title: Clinical and biochemical features guiding the diagnostics in neurometabolic cutis laxa.
abstract: 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.
authors: Department of Pediatrics, Institute for Metabolic and Genetic Disease, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors: Thatjana
authors: T
authors: Gardeitchik
authors: Department of Pediatrics, Institute for Metabolic and Genetic Disease, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors: Miski
authors: M
authors: Mohamed
authors: Institute of Medical Genetics and Human Genetics, Charité Universitätsmedizin, Berlin, Germany.
authors: Björn
authors: B
authors: Fischer
authors: Department of Pathology, Institute for Metabolic and Genetic Disease, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors: Martin
authors: M
authors: Lammens
authors: Department of Neurology, Institute for Metabolic and Genetic Disease, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors: Dirk
authors: D
authors: Lefeber
authors: Medical Genetics Clinic, Children's Clinical University Hospital, Riga, Latvia.
authors: Baiba
authors: B
authors: Lace
authors: Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Sheffield, UK.
authors: Michael
authors: M
authors: Parker
authors: Department of Pediatrics, Seoul National University Hospital, Seoul, South Korea.
authors: Ki-Joong
authors: KJ
authors: Kim
authors: Department of Pediatrics, Seoul National University Hospital, Seoul, South Korea.
authors: Bing C
authors: BC
authors: Lim
authors: Department of Pediatrics, University Children's Hospital, Zürich, Switzerland.
authors: Johannes
authors: J
authors: Häberle
authors: Clinical Genetics Unit, Obstetric and Pediatric Department, Santa Maria Nuova Hospital IRCCS, Reggio Emilia, Italy.
authors: Livia
authors: L
authors: Garavelli
authors: Department of Clinical Genetics, Chennai, India.
authors: Sujatha
authors: S
authors: Jagadeesh
authors: Kariminejad-Najmabadi Pathology and Genetics Center, Teheran, Iran.
authors: Ariana
authors: A
authors: Kariminejad
authors: Department of Biomedical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors: Deanna
authors: D
authors: Guerra
authors: Pediatric Neurology Unit and Neurogenetics Unit, Hospital S João, Porto, Portugal.
authors: Michel
authors: M
authors: Leão
authors: Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland.
authors: Riikka
authors: R
authors: Keski-Filppula
authors: Department of Human Genetics, Institute for Metabolic and Genetic Disease, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors: Han
authors: H
authors: Brunner
authors: Department of Pediatrics, Institute for Metabolic and Genetic Disease, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors: Leo
authors: L
authors: Nijtmans
authors: 1] Department of Pediatrics, Institute for Metabolic and Genetic Disease, Radboud University Medical Centre, Nijmegen, The Netherlands [2] Laboratory for Genetic Endocrine and Metabolic Diseases, Institute for Metabolic and Genetic Disease, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors: Bert
authors: B
authors: van den Heuvel
authors: 1] Department of Pediatrics, Institute for Metabolic and Genetic Disease, Radboud University Medical Centre, Nijmegen, The Netherlands [2] Laboratory for Genetic Endocrine and Metabolic Diseases, Institute for Metabolic and Genetic Disease, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors: Ron
authors: R
authors: Wevers
authors: 1] Institute of Medical Genetics and Human Genetics, Charité Universitätsmedizin, Berlin, Germany [2] FG Development and Disease, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors: Uwe
authors: U
authors: Kornak
authors: 1] Department of Pediatrics, Institute for Metabolic and Genetic Disease, Radboud University Medical Centre, Nijmegen, The Netherlands [2] Hayward Genetics Center, Tulane University Medical Center, New Orleans, LA, USA.
authors: Eva
authors: E
authors: Morava
mesh_terms: D000293:Adolescent; D061085:Agenesis of Corpus Callosum / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000444:Aldehyde Dehydrogenase / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D003483:Cutis Laxa / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004827:Epilepsy / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D006031:Glycosylation; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D025261:Mitochondrial Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism; D011446:Prospective Studies; D011762:Pyrroline Carboxylate Reductases / Q000235:genetics / Q000378:metabolism; D000097502:delta-1-Pyrroline-5-Carboxylate Reductase
chemical_list: D000444:Aldehyde Dehydrogenase; D002352:Carrier Proteins; D020662:Guanine Nucleotide Exchange Factors; D025261:Mitochondrial Proton-Translocating ATPases; D011762:Pyrroline Carboxylate Reductases; D000097502:delta-1-Pyrroline-5-Carboxylate Reductase; C501005:MT-ATP6 protein, human; C447829:RIN2 protein, human
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