Severe congenital cutis laxa with cardiovascular manifestations due to homozygous deletions in ALDH18A1.

Abstract

Autosomal recessive cutis laxa (ARCL) type 2 constitutes a heterogeneous group of diseases mainly characterized by lax and wrinkled skin, skeletal anomalies, and a variable degree of intellectual disability. ALDH18A1-related ARCL is the most severe form within this disease spectrum. Here we report on the clinical and molecular findings of two affected individuals from two unrelated families. The patients presented with typical features of de Barsy syndrome and an overall progeroid appearance. However, the phenotype was highly variable including cardiovascular involvement in the more severe case. Investigation of a skin biopsy of one patient revealed not only the typical alterations of elastic fibers, but also an altered structure of mitochondria in cutaneous fibroblasts. Using conventional sequencing and copy number analysis we identified a frameshift deletion of one nucleotide and a microdeletion affecting the ALDH18A1 gene, respectively, in a homozygous state in both patients. Expression analysis in dermal fibroblasts from the patient carrying the microdeletion showed an almost complete absence of the ALDH18A1 mRNA resulting in an absence of the ALDH18A1 protein. So far, only 13 affected individuals from seven unrelated families suffering from ALDH18A1-related cutis laxa have been described in literature. Our findings provide new insights into the clinical spectrum and show that beside point mutations microdeletions are a possible cause of ALDH18A1-ARCL.

• Authors: Björn Fischer, Bert Callewaert, Phillipe Schröter, Paul J Coucke, Claire Schlack, Claus-Eric Ott, Manrico Morroni, Wolfgang Homann, Stefan Mundlos, Eva Morava, Anna Ficcadenti, Uwe Kornak
• Journal: Molecular genetics and metabolism (Mol Genet Metab) Vol. 112 Issue 4 Pg. 310-6 (Aug 2014) ISSN: 1096-7206 [Electronic] United States
• PMID: 24913064 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Amino Acids
• RNA, Messenger
• ALDH18A1 protein, human
• Aldehyde Dehydrogenase

Topics

• Aldehyde Dehydrogenase (genetics, metabolism)
• Amino Acids (blood)
• Base Sequence
• Cardiovascular Diseases (blood, complications, genetics)
• Child, Preschool
• Cutis Laxa (blood, complications, congenital, genetics)
• Fatal Outcome
• Female
• Fibroblasts (metabolism, pathology)
• Gene Deletion
• Homozygote
• Humans
• Infant, Newborn
• Male
• Molecular Sequence Data
• Pedigree
• RNA, Messenger (genetics, metabolism)
• Skin (pathology, ultrastructure)