Anti-LMNA monoclonal antibody, clone KpM6

Background: Pathogenic variants in lamin A/C (LMNA) cause a variety of progeroid disorders including Hutchinson-Gilford progeria syndrome, mandibuloacral dysplasia, and atypical progeroid syndrome. Six families with 11 patients harboring a pathogenic heterozygous LMNA c.1045C>T; p.R349W variant have been previously reported to have partial lipodystrophy, cardiomyopathy, and focal segmental glomerulosclerosis (FSGS), suggesting a distinct progeroid syndrome. Methods: We report 6 new patients with a heterozygous LMNA p.R349W variant and review the phenotype of previously reported patients to define their unique characteristics. We also performed functional studies on the skin fibroblasts of a patient to seek the underlying mechanisms of various clinical manifestations. Results: Of the total 17 patients, all 14 adults with the heterozygous LMNA p.R349W variant had peculiar lipodystrophy affecting the face, extremities, palms, and soles with variable gain of subcutaneous truncal fat. All of them had proteinuric nephropathy with FSGS documented in 7 of them. Ten developed cardiomyopathy, and 2 of them died early at ages 33 and 45 years. Other common features included premature graying, alopecia, high-pitched voice, micrognathia, hearing loss, and scoliosis. Metabolic complications, including diabetes mellitus, hypertriglyceridemia, and hepatomegaly, were highly prevalent. This variant did not show any abnormal splicing, and no abnormal nuclear morphology was noted in the affected fibroblasts. Conclusions: The heterozygous LMNA p.R349W variant in affected individuals has several distinct phenotypic features, and these patients should be classified as having multisystem progeroid syndrome (MSPS). MSPS patients should undergo careful assessment at symptom onset and yearly metabolic, renal, and cardiac evaluation because hyperglycemia, hypertriglyceridemia, FSGS, and cardiomyopathy cause major morbidity and mortality. (C) Endocrine Society 2020.

ContextPartial lipodystrophy (PL) is associated with metabolic co-morbidities but may go undiagnosed as the disease spectrum is not fully described. ObjectiveThe objective of the study was to define disease spectrum in PL using genetic, clinical (historical, morphometric) and laboratory characteristics. DesignCross-sectional evaluation. ParticipantsTwenty-three patients (22 with familial, one acquired, 783% female, aged 12-64 years) with PL and non-alcoholic fatty liver disease (NAFLD). MeasurementsGenetic, clinical and laboratory characteristics, body composition indices, liver fat content by magnetic resonance imaging (MRI), histopathological and immunofluorescence examinations of liver biopsies. ResultsSeven patients displayed heterozygous pathogenic variants in LMNA. Two related patients had a heterozygous, likely pathogenic novel variant of POLD1 (NM0026913: c.3199 G>A; p.E1067K). Most patients had high ratios (>15) of percentage fat trunk to percentage fat legs (FMR) when compared to reference normals. Liver fat quantified using MR Dixon method was high (113 63%) and correlated positively with haemoglobin A1c and triglycerides while leg fat by dual-energy X-ray absorptiometry (DEXA) correlated negatively with triglycerides. In addition to known metabolic comorbidities; chronic pain (783%), hypertension (565%) and mood disorders (522%) were highly prevalent. Mean NAFLD Activity Score (NAS) was 5 +/- 1 and 783% had fibrosis. LMNA-immunofluorescence staining from select patients (including one with the novel POLD1 variant) showed a high degree of nuclear atypia and disorganization. ConclusionsPartial lipodystrophy is a complex multi-system disorder. Metabolic parameters correlate negatively with extremity fat and positively with liver fat. DEXA-based FMR may prove useful as a diagnostic tool. Nuclear disorganization and atypia may be a common biomarker even in the absence of pathogenic variants in LMNA.