CNS Involvement in Hereditary Transthyretin Amyloidosis

Hereditary transthyretin amyloidosis (ATTRv amyloidosis) is predominantly a disease of the peripheral nerves, heart, kidney, and eye. CNS involvement has been a marginal issue in research and the clinical setting until recently. Growing evidence shows that leptomeningeal amyloid accumulation is frequent and present from early stages of ATTRv amyloidosis. Several recent studies show CNS symptoms arise as a common late complication in patients with the V30M mutation after at least 14 years of symptomatic peripheral nerve disease. Conversely, in non-V30M patients, there are several descriptions, mostly case reports, of patients presenting with severe phenotypes of ocular and CNS dysfunction (oculoleptomeningeal amyloidosis), with little systemic involvement. This phenotype is found in rare families worldwide, associated with at least 14 mutations. In both patients with late and early onset CNS dysfunction, symptoms include transient focal neurologic episodes, hemorrhagic and ischemic stroke, cognitive decline, and cranial nerve dysfunction. Pathologically, there is severe amyloid deposition in the leptomeninges and cerebral amyloid angiopathy of leptomeningeal and penetrating vessels. These amyloid aggregates are formed mostly by CSF-produced transthyretin (TTR) and seem resistant to the available ATTRv therapies that increase the stability or reduce the production of plasma TTR. This indicates that CNS involvement will become a meaningful issue in patient management in upcoming years.

Diagnostic and prognostic contribution of 99mTc-DPD scintigraphy in transthyretin V30M cardiac amyloidosis

Background Early diagnosis and prognostic stratification of hereditary transthyretin amyloidosis (ATTR) are crucial. Previous findings suggested that 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) scintigraphy presents suboptimal accuracy to detect ATTR cardiomyopathy caused by V30M mutation, particularly in patients with onset of symptoms under 50 years of age. Furthermore, its prognostic value has never been evaluated in ATTR caused by this mutation. Purpose To assess the diagnostic value of DPD scintigraphy to detect cardiomyopathy in a large cohort of patients with ATTR-V30M mutation and to explore its prognostic value regarding mortality. Methods Of the 305 ATTR-V30M mutation carriers followed prospectively and who underwent DPD scintigraphy, 288 individuals [median age 46 (39–56); 49% male] without myocardial thickening attributable to other causes were enrolled in the study. Amyloid cardiomyopathy was defined by septal thickness ≥13mm not attributable to other causes plus at least one of the following criteria: (1) late heart-to-mediastinum (H/M) 123I-metaiodobenzylguanidine (MIBG) ratio <1.60; (2) electrical heart disease (arrhythmia or cardiac conduction defect); or (3) amyloid infiltration documented in biopsy. Results Amyloid cardiomyopathy was identified in 41 (14.2%) patients and 44 (15.3%) individuals presented abnormal cardiac DPD uptake. Individuals with cardiac DPD retention had 27-fold higher likelihood of having amyloid cardiomyopathy (OR: 27.4; 95% CI 11.6–65.0; P<0.001). However, DPD scintigraphy presented suboptimal accuracy to detect ATTR cardiomyopathy (89.9%) with limitations in sensitivity (56.1%), specificity (95.6%), positive predictive value (67.7%) and negative predictive value (92.9%). During a mean follow-up 33.6±1.2 months, 16 patients died (5.6%). Mortality was 14 times higher in patients with amyloid cardiomyopathy (HR: 14.1; 95% CI 4.9–40.7; P<0.001), 13 times higher in those with abnormal cardiac DPD uptake (HR: 12.59; 95% CI % 4.56–34.72; P<0.001) and 10 times higher in those with H/M MIBG ratio <1.60 (HR: 10.40; 95% CI 2.95–36.69; P<0.001). The prognostic value of ventricular thickness and cardiac DPD uptake was additive: patients without septal thickening and no cardiac DPD retention had excellent prognosis (5-year mortality of 0.75%), while those with septal thickening and/or abnormal DPD retention presented 5-year mortality rates ranging from 39.9 to 53.3%. Conclusions DPD scintigraphy is valuable in the evaluation of ATTR-V30M mutation carriers, particularly for prognostic stratification purposes, identifying patients at higher risk of death. FUNDunding Acknowledgement Type of funding sources: None.

Early skin denervation in hereditary and iatrogenic transthyretin amyloid neuropathy

Objective:To elucidate early skin denervation in hereditary transthyretin (TTR) amyloidosis and iatrogenic TTR amyloidosis.Methods:We investigated intraepidermal nerve fiber density (IENFD) and clinical findings in 32 patients with hereditary TTR amyloidosis, 11 asymptomatic mutation carriers, 6 patients with iatrogenic TTR amyloidosis, and 23 healthy volunteers.Results:IENFD values were reduced in patients with the V30M mutation (1.9 ± 2.1 per 1 mm), patients with non-V30M mutations (5.8 ± 3.2 per 1 mm), and patients with iatrogenic TTR amyloidosis (3.5 ± 1.8 per 1 mm) compared with healthy volunteers (11.8 ± 3.2 per 1 mm) (p < 0.01). Skin denervation also occurred, even in presymptomatic V30M mutation carriers (5.0 ± 2.2 per 1 mm). The IENFD was correlated with disease duration (ρ = −0.533, p = 0.002) and various peripheral neuropathy parameters such as sensory impairment in the Kumamoto clinical score (ρ = −0.575, p = 0.001), heat-pain detection threshold (ρ = −0.704, p < 0.001), and sural sensory nerve action potential (ρ = 0.481, p = 0.005). TTR amyloid deposits frequently occurred in connective tissues and vessels of the dermal reticular layer in patients with hereditary TTR amyloidosis and those with iatrogenic TTR amyloidosis.Conclusions:Patients with hereditary TTR amyloidosis and those with iatrogenic TTR amyloidosis may show early skin denervation even in the presymptomatic stage. IENFD may thus be useful for early diagnosis and may serve as a biomarker in clinical trials for hereditary and iatrogenic TTR amyloidosis.