ABSTRACT
Objective:To study the clinical features of transthyretin amyloid polyneuropathy (ATTR-PN) caused by Ser77Tyr mutation.Methods:The clinical data of a patient with ATTR-PN caused by Ser77Tyr mutation, admitted to our hospital from Department of Neurology, Mindong Hospital Affiliated to Fujian Medical University, were retrospectively analyzed. Literature on patients with ATTR-PN caused by Ser77Tyr mutation in Pubmed, Web of Science, CNKI and Wanfang databases and those with ATTR-PN caused by Val30Met mutation in Pubmed and Web of Science were searched and screened, and clinical characteristics of these patients were extracted. The differences of clinical characteristics among patients with ATTR-PN caused by Ser77Tyr or Val30Met mutations were compared.Results:(1) Transthyroxin ( TTR) gene Sanger sequencing results showed Ser77Tyr heterozygous pathogenic mutation; Congo red staining of biopsy sample in the patient 2.5 years after onset showed amyloid deposition. (2) Seventy-eight patients with ATTR-PN caused by Ser77Tyr mutation were summarized, they mostly had onset at 50-60 years old; male patients had higher incidence (74.4%); most patients (78.0%) had positive family history; most patients had sensory symptoms as initial symptom (72.0%), which gradually progressed to extensive peripheral nerve involvement and combined with widespread heart damage (96.4%) over several years; electrophysiological examination mainly showed axonal damage and carpal tunnel syndrome; the tissue biopsy had high positive rate(84.8%). (3) There were 192 and 96 patients with ATTR-PN caused by early-onset and late-onset Val30Met mutations, respectively; compared with patients with ATTR-PN caused by early-onset Val30Met mutation, patients with ATTR-PN caused by Ser77Tyr mutation had significantly higher incidence of deep sensory disturbance (28.6% vs. 58.5%, P<0.05). Compared with patients with ATTR-PN caused by late-onset Val30Met mutation, patients with ATTR-PN caused by Ser77Tyr mutation had increased incidence of mild sensory disturbance (56.3% vs. 75.0%) and decreased incidence of limb weakness (65.6% vs. 48.3%), with significant differences ( P<0.05). ATTR-PN patients caused by Ser77Tyr mutation had significantly higher incidence of carpal tunnel syndrome than ATTR-PN patients caused by early-onset and late-onset Val30Met mutations (75.4% vs. 10.8% and 25.0%) and significantly higher incidence of cardiac damage than ATTR-PN patients caused by early-onset Val30Met mutation (96.4% vs. 80.5%, P<0.05). Conclusion:Ser77Tyr mutation has some distinctive clinical features: relatively balanced damage of large and small fibers, prominent carpal tunnel syndrome, and obvious heart disease; early identification of these features and administration of tissue biopsy and gene detection are helpful for early diagnosis.
ABSTRACT
La polineuropatía amiloidótica familiar (PAF) es un tipo de amiloidosis hereditaria. Constituye un desorden autosómico dominante caracterizado por el depósito sistémico de material amiloide en tejidos especialmente en nervios periféricos. El principal componente del amiloide es una variante mutada de la transtiretina (TTR), proteína transportadora de tiroxina y retinol. Han sido descriptas numerosas mutaciones en el gen TTR que causan alteración de la secuencia primaria de la proteína. La PAF portuguesa o PAF Tipo I se origina por la variante TTR Val30Met en la cual una valina en posición 30 es reemplazada por una metionina. Es fundamental la identificación temprana de portadores de la mutación porque una vez declarada la enfermedad el único tratamiento efectivo es el trasplante hepático, órgano de síntesis de la TTR. La PAF Tipo I ha sido muy estudiada en la Argentina debido al hallazgo de un área endémica donde habitan familias descendientes de inmigrantes portugueses. El presente trabajo ha sido enfocado a resolver la necesidad diagnóstica de la comunidad, ya que la ausencia de una metodología apropiada en nuestro país ha impedido, hasta ahora, que individuos con antecedentes familiares de PAF puedan tener un diagnóstico precoz y acceder al trasplante hepático temprano. En consecuencia, nuestro objetivo fue optimizar una metodología para detectar la mutación Val30Met adaptando técnicas previamente descriptas. La fiabilidad, sencillez y rapidez en la obtención de los resultados, así como el requerimiento de pequeño volumen de muestra, hacen que la técnica desarrollada en este trabajo sea una herramienta apropiada para procedimientos de screening, permitiendo contar con un marcador preclínico de la enfermedad.
Familial amyloid polyneuro- pathy (FAP) is an autosomal dominant inherited disease, characterized by systemic deposition of amyloid fibrils in various tissues, especially in peripheral nerves, being a variant of transthyretin (TTR) the principal component of amyloid fibrils. TTR is a normal plasma protein (previously called prealbumin) that functions as a transport protein binding tiroxine and retinol. Among many mutations that have been found in the TTR gene, the variant with a single amino acid substitution of methionine for valine at position 30 (TTR Val30Met) is the responsible of the Portuguese-type Familial Amyloidotic Polyneuropathy (FAP Type I). Interest in this pathology has arisen in Argentina because of the finding of an endemic area where a group of Portuguese immigrant families is localized. Since liver transplantation is a widely accepted treatment because it results in the disappearance of variant transthyretin from plasma, an early detection of the altered gene is essential. Thus, the objective of the present work was to optimize a methodology to detect the Val30Met mutation introducing modifications into techniques that were previously developed. The simple method here described is useful to confirm the diagnosis of the potential disease and, therefore, make it possible for patients to gain access to early liver transplantation.