Clinical and biochemical features guiding the diagnostics in neurometabolic cutis laxa

Thatjana Gardeitchik, Miski Mohamed, Björn Fischer, Martin Lammens, Dirk Lefeber, Baiba Lace, Michael Parker, Ki Joong Kim, Bing C. Lim, Johannes Häberle, Livia Garavelli, Sujatha Jagadeesh, Ariana Kariminejad, Deanna Guerra, Michel Leão, Riikka Keski-Filppula, Han Brunner, Leo Nijtmans, Bert Van Den Heuvel, Ron WeversUwe Kornak, Eva Morava

Research output: Contribution to journalArticlepeer-review

22 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)888-895
Number of pages8
JournalEuropean Journal of Human Genetics
Issue number7
StatePublished - Jul 2014


  • Cutis laxa
  • Inborn errors of glycosylation
  • Metabolic
  • Mitochondrial function
  • Mutation
  • Neurologic

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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