETREG1: reticulophagy regulator, Golgi protein responsible for regulating turnover of the endoplasmic reticulum by selective phagocytosis. Its inhibition impairs proteostasis in the endoplasmic reticulum because of accumulation of misfolded proteins, which in turn compromises neuronal survival and causes neurodegeneration
GDNF: Glial-cell Derived Neurotrophic Factor gene. neurotrophic factor essential for the development and maintenance of sensory neurons
NDGR1 polyneuropathy
Alaskan malamute + Greyhund
onset 3-9m
demyelinating
sim Charcot-Marie-Tooth
voice change, laryngeal paral, walking dif
Leonberg polyneuropathy
generalized weakness, decreased tendon refexes and laryngeal paralysis
severe form, early-onset : ARHGEF10 deletion
later age onset: GJA9 gene
polyneuropathy Black Russian Terrier
laryngeal paralysis, microphthalmia and proprioceptive ataxia
mut RAB3GAP1(Rab3 GTPase-activating protein catalytic subunit)
Warburg microsyndrome in humans
axonal neurop + spongiform encephalop (vacuols in neuronal cell bodies, axons and adrenal cells)
Rab proteins are involved in membrane trafficking in the endoplasmic reticulum, axonal transport, autophagy and synaptic transmission.
% cranial nerve involvement in polyradiculoneuritis
80%
most commonly vagal nerve (dysphonia)
antibodies in dog with polyradiculonevritis
anti-GM2 ganglioside
risk factor PRN
contact with racoon saliva
recent vaccination
upper resp or GI infection
consumption of raw chicken (Campylobacter upsaliensis)
polyneuropathy with ocular abnormalities and neuronal vacuolation
Alaskan Huskies, Black Russian, Rottweiler
onset 5m (visual pb) euthanasia around 1y
RAB3GAP1
humans: Warburg Micro syndrome 1
RAB proteins are master regulators of intracellular vesicle trafficking. RAB3 family members have their function in regulated exocytosis of hormones and neurotransmitters
bilateral microphthalmia, small pupils, and lenses with nuclear cataract +/- strabismus and/or persistent pupillary membranes
progressive severe ataxia
EMG: decremental responses of 20%
MRI: cortical cerebrum and cerebellar atrophy, triangular TL SC with thinning of dorsal part
histo: bilaterally symmetrical chronic Wallerian-type axonal degeneration in the SC
neuronal vacuolation in the cerebellar nuclei, SCGM, facial, gracile and cuneate, vestibular, oculomotor, substantia nigra, thalamic nuclei, hypothalamus, hippocampus, and cortex. Vacuoles were also observed in the surrounding neuropil. In cerebellar cortex, mild-to-severe Purkinje cell degeneration and loss
Polyneuropathy in Leonberger and Saint Bernard
CNTNAP1 gene, contactin-associated protein important for organization of myelinated axons
variable nerve fiber loss and scattered inappropriately thin myelinated fibers
English bulldogs and Irish terriers, two breeds with higher CNTNAP1 variant allele frequencies
congenital hypomyelinating polyneuropathy in Golden
affect exclusively the PNS (Charcot-Marie-Tooth )
weakness, laryngeal paral
slowed motor and sensory nerve conduction velocities
MTMR2, MPZ, and SH3TC2
“onion bulb” formations in peripheral nerve biopsies aid in determining demyelinating conditions, distinguishing these biopsies from hypomyelinating conditions
Canine leukoencephalomyelopathy
N-acyl phosphatidylethanolamine phospholipase D (NAPEPLD) gene encoding an enzyme of the endocannabinoid system. important in myelin homeostasis
Rottweiler, Leonberg
marked loss of mybilateral-symmetrical loss of myelin in the corticospinal tracts or dorsal/lateral tract, myelin was replaced by numerous fibrillary and gemistocytic astrocytes
progressive cerebellar ataxia and spasticity, combined with peripheral neuropathy in Great Pyrenees dog
onset 4m, slow progression
Purkinje cell degeneration, BS nuclei neuronal degen, SC WM degeneration, ganglion cells degen, thin myelin sheat
SACS gene
tetanus pathogenesis
tetanospasmin light chain inhibits release of glycine and GABA
Presynaptic blockade of synapses of Renshaw cells and 1a fibers of alpha motor neurons
eyes modification in tetanus
miosis
Protrusion of the 3rd eyelid and enophthalmos result from retraction of the globe, which is caused by extraocular muscle hypertonicity
