Isabelle Jéru

Dramatic beneficial effect of interleukin-1 inhibitor treatment in patients with familial Mediterranean fever complicated with amyloidosis and renal failure

BACKGROUNDnFamilial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disorder, for which systemic AA amyloidosis is the major complication revealed most of the time by renal abnormalities. Current treatment is daily colchicine that prevents both recurrent inflammatory attacks and amyloidosis deposition in most patients. However, some patients still develop amyloidosis and renal failure. Functional studies suggest that interleukin (IL)-1 is implicated in the inflammatory reaction in FMF and therefore, IL-1 inhibitors could be a new approach to treat FMF. The aim of this series study was to evaluate anakinra in patients with FMF complicated with amyloidosis and renal failure.nnnMETHODSnWe studied a series of adult patients with FMF complicated with amyloidosis and treated with anakinra in one reference centre were reviewed. A search for published patients with FMF associated amyloidosis treated with anakinra was performed by screening PubMed.nnnRESULTSnWe report four cases of patients with FMF-associated amyloidosis treated with anakinra and discuss the clinical pertinence of its use in these particular clinical settings.nnnCONCLUSIONSnAnakinra has a strong effect on both inflammatory attacks and general status in patients with FMF-associated amyloidosis. It may contribute to changing the prognosis of these patients. Long-term studies are needed to appreciate the effect of anakinra or other IL-1 inhibitors on the natural history of amyloidosis in these patients.

Clinical Utility Gene Card for: Familial partial lipodystrophy

1. DISEASE CHARACTERISTICS 1.1 Name of the disease (synonyms) There are several subclasses of familial partial lipodystrophy (FPLD): Type 1 FPLD (FPLD1), also known as Köbberling lipodystrophy; Type 2 FPLD (FPLD2), also known as Dunnigan variety; Type 3 FPLD (FPLD3); Type 4 FPLD (FPLD4); Type 5 FPLD (FPLD5); and Type 6 FPLD (FPLD6). The molecular basis of FPLD1 remains to be identified.1 It is important to underline that FPLD is an expanding group of disorders associating partial lipodystrophy and metabolic complications (see section 1.9), whose classification remains to be clarified. On one hand, FPLD4, FPLD5 and FPLD6 have been described based each on only one to five independent patients. On the other hand, a missense variant was identified in AKT2 in an autosomal dominant form of partial lipodystrophy,2 but the disorder has not entered the classification of FPLD so far. Moreover, in addition to the diseases known as FPLD in OMIM, partial lipodystrophies can be encountered in other complex syndromes with a Mendelian inheritance, as progeroid or autoinflammatory syndromes. The description of all these rare entities is beyond the scope of this clinical utility gene card, which will focus on so-called FPLD.

LMNA-associated partial lipodystrophy: anticipation of metabolic complications

Background Type-2 familial partial lipodystrophy (FPLD2) is a rare autosomal dominant lipodystrophic disorder due to mutations in LMNA encoding lamin A/C, a key epigenetic regulator. FPLD2 severity is determined by the occurrence of metabolic complications, especially diabetes and hypertriglyceridaemia. We evaluated the disease history and severity over generations. Methods This retrospective study of the largest cohort of patients with FPLD2 reported to date investigates 85 patients from 24 families comprising three generations (G1: n=39; G2: n=41; G3: n=5). Results Lipodystrophy appears with the same characteristics and at the same age in first generation (G1;18.6±1.5 years) and second generation (G2;15.9±0.8 years). Despite similar body mass index (23.7±0.6 vs 23.8±0.6u2009kg/m2), the mean delay between the onset of lipodystrophy and diabetes was far shorter in G2 (10.5±2.4 years) than in G1 (29.0±3.5 years) (p=0.0002). The same is true for the delay preceding hypertriglyceridaemia (G2: 4.5±1.4; G1: 19.3±3.2 years) (p=0.002), revealing an anticipation phenomenon. Observations in G3, and analysis within each family of disease history and diagnostic procedures, confirmed this result. Conclusions This study is a rare example of anticipation unrelated to a trinucleotide expansion. Discovery of this early occurrence of metabolic complications in young generations underlines the utility of presymptomatic genetic diagnosis, with careful metabolic screening and preventive lifestyle in all at-risk individuals.

Clinical Utility Gene Card for: Congenital Generalized Lipodystrophy

1. Name of the disease (synonyms):n There are four subclasses of Congenital Generalized Lipodystrophy (CGL), also named Berardinelli–Seip Congenital Lipodystrophy (BSCL): Type 1 CGL (CGL1). Type 2 CGL (CGL2). Type 3 CGL (CGL3). Type 4 CGL (CGL4). 2. OMIM# of the disease:n CGL1: #608594. CGL2: #269700. CGL3: #612526. CGL4: #613327. 3. Name of the analysed genes or dna/chromosome segments:n CGL1: AGPAT2. CGL2: BSCL2. CGL3: CAV1. CGL4: PTRF. 4. OMIM# of the gene(s):n AGPAT2: *603100. BSCL2: *606158. CAV1: *601047. PTRF: *603198. Review of the analytical and clinical validity as well as of the clinical utility of DNA-based testing for mutations in the four gene(s) in ⊠ diagnostic, □ predictive and ⊠ prenatal settings and for ⊠ risk assessment in relatives.

Lipodystrophic syndromes due to LMNA mutations: recent developments on biomolecular aspects, pathophysiological hypotheses and therapeutic perspectives

Abstract Mutations in LMNA, encoding A-type lamins, are responsible for laminopathies including muscular dystrophies, lipodystrophies, and premature ageing syndromes. LMNA mutations have been shown to alter nuclear structure and stiffness, binding to partners at the nuclear envelope or within the nucleoplasm, gene expression and/or prelamin A maturation. LMNA-associated lipodystrophic features, combining generalized or partial fat atrophy and metabolic alterations associated with insulin resistance, could result from altered adipocyte differentiation or from altered fat structure. Recent studies shed some light on how pathogenic A-type lamin variants could trigger lipodystrophy, metabolic complications, and precocious cardiovascular events. Alterations in adipose tissue extracellular matrix and TGF-beta signaling could initiate metabolic inflexibility. Premature senescence of vascular cells could contribute to cardiovascular complications. In affected families, metabolic alterations occur at an earlier age across generations, which could result from epigenetic deregulation induced by LMNA mutations. Novel cellular models recapitulating adipogenic developmental pathways provide scalable tools for disease modeling and therapeutic screening.

MFN2-associated lipomatosis: Clinical spectrum and impact on adipose tissue

BACKGROUNDnMultiple symmetric lipomatosis (MSL) is characterized by upper-body lipomatous masses frequently associated with metabolic and neurological signs. MFN2 pathogenic variants were recently implicated in a very rare autosomal recessive form of MSL. MFN2 encodes mitofusin-2, a mitochondrial fusion protein previously involved in Charcot-Marie-Tooth neuropathy.nnnOBJECTIVEnTo investigate the clinical, metabolic, tissular, and molecular characteristics of MFN2-associated MSL.nnnMETHODSnWe sequenced MFN2 in 66 patients referred for altered fat distribution with one or several lipomas or lipoma-like regions and performed clinical and metabolic investigations in patients with positive genetic testing. Lipomatous tissues were studied in 3 patients.nnnRESULTSnSix patients from 5 families carried a homozygous p.Arg707Trp pathogenic variant, representing the largest reported series of MFN2-associated MSL. Patients presented both lipomatous masses and a lipodystrophic syndrome (lipoatrophy, low leptinemia and adiponectinemia, hypertriglyceridemia, insulin resistance and/or diabetes). Charcot-Marie-Tooth neuropathy was of highly variable clinical severity. Lipomatous tissue mainly contained hyperplastic unilocular adipocytes, with few multilocular cells. It displayed numerous mitochondrial alterations (increased number and size, structural defects). As compared to control subcutaneous fat, mRNA and protein expression of leptin and adiponectin was strikingly decreased, whereas the CITED1 and fibroblast growth factor 21 (FGF21) thermogenic markers were strongly overexpressed. Consistently, serum FGF21 was markedly increased, and 18F-FDG-PET-scan revealed increased fat metabolic activity.nnnCONCLUSIONnMFN2-related MSL is a novel mitochondrial lipodystrophic syndrome involving both lipomatous masses and lipoatrophy. Its complex neurological and metabolic phenotype justifies careful clinical evaluation and multidisciplinary care. Low leptinemia and adiponectinemia, high serum FGF21, and increased 18F-FDG body fat uptake may be disease markers.

Monogenic forms of lipodystrophic syndromes: diagnosis, detection, and practical management considerations from clinical cases

Abstract Background: Lipodystrophic syndromes are rare diseases of genetic or acquired origin characterized by partial or generalized lack of body fat. Early detection and diagnosis are crucial to prevent and manage associated metabolic dysfunctions, i.e. insulin resistance, dyslipidemia, fatty liver, and diabetes, and to provide appropriate genetic counseling. By means of several representative case studies, this article illustrates the diagnostic and management challenges of lipodystrophic syndromes. Review: Berardinelli-Seip congenital lipodystrophy (BSCL) is typically diagnosed at birth, or soon thereafter, with generalized lipoatrophy and hepatomegaly secondary to hepatic steatosis. Physicians must also consider this diagnosis in adults with atypical non-autoimmune diabetes, hypertriglyceridemia, and a lean and muscular phenotype. The BSCL1 subtype due to mutations in the AGPAT2 gene can have an unusual presentation, especially in neonates and infants. Particular attention should be paid to infants presenting failure to thrive who also have hepatomegaly and metabolic derangements. The BSCL2 sub-type due to mutations in the BSCL gene tends to be more severe than BSCL1, and is characterized by greater fat loss, mild intellectual disability, earlier onset of diabetes, and higher incidence of premature death. Effective management from an earlier age may moderate the natural disease course. Partial lipodystrophies may easily be confused with common central obesity and/or metabolic syndrome. In patients with unexplained pancreatitis and hypertriglyceridemia, lipodystrophies such as familial partial lipodystrophy type 2 (FPLD2; Dunnigan type, due to LMNA mutations) should be considered. Oral combined contraceptives, which can reveal the disease by inducing severe hypertriglyceridemia, are contraindicated. Endogenous estrogens may also lead to “unmasking” of the FPLD2 phenotype, which often appears at puberty, and is more severe in females than males. Conclusions: Diet and exercise, adapted to age and potential comorbidities, are essential prerequisites for therapeutic management of lipodystrophic syndromes. Metreleptin therapy can be useful to manage lipodystrophy-related metabolic complications.

PW01-022 – Dissociation between CRP and SAA in FMF

An Israeli study previously showed that dissociation between normal C-reactive protein (CRP) and elevated serum amyloid A (SAA) could be observed in Familial Mediterranean fever (FMF). Considering that elevated SAA is predictive for AA amyloidosis, this study suggested that SAA could be a better tool in the diagnosis and therapeutic management of FMF.