Werner Syndrome

Updated: Jun 05, 2017
  • Author: Camila K Janniger, MD; Chief Editor: Dirk M Elston, MD  more...
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Overview

Background

Otto Werner originally defined Werner syndrome (WS) in 1904 on the basis of sclerodermalike, thin, tight skin and bilateral cataracts. WS is also known as progeria adultorum, progeria of the adult, and pangeria. WS is the most common of the premature aging disorders. Progeria can also refer to Hutchinson-Gilford syndrome, which is described as a lamin A gene defect and has onset early in life. The term progeria is derived from a Greek term meaning "before old age." See the images below.

Werner syndrome. Werner syndrome.
Werner syndrome. Werner syndrome.

The aging process involves increasing errors in the mitotic machinery of dividing cells in the postreproductive stage of life; therefore, WS serves as a model for studying the aging process in vivo and in vitro. [1] However, many organs in patients with WS prematurely undergo changes that are usually associated with aging. No mental retardation is observed.

WS is a premature aging disorder that may serve as a model of normal human aging. [2] In vivo aging is linked with accelerated aging of fibroblasts in culture, possibly due to the genomic instability, a hallmark of WS. Genome instability activates stress kinases, implying that kinase inhibitors may form the basis of antiaging therapies for individuals with WS.

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Pathophysiology

Werner syndrome (WS) is an autosomal recessive disorder that affects connective tissue throughout the body. This segmental progeroid syndrome is caused by null mutations at the WRN locus, [3] which codes for a member of the RecQ family of DNA helicases. Enzymes in this group unwind double helix RNA and DNA. The protein is likely to be involved in the response to DNA damage during replication, as well as in the replication and transcription processes. The disease is connected with excessive synthesis of collagen types I and III, which is dependent on elevated messenger RNA (mRNA) levels.

Skin fibroblasts in WS patients demonstrate characteristics of cells in conditions of stress with slow growth rates, an elongated cell cycle, and an altered morphology that suggests stress-induced premature senescence transduced in part by the p38α MAP kinase signaling pathway. This p38 involvement has been documented in WS cells. [4]

More than 70 disease-causing mutations have been described, the majority being stop codon mutations, splice mutations, or small ins/del-producing truncations of the protein and/or non-sense–mediated decay of mutant mRNA. [5] Two novel WRN mutations were described in patients of South Asian ancestry. [6] Another patient had a homozygous novel 1bp-deletion in exon 19 of WRN, 2426/27delG, causing frameshift and protein truncation R809SfsX2. [7]

The collagenase level is also increased several times. However, a child may have characteristics of WS but with no identifiable mutation in the WRN gene. Such cases are classified as atypical WS. [8] A paper from 2010 reported 18 new mutations, including 2 genomic rearrangements, a deep intronic mutation resulting in a novel exon, a splice consensus mutation leading to utilization of the nearby splice site, and 2 rare missense mutations. [9]

WS have been classified is a member of the RecQ family of DNA helicases implicated in the resolution of DNA structures leading to the stall of replication forks. [10] Fragile sites may be DNA regions particularly sensitive to replicative stress. Evidence was recently presented of a crucial role for a helicase in protecting cells against chromosome breakage at normally occurring replication fork-stalling sites.

Human progeroid syndromes are linked with mutations in single genes accelerating some, but not all, features of normal aging. [11] Most are associated with defects in genome maintenance.

LMNA (lamin A/C) gene mutation has been described with atypical Werner syndrome, with the severe metabolic complications, the extent of the lipodystrophy being linked with A133L mutation in the LMNA gene. [12, 13]

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Epidemiology

Frequency

United States

Werner syndrome (WS) is a rare disorder. The estimated incidence is 1 case in 1 million individuals.

International

WS is more common in Japan and Sardinia than in other regions. [14] About 1000 cases are reported in the world; more than 800 of these cases are in Japan.

Race

No racial predilection is reported.

Sex

Both sexes are affected equally.

Age

The onset of WS might occur in individuals in their mid teens, or it may be delayed until an individual is as old as 30 years. The average age of patients at the time of diagnosis is 37 years.

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Prognosis

The prognosis is unfavorable. The mean survival for patients with Werner syndrome (WS) is 46 years. Death usually occurs when patients are aged 30-50 years because of atherosclerosis or malignant tumors. Adroit medical management may enhance life expectancy; one patient was described who survived until dying of acute heart failure at age 68 years. [15]

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