Tuesday, March 30, 2010

Oh my goodness! Late paternal age starts at 30?

Speaking of Biological Clocks
Women aren’t the only ones who should pay attention to their biological clocks…

While men can still have kids at 50, it turns out there are increased health and psychological risks to the child:

Is Your Sperm Too Old?

Are you still bearing healthy fruit? Turns out that it’s not just women who have a biological clock—your sperm may be going to seed a lot faster than you think.

By Kevin Conley,
Photographs by Christian Weber

While you’ve never been against the idea of a serious relationship, you are in no particular rush to become a schlub. The attendant trappings of new fatherhood—the preschool viewings, the sleepless nights, the humiliation of carrying a diaper bag—aren’t exactly calling out to you the way, say, another night slinging Pisco sours would. The ever-intensifying din of the proverbial biological clock? That’s for the opposite sex to worry about—you know, like periods, frizz, and whether Mr. Big will dump Carrie in the Sex and the City sequel. As far as you know, your little swim team of DNA carriers will be competing at Olympic level into Letterman age. So what’s the rush?

“I always thought my biological clock was the 36 hours I had left after I took my Cialis pill,” says Zack, a 30-year-old producer in Los Angeles. “That’s the only clock I’ve ever felt ticking.” Turns out, Zack might want to consider the unsung glories of fatherhood.

According to a study released last March in the Public Library of Science Medicine, children born to fathers who were 20 scored an average of 2 points higher on an IQ test than children born to 50-year-old fathers. And that’s not all. Recent studies from Israel, California, and Sweden have connected “late paternal age” with any number of serious medical conditions: The longer you wait, the more likely it is that your kid will be affected by schizophrenia, dwarfism, bipolar disorder, autism, Marfan syndrome, certain childhood cancers, or even, later in life, Alzheimer’s. In some cases, the risk factors skyrocket. A 2005 study conducted by the University of California, Los Angeles, found a fourfold rise in Down syndrome among babies born to men 50 and older. Worse still, those risk factors aren’t limited to your tweed-sporting years: Statistically, “late paternal age” starts at 30, as in Zack’s age. A 2006 study conducted by Mount Sinai School of Medicine found that fathers in their thirties have children with about 1.5 times the risk of developing autism compared with fathers in their teens and twenties. That factor jumps to five times for dads in their forties. The cherry on the cake? The American Society for Reproductive Medicine recommends that sperm banks do not accept specimens from men over 40.

“The biological clock for men and women is really the same,” says Dr. Dolores Malaspina of Bellevue Hospital Center in New York City and New York University, who conducted one of the first studies. “It’s just that men can keep having babies.”

The biology behind this isn’t hard to grasp: Starting in puberty, spermatogonia, the master copies for sperm production, replicate themselves every couple of weeks. After 300 to 500 copies—somewhere in your thirties—a meaningful number of small copy errors, or point mutations, start to emerge, which accumulate over time.

Yet, despite the alarming new science, most men greet parenthood with a sense of urgency that’s more in line with Zack’s than Angelina Jolie’s. The reason is simple: While women are inculcated with the risks of late-age motherhood in sixth-grade sex ed, men remain blissfully ignorant. Since the recent studies have been published, the bad news still doesn’t seem to be making it to the doctor’s office. Scott, a 32-year-old schoolteacher from Babylon, New York, decided to start a family when he was Zack’s age, strictly because he wanted to raise his child while he was young. “For me the doctors were like, ‘Hey, this is going to be good. You’re still active,’” Scott says. “Nobody ever told me about the medical risks of being an older dad.”

That’s because men don’t usually get this news flash until they’re looking through a microscope at a batch of fugly sperm with no sense of direction. Swain, a 37-year-old IT professional in Dallas, wishes he had heard sooner. “Who cares if the baby is born with six fingers we can’t get that far,” he says. “I’d be thrilled to have that problem.” His wife is four years younger than he is, and they decided to wait. “What I did was let her clock be the one in control,” Swain says. “I would have been happy having kids five, six years ago, but she just wasn’t ready. The female clock seems to dominate the conversation.”

But don’t expect sweeping social change anytime soon. “Tell a man he’s got a chance of having kids with genetic abnormalities, and it’s like he’s going through the stages of the acceptance of death,” says Dr. Harry Fisch, a professor of urology and the author of The Male Biological Clock. “They’ll say, ‘I’m losing my manliness, my sexual ability.’ To them it all comes under the same umbrella.”

The good news is that no one, not even Malaspina, is suggesting that older men eschew the joys of fatherhood. But if you’re a younger guy who hasn’t thought twice about postponing it, be forewarned: The female of the species is about to get her just rewards. That bell tolling? It’s for you.


Oh my goodness! Late paternal age starts at 30? I think most men don’t even consider babies until then..


Monday, March 29, 2010

The pathophysiology of neurofibromatosis: IX. Paternal age as a factor in the origin of new mutations

American Journal of Medical Genetics
Volume 18 Issue 1, Pages 169 - 176
Published Online: 3 Jun 2005

Copyright © 2004 Wiley-Liss, Inc., A Wiley Company

The pathophysiology of neurofibromatosis: IX. Paternal age as a factor in the origin of new mutations
Dr. Vincent M. Riccardi *, Christopher E. Dobson II, Ranajit Chakraborty, Catherine Bontke, John M. Opitz
Neurofibromatosis Program, Baylor College of Medicine, and the Center for Demographic and Population Genetics, Graduate School of Biomedical Sciences, University of Texas Health Science Center, Houston, Texas

*Correspondence to Vincent M. Riccardi, NF Program, Baylor College of Medicine, Texas Medical Center, Houston, TX 77030

von Recklinghausen disease • neurofibromatosis • mutation • paternal age • maternal age

Von Recklinghausen neurofibromatosis is characterized by a relatively large proportion of apparently nonfamilial cases, presumed spontaneous mutations. This paper analyzes the distribution of paternal and maternal ages for 187 patients with von Recklinghausen disease representing the first definite case in their respective families. Mean paternal age was 32.8 years and mean maternal age was 27.4 years, both being significantly greater than for control populations (P equal to or less than.001). The advanced paternal age was not accounted for by the increase in maternal age. The methodology of controlling the general population paternal ages for each patient's birth year is described.

Received: 17 September 1983; Revised: 21 November 1983

Digital Object Identifier (DOI)

10.1002/ajmg.1320180121 About DOI


Monday, March 22, 2010

Parental Age and Risk of Schizophrenia

Welcome | My Account | E-mail Alerts | Access Rights | Sign In

Home Current Issue Past Issues Topic Collections Submit Subscribe Help Information for: Authors/Reviewers Readers Institutions/Libraries Subscription Agents News Media Job Seekers/Employers Advertisers

Vol. 60 No. 7, July 2003 Archives
• Parental Age and Risk of Schizophrenia
A Case-control Study

Majella Byrne, MSc, PhD; Esben Agerbo, MSc; Henrik Ewald, MD, DMSc; William W. Eaton, PhD; Preben Bo Mortensen, MD, DMSc

Arch Gen Psychiatry. 2003;60:673-678.


Background Advanced paternal age has been suggested as a possible risk factor for schizophrenia. It is not known whether this is explained by known risk factors for schizophrenia, including sibship characteristics, death of a parent before first hospital admission, season and place of birth, and family history of psychiatric illness, or by socioeconomic factors. We investigated the risk of schizophrenia associated with parental age, adjusting for known risk factors for schizophrenia, including family psychiatric history, and controlling for socioeconomic and demographic factors.

Methods We performed a national population, nested, case-control study based on Danish longitudinal register data. The sample included 7704 patients with an ICD-8 or ICD-10 diagnosis of schizophrenia admitted to a psychiatric facility between 1981 and 1998 in Denmark, and 192 590 individually time-, age-, and sex-matched population controls, their parents, and siblings. The risk of schizophrenia associated with increasing parental age was investigated using conditional logistic regression and controlling for family socioeconomic and demographic factors and family psychiatric history.

Results Advanced paternal and maternal age was associated with increased risk of schizophrenia in univariate analyses. Controlling for socioeconomic factors and family psychiatric history, increased risk of schizophrenia was identified in those with a paternal age of 50 years or older. Sex-specific analyses revealed that the risk of schizophrenia was increased for males with fathers 55 years or older (incidence rate ratio [IRR], 2.10; 95% confidence interval [CI], 1.35-3.28); for females, the risk associated with paternal age was substantial for fathers aged 50 to 54 years (IRR, 2.22; 95% CI, 1.44-3.44) and 55 years or older (IRR, 3.53; 95% CI, 1.82-6.83).

Conclusion Increased risk of schizophrenia was associated with advanced paternal age, particularly in females, lending support to the theory that de novo mutations, possibly X-linked, associated with increased parental age might be responsible for some cases of schizophrenia.

Jump to Section
• Top
• Introduction
• Methods
• Results
• Comment
• Author information
• References

ADVANCED PARENTAL age has been suggested to be a risk factor for schizophrenia in some studies. Both advanced maternal1-4 and paternal age2-8 have been reported to be associated with increased schizophrenia risk; however, most of the effect of maternal age has been accounted for by controlling for paternal age. Recently, Malaspina et al8 suggested that de novo spermatogonia mutations that accompany advancing paternal age might be responsible for this association. The authors suggested that as many as two thirds of the cases with fathers older than 50 years could be attributable to paternal age, and the relative risk for schizophrenia increased monotonically with increasing age. For a variety of monogenic diseases, many cases are attributable to de novo mutations associated with advanced paternal age,9-10 but there may also be increased risk for offspring of young fathers.11 The mutation rate of the male germline has recently been estimated to be approximately twice that of the female germline,12 although previous studies13 have suggested it to be 5-fold higher, and it is known to be higher at specific disease loci. De novo mutations might help to account for the persistence of schizophrenia in the population despite reduced fecundity levels in persons with this disorder.14

The aim of our study was 2-fold. First, we wanted to conduct an independent replication of the results of Malaspina and colleagues8 in a national register-based sample. Second, we wanted to investigate whether the association between parental age and risk of schizophrenia could be explained by any of the identified risk factors for schizophrenia, including family psychiatric history,15-16 sibship characteristics,17 death of a parent before admission,5, 18 season of birth,14, 19-20 and place of birth,16, 21 while assessing the possible confounding or modifying effect of socioeconomic factors (parental wealth, education, and marital status).

Jump to Section
• Top
• Introduction
• Methods
• Results
• Comment
• Author information
• References

The data were based on Danish longitudinal registers that were merged using a unique personal identification number known as the CPR (central person registration) number, which is used across all registration systems in Denmark. All live-born children and new residents in Denmark are assigned a unique personal identification number, and information is kept under this number in all national registers, thus ensuring accurate linkage of information between registers without the necessity to reveal a person's identity. The CPR registry was instigated in 1968.22 Parents' date of birth was identified through the CPR register.

The Danish Psychiatric Central Register has monitored all psychiatric inpatient facilities in Denmark since 1969.23 There are no private psychiatric facilities in Denmark, and all treatment is free of charge. All diagnoses were according to International Classification of Diseases, 8th Revision (ICD-8)24 until December 31, 1993, and according to International Classification of Diseases, 10th Revision (ICD-10)25 beginning January 1, 1994. Parental and sibling psychiatric information relates to the status just before the date of first contact of the case. In this manner, only family members who are affected before this date contribute information to the calculation of the risk associated with family history.

The socioeconomic data were obtained from the Integrated Database for Longitudinal Labour Market Research, which includes linked information on employees and establishments26 and for which there is continuous annual information available from 1980 to 1998. The register covers the total population and includes detailed socioeconomic information. We obtained information on parental education, wealth status, and marital status. We also obtained information on number of siblings as a proxy for family size. For our purposes, a random 5% of this register in addition to the patients and their families was used as the sample base from which the controls and their families were extracted.


A time-matched, nested, case-control design27 was used to select the control sample. For each case, 25 controls were randomly selected from a subsample of all available controls fulfilling the matching criteria: born in the same calendar year, same age in days, same sex, no admissions to a psychiatric facility in Denmark, and alive on the date that the case was first admitted.


The study sample was composed of all persons older than 15 years admitted to a Danish psychiatric facility for the first time between 1981 and 1998 with a diagnosis of schizophrenia and known maternal identity. A total of 7704 persons with schizophrenia were identified, 92% had links to a father (that is, paternity was not known or declared in 8%), and 66% were male. The control sample consisted of 192 590 individuals, representing 25 controls per case. Of the controls, 96% had links to a father.


We defined parental age in a similar manner to Malaspina et al.8 Paternal age was categorized into the following age groups: younger than 20 years, 20 through 24 years, 25 through 29 years, 30 through 34 years, 35 through 39 years, 40 through 44 years, 45 through 49 years, and 50 years or older. Maternal age was defined as younger than 20 years, 20 through 24 years, 25 through 29 years, 30 through 34 years, 35 through 39 years, and 40 years or older. Because we had a substantial number of patients and controls, we were in a position to investigate the effect of paternal and maternal age on the risk for schizophrenia in greater detail than Malaspina et al.8 We extended the age categories to 50 through 54 years and 55 years or older for paternal age and 40 through 45 years and 45 years or older for maternal age.


It was possible to obtain information relating to family history of psychiatric contact for mothers, fathers, and siblings by linking with the Danish Psychiatric Central Register. In line with previous studies using similar data,15-16 history of psychiatric disorders in family members was defined in a hierarchical manner as follows: (1) schizophrenia, schizo-affective disorder, and schizophrenia-like psychosis (ICD-8 codes: 295, 295.7, 297, 298.39, 301.83; ICD-10 codes: F20, F25, F21-F24, F28, F29); (2) bipolar illness and other affective illness (ICD-8 codes: 296.1, 296.3, 296, 300.4; ICD-10 codes: F30, F31, F34.0, F32-F39) and no history of disorders in category 1; and (3) other psychiatric disorder (any other diagnosis) but no history of disorders in either category 1 or 2. In addition, and not included in the hierarchy, we assessed the risk associated with a history of substance abuse disorders (ICD-8 codes: 303, 304; ICD-10 codes: F10.2, F11.2, F12.2, F13.2, F14.2, F15.2, F16.2, F17.2, F18.2, F19.2) and a history of suicide for mother, father, and siblings.


Socioeconomic and demographic variables included information about parental education level (organized according to 4 categories: basic/primary education, high school education and vocational training, university level education, and no available information) and information on parental wealth (organized into quartiles based on the distribution of these variables in the 5% sample of the Integrated Database for Longitudinal Labour Market Research). Other variables included were parental marital status, defined as single or married (including cohabiting); death of a parent or sibling before first hospital admission (not due to suicide); reference to father at birth; number of siblings (0, 1, 2, or 3 or more); and place of birth (defined as the capital [Copenhagen], capital suburbs, provincial city [population >100 000], provincial town [population <100 000], rural area, and birth outside Denmark, according to Pedersen and Mortensen16). All variables were treated categorically and entered into the analysis as covariates.

We modeled month of birth as 11 dummy variables, with June as the reference category. The interaction between parental age and season of birth was modeled.


The data were analyzed in a conditional logistic regression model using the PhReg procedure of SAS statistical software version 8.1 (SAS Institute Inc, Cary, NC),28 and asymptotic 95% confidence intervals (CIs) were calculated. Variables were assessed the last full year before the first admission ever to a psychiatric hospital irrespective of whether schizophrenia was diagnosed at first admission or later. The method of sampling controls, that is, risk set sampling, means that the odds ratio estimate in the analyses can be interpreted as an incidence rate ratio (IRR) between exposed and unexposed categories.29 Sex interactions were modeled for each category of paternal and maternal age. We conducted analyses separately for males and females as a result of significant sex interactions with parental age.

Jump to Section
• Top
• Introduction
• Methods
• Results
• Comment
• Author information
• References


In Table 1, the number and percentage of cases and controls in each category of parental age are presented, along with the mean age at onset of cases in each category and the sex distribution. We conducted a series of models of increasing complexity, the results of which are described in Table 2. In Table 2, the age categories according to Malaspina et al8 are presented along with the extended age categories.

View this table:
[in this window]
[in a new window]
Table 1. Mean Age at Onset and Sex Distribution for Each Category of Parental Age

View this table:
[in this window]
[in a new window]
Table 2. Incidence Rate Ratios (IRRs) for Schizophrenia Associated With Parental Age

For all analyses, the reference group was parental age of 20 through 24 years. In Table 2, the IRRs for the unadjusted models are presented, where paternal (model 1a) and maternal (model 1b) age groups were modeled in separate univariate models (all models, including paternal age, controlled for whether there was a reference to a father). A significantly increased risk of schizophrenia was associated with paternal age younger than 20 years and with all age groups 40 years or older (model 1a). A significantly increased risk was associated with maternal age younger than 20 years and with all age groups 30 years or older (model 1b). Paternal age and maternal age were then entered into the same model (model 2) to adjust the IRRs for the effects of age of the other parent. Once paternal age was controlled for in the model, there seemed to be no significant overall association between maternal age and risk of schizophrenia. A significant association remained for the paternal age groups of 40 through 44 years and 50 years or older. The next step was to introduce the psychiatric history of both parents into the model to control for the effect of psychiatric history on the association between parental age and risk of schizophrenia (model 3). For paternal age a significant association remained for the age groups of 40 through 44 years and 50 years or older. We found a weak but significant association between the maternal age group of 30 through 34 years and risk of schizophrenia and a significant association for the maternal age group of 40 years or older. In the next model (model 4), we included the socioeconomic and demographic factors that might independently account for the relationship between parental age and risk of schizophrenia, including parental education, wealth, marital status, history of death before the case was first admitted, place of birth of cases and controls, family size, and, in addition to family psychiatric history, history of suicide and substance abuse in a parent or sibling and reference to father. These data were forced into the model regardless of significance of the estimates. Controlling for this range of factors (possible confounders), there remained a significantly increased risk in those with a paternal age of 50 years or older. We reanalyzed the data to include only those cases (n = 5413) and controls (n = 118 930) without a family history of schizophrenia or other psychiatric admissions, and these are presented in Table 2 (model 5). The results are similar to those of model 4.

When the risks were estimated in the extended parental age groups (paternal age, 50-54 years and 55 years; maternal age, 40-44 years and 45 years), the increased risk was most marked in the oldest paternal age group. The increased risk of schizophrenia associated with paternal age of 55 years or older remained significant after adjustment for the range of familial socioeconomic variables (model 4), although the association for the paternal age category of 50 through 54 years remained relatively unchanged in magnitude. The different models uniformly suggested a thresholdlike effect for the oldest category of fathers rather than a monotonic association as suggested by Malaspina et al,8 and this finding was not modified by any of the other factors included in our study. In fact, it can be seen in Table 2 that the estimates changed little between models. The estimated IRR for any age category within a model was contained within the 95% CIs of the respective estimate from the other models.


We investigated the interactions between parental age in each category and sex of the patients and between parental age and age at first admission of the patients. We also included a 3-way interaction composed of age group of parent, sex, and age at first admission. Age at first admission was entered into the analysis as a mean-centered variable (the difference between age at first admission and mean age at first admission).15 We did not find any interactions between age at first admission and parental age in this sample. Significant sex interactions were observed for the paternal age groups of 35 through 39 years and 50 years or older, the extended age group of 50 through 54 years, and the maternal age group of 45 years or older. Analyses were conducted separately for males and females and the results are displayed in Table 3. The risk of schizophrenia was significantly increased in the 35- through 39-year age group of paternal age for females only. However, this effect was no longer significant once age of the other parent was controlled for (model 2; the models displayed in Table 3 are named to coincide with those in Table 2; for consistency, model 3 is not presented on this table). The risk associated with paternal age of 50 years or older was significantly increased for females in models 2 and 4. In the paternal age group of 50 through 54 years, the significant effect of paternal age on increased schizophrenia risk was present exclusively for females. The risk was higher for females in the paternal age group of 55 years or older than for males (model 4: IRR, 3.53; 95% CI, 1.82-6.83; vs IRR, 2.10; 95% CI, 1.35-3.28); however, the interaction was not significant. In terms of maternal age, there was a significant increase in the risk for males with mothers 45 years or older but not for females in all models. The estimates associated with the extended maternal age group (age, 45 years) were based on only a few cases (n = 3 females; n = 20 males).

View this table:
[in this window]
[in a new window]
Table 3. Sex-Specific Estimates of the Incidence Rate Ratios (IRRs) for Schizophrenia by Parental Age

There was no significant increase in the risk of schizophrenia for any month of birth. We did not find any significant interaction between month of birth and parental age.

Jump to Section
• Top
• Introduction
• Methods
• Results
• Comment
• Author information
• References

In this national, population-based, epidemiologic sample, controlling for a range of familial socioeconomic and psychiatric factors, advanced paternal age (50 years) was associated with an increased risk of schizophrenia. In addition, we identified a sex effect, in which the increased risk associated with advanced paternal age was particularly prominent for females. A particular strength of our study was the ability to control for the presence of psychiatric disorders in the parents and siblings and for possible confounding due to family socioeconomic factors, family size, and whether a parent had died before the first hospital admission. The data are register based and so are bound by the same limitations of all register-based research, including the fact that the cases represent treated incidence cases.

In our analyses, unlike that of Malaspina et al,8 in which the authors found a monotonic relationship between paternal age and risk of schizophrenia, the increased risk was confined to the older (50 years) paternal ages in our final model (model 4). However, in our study, we were in a position to control for factors that Malaspina et al8 could not control for, namely, parental psychiatric history and information relating to the death of the parents before admission. We identified a U-shaped distribution in the risk for schizophrenia associated with parental age in the initial models; however, after controlling for family psychiatric history and social factors, this U shape was no longer visible for paternal age, and only a weak and nonsignificant effect remained for maternal age. Furthermore, the present study did not find an increased risk in the relatively younger groups of parents. It is possible that environmental and genetic risk factors differ between the Danish population investigated by us and the Israeli population.8 A simple explanation might include the relatively higher ambient temperatures in Israel, since heat exposure may increase the exposure of spermatozoa to mutagenic metabolites,30 leading to more and earlier mutations among Israeli fathers and a paternal effect in younger age groups as well.

A variety of possible explanations for the association between risk of schizophrenia and paternal age have been discussed, including an increase in the rate of de novo genetic mutations in older fathers, attributes of the parents that lead to marriage at an older age than normal that are related to schizophrenia in the offspring,5 and the adverse psychological consequences of losing a parent by death because of the parents' increased age.5

We examined the risk of schizophrenia associated with the death of a parent other than by suicide; however, no increase in risk was identified in the final model. This suggests that the psychological distress caused by the death of an aging parent does not account for the relationship between risk of schizophrenia and advanced paternal age. Although we could not control for birth order in this sample, we controlled for sibship size. In a previous study, sibship size but not birth order was associated with increased risk of schizophrenia.17 We found an independent, small but significant increase in the risk of schizophrenia among those from families with 3 or more siblings compared with being an only child (IRR, 1.15; 95% CI, 1.05-1.26), controlling for family history of psychiatric diagnoses in parents and siblings and socioeconomic factors. This finding suggests that the advanced paternal age effect is independent of factors operating in larger families, such as environmental exposure, perhaps to common infections in childhood, that may increase the risk of schizophrenia.17

We found a sex difference insofar as there was a significant increase in the risk of schizophrenia in females with older fathers in all age groups 50 years or older (50 years, 50-54 years, 55 years) compared with males, for whom the increased risk was confined to the 55-year-or-older age group. Males had an increased risk associated with older mothers (45 years); however, the estimates were based on a small sample size. The de novo mutations that occur with advancing age in parents not only might be point mutations but also could involve trinucleotide repeated expansions, imprinting, or small structural chromosomal rearrangements.13 The data from the present study suggest that the parental effect is particularly related to paternal age in female cases. Therefore, a gene on the X chromosome might be involved, because these are always passed from fathers to daughters. It is well-known that the X chromosome contains a relatively high number of genes expressed in the central nervous system and that the gene for many diseases with cognitive impairment are located on the X chromosomes. Furthermore, a few linkage studies have suggested possible risk loci for schizophrenia on the X chromosome.31 However, the increased mutation rate in males can occur on 2 autosomes in each chromosome pair but only on 1 X chromosome, at least outside the pseudoautosomal region. Imprinted autosomal genes may also explain that an increased risk depends on the sex of the parent.

In our sample, the effect was not restricted to those with a family history of psychiatric illness. When we reanalyzed the data, including only those cases (n = 5413) and controls (n = 118 930) without a family history of schizophrenia or any other psychiatric disorder, the results were similar (Table 2, model 5), indicating that the effect of parental age is not restricted to those with or without a family history of schizophrenia or other psychiatric disorders in this sample and suggesting that family history of psychiatric disorders does not explain the association.

Our findings support the theory that de novo mutations might occur in the offspring of older parents, particularly fathers, leading to an increased risk of schizophrenia and that this might help explain the fact that schizophrenia persists in the population despite reduced fertility levels.14 However, this effect seems to be restricted to fathers older than 50 years. The findings of interactions between sex and age of parent of origin lead to speculation about involvement of de novo genetic mutations occurring on the X chromosome in the etiology of schizophrenia, particularly in the female offspring of older fathers. However, males with older fathers (55 years) also had an increased risk. Focusing efforts on a specific chromosome may facilitate the final identification of risk genes possibly involved in the parental age effect. Such a risk gene might either be a gene of importance for brain development and function or might predispose to de novo mutations in such genes by causing decreased DNA repair and/or increased environmental susceptibility.

Jump to Section
• Top
• Introduction
• Methods
• Results
• Comment
• Author information
• References

Corresponding author and reprints: Majella Byrne, MSc, PhD, National Centre for Register-based Research, Aarhus University, Taasingegade 1, Aarhus 8000 C, Denmark (e-mail: mb@ncrr.dk).

Submitted for publication May 7, 2002; final revision received December 20, 2002; accepted January 14, 2003.

This study was funded by the Stanley Medical Research Institute and by grant MH53188 from the National Institutes of Mental Health, Bethesda, Md. The National Centre for Register-based Research is supported by the Danish National Research Foundation, Copenhagen, Denmark.

From the National Centre for Register-based Research, Aarhus University, Aarhus, Denmark (Drs Byrne and Mortensen and Mr Agerbo); Institute for Basic Psychiatric Research, Psychiatric Hospital, Aarhus, Risskov, Denmark (Dr Ewald); and Department of Mental Hygiene, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, Md (Dr Eaton).

Jump to Section
• Top
• Introduction
• Methods
• Results
• Comment
• Author information
• References

1. Goodman N. Relation between maternal age at parturition and incidence of mental disorder in the offspring. Br J Prev Soc Med. 1957;11:203-213. PUBMED
2. Johanson E. A study of schizophrenia in the male. Acta Psychiatr Scand Suppl. 1958;33(suppl 125):7-107.
3. Gregory I. An analysis of family data on 1,000 patients admitted to a Canadian mental hospital. Acta Genet Stat Med. 1959;9:54-96.
4. Bojanovsky J, Gerylovova A. The relation of schizophrenia to the age of parents of the patient. Nervenarzt. 1967;38:40-42. PUBMED
5. Hare EH, Moran PA. Raised parental age in psychiatric patients: evidence for the constitutional hypothesis. Br J Psychiatry. 1979;134:169-177. FREE FULL TEXT
6. Kinnell HG. Parental age in schizophrenia. Br J Psychiatry. 1983;142:204.
7. Raschka LB. Parental age and schizophrenia. Magyar Andrologia. 1998;3:47-50.
8. Malaspina D, Harlap S, Fennig S, Heiman D, Nahon D, Feldman D, Susser ES. Advancing paternal age and the risk of schizophrenia. Arch Gen Psychiatry. 2001;58:361-367. FREE FULL TEXT
9. Malaspina D. Paternal factors and schizophrenia risk: de novo mutations and imprinting. Schizophr Bull. 2001;27:379-393.
10. Malaspina D, Corcoran C, Fahim C, Berman A, Harkavy-Friedman J, Yale S, Goetz D, Goetz R, Harlap S, Gorman J. Paternal age and sporadic schizophrenia: evidence for de novo mutations. Am J Med Genet. 2002;114:299-303. FULL TEXT | WEB OF SCIENCE | PUBMED
11. McIntosh GC, Olshan AF, Baird PA. Paternal age and the risk of birth defects in offspring. Epidemiology. 1995;6:282-288. WEB OF SCIENCE | PUBMED
12. Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, et al. Initial sequencing and analysis of the human genome. Nature. 2001;409:860-921. FULL TEXT | PUBMED
13. Crow JF. The origins, patterns and implications of human spontaneous mutation. Nat Rev Genet. 2000;1:40-47. WEB OF SCIENCE | PUBMED
14. McGrath JJ, Hearle J, Jenner L, Plant K, Drummond A, Barkla JM. The fertility and fecundity of patients with psychoses. Acta Psychiatr Scand. 1999;99:441-446. WEB OF SCIENCE | PUBMED
15. Byrne M, Agerbo E, Mortensen PB. Family history of psychiatric disorders and age at first contact in schizophrenia: an epidemiological study. Br J Psychiatry. 2002;181(suppl 43):S19-S25.
16. Pedersen CB, Mortensen PB. Family history, place and season of birth as risk factors for schizophrenia in Denmark: a replication and reanalysis. Br J Psychiatry. 2001;179:46-52. FREE FULL TEXT
17. Westergaard T, Mortensen PB, Pedersen CB, Wohlfahrt J, Melbye M. Exposure to prenatal and childhood infections and the risk of schizophrenia: suggestions from a study of sibship characteristics and influenza prevalence. Arch Gen Psychiatry. 1999;56:993-998. FREE FULL TEXT
18. Agid O, Shapira B, Zislin J, Ritsner M, Hanin B, Murad H, Troudart T, Bloch M, Heresco-Levy U, Lerer B. Environment and vulnerability to major psychiatric illness: a case control study of early parental loss in major depression, bipolar disorder and schizophrenia. Mol Psychiatry. 1999;4:163-172. FULL TEXT | WEB OF SCIENCE | PUBMED
19. Crow TJ. Mutation and psychosis: a suggested explanation of seasonality of birth. Psychol Med. 1987;17:821-828. PUBMED
20. Torrey EF, Miller J, Rawlings R, Yolken RH. Seasonality of births in schizophrenia and bipolar disorder: a review of the literature. Schizophr Res. 1997;28:1-38. FULL TEXT | WEB OF SCIENCE | PUBMED
21. Mortensen PB, Pedersen CB, Westergaard T, Wohlfahrt J, Ewald H, Mors O, Andersen PK, Melbye M. Effects of family history and place and season of birth on the risk of schizophrenia. N Engl J Med. 1999;340:603-608. FREE FULL TEXT
22. Malig C. The civil registration system in Denmark. Tech Pap Int Inst Vital Regist Stat. 1996;66:1-6.
23. Munk-Jorgensen P, Mortensen PB. The Danish Psychiatric Central Register. Dan Med Bull. 1997;44:82-84. WEB OF SCIENCE | PUBMED
24. World Health Organization. Manual of the International Statistical Classification of Diseases, Injuries, and Causes of Death (ICD-8). Geneva, Switzerland: World Health Organization; 1967.
25. World Health Organization. The ICD-10 Classification of Mental and Behavioural Disorders: Clinical Descriptions and Diagnostic Guidelines. Geneva, Switzerland: World Health Organization; 1992.
26. Danmarks Statistiks. IDA-en Integreret Database for Arbejdsmarkedsforskning. København: Danmarks Statistik Trykkeri; 1991.
27. Clayton D, Hills M. Statistical Models in Epidemiology. New York, NY: Oxford University Press; 1993.
28. SAS Institute Inc. The PhReg procedure. In: SAS/STAT User's Guide, Version 8. Cary, NC: SAS Institute Inc; 1999:2571-2657.
29. Borgan O, Langholz B. Nonparametric estimation of relative mortality from nested case-control studies. Biometrics. 1993;49:593-602. FULL TEXT | WEB OF SCIENCE | PUBMED
30. Setchell BP. The Parkes Lecture: heat and the testis. J Reprod Fertil. 1998;114:179-194. FREE FULL TEXT
31. Baron M. Genetics of schizophrenia and the new millennium: progress and pitfalls. Am J Hum Genet. 2001;68:299-312. FULL TEXT | WEB OF SCIENCE | PUBMED

CiteULike Connotea Del.icio.us Digg Facebook Reddit Technorati Twitter What's this?


Parental age at childbirth and age of menarche in the offspring
Shrestha et al.
Hum Reprod 2010;25:799-804.

Meta-analysis of Paternal Age and Schizophrenia Risk in Male Versus Female Offspring
Miller et al.
Schizophr Bull 2010;0:sbq011v1-sbq011.

Association Between Prepartum Maternal Iron Deficiency and Offspring Risk of Schizophrenia: Population-Based Cohort Study With Linkage of Danish National Registers
Sorensen et al.
Schizophr Bull 2010;:sbp167v1-sbp167.

Epigenetic Mediation of Environmental Influences in Major Psychotic Disorders
Rutten and Mill
Schizophr Bull 2009;35:1045-1056.

Psychosis and Place
March et al.
Epidemiol Rev 2008;30:84-100.

Is Schizophrenia a Syndrome of Accelerated Aging?
Kirkpatrick et al.
Schizophr Bull 2008;34:1024-1032.

Gene-Environment Interactions in Schizophrenia: Review of Epidemiological Findings and Future Directions
van Os et al.
Schizophr Bull 2008;34:1066-1082.

Advanced Parental Age at Birth Is Associated With Poorer Social Functioning in Adolescent Males: Shedding Light on a Core Symptom of Schizophrenia and Autism
Weiser et al.
Schizophr Bull 2008;34:1042-1046.

Advancing Paternal Age and Bipolar Disorder
Frans et al.
Arch Gen Psychiatry 2008;65:1034-1040.

Aberrant Epigenetic Regulation Could Explain the Relationship of Paternal Age to Schizophrenia
Perrin et al.
Schizophr Bull 2007;33:1270-1273.

Maternal and Paternal Age and Risk of Autism Spectrum Disorders
Croen et al.
Arch Pediatr Adolesc Med 2007;161:334-340.

Schizophrenia: a common disease caused by multiple rare alleles
McClellan et al.
Br. J. Psychiatry 2007;190:194-199.

Association of Schizophrenia and Autoimmune Diseases: Linkage of Danish National Registers
Eaton et al.
Am. J. Psychiatry 2006;163:521-528.

The Role of Obstetric Events in Schizophrenia
Clarke et al.
Schizophr Bull 2006;32:3-8.

Paternal age and schizophrenia: Authors' reply
Sipos et al.
BMJ 2005;330:148-148.

Paternal age and schizophrenia: a population based cohort study
Sipos et al.
BMJ 2004;329:1070.


Friday, March 19, 2010

Monday, March 01, 2010



Kamal Singh Rathore, Sunita P., Khushboo Sharma, R.K.Nema


Progeria is a rare disease, fatal genetic condition that produces rapid aging, beginning in childhood also known as “Hutchinson–Gilford progeria syndrome” or “HGPS” and “Hutchinson–Gilford syndrome” wherein symptoms resembling aspects of aging are manifested at an early age. Progeria was first described in an academic journal by Dr. Jonathan Hutchinson in 1886, and Dr. Hastings Gilford in 1897 – both in England.

 Its name is derived from the Greek and means “prematurely old.” Approximately 1 in 4000000 people are diagnosed with this condition. Those born with progeria typically live about 13-20 years, It is a genetic condition that occurs as a new mutation and is not usually inherited, although there is a uniquely inheritable form. This is in contrast to another rare but similar premature aging syndrome, dyskeratosis congenita (DKC), which is inheritable and will often be expressed multiple times in a family line.

Although they are born looking healthy, children with Progeria begin to display many characteristics of accelerated aging at around 18-24 months of age. Progeria signs include growth failure, loss of body fat and hair, aged-looking skin, stiffness of joints, hip dislocation, generalized atherosclerosis, cardiovascular (heart) disease and stroke. The children have a remarkably similar appearance, despite differing ethnic background. Children with Progeria die of atherosclerosis (heart disease) at an average age of thirteen years (with a range of about 8 – 21 years). According to Hayley’s Page “At present there are 53 known cases of Progeria around the world and only 2 in the UK”. There is a reported incidence of Progeria of approximately 1 in every 4 to 8 million newborns. Both boys and girls run an equal risk of having Progeria.


Progeria is a progressive genetic disorder that causes children to age rapidly, beginning in their first two years of life. The condition is rare; since 1886, only about 130 cases of progeria have been documented in the scientific literature. Usually within the first year of life, growth of a child with progeria slows markedly so that height and weight fall below average for his or her age, and weight falls low for height. Motor development and mental development remain normal.

Signs and symptoms of this progressive disorder include:

Limited growth or Growth failure during the first year of life Narrow, shrunken or wrinkled face failure to thrive Baldness (alopecia) Insulin-resistant diabetes (diabetes that does not respond readily to insulin injections) Skin changes similar to that seen in scleroderma (the connective tissue becomes tough and hardened) Loss of eyebrows and eyelashes a distinctive appearance (small face and jaw, pinched nose) Short stature and small, fragile bodies, like those of elderly people Large head for size of face (macrocephaly) Open soft spot (fontanelle) Small jaw (micrognathia) Dry, scaly, thin skin Limited range of motion Teeth – delayed or absent formation Later, the condition causes wrinkled skin, atherosclerosis, and cardiovascular problems. Slowed growth, with below-average height and weight A narrowed face and beaked nose, which makes the child look old Head too large for face Prominent scalp veins Prominent eyes Small lower jaw (micrognathia) High-pitched voice Delayed and abnormal tooth formation Loss of body fat and muscle Stiff joints Hip dislocation


Progeria usually occurs without cause – it is not seen in siblings of affected children. In extremely rare cases more than one child in the same family may have the condition.

 It is only very rarely seen in more than one child in a family. Progeria is a childhood disorder caused by a point mutation in position 1824 of the LMNA gene (Lamin A), replacing cytosine with thymine, creating an unusable form of the protein Lamin A. Lamin A is part of the building blocks of the nuclear envelope. 90% of children with progeria have a mutation on the gene that encodes the protein lamin A. a protein that holds the nucleus of the cell together. It is believed that the defective Lamin A protein makes the nucleus unstable. This instability seems to lead to the process of premature aging among Progeria patients.


Diagnosis is suspected according to signs and symptoms, such as skin changes, abnormal growth, and loss of hair. It can be confirmed through a genetic test. The health care professional will possibly suspect Progeria if the signs and symptoms are there – aging skin, loss of hair, stiffness of joints, etc. This can then be confirmed through a genetic test. The Progeria Research Foundation has created a Diagnostic Testing Program.

No diagnostic test confirms progeria. Doctors typically make a diagnosis based on signs and symptoms, such as failure to grow and hair loss, which typically aren’t fully evident until your child is nearly 2. However, with the discovery of the genetic mutation that causes progeria, it’s possible to use genetic testing for LMNA mutations at the first suspicion of progeria. The sooner you know your child has progeria, the sooner your doctor can recommend treatments that may help ease the signs and symptoms of the disorder.

A blood test may reveal that your child has a low level of high-density lipoprotein (HDL) cholesterol, the so-called good cholesterol that helps keep arteries open. This laboratory finding isn’t diagnostic by itself, but may lend support to a diagnosis of progeria.


No treatments have been proven effective.

Most treatment focuses on reducing complications (such as cardiovascular disease) with heart bypass surgery or low-dose aspirin. A daily dose may help prevent heart attacks and stroke. Growth hormone treatment has been attempted. Drugs known as farnesyltransferase inhibitors (FTIs), which were developed for treating cancer, have shown promise in laboratory studies in correcting the cell defects that cause progeria. FTIs are currently being studied in human clinical trials for treatment of progeria. it has been proposed, but their use has been mostly limited to animal models. A Phase II clinical trial using the FTI Lonafarnib began in May 2007. Physical and occupational therapy. These may help with joint stiffness and hip problems, and may allow your child to remain active. High-calorie dietary supplements. Including extra calories in your child’s daily diet may help prevent weight loss and ensure adequate nutrition. Feeding tube. Infants who feed poorly may benefit from a feeding tube and a syringe. You can use the syringe to push pumped breast milk or formula through the tube to make it easier for your child to feed. Extraction of primary teeth. Your child’s permanent teeth may start coming in before his or her baby teeth fall out. Extraction may help prevent problems associated with the delayed loss of baby teeth, including overcrowding and developing a second row of teeth when permanent teeth come in.


There is no known cure. Few people with progeria exceed 13 years of age. At least 90% of patients die from complications of atherosclerosis, such as heart attack or stroke.

Mental development is not affected. The development of symptoms is comparable to aging at a rate six to eight times faster than normal, although certain age-related conditions do not occur. Specifically, patients show no neurodegeneration or cancer predisposition. They do not develop physically mediated “wear and tear” conditions commonly associated with aging, like cataracts (caused by UV exposure) and osteoarthritis (caused by mechanical wear).


Classical Hutchinson-Gilford Progeria Syndrome is almost never passed on from parent to child. It is usually caused by a new (sporadic) mutation during the early division of the cells in the child. It is usually genetically dominant; therefore, parents who are healthy will normally not pass it on to their children. Affected children rarely live long enough to have children themselves.

Research indicates that a chemical (hyaluronic acid) may be found in greatly elevated levels in the urine of Hutchinson-Gilford Progeria Syndrome patients. The same abnormality has been found in Werner Syndrome, which is sometimes called ‘progeria of the adult’.

Lamin A

Nuclear lamin A is a protein scaffold on the inner edge of the nucleus that helps organize nuclear processes such as RNA and DNA synthesis.

Prelamin A contains a CAAX box at the C-terminus of the protein (where C is a cysteine and A is any aliphatic amino acids). This ensures that the cysteine is farnesylated and allows prelamin A to bind membranes, specifically the nuclear membrane. After prelamin A has been localized to the cell nuclear membrane, the C-terminal amino acids, including the farnesylated cysteine, are cleaved off by a specific protease. The resulting protein is now lamin A, is no longer membrane-bound, and carries out functions inside the nucleus.

In 2003, NHGRI researchers, together with colleagues at the Progeria Research Foundation, the New York State Institute for Basic Research in Developmental Disabilities, and the University of Michigan, discovered that Hutchinson-Gilford progeria is caused by a tiny, point mutation in a single gene, known as lamin A (LMNA). Parents and siblings of children with progeria are virtually never affected by the disease. In accordance with this clinical observation, the genetic mutation appears in nearly all instances to occur in the sperm prior to conception. It is remarkable that nearly all cases are found to arise from the substitution of just one base pair among the approximately 25,000 DNA base pairs that make up the LMNA gene. The LMNA gene codes for two proteins, lamin A and lamin C, that are known to play a key role in stabilizing the inner membrane of the cell’s nucleus. In laboratory tests involving cells taken from progeria patients, researchers have found that the mutation responsible for Hutchinson-Gilford progeria causes the LMNA gene to produce an abnormal form of the lamin A protein. That abnormal protein appears to destabilize the cell’s nuclear membrane in a way that may be particularly harmful to tissues routinely subjected to intense physical force, such as the cardiovascular and musculoskeletal systems. Interestingly, different mutations in the same LMNA gene have been shown to be responsible for at least a half-dozen other genetic disorders, including two rare forms of muscular dystrophy. In addition to its implications for diagnosis and possible treatment of progeria, the discovery of the underlying genetics of this model of premature aging may help to shed new light on humans’ normal aging process.

Possible Complications

Heart attack (myocardial infarction)


How we can help children with Progeria?

Make a financial contribution. Donations are needed to continue the vital work. No donation is too little or too big – every penny counts in our fight for a cure! Donate your time. Volunteers are also important to  success. Hold a special event like a bake sale or letter writing campaign; translate documents for the families; help with a mailing – we’ll find something for you to do that fits your schedule, location and talents! Donate in-kind services or items. Do you own a printing or office supply business? Do you have a background in non-profit development? These are just some of the many types of talents and connections. The more tasks we can get accomplished on a pro bono basis, the more we can spend on research! Spread the word and tap into your connections. Do you know anyone who can do any of the above.

Care, Coping and support

Learning your child has progeria can be emotionally devastating. Suddenly you know that your child is facing numerous, difficult challenges and a shortened life span. For you and your family, coping with the disorder involves a major commitment of physical, emotional and financial effort. In dealing with a disorder such as progeria, support groups can be a valuable part of a wider network of social support that includes health care professionals, family and friends. In a support group, you’ll be with people who are facing challenges similar to the one that you are. Talking to group members can help you cope with your own feelings about your child’s condition. If a group isn’t for you, talking to a therapist or clergy member may be beneficial. Ask your doctor about self-help groups or therapists in your community. Your local health department, public library, telephone book and the Internet also may be good sources for finding a support group in your area.

Helping the child to cope

If your child has progeria, he or she is also likely to experience fear and grief as awareness grows that progeria shortens life span. Your child eventually will need your help coping with the concept of death, and may have a number of difficult but important questions about God and religion. Your child also may ask questions about what will happen in your family after he or she dies. It’s critical that you are able to talk openly and honestly with your child, and offer reassurance that’s compatible with your belief system. Ask your doctor, therapist or clergy member to help you prepare for such conversations with your child. Friends who you meet through support groups also may be able to offer valuable guidance.

Conclusion and General Discussion

Progeria, or Hutchinson-Gilford progeria syndrome, is a rare, fatal, genetic condition of childhood with striking features resembling premature aging. Children with progeria usually have a normal appearance in early infancy. At approximately nine to 24 months of age, affected children begin to experience profound growth delays, resulting in short stature and low weight. They also develop a distinctive facial appearance characterized by a disproportionately small face in comparison to the head; an underdeveloped jaw (micrognathia); malformation and crowding of the teeth; abnormally prominent eyes; a small, nose; prominent eyes and a subtle blueness around the mouth. In addition, by the second year of life, the scalp hair, eyebrows, and eyelashes are lost (alopecia), and the scalp hair may be replaced by small, downy, white or blond hairs. Additional characteristic features include generalized atherosclerosis, cardiovascular disease and stroke, hip dislocations, unusually prominent veins of the scalp, loss of the layer of fat beneath the skin (subcutaneous adipose tissue), defects of the nails, joint stiffness, skeletal defects, and/or other abnormalities. According to reports in the medical literature, individuals with Hutchinson-Gilford progeria syndrome develop premature, widespread thickening and loss of elasticity of artery walls (arteriosclerosis), which result in life-threatening complications during childhood, adolescence, or early adulthood. Children with progeria die of heart disease (atherosclerosis) at an average age of 13 years, with a range of about eight to 21 years.

Progeria is caused by a mutation of the gene LMNA, or lamin A. The lamin A protein is the scaffolding that holds the nucleus of a cell together. Researchers now believe that the defective lamin A protein makes the nucleus unstable. That cellular instability appears to lead to the process of premature aging in progeria. Because neither parent carries or expresses the mutation, each case is believed to represent a sporadic, new mutation that happens most notably in a single sperm or egg immediately prior to conception.


Ayres, S. C.; Mihan, R. : Progeria: a possible therapeutic approach. (Letter) JAMA 227: 1381-1382, 1974. Brown, W. T. : Human mutations affecting aging–a review. Mech. Aging Dev. 9: 325-336, 1979. Brown, W. T.; Abdenur, J.; Goonewardena, P.; Alemzadeh, R.; Smith, M.; Friedman, S.; Cervantes, C.; Bandyopadhyay, S.; Zaslav, A.; Kunaporn, S.; Serotkin, A.; Lifshitz, F. : Hutchinson-Gilford progeria syndrome: clinical, chromosomal and metabolic abnormalities. (Abstract) Am. J. Hum. Genet. 47 (suppl.): A50 only, 1990. Brown, W. T.; Darlington, G. J. : Thermolabile enzymes in progeria and Werner syndrome: evidence contrary to the protein error hypothesis. Am. J. Hum. Genet. 32: 614-619, 1980. Brown, W. T.; Darlington, G. J.; Arnold, A.; Fotino, M. : Detection of HLA antigens on progeria syndrome fibroblasts. Clin. Genet. 17: 213-219, 1980. Cao, H.; Hegele, R. A. : LMNA is mutated in Hutchinson-Gilford progeria (MIM 176670) but not in Wiedemann-Rautenstrauch progeroid syndrome (MIM 264090). J. Hum. Genet. 48: 271-274, 2003. Dahl, K. N.; Scaffidi, P.; Islam, M. F.; Yodh, A. G.; Wilson, K. L.; Misteli, T. istinct structural and mechanical properties of the nuclear lamina in Hutchinson-Gilford progeria syndrome. Proc. Nat. Acad. Sci. 103: 10271-10276, 2006. DeBusk, F. L. : The Hutchinson-Gilford progeria syndrome. J. Pediat. 80: 697-724, 1972. De Martinville, B.; Sorin, M.; Briard, M. L.; Frezal, J. : Progeria de Gilford-Hutchinson a debut neonatal chez des jumeaux monozygotes. Arch. Fr. Pediat. 37: 679-681, 1980. de Paula Rodrigues, G. H.; das Eiras Tamega, I.; Duque, G.; Spinola Dias Neto, V. : Severe bone changes in a case of Hutchinson-Gilford syndrome. Ann. Genet. 45: 151-155, 2002. De Sandre-Giovannoli, A.; Bernard, R.; Cau, P.; Navarro, C.; Amiel, J.; Boccaccio, I.; Lyonnet, S.; Stewart, C. L.; Munnich, A.; Le Merrer, M.; Levy, N. : Lamin A truncation in Hutchinson-Gilford progeria. Science 300: 2055 only, 2003. Dyck, J. D.; David, T. E.; Burke, B.; Webb, G. D.; Henderson, M. A.; Fowler, R. S. : Management of coronary artery disease in Hutchinson-Gilford syndrome. J. Pediat. 111: 407-410, 1987. Erecinski, K.; Bittel-Dobrzynska, N.; Mostowiec, S. : Zespol progerii u dwoch braci. Pol. Tyg. Lek. 16: 806-809, 1961. Eriksson, M.; Brown, W. T.; Gordon, L. B.; Glynn, M. W.; Singer, J.; Scott, L.; Erdos, M. R.; Robbins, C. M.; Moses, T. Y.; Berglund, P.; Dutra, A.; Pak, E.; Durkin, S.; Csoka, A. B.; Boehnke, M.; Glover, T. W.; Collins, F. S. : Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature 423: 293-298, 2003. Faivre, L.; Van Kien, P. K.; Madinier-Chappat, N.; Nivelon-Chevallier, A.; Beer, F.; LeMerrer, M. : Can Hutchinson-Gilford progeria syndrome be a neonatal condition? (Letter) Am. J. Med. Genet. 87: 450-452, 1999. Fatunde, O. J.; Benka-Coker, L. B. O.; Scott-Emuakpor, A. B. : Familial occurrence of progeria (Hutchinson-Gilford progeria syndrome). (Abstract) Am. J. Hum. Genet. 47 (suppl.): A55 only, 1990. Fong, L. G.; Frost, D.; Meta, M.; Qiao, X.; Yang, S. H.; Coffinier, C.; Young, S. G. :A protein farnesyltransferase inhibitor ameliorates disease in a mouse model of progeria. Science 311: 1621-1623, 2006. Gabr, M.; Hashem, N.; Hashem, M.; Fahmi, A.; Safouh, M. : Progeria, a pathologic study. J. Pediat. 57: 70-77, 1960. Gilford, H. : Ateleiosis and progeria: continuous youth and premature old age. Brit. Med. J. 2: 914-918, 1904. Glynn, M. W.; Glover, T. W. : Incomplete processing of mutant lamin A in Hutchinson-Gilford progeria leads to nuclear abnormalities, which are reversed by farnesyltransferase inhibition. Hum. Molec. Genet. 14: 2959-2969, 2005. Goldman, R. D.; Shumaker, D. K.; Erdos, M. R.; Eriksson, M.; Goldman, A. E.; Gordon, L. B.; Gruenbaum, Y.; Khuon, S.; Mendez, M.; Varga, R.; Collins, F. S. : Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson-Gilford progeria syndrome. Proc. Nat. Acad. Sci. 101: 8963-8968, 2004. Goldstein, S.; Moerman, E. J. : Heat-labile enzymes in skin fibroblasts from subjects with progeria. New Eng. J. Med. 292: 1305-1309, 1975. Goldstein, S.; Moerman, E. J. : Heat-labile enzymes in circulating erythrocytes of a progeria family. Am. J. Hum. Genet. 30: 167-173, 1978. Harley, C. B.; Goldstein, S.; Posner, B. I.; Guyda, H. : Decreased sensitivity of old and progeric human fibroblasts to a preparation of factors with insulinlike activity. J. Clin. Invest. 68: 988-994, 1981. Hennekam, R. C. M. : Hutchinson-Gilford progeria syndrome: review of the phenotype. Am. J. Med. Genet. 140A: 2603-2624, 2006. Hutchinson, J. : Case of congenital absence of hair, with atrophic condition of the skin and its appendages, in a boy whose mother had been almost wholly bald from alopecia areata from the age of six. Lancet I: 923 only, 1886. Jones, K. L.; Smith, D. W.; Harvey, M. A. S.; Hall, B. D.; Quan, L. : Older paternal age and fresh gene mutation: data on additional disorders. J. Pediat. 86: 84-88, 1975. Khalifa, M. M. : Hutchinson-Gilford progeria syndrome: report of a Libyan family and evidence of autosomal recessive inheritance. Clin. Genet. 35: 125-132, 1989. Kirschner, J.; Brune, T.; Wehnert, M.; Denecke, J.; Wasner, C.; Feuer, A.; Marquardt, T.; Ketelsen, U.-P.; Wieacker, P.; Bonnemann, C. G.; Korinthenberg, R. : p.S143F mutation in lamin A/C: a new phenotype combining myopathy and progeria. Ann. Neurol. 57: 148-151, 2005. Labeille, B.; Dupuy, P.; Frey-Follezou, I.; Larregue, M.; Maquart, F. X.; Borel, J. P.; Gallet, M.; Risbourg, B.; Denceux, J. P. : Progeria de Hutchinson-Gilford neonatale avec atteinte cutanee sclerodermiforme. Ann. Derm. Venerol. 114: 233-242, 1987. Lewis, M. : PRELP, collagen, and a theory of Hutchinson-Gilford progeria. Ageing Res. Rev. 2: 95-105, 2003. Luengo, W. D.; Martinez, A. R.; Lopez, R. O.; Basalo, C. M.; Rojas-Atencio, A.; Quintero, M.; Borjas, L.; Morales-Machin, A.; Ferrer, S. G.; Bernal, L. P.; Canizalez-Tarazona, J.; Pena, J.; Luengo, J. D.; Hernandez, J. C.; Chang, J. C. : Del(1)(q23) in a patient with Hutchinson-Gilford progeria. Am. J. Med. Genet. 113: 298-301, 2002. Maciel, A. T. : Evidence for autosomal recessive inheritance of progeria (Hutchinson Gilford). Am. J. Med. Genet. 31: 483-487, 1988. Mallampalli, M. P.; Huyer, G.; Bendale, P.; Gelb, M. H.; Michaelis, S. : Inhibiting farnesylation reverses the nuclear morphology defect in a HeLa cell model for Hutchinson-Gilford progeria syndrome. Proc. Nat. Acad. Sci. 102: 14416-14421, 2005. McKusick, V. A. : The clinical observations of Jonathan Hutchinson. Am. J. Syph. 36: 101-126, 1952. Merideth, M. A.; Gordon, L. B.; Clauss, S.; Sachdev, V.; Smith, A. C. M.; Perry, M. B.; Brewer, C. C.; Zalewski, C.; Kim, H. J.; and 13 others : Phenotype and course of Hutchinson-Gilford progeria syndrome. New Eng. J. Med. 358: 592-604, 2008. Moulson, C. L.; Fong, L. G.; Gardner, J. M.; Farber, E. A.; Go, G.; Passariello, A.; Grange, D. K.; Young, S. G.; Miner, J. H. : Increased progerin expression associated with unusual LMNA mutations causes severe progeroid syndromes. Hum. Mutat. 28: 882-889, 2007. Ogihara, T.; Hata, T.; Tanaka, K.; Fukuchi, K.; Tabuchi, Y.; Kumahara, Y. : Hutchinson-Gilford progeria syndrome in a 45-year-old man. Am. J. Med. 81: 135-138, 1986. Parkash, H.; Sidhu, S. S.; Raghavan, R.; Deshmukh, R. N. : Hutchinson-Gilford progeria: familial occurrence. Am. J. Med. Genet. 36: 431-433, 1990. Plasilova, M.; Chattopadhyay, C.; Pal, P.; Schaub, N. A.; Buechner, S. A.; Mueller, H.; Miny, P.; Ghosh, A.; Heinimann, K. : Homozygous missense mutation in the lamin A/C gene causes autosomal recessive Hutchinson-Gilford progeria syndrome. J. Med. Genet. 41: 609-614, 2004. Rautenstrauch, T.; Snigula, F.; Krieg, T.; Gay, S.; Muller, P. K. : Progeria: a cell culture study and clinical report of a familial incidence. Europ. J. Pediat. 124: 101-112, 1977. Rava, G. : Su un nucleo familiare di progeria. Minerva Med. 58: 1502-1509, 1967. Rodriguez, J. I.; Perez-Alonso, P. : Diagnosis of progeria syndrome is the only one possible. (Letter) Am. J. Med. Genet. 87: 453-454, 1999. Rodriguez, J. I.; Perez-Alonso, P.; Funes, R.; Perez-Rodriguez, J. : Lethal neonatal Hutchinson-Gilford progeria syndrome. Am. J. Med. Genet. 82: 242-248, 1999. Sagelius, H.; Rosengardten, Y.; Schmidt, E.; Sonnabend, C.; Rozell, B.; Eriksson, M. : Reversible phenotype in a mouse model of Hutchinson-Gilford progeria syndrome. J. Med. Genet. 45: 794-801, 2008. Varela, I.; Pereira, S.; Ugalde, A. P.; Navarro, C. L.; Suarez, M. F.; Cau, P.; Cadinanos, J.; Osorio, F. G.; Foray, N.; Cobo, J.; de Carlos, F.; Levy, N.; Freije, J. M. P.; Lopez-Otin, C. : Combined treatment with statins and aminobisphosphonates extends longevity in a mouse model of human premature aging. (Letter) Nature Med. 14: 767-772, 2008. Viegas, J.; Souza, P. L. R.; Salzano, F. M. : Progeria in twins. J. Med. Genet. 11: 384-386, 1974. Wang, J.; Robinson, J. F.; O’Neil, C. H.; Edwards, J. Y.; Williams, C. M.; Huff, M. W.; Pickering, J. G.; Hegele, R. A. : Ankyrin G overexpression in Hutchinson-Gilford progeria syndrome fibroblasts identified through biological filtering of expression profiles. J. Hum. Genet. 51: 934-942, 2006. Wuyts, W.; Biervliet, M.; Reyniers, E.; D’Apice, M. R.; Novelli, G.; Storm, K. : Somatic and gonadal mosaicism in Hutchinson-Gilford progeria. Am. J. Med. Genet. 135A: 66-68, 2005. Yang, S. H.; Meta, M.; Qiao, X.; Frost, D.; Bauch, J.; Coffinier, C.; Majumdar, S.; Bergo, M. O.; Young, S. G.; Fong, L. G. : A farnesyltransferase inhibitor improves disease phenotypes in mice with a Hutchinson-Gilford progeria syndrome mutation. J. Clin. Invest. 116: 2115-2121, 2006. Brown WT. Progeria. In: Kliegman RM, Behrman RE, Jenson HB, Stanton BF, eds. Nelson Textbook of Pediatrics. 18th Ed. Philadelphia, Pa: Saunders Elsevier; 2007: chap 90. Learning about progeria. National Genome Research Institute. http://www.genome.gov/11007255. Accessed March 5, 2009. Progeria. National Institutes of Health. http://www.nih.gov/about/researchresultsforthepublic/Progeria.pdf. Accessed March 5, 2009. Progeria (Hutchinson-Gilford syndrome). The Merck Manuals Online Medical Library: The Merck Manual for Healthcare Professionals. http://www.merck.com/mmpe/sec19/ch286/ch286d.html. Accessed March 5, 2009. Brown TW. Progeria. In: Kliegman RM, et al. Kliegman: Nelson Textbook of Pediatrics. 18th ed. Saunders Elsevier; 2007. http://www.mdconsult.com/book/player/book.do?method=display&type=bookPage&decorator=header&eid=4-u1.0-B978-1-4160-2450-7..50092-X&uniq=124224571&isbn=978-1-4160-2450-7&sid=812951456. Accessed March 5, 2009. Brown TW. Hutchinson-Gilford progeria syndrome. National Institutes of Health: Gene Reviews. http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=hgps. Accessed March 5, 2009. Hutchison-Gilford progeria syndrome. Genetics Home Reference. http://ghr.nlm.nih.gov/condition=hutchinsongilfordprogeriasyndrome. Accessed March 5, 2009. Anti-cancer drug prevents, reverses cardiovascular damage in mouse model of premature aging disorder. National Institutes of Health. http://www.nih.gov/news/health/oct2008/nhgri-06.htm. Accessed March 5, 2009. Martini R. Helping children cope with chronic illness. American Academy of Child and Adolescent Psychiatry. Accessed March 5, 2009. Paterson, D. : Case of progeria. Proc. Roy. Soc. Med. 16: 42 only, 1922. Brown, W. T. : Personal Communication. Staten Island, N.Y., 1/12/2004.

Support Groups

Progeria Research Foundation, Inc. – www.progeriaresearch.org

Reader, Bhupal Nobles’ Girls’ College of Pharmacy, Udaipur-Raj.313002 INDIA
Email: kamalsrathore@yahoo.com
Mobile: +919828325713

This entry was posted on Monday, March 1st, 2010 at 12:34 am and is filed under anti aging beauty. You can follow any responses to this entry through the RSS 2.0 feed. You can leave a response, or trackback from your own site.

Leave a Reply
Name (required)

Mail (will not be published) (required)


Enter your search terms Submit search form
Web www.antiagingarticles.cn

◦anti aging beauty (2356)
◦anti aging cream (232)
◦anti aging skin (174)
◦moisturizer anti aging (151)
◦natural anti aging (405)
◦Uncategorized (227)
◦March 2010
◦February 2010
◦January 2010
◦December 2009


anti aging is proudly powered by WordPress and Pilkster's SEO Adsense Wordpress Themes
Entries (RSS) and