2/16/2018 Patient Summary Recent Advances in Neurology 2018 71 year-old right-handed man with HTN and hyperlipidemia referred for progressive numbness Had bilateral CTS underwent bilateral releases with success Difficult Diagnosis: In the last 18-months: A Polyneuropathy That Made a Turn for the Worse Numbness in the soles of the feet When it reached the ankles, he noticed numbness in the lateral right hand and forearm In time, the numbness extended up to the knees He then developed mirror symptoms in the left hand and forearm 15-20 lbs. weight loss over the past year Negatives: No pain or radicular symptoms No bowel or bladder control problems No fevers, chills, or night sweats Up to date on cancer screening Jeffrey W. Ralph, MD Testing From Care Everywhere HgbA1c: 5.4; SPEP/IFE: Normal; ESR: 2; RPR: NR; GM-1AB: Negative; TSH .98 “Suspicion of _________ given EMG 1/2016: the sequence of events to date.” IMPRESSION: 1) a moderate distal axonal sensorimotor polyneuropathy 2) a severe right median neuropathy at the wrist (carpal tunnel syndrome). Dr. Raymond Stephens Similar to those obtained by Dr. R. Stephens on 7/8/2015. 1
2/16/2018 Six Months Later… Recent Exam cont. Speech now slurred; numbness up to the Moderate weakness in proximal muscle groups in UEs + LEs; severe weakness of distal muscles in UEs + LEs thighs; numbness in the anus and perianal No reflexes; flexor plantar responses bilat region; could not open bottles. LT and pain sensation diffusely, severely impaired in the CN: moderate lingual dysarthria; tip of limbs tongue numb; tongue-scalloped Vibration sensation intact at fingers; absent in RLE; absent distal to knee in LLE appearance w/ fasciculations JPS very impaired at toes Fasciculations seen in the shoulders and HKS clumsy with eyes closed quadriceps Wide based gait; could not walk on heels or toes; Romberg-moderate sway Atrophy of the hand and leg muscles Which of the following genetic What would you do next? neurological disorders has an effective medical treatment? Repeat EMG/NCS A. 55% Nerve Biopsy B. Pompe disease A. 55% Lumbar Puncture C. Familial amyloidosis B. 21% 17% Genetic testing 32% D. C. Spinal Muscular Atrophy No more testing… 4% 3% E. 8% 5% time for IVIG trial. D. All of the above S y e g C s . . r n . N p u o t i / o t f i c s G B e e n M t m e u c E v P i i e s e t t s i y r r e s h v t e … a o o a a n e p N b g s d o b e e i p m n d i o r a G l t e t i y A e u e h R s p m r L e t m a a f t l o o l u e a c l P i s l r l A o i u m M m a F l o a N n i p S 2
2/16/2018 Back to the patient… Genetic testing Left gastrocnemius and sural nerve TTR gene biopsies: Congo red: deposits of salmon- c.250T>C heterozygous pink material that demonstrate apple- p.Phe84Leu green birefringence on polarization MUTATION Transthyretin stain is positive; amyloid A, kappa, and lambda stains negative. Dx: amyloid myopathy; amyloid neuropathy Transthyretin: the transporter Amyloidosis for thyroxine and retinol Binds: Thyroxine (20%); Retinol binding protein 4 exons & 127 amino acids Extracellular deposition of soluble precursor Normal configuration: tetramer protein that aggregates in the form of insoluble fibrils Amyloidogenesis: tetramer dimers Molecular β-pleated sheet structure with peptides monomers dissociate & may fold aberrantly in antiparallel configuration aberrantly folded monomers aggregate to form Serum amyloid P, a glycoprotein, is a constituent amyloid of all amyloid Damage mainly secondary to tissue infiltration and swelling 3
2/16/2018 Familial Transthyretrin Both Wild-Type and Mutant TTR Cause Amyloidosis Amyloidosis Mutant TTR; ATTRM Wild-type TTR (no AND mutation); ATTRWT >150 mutations Age > 30 AND Age > 70 Almost all missense point mutations Familial Transthyretin Senile Amyloidosis Autosomal dominant Amyloidosis de novo mutations occur, but Cardiac TTR amyloid frequency not known Amyloidosis TTR neuropathy leptomeningeal/CNS (TTR-FAP) amyloidosis Poly- Carpal tunnel neuropathy syndrome (?) TTR cardiac amyloidosis True or false: The absence of a family history DISEASE PHENOTYPE DEPENDS ON TTR MUTATION, makes transthyretin familial amyloid GEOGRAPHIC REGION, AND GENETIC MILLEAU polyneuropathy unlikely. Penetrance and age of onset is variable 94% Val30Met mutation TRUE A. In Portugal, 80% by age 50, and 91% by age 70 FALSE B. In French, 13% by age 30, 50% by age 70 In Sweden, 1.7% by age 30, 5% by age 40, 11% by age 50, 22% by age 60, 36% by age 70, 52% by age 80, and 69% by age 90. 6% E E U S L R A T F 4
2/16/2018 TTR-Familial Amyloid TTR Familial Amyloid Polyneuropathhy Neuropathy In the US Neuropathy Late onset is common and family history often Usually starts in the lower extremities negative (50%) Sensory symptoms—burning, shooting pains 21 % have Val30Met variant (In Portugal, 90-100%) Loss of small > large fibers (but sometimes small and large fiber dropout are =) Epidemiology-Prevalence Motor symptoms—Foot drop, wrist drop, and Worldwide disability of the hands and fingers common TTR-FAP prevalence 0.87-1.1 / 1,000,000 Autonomic neuropathy—Constipation, constipation Endemic areas altering with diarrhea, delayed gastric emptying, Portugal , 1:909 people anhidrosis, and urinary incontinence Japan, Nagano prefecture, 1:1108 people Diagnosis: Tissue is the Issue Management Neurologist Abdominal fat Clinical examination Gastric or rectal Disability scores Deposition of mucosa Cardiologist – early diastolic dysfunction and Amyloid – Immuno- later systolic failure Sural nerve Congo Red histochemistry Interventions Staining Cardiac Carpal tunnel release for CTS Pacemaker implantation for second-degree or third- Van Selby, MD Peritendinous fat degree AV block OR Mass Spectrometry- Based Proteomics If TTR Sequence the gene 5
2/16/2018 Treatments for Slowing Progression Liver Transplantation of TTR-FAP Purpose: Removes the source of mutant TTR Liver transplantation Stabilizes polyneuropathy – little objective improvement TTR Stabilizers Until recently, the “Standard of Care” treatment for TTR- FAP Tafamadis (Europe only) OLTX for early onset V30M-ATTR: 10 year survival Diflunisal (US) 100% vs. 56% for nontransplanted patients (Yamashita et al. Neurology 78:637-643) TTR Gene Silencing Antisense Oligonucleotides (ASOs) – Inotersen Small Interfering RNA (siRNA) – Patisiran Immune-Mediated Amyloid Clearance Anti-SAP Monoclonal Antibodies (hu-SAPMab) Liver Transplantation II TTR Stabilizer: Tafamidis Eligibility Function Inhibits dissociation of TTR tetramers in vitro Age younger than 60 years Safe and well tolerated Disease duration less than 5 years Pivotal study* Either polyneuropathy that is restricted to the Intention to treat analysis – benefit not significant lower extremities or autonomic neuropathy 87/128 patients evaluated – benefit significant alone Regulatory Status 2012 – Approved in Europe for stage I ATTR polyneuropathy No significant cardiac or renal dysfunction Must be biopsy proven OLTX not effective in non-neuropathic TTR amyloidosis Not approved in the US Cardiac amyloidosis – may progress; even accelerate after OLTX in non Val30Met patients Coelho T et al., Neurology 2012;79:785–792 6
2/16/2018 Formation of Disease-Causing Proteins TTR Stabilizer: Diflunisal NSAID, 250mg twice daily Gene RNA Disease-Causing Randomized, double blind study of 130 patients Protein Patients had different mutations TRANSCRIPTION TRANSLATION Endpoint – difference in neuropathy progression as measured by Neuropathy Impairment Score + 7 nerve tests 87 patients completed year 1 and 68 completed year 2 Results: NIS+7 Score difference 6.1 @ 1 year (p 0.02) and 16.3 @ 2 yrs (<0.001) Adverse events 4 stopped treatment (GI bleeding, CHF, glaucoma, and nausea) Promising drug for TTR-FAP, and it’s cheap. Courtesy of Ionis 26 Inotersen Addresses the Underlying Cause of Small Molecules & Biologics Target Proteins All Forms of ATTR SMALL MOLECULES Gene Gene TRADITIONAL MEDICINE ANTISENSE DRUG Inotersen mRNA DISEASE RNA MODIFICATION (Mutant and wild-type) Prevents Formation of All Types of TTR Protein Blocks Disease-Causing Translation Protein TRANSCRIPTION TRANSLATION TRANSCRIPTION DISEASE Designed to Cause Destruction of RNA DISEASE MODIFICATION Less RNA = Less PROTEIN Courtesy of Ionis BIOLOGICS Courtesy of Ionis 27 28 ANTIBODIES 7
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