Further expansion of the phenotypic spectrum associated with mutations in ALDH18A1, encoding Δ¹‐pyrroline‐5‐carboxylate synthase (P5CS)

Abstract

We report on the third case of cutis laxa and progeroid features caused by a homozygous mutation in ALDH18A1 that encodes Δ¹-pyrroline-5-carboxylate-synthase (P5CS). This severely affected child, born to consanguineous parents of Pakistani origin, presented with lax, wrinkled and thin skin with dilated and tortuous subcutaneous blood vessels, corneal clouding, and hypotonia. The child had severe global developmental delay and feeding difficulties and died in infancy for an unknown reason. The proband was homozygous for a mutation in ALDH18A1, c.1923 + 1G > A which results in the production of two anomalous transcripts that are predicted to encode proteins lacking the catalytic site for the enzyme. The cellular phenotype is characterized by diminished production of collagen types I and III, altered elastin ultrastructure, and diminished cell proliferation of cultured dermal fibroblasts. This severe clinical and cellular phenotype overlaps with a broad group of neurocutaneous syndromes that include cutis laxa type II, wrinkly skin syndrome, de Barsy syndrome, and gerodermia osteodysplastica. The findings presented here emphasize the pleiotropic presentation of this group of conditions and suggest that multiple components of the extracellular matrix are perturbed in these disorders.

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

“…So far, only 13 affected individuals with ALDH18A1 mutations from seven unrelated families have been described, mainly with missense or splice site mutations [11,14,16,17,[22][23][24]. The~1.6 kb microdeletion identified here is the first mutation of this class found in ALDH18A1-related CL.…”

“…However, the intracranial arterial malformation of patient 2 is previously unreported and had dramatic consequences. In two patients with ALDH18A1-related CL, kinky tortuosity of brain vessels was reported [16,17] demonstrating that in this severe form of CL vessels are especially vulnerable. Therefore, vessels should not only be assessed in ADCL, ARCL1, and ATS that are well known for their arterial malformations [1,18,19], but also in proline biosynthesis pathologies.…”

“…Due to the fact that no microhomologies were found and given the insertion of a guanosine, the underlying mechanism for this genomic rearrangement most likely is a non-homologous end joining (NHEJ), a frequent cause for such non-recurrent rearrangements [25]. Recently, one patient was described carrying a homozygous splice site mutation in ALDH18A1 [17]. In the case presented here, the underlying mechanism is more likely a nonsense-mediated decay, shown by the almost complete absence of the ALDH18A1 mRNA whereas in the case by Skidmore et al at least the splice product with open reading frame could be partially stable.…”

Clinical and biochemical features guiding the diagnostics in neurometabolic cutis laxa

“…21,22,38,42,43 The two patients, presented by Baumgartner et al, 22 showed low ornithine, arginine, citrulline and proline. Except for low ornithine levels in two of the patients described by Bicknell et al, 21 no amino-acid profile abnormalities have been described in the other patients.…”

Amino acid synthesis deficiencies

“…In this first family, P5CS deficiency was a slowly progressive neurodegenerative disorder affecting both the central and peripheral nervous system, combined with cataracts and extensive connective tissue involvement. However, the majority of patients with P5CS deficiency subsequently reported were shown to have a cutis laxa syndrome (Bicknell et al 2008, Skidmore et al 2011, Martinelli et al 2012.…”