Two Decades after Mandibuloacral Dysplasia Discovery: Additional Cases and Comprehensive View of Disease Characteristics

Pathogenic variants in the LMNA gene cause a group of heterogeneous genetic disorders, called laminopathies. In particular, homozygous or compound heterozygous variants in LMNA have been associated with “mandibuloacral dysplasia type A” (MADA), an autosomal recessive disorder, characterized by mandibular hypoplasia, growth retardation mainly postnatal, pigmentary skin changes, progressive osteolysis of the distal phalanges and/or clavicles, and partial lipodystrophy. The detailed characteristics of this multisystemic disease have yet to be specified due to its rarity and the limited number of cases described. Here, we report three unrelated Egyptian patients with variable severity of MAD features. Next-generation sequencing using a gene panel revealed a homozygous c.1580G>A-p.Arg527His missense variant in LMNA exon 9 in an affected individual with a typical MADA phenotype. Another homozygous c.1580G>T-p.Arg527Leu variant affecting the same amino acid was identified in two additional patients, who both presented with severe manifestations very early in life. We combined our observations together with data from all MADA cases reported in the literature to get a clearer picture of the phenotypic variability in this disease. This work raises the number of reported MADA families, argues for the presence of the founder effect in Egypt, and strengthens genotype–phenotype correlations.

Atypical progeroid syndrome (p.E262K LMNA mutation): a rare cause of short stature and osteoporosis

Summary Lamin A/C (LMNA) gene mutations cause a heterogeneous group of progeroid disorders, including Hutchinson–Gilford progeria syndrome, mandibuloacral dysplasia, atypical progeroid syndrome (APS) and generalized lipodystrophy-associated progeroid syndrome (GLPS). All of those syndromes are associated with some progeroid features, lipodystrophy and metabolic complications but vary differently depending on a particular mutation and even patients carrying the same gene variant are known to have clinical heterogeneity. We report a new 30-year-old female patient from Russia with an APS and generalized lipodystrophy (GL) due to the heterozygous de novo LMNA p.E262K mutation and compare her clinical and metabolic features to those of other described patients with APS. Despite many health issues, short stature, skeletal problems, GL and late diagnosis of APS, our patient seems to be relatively metabolically healthy for her age when compared to previously described patients with APS. Learning points Atypical progeroid syndromes (APS) are rare and heterogenic with different age of onset and degree of metabolic disorders, which makes this diagnosis very challenging for clinicians and may be missed until the adulthood. The clinical picture of the APS depends on a particular mutation in the LMNA gene, but may vary even between the patients with the same mutation. The APS due to a heterozygous LMNA p.E262K mutation, which we report in this patient, seems to have association with the generalized lipodystrophy, short stature and osteoporosis, but otherwise, it seems to cause relatively mild metabolic complications by the age of 30. The patients with APS and lipodystrophy syndromes require a personalized and multidisciplinary approach, and so they should be referred to highly specialized reference-centres for diagnostics and treatment as early as possible. Because of the high heterogeneity of such a rare disease as APS, every patient’s description is noteworthy for a better understanding of this challenging syndrome, including the analysis of genotype-phenotype correlations.

Author Correction: Loss of MTX2 causes mandibuloacral dysplasia and links mitochondrial dysfunction to altered nuclear morphology

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Loss of MTX2 causes mandibuloacral dysplasia and links mitochondrial dysfunction to altered nuclear morphology

Mandibuloacral dysplasia syndromes are mainly due to recessive LMNA or ZMPSTE24 mutations, with cardinal nuclear morphological abnormalities and dysfunction. We report five homozygous null mutations in MTX2, encoding Metaxin-2 (MTX2), an outer mitochondrial membrane protein, in patients presenting with a severe laminopathy-like mandibuloacral dysplasia characterized by growth retardation, bone resorption, arterial calcification, renal glomerulosclerosis and severe hypertension. Loss of MTX2 in patients’ primary fibroblasts leads to loss of Metaxin-1 (MTX1) and mitochondrial dysfunction, including network fragmentation and oxidative phosphorylation impairment. Furthermore, patients’ fibroblasts are resistant to induced apoptosis, leading to increased cell senescence and mitophagy and reduced proliferation. Interestingly, secondary nuclear morphological defects are observed in both MTX2-mutant fibroblasts and mtx-2-depleted C. elegans. We thus report the identification of a severe premature aging syndrome revealing an unsuspected link between mitochondrial composition and function and nuclear morphology, establishing a pathophysiological link with premature aging laminopathies and likely explaining common clinical features.

A novel autosomal recessive lipodystrophy syndrome due to homozygous LMNA variant

BackgroundDespite major advances in understanding the molecular basis of various genetic lipodystrophy syndromes, some rare patients still remain unexplained.CasesWe report a novel autosomal recessive lipodystrophy affecting two sisters aged 17 and 19 years and characterised by early onset intellectual disability, and subsequent development of near-generalised loss of subcutaneous fat with diabetes mellitus, extreme hypertriglyceridemia, hepatic steatosis, short stature, clinodactyly, joint contractures, leiomyoma of uterus and cataracts in childhood. The lipodystrophy was more pronounced in the upper and lower extremities, and there was no associated muscular hypertrophy. Using whole exome sequencing in this consanguineous Hispanic pedigree, we report disease-causing homozygous p.Arg545His LMNA variant in the affected subjects, and confirm the lack of pathogenic variants in other known lipodystrophy genes. The mother and a younger brother were both heterozygous for p.Arg545His LMNA variant and were overweight with acanthosis nigricans without any evidence of lipodystrophy. Our patients are distinct from previously reported autosomal recessive lipodystrophy syndromes and have no overlap with other autosomal recessive laminopathies, including mandibuloacral dysplasia, Emery-Dreifuss muscular dystrophy and Charcot-Marie-Tooth neuropathy.ConclusionOur report of this unusual familial generalised lipodystrophy syndrome adds to the pleiotropy associated with biallelic autosomal recessive LMNA variants.