Expanding the phenotype of metabolic cutis laxa with an additional disorder of N-linked protein glycosylation

Abstract

Genetic syndromes associated with cutis laxa (CL) and wrinkled skin are multisystem disorders with progeroid features, including sagging, lax and wrinkled skin [1, 2]. Metabolic CL is genetically heterogeneous. We previously reported on the frequently overlapping clinical phenotypes, including X-linked and autosomal recessive forms [2]. However, recently new forms of CL have been described. "Metabolic" CL is related to different inborn errors of metabolism; the historic example is the X-linked defect in ATP7A (MIM 309400). Autosomal recessive metabolic CL types are ARCL2 and ARCL3. ARCL2 patients present with a characteristic face, skeletal and joint abnormalities, developmental and growth delay due to mutations in different genes, including ATP6V0A2 (MIM 219200, 278250), RIN2 (MIM 613075), COG7(MIM 608779), GORAB (MIM 231070), and PYCR1 (MIM 612940, 614438) [2-4]. These encode endosomal and Golgi proteins (ARCL2A), and affect trafficking and glycosylation, except for PYCR1, which is involved in mitochondrial proline synthesis (ARCL2B). ARCL3 patients have parchment-like, progeroid skin, cataracts, corneal clouding, and significant neurologic disease [5], caused by mutations in PYCR1 or ALDH18A1 (MIM 616603, 219150), also involved in mitochondrial proline synthesis [2]. Additional inborn

Clinical, biochemical and molecular phenotype of congenital disorders of glycosylation: long-term follow-up

“…The most common pathogenic variant in the PMM2 gene was p.V231M and p.R141H. The latter is also the most commonly reported in the literature [38]. The compound heterozygotes for p.R141H noted in our study and in the literature as well, were associated with a mild phenotype.…”

“…In our cohort, the predominant liver phenotype was observed in MPI-CDG patients, while other CDG like PMM2-CDG, ATP6AP1-CDG were associated with liver disease. Up to now, 14 patients have been reported with the X-linked ATP6AP1 deficiency and the key features were immunodeficiency and liver involvement ranging from a mild elevation of serum transaminases to liver failure [15,[29][30]. The clinical outcome of PMM2-CDG varies among patients [25].…”

“…In SRD5A3-CDG patients, cerebellar ataxia and signs of visual impairment and variable eye malformations, including optic disc hypoplasia, nystagmus, were the characteristic features. ATP6V0A2-CDG, as well as COG7-CDG, were described as cutis laxa syndrome with defective protein glycosylation [37][38]. About 50% of patients with ATP6V0A2-CDG showed cortical malformations, especially pachygyria, in brain MRI.…”

Liver failure and x‐linked immunodeficiency type 47

“…The variants in this Jansen et al manuscript were clustered in the C‐terminal region of the gene, a feature in common with the variant identified in the brothers. Witters et al describe a male patient with a hemizygous mutation in the gene ATP6AP1 with many connective tissue manifestations: cutis laxa, dilation of the aortic root, diaphragmatic hernia and wrinkled skin, and a hepatopathy and frequent infections 3 . Although the ATP6AP1 variant identified in both boys was classified as a variant of unknown significance, their phenotypes fit well with what has been described about ATP6AP1‐related disorders and is likely diagnostic for their clinical presentation.…”

ATP6AP1‐CDG: Follow‐up and female phenotype

“…Fourteen patients have been reported with the X‐linked ATP6AP1 deficiency (ATP6AP1‐CDG) . Key features were immunodeficiency and liver involvement .…”