Phenotypes Associated With the Val122Ile, Leu58His, and Late-Onset Val30Met Variants in Patients With Hereditary Transthyretin Amyloidosis.

BACKGROUND AND OBJECTIVES: Hereditary transthyretin amyloidosis (hATTR) is a rare autosomal dominant systemic disease with variable penetrance and heterogeneous clinical presentation. Several effective treatments can reduce mortality and disability, though diagnosis remains challenging, especially in the United States where disease is nonendemic. Our aim is to describe the neurologic and cardiac characteristics of common US ATTR variants V122I, L58H, and late-onset V30M at presentation. METHODS: We conducted a retrospective case series of patients with a new diagnosis of ATTRv between January 2008 and January 2020 to characterize features of prominent US variants. The neurologic (examination, EMG, and skin biopsy), cardiac (echo), and laboratory assessments (pro b-type natriuretic peptide [proBNP] and reversible neuropathy screens) are described. RESULTS: A total of 56 patients with treatment-naïve ATTRv with symptoms/signs of peripheral neuropathy (PN) or cardiomyopathy and confirmatory genetic testing presenting with Val122Ile (N = 31), late-onset Val30Met (N = 12), and Leu58His ATTRv (N = 13) were included. The age at onset and sex distributions were similar (V122I: 71.5 ± 8.0, V30M: 64.8 ± 2.6, and L58H: 62.4 ± 9.8 years; 26, 25, 31% female). Only 10% of patients with V122I and 17% of patients with V30M were aware of an ATTRv family history, while 69% of patients with L58H were aware. PN was present in all 3 variants at diagnosis (90%, 100%, and 100%), though neurologic impairment scores differed: V122I: 22 ± 16, V30M: 61 ± 31, and L58H: 57 ± 25. Most points (deficits) were attributed to loss of strength. Carpal tunnel syndrome (CTS) and a positive Romberg sign were common across all groups (V122I: 97%, 39%; V30M: 58%, 58%; and L58H: 77%, 77%). ProBNP levels and interventricular septum thickness were highest among patients with V122I (5,939 ± 962 pg/mL, 1.70 ± 0.29 cm), followed by V30M (796 ± 970 pg/mL, 1.42 ± 0.38 cm) and L58H (404 ± 677 pg/mL, 1.23 ± 0.36 cm). Atrial fibrillation was present among 39% of cases with V122I and only 8% of cases with V30M and L58H. Gastrointestinal symptoms were rare (6%) among patients with V122I and common in patients with V30M (42%) and L58H (54%). DISCUSSION: Important clinical differences exist between ATTRv genotypes. While V122I is perceived to be a cardiac disease, PN is common and clinically relevant. Most patients with V30M and V122I were diagnosed de novo and therefore require clinical suspicion for diagnosis. A history of CTS and a positive Romberg sign are helpful diagnostic clues.

Mycobacterium leprae induces Schwann cell proliferation and migration in a denervated milieu following intracutaneous excision axotomy in nine-banded armadillos.

Nine-banded armadillos develop peripheral neuropathy after experimental Mycobacterium leprae infection that recapitulates human disease. We used an intracutaneous excision axotomy model to assess the effect of infection duration by M. leprae on axonal sprouting and Schwan cell density. 34 armadillos (17 naïve and 17 M. leprae-infected) underwent 3 mm skin biopsies to create an intracutaneous excision axotomy followed by a concentric 4-mm overlapping biopsy 3 and 12-months post M. leprae inoculation. A traditional distal leg biopsy was obtained at 15mo for intraepidermal nerve fiber (IENF) density. Serial skin sections were immunostained against a axons (PGP9.5, GAP43), and Schwann cells (p75, s100) to visualize regenerating nerves. Regenerative axons and proliferation of Schwann cells was measured and the rate of growth at each time point was assessed. Increasing anti-PGL antibody titers and intraneural M. leprae confirmed infection. 15mo following infection, there was evidence of axon loss with reduced distal leg IENF versus naïve armadillos, p < 0.05. This was associated with an increase in Schwann cell density (11,062 ± 2905 vs. 7561 ± 2715 cells/mm3, p < 0.01). Following excisional biopsy epidermal reinnervation increased monotonically at 30, 60 and 90 days; the regeneration rate was highest at 30 days, and decreased at 60 and 90 days. The reinnervation rate was highest among animals infected for 3mo vs those infected for 12mo or naïve animals (mean ± SD, 27.8 ± 7.2 vs.16.2 ± 5.8vs. 15.3 ± 6.5 mm/mm3, p < 0.05). The infected armadillos displayed a sustained Schwann cell proliferation across axotomy time points and duration of infection (3mo:182 ± 26, 12mo: 256 ± 126, naive: 139 ± 49 cells/day, p < 0.05). M. leprae infection is associated with sustained Schwann cell proliferation and distal limb nerve fiber loss. Rates of epidermal reinnervation were highest 3mo after infection and normalized by 12 mo of infection. We postulate that excess Schwann cell proliferation is the main pathogenic process and is deleterious to sensory axons. There is a compensatory initial increase in regeneration rates that may be an attempt to compensate for the injury, but it is not sustained and eventually followed by axon loss. Aberrant Schwann cell proliferation may be a novel therapeutic target to interrupt the pathogenic cascade of M. leprae.

Characteristics of children with leprosy: Factors associated with delay in disease diagnosis.

OBJECTIVES: The objectives of the study were to characterize the clinical profile of childhood leprosy presenting at tertiary leprosy care hospitals in the states of Bihar, West Bengal and Uttar Pradesh in India, and to determine the possible risk factors associated with disabilities at presentation. METHODS: Subjects were children with newly diagnosed leprosy registered for treatment at tertiary Leprosy Mission Hospitals in Muzaffarpur (Bihar), Purulia (West Bengal) and Faizabad (Uttar Pradesh), India, between June and December 2019. Demographic and leprosy characteristics were collected at the time of diagnosis. Parents/guardians were interviewed on reasons for delay in presenting at the hospital. Associations between various factors and delay in diagnosis were assessed. RESULTS: Among the 84 children, the mean (SD) age was 10 (3) years with a range of 4-14 years. There were more boys (58%) and most children were currently in school (93%), resident in rural areas (90%) and belonged to a lower socioeconomic status (68%). More children were diagnosed with multibacillary leprosy (69%), one-third of them being skin smear positive for Mycobacterium leprae. On presentation, 17% had deformity (5% grade 1 deformity and 12% grade 2), 29% had nerve involvement and skin lesions were spread across the body in half of the children. Mean (SD) duration of delay was 10.5 (9.8) months. Delayed presentation was more in boys (43% vs. 17%; P = 0.01), those without a history of migration for work compared to those who had a history of migration (40% vs. 9%; P = 0.008) and in those children who were from a poor economic status compared with those that came from a better economic status (44% vs. 7%; P = 0.001) Limitations: Because our study was conducted at tertiary care hospitals, the findings are not representative of the situation in the field. Furthermore, a comparison group of newly diagnosed adult leprosy patients with disability could have been included in the study. CONCLUSION: Childhood leprosy continues to occur in endemic pockets in India and a substantial number present with skin smear positivity and deformity. Guardians of these children cite many reasons for the delay in presentation.