Progeria

In Hutchinson-Gilford syndrome (left), a mutation leads to a deformation of the cell nucleus (bottom right). For comparison, a normal cell nucleus (top right)

Classification according to ICD-10
E34.8	Other specified endocrine disorders
ICD-10 online (WHO version 2019)

Progeria , also Progeria and premature aging (derived from ancient Greek πρό (pró) - before and τὸ γῆρας (γήρας), -ως or γῆρος, -ους (gäras) - aging, senescence (from Latin senescere - to age)), im In a narrower sense, the Hutchinson-Gilford progeria syndrome ( HGPS ), also called Progeria infantilis , belongs to the segmental progeroid syndromes (SPS; rare diseases with signs of premature aging in more than one organ or tissue) or progeria syndromes and is a Symptoms of various hereditary diseases that are associated with rapid aging in children ( acrogeria , Bloom syndrome , Cockayne syndrome , geroderma osteodysplastica , xeroderma pigmentosum ). The clinical picture was first described in 1886 by Jonathan Hutchinson and Hastings Gilford . The most striking feature is the premature aging of the affected children.

There is also the form of Progeria adultorum ( Werner syndrome ), which leads to accelerated aging in adults from around mid - life.

Signs of illness

Children affected by this disease are born without any abnormalities and develop symptoms between six and twelve months of age. Symptoms are hair loss , hardening of the arteries , short stature , craniofacial malformation with u. a. Relocation of the lower jaw in relation to the base of the skull ( micrognathia ), further loss of subcutaneous fatty tissue and bone loss ( osteoporosis ).

Frequency and course of disease

Those affected age five to ten times faster than people without the disease. The most common causes of death are heart attacks and strokes , which occur in childhood or adolescence. However, many of the phenomena of normal aging do not occur in children with HGPS; the tumor risk is not significantly increased, and neurodegenerative diseases such as Alzheimer's disease do not occur more frequently. So HGPS is not an exact copy of normal aging. The life expectancy is fourteen. The prevalence is estimated at 1 in 4,000,000. Around 200–250 children around the world are believed to be living with HGPS. Around 100 cases had been identified by 2013.

Since the molecular mechanisms of the regulation of aging processes are only incompletely known, there is no possibility of prevention or therapy by influencing currently researched molecular processes in age-associated diseases such as segmental progeroid syndromes.

root cause

One cause of progeria is a point mutation c.794 A → G (N265S) ( chromosome 1 gene locus p34.2) in ZMPSTE24 - gene , which is the enzyme CAAX Prenylprotease or zinc Metallopeptitase-Ste-24-homologous coding . This is essential for the formation of the structural protein Lamin A , which is an important part of the inner cell nuclear membrane. Mutant ZMPSTE24 cannot necessarily separate prelamine A at amino acid 647 to eliminate prenylation and produce the final, 646 AA (amino acids) long lamin A. In the majority of cases of HGPS, however, there is a mutation of the prelamine gene in codon 608 on chromosome 1 gene locus q23 itself, which changes the trinucleotide GGC to GGT. Although this codes for the same amino acid (Gly), a splice point (5'AC) is inserted in the corresponding pre-mRNA due to the changed base sequence. This faulty splicing results in a 150 base shorter prelamin RNA and a 50 AA shorter lamin A, which is also known as progerin. The interface for processing to lamin A is missing, and ZMPSTE24 cannot cut prelamin A. A prenylated laminate that is too short remains. A change of codon 608 in AGT or a mutation of codon 145 is less common.

Lamin A (structural protein of the nuclear membrane, which is encoded by the LMNA gene containing twelve exons ) is part of a protein chain that binds to numerous other proteins in the cell nucleus and the cell nuclear membrane as well as to transcription factors and DNA . It performs a stabilizing function of the cell nucleus as well as regulatory functions. Among other things, it takes part in the activation of genes. The inheritance of Hutchinson-Gilford progeria is autosomal - dominant . One defective allele is enough to cause the disease. This is due to the chain structure formed by Lamin A. Even a few defective Lamin A proteins lead to instability of the entire chain. The cell nuclei of people with HGPS are therefore largely deformed.

Since children generally do not reach reproductive age, a new disease is almost always a spontaneous mutation in the lamin A gene ( dominant lethal factor ). Few hereditary cases of HGPS have been described. Often these children do not have the typical picture of the disease, but variants with further clinical abnormalities and a different life expectancy. Autosomal recessive inheritance has also been described here; partly due to other mutations in the lamin A gene, partly due to mutations in genes that contribute to the maturation (processing) of a precursor protein, prelamin A, to lamin A.

Differential diagnosis

A distinction must be made between mandibuloacral dysplasia , Wiedemann-Rautenstrauch syndrome (a congenital segmental progeroid syndrome due to mutations in the POLR3A gene), GAPO syndrome , CARASIL and acrogeria .

Like Hutchinson-Gilford progeria syndrome, mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome ( MDPL ) belong to the infantile segmental progeroid syndromes. The genetic cause of the MDPL is heterozygous mutations in the POLD1 gene.

Others

• One of the main characters in Tad Williams ' Otherland novels , Orlando Gardiner, suffers from progeria.
• The South African painter and hip-hop DJ Leon Botha (1985-2011) also suffered from progeria and died from it. He was 26 years old.
• The disease gained public attention in the United States through Sam Berns and the HBO reality show Life according to Sam .

literature

• MA Merideth u. a .: Phenotype and Course of Hutchinson-Gilford Progeria Syndrome . In: New England Journal of Medicine . No. 358 , 2008, p. 592-604 ( abstract ).
• Michael Schophaus : Too young to be old: the story of a puzzling disease. Goldmann, Munich 2004, ISBN 978-3-442-15279-7 .
• Bruno Schrep: Why my child? In: Der Spiegel No. 38 of September 16, 2002, p. 178ff.
• Hayley Okines et al. a .: Old Before My Time: Hayley Okines' Life with Progeria . 2011, ISBN 978-1-908192-55-4 .
• Davor Lessel, Christian Kubisch: Genetically determined syndromes with signs of premature aging. In: Deutsches Ärzteblatt. Volume 116, issue 29 f., July 22, 2019, pp. 489-496, in particular (on the Hutchinson-Gilford progeria syndrome) pp. 491-493.

Movies

• Jack (1996), American drama directed by Francis Ford Coppola
• Sarah's short life (2003 / ORF) by Manfred Corrine
• Sabrina - Too young to be old (2000 / Swiss television) by Elsbeth Leisinger
• Paa - A very Rare Father-Son, Son-Father Story (2009) by R. Balki
• Bjorn, gewoon YOLO (2015 / ZAPP , Netherlands), documentation by Siham Raijoul
• My philosophy for a happy life , TED talk by Sam Berns, a teenager suffering from progeria, in English

Web links

Wiktionary: Progeria  - explanations of meanings, word origins, synonyms, translations

Commons : Progerie  - collection of images, videos and audio files

• Progeria type I, Onmeda.de
• Progeria type II, Onmeda.de
• Progeria

Individual evidence

1. ↑ Davor Lessel, Christian Kubisch: Genetically determined syndromes with signs of premature aging. In: Deutsches Ärzteblatt. Volume 116, Issue 29 f., July 22, 2019, pp. 489–496.
2. ^ F. Coppedè: The epidemiology of premature aging and associated comorbidities. In: Clinical interventions in aging. Volume 8, 2013, pp. 1023-1032, doi : 10.2147 / CIA.S37213 , PMID 24019745 , PMC 3760297 (free full text) (review).
3. ↑ Davor Lessel, Christian Kubisch: Genetically determined syndromes with signs of premature aging. In: Deutsches Ärzteblatt. Volume 116, Issue 29 f., July 22, 2019, pp. 489–496.
4. ^ S. Shackleton et al. a .: Compound heterozygous ZMPSTE24 mutations reduce prelamin A processing and result in a severe progeroid phenotype. In: J Med Genet 2005, 42; e36. doi: 10.1136 / jmg.2004.029751 .
5. ↑ M. Eriksson et al. a .: Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. In: Nature 423, 2003, pp. 293-298. PMID 12714972
6. ↑ Davor Lessel, Christian Kubisch: Genetically determined syndromes with signs of premature aging. In: Deutsches Ärzteblatt. Volume 116, Issue 29 f., July 22, 2019, pp. 489–496, here: p. 490 f.
7. ↑ Davor Lessel, Christian Kubisch: Genetically determined syndromes with signs of premature aging. In: Deutsches Ärzteblatt. Volume 116, Issue 29 f., July 22, 2019, pp. 489–496, here: p. 491 f.
8. ↑ Advice of a dying person - “Never miss a party” In: welt.de , accessed on May 24, 2019
9. ↑ http://jeugdjournaal.nl/item/767469-bjorn-gewoon-yolo.html the documentation Bjorn, gewoon YOLO on jeugdjournaal.nl (Dutch)
10. ↑ My philosophy for a happy life | Sam Berns | TEDxMidAtlantic In: YouTube, Retrieved May 24, 2019

This article is about a health issue. It is not used for self-diagnosis and does not replace a diagnosis by a doctor. Please note the information on health issues !