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.

ATP6V0A2‐related cutis laxa in 10 novel patients: Focus on clinical variability and expansion of the phenotype

“…Of note, in our patients, the evolution of the skeletal features seems much less severe than previously reported . Two patients presented with cataract, an uncommon finding in ARCL2A in contrast to ARCL3 caused by PYCR1 or ALDH18A1 mutations . Patient 6 had retinal detachment, unrelated to severe myopia.…”

Recurrent De Novo Mutations Affecting Residue Arg138 of Pyrroline-5-Carboxylate Synthase Cause a Progeroid Form of Autosomal-Dominant Cutis Laxa

“…Only 13 affected individuals from 7 unrelated families carrying biallelic ALDH18A1 mutations have been described so far. 31 The present study shows de novo heterozygous mutations in ALDH18A1 affecting the highly conserved amino acid Arg138 of P5CS as the cause of a similar but milder progeroid cutis laxa phenotype, which has important impact for diagnostics and genetic counseling. All probands showed cataract or corneal clouding, thin skin with visible veins and wrinkles, moderate intellectual disability, clenched fingers, and pre-and postnatal growth retardation.…”

“…29 Mutations in ALDH18A1 (MIM: 138250), which encodes the mitochondrial enzyme pyrroline-5carboxylate synthase (P5CS) responsible for the conversion of glutamic acid to P5C, have been found in the most severely affected ARCL3 individuals. 25,[30][31][32][33][34][35] PYCR1/2 and the enzyme proline dehydrogenase (PRODH) catalyzing the reverse reaction are key components of the proline cycle, which shuttles redox equivalents in and out mitochondria. 36 Furthermore, this pathway is tightly connected to the urea cycle via ornithine aminotransferase (OAT) and to the TCA cycle via glutamate dehydrogenase (GLDH).…”

“…To identify the molecular genetic basis of the observed De Barsy-like phenotype, we investigated the genes ALDH18A1 (GenBank: NM_002860.3) and PYCR1 (GenBank: NM_ 001282280.1) by conventional Sanger sequencing in families 1-4 and 6-8 as described previously. 31,34 In proband 5-II:3 we used a gene panel approach capturing the most relevant genes linked to connective tissue disorders ( Figure S1A). In all affected individuals, sequencing of PYCR1, the most frequently affected gene in ARCL3, revealed no pathogenic sequence alteration.…”

“…(B) Native gel electrophoresis of P5CS-containing protein complexes isolated from fibroblasts from control individuals, probands (P) 2-II:1 and 3-II:1, and fibroblasts from an individual with the homozygous P5CS substitution p.Val601Glyfs*24. 31 Cells were lysed with modified RIPA (50 mM Tris-HCl, 1% NP40, 0.25% Na-deoxycholat, 150 mM NaCl, 1 mM EDTA þ Complete proteinase inhibitor cocktail [Roche]) and protein concentrations were determined with the BCA-Kit (Pierce). A total amount of 5 mg protein was separated on a native-PAGE gel.…”