Peripheral Neuropathies Flashcards
Peripheral Myelin Protein 22 (PMP22)
Compact myelin
Duplicated in CMT1a and deleted in HNPP
Myelin protein zero (MPZ) P0
Compact myelin
Adhesion melecule
Point mutation of P0 in CMT1B
some cases of CMT 2
Connexin 32 (Cx32 or GJB1)
Uncompacted paranodal myelin
Gap juntion protein
CMT X
Transthyretin (TTR)
Familial amyloidosis
IKBKAP
All cases of HSAN III with full penetrance
Important for carrier detection and egg selection
SMN 1
Commonly deleted in patients with SMA 1-3
Abdominal pain and neuroapthy
Porphyria, MNGIE, MEN2B
Trinucleotide Repeat or Peripheral Nerve
Frataxin: GAA (FA)
Polyglutamine diseases (CAG)
- Androgen receptor (Kennedy’s Disease)
- Ataxin (SCA 1,2,3)
INHERITED NEUROPATHIES
A 47 year old with N/V and epigasgtric pain. Two days later he develops a rapidly ascending weakness and sensory loss. After 2 weeks he develops substantial hair loss. Exposure to which agent is most likely.
A. Lead
B. Organophosphate
C. Thalium
D. Gold
E. Organic Mercury
Thallium exposure is associated with GI dysfunction and peripheral neuropathy. Severe cases may be associated with central nervous system dysfunction with ataxia, encephalopathy or coma. A distal axonal peripheral neuropathy develops 24-48 hours after exposure, follwed by allopecia 2-4 weeks after acute exposure.
ORANGE TONSILS
TANGIER’S DISEASE
ANGIOKERATOMA
FABRY’S DISEASE
RETINITIS PIGMENTOSA
HMSN VII
SCA 7
MITOCHONDRIAL DISEASE
REFSUM’S DISEASE
HYPERTROPHIC NERVES
HMSN 1
REFSUM’S DISEDASE
DEJERINE-SOTTAS DISEASE (HMSN III)
HYPERTELORISM, SHORT STATURE
HERIDITARY BRACHIAL PLEXOPATHY
ABSENSE OF FUNGIFORM TONGUE PAPILLAE
HSAN IV
TONGUE NODULES
MEN 2B
TIGHTLY CURLED HAIR
GIANT AXONAL NEUROPATHY
GYNACOMASTIA
KENNEDY’S DISEASE
EXTENSOR PLANTAR’S AND ABSENT ANKLE REFLEXES
FRIEDREICH’S ATAXIA
VITAMIN B12 DEFICIENCY
CARDIOMYOPATHY
AMYLOIDOSIS
FRIEDRICH’S ATAXIA
FABRY’S DISEASE
LOW HDL CHOLESTEROL
TANGIER DISEASE
ELEVATED SERUM PHYTANIC ACID
REFSUM’S DISEASE
DISPROPORTIONATE PROLONGATION OF DISTAL MOTOR LATENCIES
HNPP
ANTI-MAG-RELATED NEUROPATHY
ONION BULBS
HMSN I
REFSUM’S DISEASE
DEJERINE-SOTTAS DISEASE
CIDP
TOMACULAE
HNPP
LESS PROMINANT IN HMSN 1 AND CIDP
GIANT AXONS WITH DENSE CYTOPLASM
GIANT AXONAL NEUROPATHY
BROWN GRANULES IN SCHWANN CELL CYTOPLASM
METACHROMATIC LEUKODYSTROPHY
APPLE-GREEN BIREFRINGENCE
TTR
GELSOLIN OR A-I FAMILIAL AMYLOIDOSIS
MOST COMMON PATTERN OF INHERITANCE IS AUTOSOMAL DOMINANT
EXCEPT:
X-LINKED
- HMSN X
- FABRY’S DISEASE
- KENNEDY’S
AUTOSOMAL RECESSIVE
- MOST OF THE METABOLIC DISORDERS
- HMSN IV
- HSAN II-V
- FRIEDREICH’S ATAXIA
47 year old male experiences
A teased fiber preparation is most useful for demonstrating diagnostic findings in which of the following.
A. HNPP
B. DM Neuropathy
C. Neurofibromatosis
D. Peripheral nerve vaculitis
E. VIncristine neuropathy.
Teased fiver allows for evaluation of consecutive internodes or segments of the same myelinated nerve fiber over long distances. Peripheral nerve tomacula (latin = sausage) representing myelin redupilications are demonstrated in teased fiber preparations in HNPP. Myelin reduplication does not take place int eh other disorders listed.
A 75 YOF develops slowly progressive lower extremity spasticity. NCS demonstrate an axonal sensorimotor polyneuropathy. Her physician suspects zinc toxicity from excessive denture cream ingestion. Which lab fidning would support this diagnosis?
A. Pancytompenia.
B. Elevated ceruloplasm
C. Increased urinary copper
D. Low serum mag
E. Elevated methylmalonic acid
Excessive zinc ingestion can lead to impaired absorption of copper. Copper deficiency leads to degeneration of the poterios and lateral columns and can be associated with hematologic manifestionations including anema and leukopenia. Serum and urine copper levels would be decrased as weould ceruloplasm.
Elevatged methylmalonic acid levels would suggest vitamin B12 deficiency as an alternate for superimposed cause of her myeloneruopathy.
A male with DM develops a one year history of progressive numbness in the legs and decreased balance. Evaluation shows normal labs. EDX shows slowing of nerve conduction elcoities in the arms and legs with condcution block of the median and fibular motor nerves between the distal and proximal stimulations sites. Sensory potentials are absent. Needle shows decreased recruitment. Which of the following is the best treatment choice.
A. Oral CS
B. IV cyclophosphamide
C. Oral cyclopsorine
D. IV IG
E. Oral pregabalin
CIDP - IVIG drug of choice in setting of DM. Oral and IV cyclosporine and cyclophosphamide are used in refractory cases and have more serious side effect profiles.
The most common neuropathy in DM is:
A. Distal symmetric sensorimotor neuropathy.
B. Ulnar neuropathy at the elbow
C. Lumbosacral radiculoplexus neuropathy
D. Thoracoabdominal neuropathy
E. Cranial neuropathy
A. Affects 50% of patients with DM mkore than 20 years.
Median neuropathy at the wrist affects 30%
Autonomic and cranial neuropathies are found in 1%.
Mitochondrial neurogastrointestinal encephalopathy
MNGIE, also called myopathy, neuropathy, hastrointestinal encephalopathy
Which of the following agents may cause an acquired demyelinating polyneuropathy.
A. Chloroquine
B. Simvastatin
C. Thalidomide
D. Etanercept
D. Colchicine
D. All commercially available tumor necrosis factor antagonists (adalimumab, etanercept and infliximab) have been associated with chronic inflammatory demyelinating polyneuropathy0-like illness. Tacrolimus may induce a similar immune-mediated disorder.
Chronic use of which of the follwing agents is most likely to cause both a peripheral neuropathy and a myopathy?
A. Cisplastin
B. Vincristine
C. Amiodarone
D. Lithium
E. Arsenic
C. Neuromyelopthy my accur after 2-3 year of use. The remaining drugs are associated with a peripheral polyneuropathy but not myelopathy.
Treatment of Fabry’s disease
Fabry’s disease: enzyme replacment
Treatment of Transthyretin amyloidosis
Liver transplantation
Refsum’s disease
phytanic acid-free diet
Kennedy’s Disease
Possible role for antiandrogen therapy
HMSN II Subtypes
Heterozygous and less defined than I
At least six identified (a-f)
IIa- MFN2 and KIF1B
IIb - RAB-7, similar to HSAN 1
IId: GARS: may present as a motor neruonopathy
HMSN IIe: NFL
MFN2
Most common subtype in CMT 2,
Nuclear gene that encoudes for mitochonidral protein mitofusin 2
Mitofusin is imp in movement of mitochondria along microtubule by fusion, deprives the distal axon of an energy source
Features of CMT 2
Presents later in life
less upper limb weakness
IIb- severe sensory loss
IIc- diaphragm and vocal cord paresis
IId - upper limb envolvment early in the disease
HMSN III (Dejerine-Sottas disease)
Infantile onset of severe demyelinating neuropathy
Genetially heterogeneous PMP22, MPZ and EGR2
HMSN III (Dejerine-Sottas disease): Clinical features and EDX findings
Markedly reduced conduction velocities less than 10 m/s
Delayed motor milestones
wheelchair bound by early adulthood
palpable nerve hypertrophy
Prominant onion bulbs on nerve bx
*marked protein elevation (unlike other inherited neuropathies)
HMSN IV
Autosomal recessive
Rare
Previously referred to as Refsum’s disease
Severely early -onset demyelinating
HMSN IVa
mutation of GDAP1 gene of unown function) causes basal lamina onion bulbs without intervening layers of schwann cell cytoplasm
HMSN X
Rare - X-linked reessive
GJB1 (gap junction beta) gene encoding Cx32 which is a s Schwann cell transmembrane gap junction protein located in uncompacted myelin (in contrast to MPZ and PMP22) at the paranodal regions.
HMSN X
Resembles CMT1
with onset in adolescence, early proprio loss and sensory ataxia
Central hearing loss
Transient encephalopathy with exercie at altidue (>8000ft)
symmetric nonenhancing white matter abn
HMSN X: EDX
Mixed axonal and demyelinating with conduction velocities intermediate bw CMT 1 and CMT2
Upper limb CV around 30-38m/s
Rare forms of HMSN
HMSN - V: AD; assoc with spastic paraplegia
HMSN VI: AR associated with optic atrophy
HMSN VII: associated with ratinitis pigmentosia
Giant cell neuropathy
Giant cell neuropathy
Giant cell neuropathy: Rare, AR, mutation of the GAN gene on chromosome 16q24. encodes gigatoxin (PNS and CNS)
patients walk on inner edges of feet
spinocerebellar degeneration
tightly curled hair
death by the end of the third decade
Giant cell neuropathy Nerve biopsy
giant axonal swellings
dense cytoplasm
HNPP
AD
Deletion of portion of chromosome 17 containing PMP22
20% of cases do not have a macrodeletion therefore sequencing of pmp22 may show point mutations
Generalized multifocal demyelinating periopheral neuropathy
focal condcution slowing of black at common sites of compression
tomoculae
Hereditary Brachial Plexopathy: background
AD
Chromosome 17, gene not identified
Ocular hypotelorism (close set yes)
prominant epicanthal folds
Short stature
Hereditary brachial plexopathy: Clinical
preferential effects C5-C6
Patchy involvement of the plxus
HSAN 1
only AD form of HSAN
only adult form of HSAN
Slowly progressive Restricted to lower limbs
HSAN I: Genetics
SPTLC - chromosome 9q22 synthasizes sphingomyelin via enzyme palmitoyltransferease found in neurilemma (Long chain base 1) (LCB1)
and RAB7
- slow progression but restricted to lower limbs
- loss of sweat response
HSAN II: background
Onset early in life
severe panmodality senosry loss affecting upper and lower limbs, trunk and face
Mutilating acropathy
HSAN II: genetics
AR
mutation of one gene at chromosome 12q13.33
HSAN III: background
also called familial dysautonomia or Riley-Day syndrome
Presents at birth with widespread autonomic failure
Alacrima (absense of tears)
Dry respiratory secretions with frequent infections
GI dysmotility
autonomic dysregulation: tachycardia, HTN, sweating
**absense of tongue fungiform papillae
Pain sensation is preserved early - lost later in life
Poor prognosis : death in infancy and childhood
HSAN III: genetics
AR
Jews
IKBKAP (kinase complex associated protein)
HSAN IV:Genetics
AR
Mutation in the TRKA protein tyrosine receptor kinase A (TrKA)
insensitivity to pain with anhidrosis
hypertheramia
mild mental retardation
Normal SNAPs
HSAN V
similar to IV but different apthology
loss of small myelinated fibers mild decrease in unmyelinated fibers
Mutations in TRKA, NGFB
*Normal SNAPs
Demyelinating neuropathy with CNS disease
Metachromatic leukodystrophy
Krabbe’s disease
Adrenomyeloneuropathy
Refsum’s disease
Small Fiber sensory neuropathy
Fabry’s disease
Tangier disease
lysosomal enzymes
Metachromatic leukodystrophy
krabbe’s disedase
Metachromatic leukodystrophy
Inheritance: AR
Metabolic abn: arylsulfatase A deficency
lysosomal enzyme
Can meaures enzyme activity by skin fibroblast or leukocytes
Peroxisomal enzyems
Adrenokeukodystrophy and adrenomyeloneuropathy
fabry’s disease
refsum’s disease
lipoproten deficiency
Tangier disease
MCLD
childhood or adult onset
PNS and CNS involvement
spasticity, mental retardation, optic atrophy, MRI: white matter plaques and atrophy
EDX: demyelinating feateures
Path: metachromatic granules
Tx: bone marrow transplant
Globoid Cell leukodystrophy
AR
galactosylceramidase (lysosomal enzyme)
Clinical: PNS and CNS (similar to MCLD)
EDX: demyelinating
path: globoid cells
giant multinucleated epitheloid cells in brain and white matter
Bone marrow transplant if early in disease
Adrenomyelonneuropathy
X-linked recessive
Allelic with adrenoleukodystrophy
mutation on the ABCD1 on chromosome Xq28
ADLP - ATP-binding cassete (ABC) transport protein
transports VLCFA into peroxisome
deficiency causes accumulation of VLCFA
MIlder spastic paraplegia in third and fouthe decades, usually adult men with mild adrenal insufficiency
Refsum: previously classifed as HMSN IV
AR
phytanoyl-CoA hydroxylase - oxidizes phytanic acid
inital sympotms: night blindness
palp nerve hypertrophy
CNS involvement: ataxia, anosmia and deafness
*short fourth metatarsal
high CSF protein
elevated serum phytanic acid
TX: restriction of phytanic acid
Fabry’s disease
X-linked recessive
deficient of alpha galactasidase
results in accumulation of ceremide trihexoside in PNS in kidney and heart and PNS
enzyme replacement treatment early
tangier disease
AR
ABCA encoding ABCA 1 protein
defect lipid transport low HDL
