Compound heterozygosity for mutations in LMNA in a patient with a myopathic and lipodystrophic mandibuloacral dysplasia type a phenotype

Context: Mandibuloacral dysplasia type A ( MADA; OMIM 248370) is a rare progeroid syndrome characterized by dysmorphic craniofacial and skeletal features, lipodystrophy, and metabolic complications. Most Italian patients carry the same homozygous missense mutation ( p. R527H) in the C- terminal tail domain of the LMNA gene, which encodes lamin A/ C, an intermediate filament component of the nuclear envelope. Objective: The objective of the study was to identify novel LMNA mutations in individuals with clinical characteristics ( bird- like facies, mandibular and clavicular hypoplasia, acroosteolysis, lipodystrophy, alopecia) observed in other well- known patients. Design: The LMNA gene was sequenced. Functional properties of the mutant alleles were investigated. Patient: We report a 27- yr- old Italian woman showing a MADA- like phenotype. Features include a hypoplastic mandible, acroosteolysis, pointed nose, partial loss of sc fat, and a progeric appearance. Due to the absence of clavicular dysplasia and normal metabolic profiles, generally associated with muscle hyposthenia and generalized hypotonia, this phenotype can be considered an atypical laminopathy. Results: We identified a patient compound heterozygote for the p. R527H and p. V440M alleles. The patient's cells showed nuclear shape abnormalities, accumulation of pre- lamin A, and irregular lamina thickness. Lamins A and C showed normal expression and localization. The electron microscopy detected heterochromatin defects with a pattern similar to those observed in other laminopathies. However, chromatin analysis showed a normal distribution pattern of the major heterochromatin proteins: heterochromatin protein- 1 beta and histone H3 methylated at lysine 9. Conclusions: The clinical and cellular features of this patient show overlapping laminopathy phenotypes that could be due to the combination of p. R527H and p. V440M alleles.