Is it possible to achieve an acceptable disease control by dietary therapy alone in Berardinelli Seip type 1? Experience from a case report.

Background and objective: Severe metabolic complications generally manifest at an early age in Berardinelli - Seip congenital lipodystrophy (BSCL) and their management is especially challenging. Nutritional intervention with low lipid diets is considered by experts to be fundamental in treating the disease when associated with medical therapy, however little is known about the beneficial effects of dietary interventions alone. Aim: To underline the importance of a well-structured low-fat diet in BSCL patients. Methods and results: A BSCL male patient strictly followed a hypocaloric hypolipemic diet (60% carbohydrates, 22% fats and 18% proteins) since clinical diagnosis at the age of one year. Interestingly, pharmacological interventions were not required at any point during the follow-up. Aged 16 years the patient was referred to our center. Biochemistry, hormonal evaluation, 75 mg oral glucose tolerance test, cardiac evaluation and abdominal ultrasound were performed, revealing no abnormalities. Genetic analysis and leptin dosage were carried out, confirming the diagnosis of BSCL type 1 (homozygosity for c.493-1G>C pathogenic variant in AGPAT2 gene) and showing undetectable circulating levels of leptin (< 0.2 mcg/L). Diet therapy alone was therefore maintained, scheduling follow-up visits every six months, with acceptable disease control ever since. Conclusions: This report proves how a low-fat diet is of great help in the management of BSCL and its complications. In addition, a specific hypolipemic diet could be used alone as an effective treatment in selected cases with high compliance and, probably, a milder phenotype.

Case Report: An Atypical Form of Familial Partial Lipodystrophy Type 2 Due to Mutation in the Rod Domain of Lamin A/C.

Purpose: Familial partial lipodystrophy type 2 (FPLD2) patients generally develop a wide variety of severe metabolic complications. However, they are not usually affected by primary cardiomyopathy and conduction system disturbances, although a few cases of FPLD2 and cardiomyopathy have been reported in the literature. These were all due to amino-terminal heterozygous lamin A/C mutations, which are considered as new forms of overlapping syndromes. Methods and Results: Here we report the identification of a female patient with FPLD2 due to a heterozygous missense variant c.604G>A in the exon 3 of the LMNA gene, leading to amino acid substitution (p.Glu202Lys) in the central alpha-helical rod domain of lamin A/C with a high propensity to form coiled-coil dimers. The patient's cardiac evaluations that followed the genetic diagnosis revealed cardiac rhythm disturbances which were promptly treated pharmacologically. Conclusions: This report supports the idea that there are "atypical forms" of FPLD2 with cardiomyopathy, especially when a pathogenic variant affects the lamin A/C head or alpha-helical rod domain. It also highlights how increased understanding of the genotype-phenotype correlation could help clinicians to schedule personalized monitoring of the lipodystrophic patient, in order to prevent uncommon but possible devastating manifestations, including arrhythmias and sudden death.

Drugs affecting prelamin A processing: effects on heterochromatin organization.

Increasing interest in drugs acting on prelamin A has derived from the finding of prelamin A involvement in severe laminopathies. Amelioration of the nuclear morphology by inhibitors of prelamin A farnesylation has been widely reported in progeroid laminopathies. We investigated the effects on chromatin organization of two drugs inhibiting prelamin A processing by an ultrastructural and biochemical approach. The farnesyltransferase inhibitor FTI-277 and the non-peptidomimetic drug N-acetyl-S-farnesyl-l-cysteine methylester (AFCMe) were administered to cultured control human fibroblasts for 6 or 18 h. FTI-277 interferes with protein farnesylation causing accumulation of non-farnesylated prelamin A, while AFCMe impairs the last cleavage of the lamin A precursor and is expected to accumulate farnesylated prelamin A. FTI-277 caused redistribution of heterochromatin domains at the nuclear interior, while AFCMe caused loss of heterochromatin domains, increase of nuclear size and nuclear lamina thickening. At the biochemical level, heterochromatin-associated proteins and LAP2 alpha were clustered at the nuclear interior following FTI-277 treatment, while they were unevenly distributed or absent in AFCMe-treated nuclei. The reported effects show that chromatin is an immediate target of FTI-277 and AFCMe and that dramatic remodeling of chromatin domains occurs following treatment with the drugs. These effects appear to depend, at least in part, on the accumulation of prelamin A forms, since impairment of prelamin A accumulation, here obtained by 5-azadeoxycytidine treatment, abolishes the chromatin effects. These results may be used to evaluate downstream effects of FTIs or other prelamin A inhibitors potentially useful for the therapy of laminopathies.

Mutational analysis of Peroxiredoxin IV: exclusion of a positional candidate for multinodular goitre.

BACKGROUND: Multinodular goitre (MNG) is a common disorder characterised by an enlargement of the thyroid, occurring as a compensatory response to hormonogenesis impairment. The incidence of MNG is dependent on sex (female:male ratio 5:1) and several reports have documented a genetic basis for the disease. Last year we mapped a MNG locus to chromosome Xp22 in a region containing the peroxiredoxin IV (Prx-IV) gene. Since Prx-IV is involved in the removal of H2O2 in thyroid cells, we hypothesize that mutations in Prx-IV gene are involved in pathogenesis of MNG. METHODS: Four individuals (2 affected, 2 unrelated unaffected) were sequenced using automated methods. All individuals were originated from the original three-generation Italian family described in previous studies. A Southern blot analysis using a Prx-IV full-length cDNA as a probe was performed in order to exclude genomic rearrangements and/or intronic mutations. In addition a RT-PCR of PRX-IV was performed in order to investigate expression alterations. RESULTS: No causative mutations were found. Two adjacent nucleotide substitutions were detected within introns 1 and 4. These changes were also detected in unaffected individuals, suggesting that they were innocuous polymorphisms. No gross genomic rearrangements and/or restriction fragment alterations were observed on Southern analysis. Finally, using RT-PCR from tissue-specific RNA, no differences of PRX-IV expression-levels were detected between affected and unaffected samples. CONCLUSIONS: Based on sequence and genomic analysis, Prx-IV is very unlikely to be the MNG2 gene.