Genotype–phenotype spectrum of PYCR1-related autosomal recessive cutis laxa

Dimopoulou, Aikaterini; Fischer, Björn; Gardeitchik, Thatjana; Schröter, Phillipe; Kayserili, Hülya; Schlack, Claire; Li, Yun; Brum, Jaime Moritz; Barišić, Ingeborg; Castori, Marco; Spaich, Christiane; Fletcher, Elaine; Mahayri, Zeina N.; Bhat, Meenakshi; Girisha, Katta M.; Lachlan, Katherine; Johnson, Diana; Phadke, Shubha R.; Gupta, Neerja; Simandlová, Martina; Kabra, Madhulika; David, Albert; Nijtmans, Leo; Chitayat, David; Tüysüz, Beyhan; Brancati, Francesco; Mundlos, Stefan; Maldergem, Lionel Van; Morava, Éva; Wollnik, Bernd; Kornak, Uwe

doi:10.1016/j.ymgme.2013.08.009

Cited by 66 publications

(59 citation statements)

References 37 publications

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“…Although the etiology of the severe neurocutaneous disorder in the family originally described by de Barsy remains unknown it was shown that de Barsy-like disorders can be due to mutations either in PYCR1 or ALDH18A1 [11,12,14,15]. In our patients, we found clinical features like facial dysmorphism, hypotonia, adducted thumbs and cutis laxa, which are frequently found in progeroid cutis laxa syndromes.…”

Section: Discussionmentioning

confidence: 46%

“…In our patients, we found clinical features like facial dysmorphism, hypotonia, adducted thumbs and cutis laxa, which are frequently found in progeroid cutis laxa syndromes. However, while osteoporosis or osteopenia is a skeletal feature found in most CL disorders [6,8,15] absence or abnormal shape of distal skeletal elements found in patient 1 is unusual. Clenched or adducted thumbs are a typical sign for ARCL due to PYCR1 or ALDH18A1 mutations.…”

Section: Discussionmentioning

confidence: 88%

“…This might be a potential diagnostic feature to differentiate between PYCR1-and ALDH18A1-related CL [12,15,20,21].…”

Section: Discussionmentioning

confidence: 99%

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

Fischer

Callewaert

Schröter

et al. 2014

Molecular Genetics and Metabolism

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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.

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Section: Discussionmentioning

confidence: 46%

Section: Discussionmentioning

confidence: 88%

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

Fischer

Callewaert

Schröter

et al. 2014

Molecular Genetics and Metabolism

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“…PYCR1 -related cutis laxa and progeroid syndrome presents with the core features of intrauterine growth retardation, wrinkled skin, joint hyperlaxity, and a typical progeroid gestalt. 20 Some of the facial features such as triangular face, bulbous upturned nose and long philtrum mirror PYCR2-facies, but cutis laxa and progeroid features are missing. Furthermore, PYCR1 mutations usually associate with milder intellectual disability and can have normal head circumference.…”

Section: Discussionmentioning

confidence: 99%

PYCR2 Mutations cause a lethal syndrome of microcephaly and failure to thrive

Zaki

Bhat

Sultan³

et al. 2016

Annals of Neurology

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Objective A study was undertaken to characterize the clinical features of the newly described hypomyelinating leukodystrophy type 10 with microcephaly. This is an autosomal recessive disorder mapped to chromosome 1q42.12 due to mutations in PYCR2 gene, encoding an enzyme involved in proline synthesis in mitochondria. Methods From several international clinics, eleven consanguineous families were identified with PYCR2 mutations by whole exome or targeted sequencing, with detailed clinical and radiological phenotyping. Selective mutations from patients were tested for effect on protein function. Results The characteristic clinical presentation of patients with PYCR2 mutations included failure to thrive, microcephaly, craniofacial dysmorphism, progressive psychomotor disability, hyperkinetic movements, and axial hypotonia with variable appendicular spasticity. Patients did not survive beyond the first decade of life. Brain magnetic resonance imaging (MRI) showed global brain atrophy and white matter T2 hyperintensities. Routine serum metabolic profiles were unremarkable. Both nonsense and missense mutations were identified, which impaired protein multimerization. Interpretation PYCR2-related syndrome represents a clinically recognizable condition in which PYCR2 mutations lead to protein dysfunction, not detectable on routine biochemical assessments. Mutations predict a poor outcome, probably as a result of impaired mitochondrial function.

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“…Dimopoulou et al (2013) reported a genotype-phenotype correlation and demonstrated that patients with mutations in the first two exons were clinically less severely affected and had no or very mild intellectual disability.…”

Section: Treatmentmentioning

confidence: 99%