Dr. Björn Fischer-Zirnsak (Berlin, Germany) : The Mitonchondrion and CL

The best known function of mithocondria is energy production (ATP synthesis) via the respiratory chain.

However, this organelle is also central in several metabolic processes like the tricarboxylic acid (TCA) cycle, the urea cycle and important for cellular stress response processes and programmed cell death.

This presentation will focus on the clinical differences between and within the single entities, discussed in relation to known and novel findings from cellular and animal models.

By this, an overview about the research on the mitochondria related cutis laxa disorders will be given.

Dr. Thatjana Gardeitchik, MD (Nijmegen, the Netherlands) : Neurometabolic Defects in CL

The underlying molecular defects in Cutis Laxa Sybdromes can also be roughly divided in two groups,

based on type of involved pathomechanism : defects in genes coding a « structural » ECM-component or in genes in which mutations can inborn errors of metabolism (IEM) presenting with Cutis Laxa.

The exact way these divergent molecular lead to elastin abnormalities remain unclarified.

Prof. Dr. Uwe Kornak, MD (Göttingen, Germany): The Secretory Pathway, Glycosylation, and Cutis Laxa

Secreted proteins and membrane proteins have to pass through the secretory pathway, which is not only responsible for the transport to the correct cellular compartment, but also for the maturation and modification of these proteins. A central part of the secretory pathway is the Golgi compartment, which consists of several « pancake-like » membrane sacks (cisternae).

One important modification is glycosylation, which has been found altered in a whole group of Cutis Laxa disorders, that are also named congenital disorders of glycosylation (CDG).

Mrs Aude Beyens, MD (Ghent, Belgium): Structural defects of Connective Tissue Proteins and CL

Elastic fiber assembly, or elastogenesis, is a complex process that is precisely regulated in a spatiotemporal manner and depends on proper growth factor signaling and mechanosensing.

 

The underlying molecular defect in cutis laxa syndromes affect the synthesis and/or association associated extracellular matrix proteins.

Prof. Gerhard Sengle (Köln, Germany): Matrix Biology – What can we learn from animal modelling ?

Understanding how the fine tune mechanisms of elastic fibers formation is perturbed in the different types of Cutis Laxa is crucial to design molecular therapies in preclinical trials using animal models.

FIMARAD ANNUAL METING

24th & 25th November 2022 :

National and Scientific Days of the FIMARAD network for rare skin disorders.

 

Besides the important progress made by the network’s members, together with patient representatives in the workgroups,

it was the opportunity to strengthen the collaboration between FIMARAD and the French Federation for Skin (FFP).

1st WORLD CONGRESS ON RARE SKIN DISORDERS

The 1st WCRSD (First International Congress on Rare Skin Disorders) was held in Paris

7th to 9th June 2022.

Organised by ERN-Skin, René Touraine Foundation, Fimarad as well as Patients Representatives and Globalskin for the Patient Session, it was a huge success !!

With a successful Patient Forum,

Presentation on Cutis Laxa new classification,

It was also the occasion to meet with other organisations.

NEW MUTATIONS

4 new genetic mutations were recently found:

 

LOX : This gene of the 5-Lysyl oxidase family is involved in initiating of cross-linking of Elastin and Collagen. The mutation leads to cardiovascular, respiratory and bone symptoms, especially fractures. This is why it was initially considered to be a new type of osteogenesis imperfecta (glass bones disorder). But the discovery of fragmented elastic fibers allowed this mutation to be included in Cutis Laxa Syndroms. It is a recessive form.

 

EFEMP1 (Fibulin3): The consequences, besides lax skin, of this mutation are multiple hernias and joint hypermobility as well as mild intellectual/learning disability. It is a new recessive type of Cutis Laxa.

 

LTBP1 : This mutation is distinguished by lax skin, inguinal hernias, craniofacial dysmorphology, various heart defects and prominent skeletal features (short stature, brachydactyly, craniosynostosis,..). It is another new recessive type of Cutis Laxa.

 

PI4K2A : This 4th new mutation is characterised by the following clinical signs : lax skin, involuntary movements (neurological issue), dysmorphism and intellectual/learning disability. It is also a recessive type.

 

A 5th new mutation has recently been found and we are longing for it to be published so we can tell you about it.

 

Thanks to all the researchers for their amazing work in basic knowledge of Cutis Laxa. All these findings are essential to give patients better care and offer them a better quality of life.

 

Diagnosis Roving and Deadlock

The workgroup of FIMARAD (Rare Dermatologic Disorders French Network), of which Marie-Claude Boiteux is a member, is interested in Diagnosis Odyssey. An important piece of work for Cutis Laxa was presented during the FIMARAD meeting in November.

Due to the great diversity of types and symptoms, the quality of the healthcare journey for CL patients is intimately linked to diagnosis. So, it is not enough to diagnose a Cutis Laxa one needs to be really precise about which type of CL with the help of a molecular analysis (genetic testing).

The quality of the patient’s healthcare as well as the quality of their life depend on the swiftness of the molecular diagnosis. In France, a number of systematic tests are carried out immediately after birth to evaluate the newborn’s health (hernias, tone, mobility, hips,etc)..

A table has been created associating these systematic examinations with various CL symptoms to allow a faster clinical and molecular diagnosis. So, for instance, if the systematic examination of a newborn shows hip dysplasia, the next simple step is to see if the skin is lax and the newborn has hernias to suspect ARCL2A or Geroderma Osteodysplastica. The diagnosis can then be confirmed with a genetic test. Concordance of symptoms is the first step to a faster diagnosis.

ERN-Skin : Cutis Laxa Webinar

14th December 2021

Pr Bert CALLEWAERT and Pr Raoul ENGELBERT

shared the latest results of the work done by the Mendelian Connective Tissue Disorders thematic group in ERN-Skin.

Especially regarding the latest finding on Cutis Laxa Syndroms. The classification is still in progress.