Phenotypic diversity in patients with lipodystrophy associated with LMNA mutations.

OBJECTIVE: Mutations in LMNA have been linked to diverse disorders called laminopathies, which display heterogeneous phenotypes and include diseases affecting muscles, axonal neurons, progeroid syndromes, and lipodystrophies. Among the lipodystrophies, LMNA mutations have been reported most frequently in patients with familial partial lipodystrophy (FPLD) of the Dunnigan variety; however, phenotypic heterogeneity in the pattern of body fat loss has been observed. In this study, we searched for LMNA mutations in patients with various forms of lipodystrophy. DESIGN AND METHODS: We studied 21 unrelated individuals with lipodystrophy. Subjects underwent a complete clinical evaluation and were classified as typical FPLD (n=12), atypical partial lipodystrophy (n=7), or generalized lipodystrophy (n=2). Molecular analysis of LMNA gene, analysis of body fat by dual-energy X-ray absorptiometry, and biochemical measurements were performed. RESULTS: ALL PATIENTS WITH TYPICAL FPLD WERE FOUND TO CARRY LMNA MUTATIONS: seven patients harbored the heterozygous p.R482W (c.1444C>T), two patients harbored the p.R482Q (c.1445G>A), and two individuals harbored the novel heterozygous variant p.N466D (c.1396A>G), all in exon 8. Also, a homozygous p.R584H (c.1751 G>A) mutation in exon 11 was found. Among patients with atypical partial lipodystrophy, two of them were found to have LMNA mutations: a novel heterozygous p.R582C variation (c.1744 C>T) in exon 11 and a heterozygous substitution p.R349W (c.1045C>T) in exon 6. Among patients with generalized lipodystrophy, only one harbored LMNA mutation, a heterozygous p.T10I (c.29C>T) in exon 1. CONCLUSIONS: We have identified LMNA mutations in phenotypically diverse lipodystrophies. Also, our study broadens the spectrum of LMNA mutations in lipodystrophy.

The relationship between arterial elasticity and lipid profile in people with type 1 diabetes mellitus.

A cross-sectional study was carried out to assess small (SAEI) and large (LAEI) arterial elasticity indexes of individuals with T1DM, and its relationship with their lipid profile. There were associations between SAEI and total cholesterol and waist-hip ratio (R(2)=0.29). Most of the individuals investigated showed low measures of SAEI.

Identification of novel mutations of the WFS1 gene in Brazilian patients with Wolfram syndrome.

OBJECTIVE: Wolfram syndrome (WS) is a rare, progressive, neurodegenerative disorder with an autosomal recessive pattern of inheritance. The gene for WS, WFS1, was identified on chromosome 4p16 and most WS patients carry mutations in this gene. However, some studies have provided evidence for genetic heterogeneity and the genotype-phenotype relationships are not clear. Our aim was to ascertain the spectrum of WFS1 mutations in Brazilian patients with WS and to examine the phenotype-genotype relationships in these patients. DESIGN AND METHODS: Clinical characterization and analyses of the WFS1 gene were performed in 27 Brazilian patients with WS from 19 families. RESULTS: We identified 15 different mutations in the WFS1 gene in 26 patients, among which nine are novel. All mutations occurred in exon 8, except for one missense mutation which was located in exon 5. Although we did not find any clear phenotype-genotype relationship in patients with mutations in exon 8, the homozygous missense mutation in exon 5 was associated with a mild phenotype: onset of diabetes mellitus and optic atrophy during adulthood with good metabolic control being achieved with low doses of sulfonylurea. CONCLUSIONS: Our data show that WFS1 is the major gene involved in WS in Brazilian patients and most mutations are concentrated in exon 8. Also, our study increases the spectrum of WFS1 mutations. Although no clear phenotype-genotype relationship was found for mutations in exon 8, a mild phenotype was associated with a homozygous missense mutation in exon 5.

A case of type II diabetes of early onset presenting with malignant diabetic microangiopathy at diagnosis

In 1987 O'Rahilly described a distinct clinical and genetic syndrome called type II diabetes of early onset (13). Different from Maturity Onset Diabetes of the Young (MODY), that is consistent with autossomal dominant inheritance, this group of patients may have inherited a diabetogenic gene or genes from both parents. Also, in contrast with classical type II diabetes, this syndrome affects mainly younger subjects and has a greater prevalence of severe diabetic microangiopathy. In this paper, we report a 25 year old patient who presented with clinical nephropathy and proliferative retiopathy at the time of diabetes diagnosis. Her mother and a paternal aunt had type II diabetes. Her glicemíc control did not require insulin administration and despite panphotocoagulation and antihypertensive therapy she became blind due to retinal detachment and progressed to chronic renal insufficiency in a few months. To our knowledge this is the first report of an young non-insulin dependent diabetic patient in whom clinical diabetes arose together with severe microangiopathy affecting the kidney and the retina simultaneously. We should call attention to the early diagnosis of this type of diabetes in subjects at risk, in order to institute prompt therapeutic measures able to ameliorate the course of microvascular complications.