Atypical Progeroid Syndrome and Partial Lipodystrophy Due to LMNA Gene p.R349W Mutation

Abstract

Atypical Progeroid Syndrome (APS) are heterogeneous disorders characterized by variable degrees of fat loss, metabolic alterations and comorbidities that affect skeleton, muscles and/or the heart. We describe 3 patients that were referred to our Center for the suspicion of lipodystrophy. They had precocious aging traits such as short stature, mandibular hypoplasia, beaked nose and partial alopecia manifesting around 10-15 years of age recurrently associated with: 1) partial lipodystrophy; 2) proteinuric nephropathy; 3) heart disease (rhythm disorders, valvular abnormalities, and cardiomyopathy); 4) sensorineural hearing impairment. In all patients genetic testing revealed a missense heterozygous LMNA mutation c.1045 C>T (p.Arg349Trp). Ten patients with LMNA p.R349W mutation have been reported so far, all presenting with similar features, which represent the key pathological hallmarks of this subtype of APS. The associated kidney and cardiac complications occurring in the natural history of the disease may reduce life-expectancy. Therefore, in these patients a careful and periodic cardiac and kidney function evaluation is required.

Post-acute cardiac complications following SARS-CoV-2 infection in partial lipodystrophy due to LMNA gene p.R349W mutation

“…Patient 1 is a 46-year-old Caucasian female affected by APS due to LMNA Gene p.R349W mutation [ 4 ]. She had precocious aging traits such as short stature, mandibular hypoplasia, beaked nose, and partial alopecia, partial lipodystrophy, sensorineural hearing impairment, proteinuric nephropathy, hypertension and metabolic abnormalities including dyslipidemia, hepatic steatosis, insulin resistance, and impaired glucose tolerance.…”

“…The patient’s 18-year-old son, also affected by atypical progeroid syndrome, was infected by SARS-CoV-2 at the same time and complained of fever, cold, anosmia and ageusia. He has the same key features of the mother, but does not display yet metabolic alterations and cardiovascular disease [ 4 ].…”

“…Patient 2 is a 41-year-old Caucasian male affected by APS due to LMNA Gene p.R349W mutation [ 4 ]. At physical exam, he presents with short stature, beaked nose, partial alopecia, skin atrophy, thin lips and small mandible associated with partial lipodystrophy, reduced sensorineural hearing acuity, diabetes mellitus type 2, dyslipidemia, liver steatosis and hypertension.…”

“…APS is caused by different LMNA mutations that have in common an early and accelerated aging process and is also characterized by variable degrees of fat loss (partial or generalized lipodystrophy), metabolic alterations and comorbidities that affect skeleton, muscles and heart. Twenty patients with LMNA p.R349W mutation have been reported so far, all presenting with very similar features [ 3 , 4 ]. Lipodystrophic patients display reduced or absent adipose tissue amounts and this condition cause a proportional reduction of circulating levels of adipocyte-derived hormones, especially leptin.…”

Partial Lipodystrophy and LMNA p.R545H Variant

“…Mutations in the LMNA gene can result in a wide range of disease phenotypes, collectively termed laminopathies, which involve different tissues and organ systems causing cardiomyopathies (conduction-system diseases and dilated cardiomyopathy), myopathies (type 2 Emery-Dreifuss muscular dystrophy-EDMD2, type 1B limb-girdle muscular dystrophy-LGMD1B), neuropathies (Charcot–Marie–Tooth disease type 2B1- CMT2B1), lipodystrophies (most commonly type 2 familial partial lipodystrophy), premature aging syndromes (Hutchinson-Gilford progeria syndrome-HGPS, Type A mandibuloacral dysplasia-MADA, restrictive dermopathy-RD, atypical progeroid syndrome-APS), and overlap syndromes characterized by a combination of various phenotypes in the same subject, involving adipose tissue, skeletal/cardiac muscle, and/or the peripheral nervous system [ 1 , 2 , 3 , 4 ]. The causative molecular mechanisms behind this clinical heterogeneity and tissue specificity are still poorly understood [ 3 , 5 ].…”