De Barsy Syndrome: A genetically heterogeneous autosomal recessive cutis laxa syndrome related to P5CS and PYCR1 dysfunction

Zampatti, Stefania; Castori, Marco; Fischer, Bjoern; Garavelli, Livia; Dionisi‐Vici, Carlo; Agolini, Emanuele; Wischmeijer, Anita; Morava, Éva; Novelli, Giuseppe; Häberle, Johannes; Kornak, Uwe; Brancati, Francesco

doi:10.1002/ajmg.a.35231

Cited by 43 publications

(40 citation statements)

References 23 publications

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“…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.…”

Section: Discussionmentioning

confidence: 81%

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: 81%

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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“…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.…”

Section: Metabolic Abnormalitiesmentioning

confidence: 95%

“…This is in line with the findings of Kornak et al, demonstrating mitochondrial dysfunction, altered membrane potential and apoptosis rate, abnormal mitochondrial network on oxidative stress and ultrastructural changes by electomicroscopy. 18 In the medical literature, no metabolic abnormalities have been described in patients carrying PYCR1 mutations, however, out of the almost 30 reported patients [17][18][19][20][38][39][40][41] metabolic studies have been only performed in four cases.…”

Section: Metabolic Abnormalitiesmentioning

confidence: 99%

Clinical and biochemical features guiding the diagnostics in neurometabolic cutis laxa

et al. 2013

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Patients with cutis laxa (CL) have wrinkled, sagging skin with decreased elasticity. Skin symptoms are associated with variable systemic involvement. The most common, genetically highly heterogeneous form of autosomal recessive CL, ARCL2, is frequently associated with variable metabolic and neurological symptoms. Progeroid symptoms, dysmorphic features, hypotonia and psychomotor retardation are highly overlapping in the early phase of these disorders. This makes the genetic diagnosis often challenging. In search for discriminatory symptoms, we prospectively evaluated clinical, neurologic, metabolic and genetic features in our patient cohort referred for suspected ARCL. From a cohort of 26 children, we confirmed mutations in genes associated with ARCL in 16 children (14 probands), including 12 novel mutations. Abnormal glycosylation and gyration abnormalities were mostly, but not always associated with ATP6V0A2 mutations. Epilepsy was most common in ATP6V0A2 defects. Corpus callosum dysgenesis was associated with PYCR1 and ALDH18A1 mutations. Dystonic posturing was discriminatory for PYCR1 and ALDH18A1 defects. Metabolic markers of mitochondrial dysfunction were found in one patient with PYCR1 mutations. So far unreported white matter abnormalities were found associated with GORAB and RIN2 mutations. We describe a large cohort of CL patients with neurologic involvement. Migration defects and corpus callosum hypoplasia were not always diagnostic for a specific genetic defect in CL. All patients with ATP6V0A2 defects had abnormal glycosylation. To conclude, central nervous system and metabolic abnormalities were discriminatory in this genetically heterogeneous group, although not always diagnostic for a certain genetic defect in CL.

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“…In some patients, additional movement disorders such as tremor and dystonia were also present (Mohamed et al 2011;Zampatti et al 2012;Wolthuis et al 2014). On cranial MRI, hypomyelination with a thin corpus callosum can be found, sometimes with cerebellar abnormalities.…”

Section: Infantile Cutis Laxa Phenotypementioning

confidence: 99%

Amino acid synthesis deficiencies

Koning

2013

Handbook of Clinical Neurology

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De Barsy Syndrome: A genetically heterogeneous autosomal recessive cutis laxa syndrome related to P5CS and PYCR1 dysfunction

Cited by 43 publications

References 23 publications

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

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

Clinical and biochemical features guiding the diagnostics in neurometabolic cutis laxa

Amino acid synthesis deficiencies

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