Renal tubular acidosis in hereditary transthyretin amyloidosis (ATTRv) / Acidose tubular renal na amiloidose hereditária por transtirretina (ATTRv)

Abstract Introduction: Hereditary transthyretin amyloidosis (ATTRv) is a severe autosomal dominant systemic disease. It affects the peripheral and autonomic nervous systems, heart, kidneys, and eyes. Amyloid deposition has been demonstrated in the glomerular and tubulointerstitial compartments of the kidney. Therefore, urinary acidification disorders such as renal tubular acidosis (RTA) may be early manifestations of renal involvement in this population. Objective: To evaluate the prevalence of RTA in individuals with ATTRv. Methods: We included symptomatic and asymptomatic individuals with TTR mutation, older than 18 years, GFR >45 mL/min/1.73m2, without systemic metabolic acidosis. Urinary acidification protocol was performed with furosemide and fludrocortisone after 12 h of water deprivation (water deprivation test - WDT) and measurements of urine ammonium ( UNH 4 +) and titratable acidity (UTA). Proximal RTA (pRTA) was diagnosed when FEHCO3>10%. Incomplete form distal RTA (dRTA) was diagnosed if UpH>5.3. Results: We selected 49 individuals with a mean age of 40 (35.5-56.5) years, 63% of which were female, 84% were Caucasian, and mean GFR was 85.5 ± 20.5 mL/min/1.73m2. 94% had the genetic variant Val50Met and 57% were symptomatic. The prevalence of pRTA was 2% and of dRTA was 16.3%. In the subgroup with dRTA, there was no significant increase in excretion of UNH 4 + and UTA. We observed a good correlation between UpH by potentiometry and UpH dipstick. A UpH<5.5 on the dipstick had 100% sensitivity and negative predictive value to exclude dRTA. Conclusion: A high prevalence of RTA was found in individuals with TTR mutations. The UpH dipstick after WDT had good accuracy for screening for dRTA. Further studies are needed to evaluate the impact of early diagnosis and treatment of RTA in this population.

Resumo Introdução: A amiloidose hereditária por transtirretina (ATTRv) é uma doença sistêmica autossômica dominante grave. Afeta os sistemas nervoso periférico e autônomo, coração, rins e olhos. A deposição de amiloide foi demonstrada nos compartimentos glomerular e tubulointersticial do rim. Portanto, distúrbios de acidificação urinária, como acidose tubular renal (ATR), podem ser manifestações precoces de envolvimento renal nessa população. Objetivo: Avaliar a prevalência de ATR em indivíduos com ATTRv. Métodos: Incluímos indivíduos sintomáticos e assintomáticos com mutação na TTR, maiores de 18 anos, TFG >45 mL/min/1,73m2, sem acidose metabólica sistêmica. Realizou-se protocolo de acidificação urinária com furosemida e fludrocortisona após 12 horas de privação hídrica (teste de restrição hídrica - TRH) e medições de amônia urinária ( uNH 4 +) e acidez titulável (uTA) na urina. ATR proximal (ATRp) foi diagnosticada quando FEHCO3>10%. ATR distal (ATRd) de forma incompleta foi diagnosticada se pHu>5,3. Resultados: Selecionamos 49 indivíduos com idade média de 40 (35,5-56,5) anos, 63% mulheres, 84% caucasianos e TFG média de 85,5 ± 20,5 mL/min/1,73m2. 94% apresentaram a variante genética Val50Met; 57% eram sintomáticos. A prevalência de ATRp foi 2% e a de ATRd foi 16,3%. No subgrupo com ATRd, não houve aumento significativo na excreção de uNH 4 + e uTA. Observamos uma boa correlação entre pHU por potenciometria e pHU por fita reagente. Um pHU<5,5 na fita reagente apresentou 100% de sensibilidade e valor preditivo negativo para excluir a ATRd. ConclusÃO: Uma alta prevalência de ATR foi encontrada em indivíduos com mutações na TTR. O pHU por fita reagente após TRH teve boa precisão para triagem de ATRd. São necessários mais estudos para avaliar o impacto do diagnóstico e tratamento precoces da ATR nessa população.

Long-term follow-up observation after vitrectomy in a family with vitreous amyloidosis due to transthyretin gene Gly83Arg mutation / 中华眼底病杂志

Objective:To investigate the causes of secondary glaucoma after vitrectomy for familial vitreous amyloidosis associated with transthyretin (TTR) gene Gly83Arg mutation.Methods:A retrospective case study. From January 2008 to January 2020, 13 cases (23 eyes) with hereditary vitreous amyloidosis and treated by vitrectomy in the Affiliated Hospital of Zunyi Medical University were collected. Among them, there were 7 males with 12 eyes and 6 females with 11 eyes. The average age was 43.0±4.8 years. All the affected eyes underwent standard three-channel vitrectomy through the flat part of the ciliary body. According to whether complete vitreous detachment (PVD) was formed during the operation, it was divided into complete PVD group and incomplete PVD group; according to the occurrence time of secondary glaucoma and vitreous amyloidosis after surgery, it was divided into 1-12 months group and 13-36 months group, >37 months group. The average follow-up time after surgery was 36.7±6.0 months. The incidence of secondary glaucoma and the recurrence rate of vitreous amyloidosis between groups were compared by χ2 test; the correlation between recurrence of vitreous amyloidosis and secondary glaucoma after surgery was analyzed by Spearman rank correlation analysis. Results:Among the 23 eyes, there were 8 eyes in the complete PVD group and 15 eyes in the incomplete PVD group, respectively. Vitreous amyloidosis recurred in 15 eyes (65.22%, 15/23) after surgery. There were 14 (93.30%, 14/15) and 1 (6.70%, 1/15) eyes in the incomplete PVD group and the complete PVD group, respectively; the comparison of the recurrence rate of vitreous amyloidosis between the two groups was statistically significant ( χ2=11.676, P<0.01). 1-12 months group, 13-36 months group, >37 months group included 1 (4.35%, 1/23), 12 (52.17%, 12/23), 2 (8.70%, 2/23) Only eye. The recurrence rate in the 13-36 months group was significantly higher than that in the 1-12 months group and >37 month group. Secondary glaucoma occurred in 11 eyes (47.80%, 11/23) after surgery. 1-12 months group, 13-36 months group, above 37 months group were 1 (4.35%, 1/23), 8 (34.78%, 8/23), 2 (8.70%, 2/23) eyes. The incidence of secondary glaucoma in the 13-36 months group was higher than that in the 1-12 months group and >37 months group. Among 11 eyes with secondary glaucoma, 10 eyes had recurrence of vitreous amyloidosis after surgery, and 1 eye had no recurrence. The results of Spearman rank correlation analysis showed that there was a positive correlation between the recurrence of vitreous amyloidosis and the occurrence of secondary glaucoma ( rs=0.516, P=0.012). Conclusion:The incidence of secondary glaucoma after vitrectomy in a family with vitreous amyloidosis caused by the Gly83Arg mutation of TTR gene is higher, and its occurrence is significantly positively correlated with the recurrence of vitreous amyloidosis.

Diagnostic challenges in systemic amyloidosis: a case report with clinical and laboratorial pitfalls

Currently, there is growing evidence in the literature warning of misdiagnosis involving amyloidosis and chronic inflammatory demyelinating polyneuropathy (CIDP). Although inducing clinical manifestations outside the peripheral nervous system, light chain and transthyretin amyloidosis may initially present with peripheral neuropathy, which can be indistinguishable from CIDP, leading to a delay in the correct diagnosis. Besides, the precise identification of the amyloid subtype is often challenging. This case report exemplifies clinical and laboratory pitfalls in diagnosing amyloidosis and subtyping amyloid, exposing the patient to potentially harmful procedures.

Speckle Tracking and Transthyretin Amyloid Cardiomyopathy / Rastreamento de Pontilhados e Cardiomiopatia Amiloidótica por Mutação da Transtirretina

Abstract Background: Amyloidosis is a disease caused by deposits of insoluble fibrils in extracellular spaces. The most common type of familial amyloidosis is mediated by mutation of transthyretin, especially Val30Met. Symptoms and ejection fraction decrease may occur in cardiac amyloidosis only in case of poor prognosis. Myocardial strain detected by two-dimensional speckle tracking echocardiography can indicate changes in myocardial function at early stages of the disease. Objective: To determine the accuracy of left ventricular longitudinal strain by two-dimensional speckle tracking echocardiography in patients with familial amyloidosis caused by Val30Met transthyretin mutation. Methods: Eighteen consecutive patients, carriers of transthyretin mutation, were evaluated by two-dimensional speckle tracking echocardiography, by which myocardial strain curves were obtained, following the American Society of Echocardiography recommendations. Results: Patients were divided into three groups: 1- Val30Met with cardiac amyloidosis; 2-Val30Met with extracardiac amyloidosis; 3 - Val30Met without evidence of disease. As the three groups were compared by the Mann-Whitney test, we found a statistically significant difference between groups 1 and 2 in the mean longitudinal tension (p=0.01), mean basal longitudinal strain (p=0.014); in mean longitudinal tension and mean longitudinal strain between groups 1 and 3 (p=0.005); and in the ratio of longitudinal strain of apical septum segment to longitudinal strain of basal septum (p=0.041) between groups 2 and 3. Conclusion: Left ventricular longitudinal strain detected by two-dimensional speckle tracking echocardiography is able to diagnose left ventricular dysfunction in early stages of familial amyloidosis caused by transthyretin Val30Met mutation.

Resumo Fundamento: A amiloidose é uma doença de depósito de fibrilas insolúveis nos espaços intercelulares. A forma mais comum de amiloidose familiar é mediada por mutação da transtirretina, sendo a Val30Met a mutação mais frequente. A amiloidose cardíaca só causa sintomas e queda da fração de ejeção em fases tardias quando o prognóstico é pobre. A deformação miocárdica obtida com speckle tracking bidimensional pode detectar alterações da função miocárdica em estágios precoces da doença. Objetivos: Determinar a acurácia da deformação longitudinal do ventrículo esquerdo obtida com speckle tracking bidimensional em um grupo de pacientes com amiloidose familial por mutação da transtirretina Val30Met. Métodos: Foram examinados 18 pacientes consecutivos com a mutação da transtirretina com speckle tracking bidimensional obtendo curvas de deformação miocárdica segundo normas da American Society of Echocardiography. Resultados: Os pacientes foram divididos em três grupos: 1- Val30Met com amiloidose cardíaca; 2- Val30Met com amiloidose extra-cardíaca; 3- Val30Met sem doença aparente. Ao compararmos os três grupos com o teste de Mann-Whitney encontramos diferença estatística significativa entre os grupos 1 e 2 na tensão longitudinal média (p=0,01), deformação longitudinal basal média (p=0,014); entre os grupos 1 e 3 na tensão longitudinal média (p=0,005), deformação longitudinal média (p=0,002); entre os grupos 2 e 3 na relação de deformação longitudinal do septo apical/deformação longitudinal do septo basal (p=0,041). Conclusão: A deformação longitudinal do ventrículo esquerdo obtida com speckle tracking bidimensional é capaz de diagnosticar disfunção do ventrículo esquerdo em fases precoces da amiloidose familial por mutação Val30Met da transtirretina.

Mutation analysis of the OSMR gene in two Chinese families with familial primary cutaneous amyloidosis / 中华皮肤科杂志

Objective To detect mutations in the OSMR gene in 2 Chinese families with familial primary cutaneous amyloidosis (FPCA),and to analyze their relationship with clinical manifestations.Methods Clinical data were collected from 2 families with FPCA,and genomic DNA was extracted from peripheral blood samples.PCR was performed to amplify 18 exons and their flanking sequences of the OSMR gene followed by DNA sequencing in 2 probands and their family members.One hundred healthy individuals served as controls.Results In the first family,a heterozygous mutation (c.2081C ＞ T) in exon 15 of the OSMR gene,which leads to a codon change at amino acid position 694 (p.P694L),was identified in the proband,as well as in the other 4 patients.In the second family,a heterozygous mutation (c.1538G ＞A) in exon 11 of the OSMR gene,which causes a codon change at amino acid position 513 (p.G513D),was identified in the other proband and her mother,suggesting the cosegregation of the gene mutation with the disease.None of the above mutations were detected in the healthy family members or controls.Conclusion The heterozygous mutations p.P694L and p.G513D in the OSMR gene may be associated with primary cutaneous amyloidosis.

Mutation analysis of the OSMR gene in a family with familial primary cutaneous amyloidosis / 中华皮肤科杂志

Objective To identify mutations in the OSMR gene in a pedigree with familial primary cutaneous amyloidosis (FPCA).Methods Clinical data were collected from a pedigree with FPCA.Peripheral blood samples were obtained from the proband,his 19 relatives,and 50 unrelated healthy human controls.Genomic DNA was extracted from these blood samples,and subjected to PCR for the amplification of 18 encoding exons and their flanking sequences of the OSMR gene followed by DNA sequencing.Results A heterozygous missense mutation c.2081C ＞ T,which leads to the substitution of proline by threonine at position 694,was detected in the OSMR gene of the proband and his affected relatives,but not in unaffected relatives or healthy controls.Conclusion The heterozygous mutation p.P694L in the OSMR gene may cause the clinical phenotype of FPCA in this family.