Hutchinson-Gilford progeria syndrome
Jump to navigation
Jump to search
Introduction
1st described in 1886.
Epidemiology
Pathology
- accelerated atherosclerosis
- premature aging
- alopecia
- atrophy of subcutaneous fat
- skeletal hypoplasia
- stiff joints
- hip dislocations
- progerin (protein protein product of mutant LMNA gene) disrupts nuclear membrane, alters transcription
Genetics
- point mutations in the LMNA gene
- mutations not found in parents, this NOT inherited
- point mutation C->T in exon 11 of the LMNA gene in 25 patients
- results in a silent Gly-Gly change at codon 608
- apparently occurs at cryptic splice site
- results in protein with deleted C-terminus (50 amino acid residues)
- C-terminus contains endoproteolytic cleavage site for normal synthesis of lamin A
- result is abnormalities in nuclear membrane
- other point mutations in exon 11 the LMNA gene have been reported
- 3 patients described without LMNA gene mutations
Clinical manifestations
- normal development during the 1st year of life
- growth retardation beginning in the 2nd year of life
- mean age of diagnosis is 19 months
- senile appearance
- farsightedness
- low-frequency conductive hearing loss
- speech deficits
- dental abnormalities
Laboratory
- prolonged prothrombin time[4]
- thrombocytosis
- increased serum phosphorus
Diagnostic procedures
- echocardiography may be useful in clinical trials[3]
Complications
- atherosclerosis
- LV diastolic dysfunction most common cardiac abnormality[3]
- prevalence increases with age
- LV systolic dysfunction & valvular heart disease less common
- seizures
Management
- lonafarnib may delay mortality[6]
- pravastatin adds no cardiovascular benefit[7]
- zoledronate may improve bone mineral density
- prognosis
- most patients die by the age of 13
More general terms
References
- ↑ Harrison's Principles of Internal Medicine, 13th ed. Isselbacher et al (eds), McGraw-Hill Inc. NY, 1994, pg 1038
- ↑ Stedman's Medical Dictionary 26th ed, Williams & Wilkins, Baltimore, 1995
- ↑ 3.0 3.1 3.2 3.3 Novelli G & D'Apice MR, Trends in Mol Med 9(9):370, 2003
- ↑ 4.0 4.1 Merideth MA et al, Phenotype and course of Hutchinson-Gilford progeria syndrome. N Engl J Med 2008, 358:592 PMID: https://www.ncbi.nlm.nih.gov/pubmed/18256394
- ↑ Prakash A, Gordon LB, Kleinman ME et al Cardiac Abnormalities in Patients With Hutchinson-Gilford Progeria Syndrome. JAMA Cardiol. Published online February 21, 2018 PMID: https://www.ncbi.nlm.nih.gov/pubmed/29466530 https://jamanetwork.com/journals/jamacardiology/article-abstract/2672949
- ↑ 6.0 6.1 6.2 Gordon LB, Shappell H, Massaro J et al Association of Lonafarnib Treatment vs No Treatment With Mortality Rate in Patients With Hutchinson-Gilford Progeria Syndrome. JAMA. 2018;319(16):1687-1695 PMID: https://www.ncbi.nlm.nih.gov/pubmed/29710166 https://jamanetwork.com/journals/jama/fullarticle/2679278?
Hisama FM, Oshima J. Precision Medicine and Progress in the Treatment of Hutchinson-Gilford Progeria Syndrome. JAMA. 2018;319(16):1663-1664. PMID: https://www.ncbi.nlm.nih.gov/pubmed/29710145 https://jamanetwork.com/journals/jama/fullarticle/2679255 - ↑ 7.0 7.1 Gordon LB, Kleinman ME, Massaro J et al Clinical Trial of the Protein Farnesylation Inhibitors Lonafarnib, Pravastatin, and Zoledronic Acid in Children With Hutchinson-Gilford Progeria Syndrome. Circulation. 2016 Jul 12;134(2):114-25. PMID: https://www.ncbi.nlm.nih.gov/pubmed/27400896 Free PMC Article