Transthyretin V122I amyloidosis with clinical and histological evidence of amyloid neuropathy and myopathy

Carr, AS; Pelayo‐Negro, Ana L.; Jaunmuktane, Zane; Scalco, R.; Hutt, David F.; Evans, Margaret C.; Heally, E.; Brandner, Sebastian; Holton, Janice L.; Blake, Julian; Whelan, Carol; Wechalekar, Ashutosh; Gillmore, Julian D.; Hawkins, Philip N.; Reilly, Mary M.

doi:10.1016/j.nmd.2015.02.001

Cited by 27 publications

(21 citation statements)

References 32 publications

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“…Whilst the latter has previously been attributed to competitive uptake of 99m Tc-DPD in the heart versus the bones, we have previously demonstrated on planar whole body imaging that the apparent attenuation of bone signal reflects uptake of tracer in the skeletal muscle and/or soft tissue overlying the bones, 11 further corroborated here by the highly significant increase in soft tissue to femur ratio observed in patients with a grade 3 99m Tc-DPD scan compared to a Perugini grade 2 99m Tc-DPD scan. Amyloid in the soft tissues and muscle has previously been reported as a clinical manifestation of ATTR amyloidosis, 19 and muscle biopsies performed in a small subset of patients in this cohort confirmed skeletal muscle amyloid in all 3 patients with Perugini grade 3 99m Tc-DPD scans, but none of 3 patients with Perugini grade 1 or 2 99m Tc-DPD scans. Whilst skeletal muscle amyloid deposits may be relatively scanty and of limited clinical significance, the total bulk of skeletal muscle in a patient may easily exceed 25 kg, compared to a typical myocardial mass of less than 0.5 kg.…”

Section: Discussionsupporting

confidence: 66%

Prognostic utility of the Perugini grading of 99mTc-DPD scintigraphy in transthyretin (ATTR) amyloidosis and its relationship with skeletal muscle and soft tissue amyloid

Hutt

Fontana

Burniston

et al. 2017

European Heart Journal - Cardiovascular Imaging

155

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High-grade (Perugini grade 2 or 3) cardiac uptake on bone scintigraphy with 99m Technetium labelled 3,3-diphosphono-1,2-propanodicarboxylic acid (99m Tc-DPD) has lately been confirmed to have high diagnostic sensitivity and specificity for cardiac transthyretin (ATTR) amyloidosis. We sought to determine whether patient stratification by Perugini grade on 99m Tc-DPD scintigraphy has prognostic significance in ATTR amyloidosis. Methods and Results Patient survival from time of 99m Tc-DPD scintigraphy was determined in 602 patients with ATTR amyloidosis, including 377 with wild-type ATTR and 225 with mutant ATTR amyloidosis (ATTRm). Patients were stratified according to Perugini grade (0-3) on 99m Tc-DPD scan. The prognostic significance of additional patient and disease-related factors at baseline were determined. In the whole cohort, the finding of a Perugini grade 0 99m Tc-DPD scan (n=28) was invariably associated with absence of cardiac amyloid according to consensus criteria as well as significantly better patient survival compared to a Perugini grade 1 (n=28), 2 (n=436) or 3 (n=110) 99m Tc-DPD scan (p<0.005). There were no differences in survival between patients with a grade 1, grade 2 or grade 3 99m Tc-DPD scan in wild-type ATTR (n=369), V122I-associated ATTRm (n=92) or T60A-associated ATTRm (n=59) amyloidosis. Cardiac amyloid burden, determined by equilibrium contrast cardiac magnetic resonance imaging, was similar between patients with Perugini grade 2 and Perugini grade 3 99m Tc-DPD scans but skeletal muscle/soft tissue to femur ratio was substantially higher in the latter group (p<0.001). Conclusion 3 99m Tc-DPD scintigraphy is exquisitely sensitive for identification of cardiac ATTR amyloid, but stratification by Perugini grade of positivity at diagnosis has no prognostic significance.

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Section: Discussionsupporting

confidence: 66%

Prognostic utility of the Perugini grading of 99mTc-DPD scintigraphy in transthyretin (ATTR) amyloidosis and its relationship with skeletal muscle and soft tissue amyloid

Hutt

Fontana

Burniston

et al. 2017

European Heart Journal - Cardiovascular Imaging

155

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“…Interestingly, subjects with Val122Ile had greater evidence of a neuropathic phenotype with more pain, numbness, tingling, and walking disability, and worse QOL. These data suggest that while the predominant phenotype of Val122Ile is cardiac, neurologic involvement -- only recently appreciated (40) -- is part of the spectrum of this condition.…”

Section: Discussionmentioning

confidence: 78%

Genotype and Phenotype of Transthyretin Cardiac Amyloidosis

Maurer

Hanna

Grogan

et al. 2016

Journal of the American College of Cardiology

405

247

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BACKGROUND Transthyretin amyloidosis (ATTR) is a heterogeneous disorder with multiorgan involvement and a genetic or nongenetic basis. OBJECTIVES We described ATTR in the United States in the THAOS (Transthyretin Amyloidosis Outcomes Survey) registry. METHODS Demographic, clinical, and genetic features of patients enrolled in the THAOS registry in the United States (n = 390) were compared to other regions of the world (ROW) (n = 2,140) with a focus on the phenotypic expression and survival in the majority of U.S. subjects with Val122Ile (n = 91) and wild-type ATTR (n = 189). RESULTS U.S. subjects are older (70 vs. 46 years), more often male (85.4% vs. 50.6%) and more often of African descent (25.4% vs. 0.5%) than ROW. A significantly higher percentage of U.S. patients with ATTR amyloid seen at cardiology sites had wild-type disease than the ROW (50.5% vs. 26.2%). In the United States, 34 different mutations (n = 201) have been reported, with the most common being Val122Ile (n = 91; 45.3%) and Thr60Ala (n = 41; 20.4%). Overall, 91 of 107 patients with Val122Ile (85%) were from the United States, where Val122Ile subjects were younger and more often women and black than wild-type patients, and had similar cardiac phenotype but a greater burden of neurologic symptoms (pain, numbness, tingling, and walking disability) and worse quality of life. Advancing age and lower mean arterial pressure, but not the presence of a TTR mutation, were independently associated with higher mortality from a multivariate analysis of survival. CONCLUSIONS In the THAOS registry, ATTR in the United States is overwhelmingly a disorder of older adult males with a cardiac-predominant phenotype. Val122Ile is the most common TTR mutation, and neurologic phenotypic expression differs between wild-type disease and Val122Ile, but survival from enrollment in THAOS does not. CLINICAL TRIAL NCT00628745

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“…Amyloidosis is characterized by extracellular and perivascular deposition of AA or AL amyloid . Rarely, amyloid myopathy occurs in patients with hereditary transthyretin amyloidosis (ATTR) . Occasionally, systemic amyloidosis due to multiple myeloma may be exclusively detectable in the skeletal muscle as ring‐fiber‐like muscle fibers, staining positive for Congo‐red .…”

Section: Resultsmentioning

confidence: 99%