Keywordsfatty aldehyde dehydrogenase; ichthyosis; mutation; Sjögren-Larsson syndrome Sjögren-Larsson syndrome (SLS; OMIM 270200) is an autosomal recessive disorder characterized by the presence of pruritic ichthyosis, mental retardation, spastic diplegia or tetraplegia, retinal perimacular 'glistening white dots' and photophobia. 1 SLS is caused by mutations in the ALDH3A2 gene, which codes for fatty aldehyde dehydrogenase (FALDH), a microsomal enzyme that catalyses the oxidation of medium-and long-chain aliphatic aldehydes. 2 More than 70 mutations have been identified in this disease.3 Most mutations are unique to each SLS family, but several common mutations have been reported among patients from Europe and the Middle East. In the first molecular genetic analysis of a cohort of patients with SLS from Brazil, we now report a common disease-causing ALDH3A2 mutation, delineate its associated phenotypic spectrum and describe a diagnostic screening test using restriction enzyme digestion. Case and methodsNine patients with SLS from three apparently unrelated Brazilian kindreds native to the south and southeastern part of the country were studied. Patients 1, 2 and 3 were previously reported 4 and were born to consanguineous parents; patients 4, 5 and 6 are sisters and patients 7 and 8 are their cousins. Patient 9 was also born to first cousins. Blood specimens, Total genomic DNA was extracted from blood using standard phenol-chloroform methods. ALDH3A2 exons and their flanking sequences were amplified by polymerase chain reaction (PCR) and sequenced. 2 To detect the c.1108-1G → C mutation more conveniently, exon 8 was digested with DdeI according to the manufacturer's instructions and restriction products separated by agarose gel electrophoresis. ALDH3A2 haplotypes were determined using four intragenic single nucleotide polymorphisms as described. 2 FALDH enzyme activity was measured in cultured skin fibroblasts. 5Results and discussion Biochemical and molecular characterizationAll patients had <10% of normal FALDH enzyme activity in cultured skin fibroblasts ( Table 1). Sequencing of the ALDH3A2 gene revealed a homozygous c.1108-1G → C mutation in intron 7 of all of the affected individuals. Their parents were heterozygous for the mutation, except for the parents of patient 9 who were not tested. The c.1108-1G → C mutation abolishes a DdeI restriction enzyme cut site in the wild-type gene. DdeI digestion of a 275-bp PCR product of exon 8 and its flanking intron 7 sequence yielded a 181-bp fragment from normal control subjects, but a 263-bp fragment from the patients with SLS (Fig. 1b). This constitutes a convenient screening test for the mutation. Haplotype analysis of the ALDH3A2 gene showed that patients from each family were homozygous for haplo-type 1 (see Rizzo et al.2).The c.1108-1G → C mutation alters the splice acceptor site at the junction of intron 7 and exon 8. Like many exons, exon 8 does not end between codons, but rather ends with part of a codon, which is completed when exon 8 is spliced to exon 9...
Nailfold videocapillaroscopy was performed in 2 groups of subjects: 14 healthy volunteers (C) and 15 patients with primary Sjögren's syndrome (PSS). This was a controlled clinical trial, matched by age and sex. The aims of this study were to evaluate (1) functional capillary density (number of capillaries with flowing red blood cells per mm 2 , FCD); (2) capillary red blood cell velocity at rest (RBV), maximum capillary red blood cell velocity (RBVmax) after 1 minute ischemia, and the time to reach it (TRBVmax), taking into account the presence or absence of Raynaud's phenomenon (RP) in the analysis; (3) nailfold capillary morphology; and (4) afferent (AFD), apical (APD), and efferent (EFD) capillary diameters. The mean values obtained for controls versus patients, respectively, were (mean ± SD): FCD (per mm 2 ) 8.0 ±1.6 and 10.1 ±3.6; RBV (mm/s) 0.9 ±0.4 and 0.7 ±0.2; RBVmax (mm/s) 1.7 ±0.9 and 1.3 ±0.3; TRBVmax (s) 4.5 ±0.8 and 5.8 ±1.6 (p=0.02); and TRBVmax (s) in patients with RP=6.7 ±1.6 and without RP=5.6 ±1.6 (p=0.52). The correlation between RBV and RBVmax for each group, using the Pearson's coefficient, was significant only for the control group (p = 0.007), estimated correlation coefficient = 0.68. Controls and patients showed, in the majority of fields examined, normal morphologic patterns of capillaries. The capillary diameters were AFD (µm) 10.8 ±1.5 and 11.3 ±1.8; APD (µm) 16.3 ±2.4 and 16.8 ±2.9; and EFD (µm) 12.3 ±1.4 and 13.7 ±1.9. These results indicate that these patients have longer time to reach RBVmax, suggesting an impairment of the reactive hyperemia response, which could correlate with clinical features of the disease, ie, abnormal macrovascular and microvascular reactivity.
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