Leslie B. Gordon

Recurrent de novo point mutations in lamin A cause Hutchinson–Gilford progeria syndrome

Hutchinson–Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by features reminiscent of marked premature ageing. Here, we present evidence of mutations in lamin A (LMNA) as the cause of this disorder. The HGPS gene was initially localized to chromosome 1q by observing two cases of uniparental isodisomy of 1q—the inheritance of both copies of this material from one parent—and one case with a 6-megabase paternal interstitial deletion. Sequencing of LMNA, located in this interval and previously implicated in several other heritable disorders, revealed that 18 out of 20 classical cases of HGPS harboured an identical de novo (that is, newly arisen and not inherited) single-base substitution, G608G(GGC > GGT), within exon 11. One additional case was identified with a different substitution within the same codon. Both of these mutations result in activation of a cryptic splice site within exon 11, resulting in production of a protein product that deletes 50 amino acids near the carboxy terminus. Immunofluorescence of HGPS fibroblasts with antibodies directed against lamin A revealed that many cells show visible abnormalities of the nuclear membrane. The discovery of the molecular basis of this disease may shed light on the general phenomenon of human ageing.

Phenotype and course of Hutchinson-Gilford progeria syndrome

BACKGROUND Hutchinson-Gilford progeria syndrome is a rare, sporadic, autosomal dominant syndrome that involves premature aging, generally leading to death at approximately 13 years of age due to myocardial infarction or stroke. The genetic basis of most cases of this syndrome is a change from glycine GGC to glycine GGT in codon 608 of the lamin A (LMNA) gene, which activates a cryptic splice donor site to produce abnormal lamin A; this disrupts the nuclear membrane and alters transcription. METHODS We enrolled 15 children between 1 and 17 years of age, representing nearly half of the worlds known patients with Hutchinson-Gilford progeria syndrome, in a comprehensive clinical protocol between February 2005 and May 2006. RESULTS Clinical investigations confirmed sclerotic skin, joint contractures, bone abnormalities, alopecia, and growth impairment in all 15 patients; cardiovascular and central nervous system sequelae were also documented. Previously unrecognized findings included prolonged prothrombin times, elevated platelet counts and serum phosphorus levels, measured reductions in joint range of motion, low-frequency conductive hearing loss, and functional oral deficits. Growth impairment was not related to inadequate nutrition, insulin unresponsiveness, or growth hormone deficiency. Growth hormone treatment in a few patients increased height growth by 10% and weight growth by 50%. Cardiovascular studies revealed diminishing vascular function with age, including elevated blood pressure, reduced vascular compliance, decreased ankle-brachial indexes, and adventitial thickening. CONCLUSIONS Establishing the detailed phenotype of Hutchinson-Gilford progeria syndrome is important because advances in understanding this syndrome may offer insight into normal aging. Abnormal lamin A (progerin) appears to accumulate with aging in normal cells. (ClinicalTrials.gov number, NCT00094393.)

The Mutant Form of Lamin A that Causes Hutchinson-Gilford Progeria Is a Biomarker of Cellular Aging in Human Skin

Hutchinson-Gilford progeria syndrome (HGPS, OMIM 176670) is a rare disorder characterized by accelerated aging and early death, frequently from stroke or coronary artery disease. 90% of HGPS cases carry the LMNA G608G (GGC>GGT) mutation within exon 11 of LMNA, activating a splice donor site that results in production of a dominant negative form of lamin A protein, denoted progerin. Screening 150 skin biopsies from unaffected individuals (newborn to 97 years) showed that a similar splicing event occurs in vivo at a low level in the skin at all ages. While progerin mRNA remains low, the protein accumulates in the skin with age in a subset of dermal fibroblasts and in a few terminally differentiated keratinocytes. Progerin-positive fibroblasts localize near the basement membrane and in the papillary dermis of young adult skin; however, their numbers increase and their distribution reaches the deep reticular dermis in elderly skin. Our findings demonstrate that progerin expression is a biomarker of normal cellular aging and may potentially be linked to terminal differentiation and senescence in elderly individuals.

Cardiovascular Pathology in Hutchinson-Gilford Progeria: Correlation With the Vascular Pathology of Aging

Objective—Children with Hutchinson-Gilford progeria syndrome (HGPS) exhibit dramatically accelerated cardiovascular disease (CVD), causing death from myocardial infarction or stroke between the ages of 7 and 20 years. We undertook the first histological comparative evaluation between genetically confirmed HGPS and the CVD of aging. Methods and Results—We present structural and immunohistological analysis of cardiovascular tissues from 2 children with HGPS who died of myocardial infarction. Both had features classically associated with the atherosclerosis of aging, as well as arteriolosclerosis of small vessels. In addition, vessels exhibited prominent adventitial fibrosis, a previously undescribed feature of HGPS. Importantly, although progerin was detected at higher rates in the HGPS coronary arteries, it was also present in non-HGPS individuals. Between the ages of 1 month and 97 years, progerin staining increased an average of 3.34% per year (P<0.0001) in coronary arteries. Conclusion—We find concordance among many aspects of cardiovascular pathology in both HGPS and geriatric patients. HGPS generates a more prominent adventitial fibrosis than typical CVD. Vascular progerin generation in young non-HGPS individuals, which significantly increases throughout life, strongly suggests that progerin has a role in cardiovascular aging of the general population.

Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson–Gilford progeria syndrome

Hutchinson–Gilford progeria syndrome (HGPS) is an extremely rare, fatal, segmental premature aging syndrome caused by a mutation in LMNA that produces the farnesylated aberrant lamin A protein, progerin. This multisystem disorder causes failure to thrive and accelerated atherosclerosis leading to early death. Farnesyltransferase inhibitors have ameliorated disease phenotypes in preclinical studies. Twenty-five patients with HGPS received the farnesyltransferase inhibitor lonafarnib for a minimum of 2 y. Primary outcome success was predefined as a 50% increase over pretherapy in estimated annual rate of weight gain, or change from pretherapy weight loss to statistically significant on-study weight gain. Nine patients experienced a ≥50% increase, six experienced a ≥50% decrease, and 10 remained stable with respect to rate of weight gain. Secondary outcomes included decreases in arterial pulse wave velocity and carotid artery echodensity and increases in skeletal rigidity and sensorineural hearing within patient subgroups. All patients improved in one or more of these outcomes. Results from this clinical treatment trial for children with HGPS provide preliminary evidence that lonafarnib may improve vascular stiffness, bone structure, and audiological status.

Progeria: a paradigm for translational medicine.

Rare diseases are powerful windows into biological processes and can serve as models for the development of therapeutic strategies. The progress made on the premature aging disorder Progeria is a shining example of the impact that studies of rare diseases can have.

Predictors of acquired lipodystrophy in juvenile-onset dermatomyositis and a gradient of severity

We describe the clinical features of 28 patients with juvenile dermatomyositis (JDM) and 1 patient with adult-onset dermatomyositis (DM), all of whom developed lipodystrophy (LD) that could be categorized into 1 of 3 phenotypes, generalized, partial, or focal, based on the pattern of fat loss distribution. LD onset was often delayed, beginning a median of 4.6 years after diagnosis of DM. Calcinosis, muscle atrophy, joint contractures, and facial rash were DM disease features found to be associated with LD. Panniculitis was associated with focal lipoatrophy while the anti-p155 autoantibody, a newly described myositis-associated autoantibody, was more associated with generalized LD. Specific LD features such as acanthosis nigricans, hirsutism, fat redistribution, and steatosis/nonalcoholic steatohepatitis were frequent in patients with LD, in a gradient of frequency and severity among the 3 sub-phenotypes. Metabolic studies frequently revealed insulin resistance and hypertriglyceridemia in patients with generalized and partial LD. Regional fat loss from the thighs, with relative sparing of fat loss from the medial thighs, was more frequent in generalized than in partial LD and absent from DM patients without LD. Cytokine polymorphisms, the C3 nephritic factor, insulin receptor antibodies, and lamin mutations did not appear to play a pathogenic role in the development of LD in our patients. LD is an under-recognized sequela of JDM, and certain DM patients with a severe, prolonged clinical course and a high frequency of calcinosis appear to be at greater risk for the development of this complication. High-risk JDM patients should be screened for metabolic abnormalities, which are common in generalized and partial LD and result in much of the LD-associated morbidity. Further study is warranted to investigate the pathogenesis of acquired LD in patients with DM. Abbreviations: CI = confidence interval, CT = computerized tomography, dlk = delta-like, DM= dermatomyositis, DXA = dual-energy X-ray absorptiometry, HDL = high-density lipoprotein, HIV = human immunodeficiency virus, HOMA-IR = homeostasis model assessment of insulin resistance, IL = interleukin, IR = insulin resistance, JDM = juvenile dermatomyositis, LA = lipoatrophy, LD = lipodystrophy, LDL = low-density lipoprotein, LMNA= lamin A, MRI = magnetic resonance imaging, NASH = nonalcoholic steatohepatitis, NIH = National Institutes of Health, OGTT = oral glucose tolerance test, OR = odds ratio, PCR = polymerase chain reaction, TNF = tumor necrosis factor, TTP = tristetraprolin.

Disease Progression in Hutchinson-Gilford Progeria Syndrome: Impact on Growth and Development

OBJECTIVES. Hutchinson-Gilford progeria syndrome is a rare and uniformly fatal segmental “premature aging” disease that affects a variety of organ systems. We sought to more clearly define the bone and weight abnormalities in patients with progeria as potential outcome parameters for prospective clinical trials. PATIENTS AND METHODS. We collected and analyzed longitudinal medical information, both retrospectively and prospectively, from a total of 41 children with Hutchinson-Gilford progeria syndrome spanning 14 countries, from the Progeria Research Foundation Medical and Research Database at the Brown University Center for Gerontology. RESULTS. In addition to a number of previously well-defined phenotypic findings in children with progeria, this study identified abnormalities in the eruption of secondary incisors lingually and palatally in the mandible and maxilla, respectively. Although bony structures appeared normal in early infancy, clavicular resorption, coxa valga, avascular necrosis of the femoral head, modeling abnormalities of long bones with slender diaphyses, flared metaphyses, and overgrown epiphyses developed. Long bones showed normal cortical thickness centrally and progressive focal demineralization peripherally. The most striking finding identified in the retrospective data set of 35 children was an average weight increase of only 0.44 kg/year, beginning at ∼24 months of age and persisting through life, with remarkable intrapatient linearity. This rate is >2 SD below normal weight gain for any corresponding age and sharply contrasts with the parabolic growth pattern for normal age- and gender-matched children. This finding was also confirmed prospectively. CONCLUSIONS. Our analysis shows evidence of a newly identified abnormal growth pattern for children with Hutchinson-Gilford progeria syndrome. The skeletal and dental findings are suggestive of a developmental dysplasia rather than a classical aging process. The presence of decreased and linear weight gain, maintained in all of the patients after the age of 2 years, provides the ideal parameter on which altered disease status can be assessed in clinical trials.

Impact of Farnesylation Inhibitors on Survival in Hutchinson-Gilford Progeria Syndrome

Background— Hutchinson-Gilford progeria syndrome is an ultrarare segmental premature aging disease resulting in early death from heart attack or stroke. There is no approved treatment, but starting in 2007, several recent single-arm clinical trials administered inhibitors of protein farnesylation aimed at reducing toxicity of the disease-producing protein progerin. No study assessed whether treatments influence patient survival. The key elements necessary for this analysis are a robust natural history of survival and comparison with a sufficiently large patient population that has been treated for a sufficient time period with disease-targeting medications. Methods and Results— We generated Kaplan–Meier survival analyses for the largest untreated Hutchinson-Gilford progeria syndrome cohort to date. Mean survival was 14.6 years. Comparing survival for treated versus age- and sex-matched untreated cohorts, hazard ratio was 0.13 (95% confidence interval, 0.04–0.37; P<0.001) with median follow-up of 5.3 years from time of treatment initiation. There were 21 of 43 deaths in untreated versus 5 of 43 deaths among treated subjects. Treatment increased mean survival by 1.6 years. Conclusions— This study provides a robust untreated disease survival profile that can be used for comparisons now and in the future to assess changes in survival with treatments for Hutchinson-Gilford progeria syndrome. The current comparisons estimating increased survival with protein farnesylation inhibitors provide the first evidence of treatments influencing survival for this fatal disease. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique Indentifiers: NCT00425607, NCT00879034, and NCT00916747.

Ovalbumin is more immunogenic when introduced into brain or cerebrospinal fluid than into extracerebral sites

The magnitudes of serum antibody responses to ovalbumin have been compared following immunization via cerebral or extracerebral sites in Sprague-Dawley rats. In central nervous system (CNS)-immunized rats, conditions were designed to ensure normal brain barrier permeability. Extracerebral immunization was via the footpad or along pathways of antigen outflow from the CNS. The relative immunogenicity of different injection sites is: CSF greater than brain tissue greater than extracerebral sites. Enhancement of the antibody response to CNS-administered antigen appears to depend on events initiated within the CNS, since ovalbumin injected into blood (which reaches the spleen) or nasal submucosa (which drains to cervical nodes) fails to elicit a similar response.