Clinical and genetic characterization of chanarin-dorfman syndrome patients: first report of large deletions in the ABHD5 gene

Eight CDS patients belonging to six different families from Mediterranean countries were enrolled for genetic study. Molecular analysis of the ABHD5 gene included the sequencing of the 7 coding exons and of the putative 5' regulatory regions, as well as reverse transcript-polymerase chain reaction analysis and sequencing of normal and aberrant ABHD5 cDNAs.Five different mutations were identified, four of which were novel, including two splice-site mutations (c.47+1G>A and c.960+5G>A) and two large deletions (c.898_*320del and c.662-1330_773+46del). All the reported mutations are predicted to be pathogenic because they lead to an early stop codon or a frameshift producing a premature termination of translation. While nonsense, missense, frameshift and splice-site mutations have been identified in CDS patients, large genomic deletions have not previously been described.These results emphasize the need for an efficient approach for genomic deletion screening to ensure an accurate molecular diagnosis of CDS. Moreover, in spite of intensive molecular screening, no mutations were identified in one patient with a confirmed clinical diagnosis of CDS, appointing to genetic heterogeneity of the syndrome.Neutral-lipid storage diseases (NLSDs) are a clinically heterogeneous group of non-lysosomal inherited disorders characterized by the cytoplasmic accumulation of lipid droplets (LDs) in most tissues. Clinical phenotypes include myopathy (skeletal and heart muscle), liver damage, ataxia, neurosensory hearing loss, ichthyosis, sub-capsular cataracts, nystagmus, strabismus, and, rarely, mental retardation [1-6]. When non-bullous congenital ichthyosiform erythroderma (NCIE), presenting as fine scaling on erythematous skin, is the dominant feature of NLSD since birth, the disorder is referred to as Chanarin-Dorfman syndrome (CDS [MIM 275630]) or neutral lipid storage disease with ichthyosis (NLSDI). Patients are sometimes born as collodion babies. Serum lipids are normal, whereas m