Congenital generalized lipodystrophy, type 4 (CGL4) associated with myopathy due to novel PTRF mutations

Abstract

Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by near total absence of body fat since birth with predisposition to insulin resistance, diabetes, hypertriglyceridemia, and hepatic steatosis. Three CGL loci, AGPAT2, BSCL2, and CAV1, have been identified previously. Recently, mutations in polymerase I and transcript release factor (PTRF) were reported in five Japanese patients presenting with myopathy and CGL (CGL4). We report novel PTRF mutations and detailed phenotypes of two male and three female patients with CGL4 belonging to two pedigrees of Mexican origin (CGL7100 and CGL178) and one pedigree of Turkish origin (CGL180). All patients had near total loss of body fat and congenital myopathy manifesting as weakness, percussion-induced muscle mounding, and high serum creatine kinase levels. Four of them had hypertriglyceridemia. Three of them had atlantoaxial instability. Two patients belonging to CGL178 pedigree required surgery for pyloric stenosis in the first month of life. None of them had prolonged QT interval on electrocardiography but both siblings belonging to CGL7100 had exercise-induced ventricular arrhythmias. Three of them had mild acanthosis nigricans but had normal glucose tolerance. Two of them had hepatic steatosis. All patients had novel null mutations in PTRF gene. In conclusion, mutations in PTRF result in a novel phenotype that includes generalized lipodystrophy with mild metabolic derangements, myopathy, cardiac arrhythmias, atlantoaxial instability, and pyloric stenosis. It is unclear how mutations in PTRF, which plays an essential role in formation of caveolae, affect a wide variety of tissues resulting in a variable phenotype.

Fig. 1

A. CGL 178.5, anterior view of a 11-year-old boy showing generalized lipodystrophy, prominent muscularity, acromegalic features such as large hands and feet. B. CGL 178.5, lateral view showing generalized lipodystrophy and protuberant abdomen. C. Percussion muscle mounding on the biceps of patient CGL 178.5. D and E, Lateral radiographs of the cervical spine of CGL 178.5 during extension and flexion of cervical spine, respectively showing atlantoaxial instability. The interdental distance (shown by space between the triangles) was 4 mm during extension but was 6 mm during flexion.

Fig 2

Pedigrees and Sequence Chromatograms of Patients. A. 1. CGL 178 pedigree. B. Normal chromatogram and that from CGL 178.5 showing homozygous c.135delG PTRF mutation. C. CGL 180 pedigree D. Normal chromatogram and that from CGL 180.3 showing homozygous insertion in exon 2 c.481-482insGTGA. E. CGL 7100 pedigree. F. Chromatograms showing two normal sequences and those from CGL 7100.3 showing heterozygous PTRF mutations c.518-521delAAGA (cloned chromatogram is shown) and c.IVS1+1G>T. WT, wild type genotype. Circles denote females and squares denote males. Half filled indicates heterozygotes. Filled symbols indicate affected and unfilled symbols indicate unaffected subjects.

Fig. 3

A, An electromyographic tracing from the biceps brachii showing neuromyotonic discharge. B, Holter monitor tracing of CGL 7100.3 showing baseline normal rhythm with four consecutive beats of ventricular tachycardia. C, Electrocardiogram, lead V2 on treadmill stress test of CGL 7100.3 after three minutes on Bruce Protocol at heart rate of 178 beats per minute, 10 METs, speed of 3.4 mph and 14% grade, showing bidirectional ventricular tachycardia suggestive of catecholaminergic polymorphic ventricular tachycardia (CPVT).