Partial lipodystrophy associated with muscular dystrophy of unknown genetic origin

Overlapping syndromes characterized by the concomitant presence of abnormal fat distribution and muscular dystrophy have been reported in association with mutations either in the LMNA or PTRF genes. LMNA mutations may cause partial lipodystrophy and muscular dystrophy, whereas PTRF mutations result in generalized lipodystrophy with muscular dystrophy. We report 2 siblings who presented with abnormal fat distribution, muscular dystrophy, and metabolism alterations. Mutations in known genes responsible for nuclear envelopathies and lipodystrophies were ruled out, as was Madelung disease. Patient 1 is the third child from healthy, consanguineous parents. She complained of menstrual irregularity since youth. At age 33 years she developed abnormal subcutaneous fat distribution with accumulation in the neck, abdomen, and axillae, and she had progressive reduction of subcutaneous fat in the legs. She was diagnosed with diabetes 10 years later. At age 50 years, physical examination showed abnormal fat accumulation in the neck, abdomen, clavicular regions, axillae, labia majora, back, and below the triceps. There was also reduction of subcutaneous fat in the legs. She had mild proximal muscle weakness (MRC 4) affecting both shoulder and hip girdle muscles. Her brother, patient 2, was evaluated at age 49 years. He had fat distribution abnormalities, with increased subcutaneous adipose tissue of the abdomen and the axillae and a reduction of subcutaneous fat in the legs. Muscle strength was normal. Blood analyses showed high creatine kinase in both patients and elevated triglycerides and cholesterol levels in patient 1. Cardiovascular investigations revealed no abnormality in either subject. Muscle biopsy from patient 1 showed dystrophic changes with normal immunohistochemical labeling of the proteins responsible for most common muscular dystrophies; trichrome and oxidative stains did not show any evidence of mitochondrial disease. Multiplex Western blot analysis of muscle was normal. In cultured skin fibroblasts and pre-adipocytes, lamin A/C, prelamin A, emerin, and SUN1 were expressed normally (Fig. 1). Magetic resonance imaging (MRI) of patient 1 disclosed fat accumulation in the cervical, dorsal, and abdominal regions; hepatic steatosis; predominant posterior thigh muscle increased T2 signal; and increased T2 signal of tibialis anterior and posterior, extensor digitorum longus, and soleus muscles. MRI of patient 2 showed inhomogeneous subcutaneous fat distribution with fat predominance in the anterior abdomen, and posterior leg muscle increased T2 signal. Lower limb subcutaneous fat was reduced on MRI in both patients (Fig. 1). Karyotype analysis of patient 1 revealed normal chromosome numbers and absence of gross structural changes; direct sequencing of the coding regions and 100–150 bp of exon–intron junctions of PTRF1, LMNA, ZMPSTE24, BANF, STA, PPARG, PLIN, CAV1, LMNB2, CIDEC, AKT2, AGPAT2, and BSCL2 genes excluded pathogenic mutations. Multiplex ligation probe amplification analysis also excluded LMNA deletions/duplications. Respiratory chain enzyme dose and sequencing of whole mitochondrial DNA were normal. Single-nucleotide polymorphism (SNP) array analysis excluded copy number variations of pathogenic relevance shared between the siblings. Given the parental consanguinity and the discordant genders, the likely mode of inheritance is autosomal recessive. We speculate that this complex phenotype is due to either a new causative gene or is a new phenotype of an already described form of myopathy. Further studies are in progress to identify the underlying disease-causing gene.