Metabolic and other morbid complications in congenital generalized lipodystrophy type 4

Abstract

Morbidity and mortality rates in patients with autosomal recessive, congenital generalized lipodystrophy type 4 (CGL4), an ultra-rare disorder, remain unclear. We report on 30 females and 16 males from 10 countries with biallelic null variants in CAVIN1 gene (mean age, 12 years; range, 2 months to 41 years). Hypertriglyceridemia was seen in 79% (34/43), hepatic steatosis in 82% (27/33) but diabetes mellitus in only 21% (8/44). Myopathy with elevated serum creatine kinase levels (346-3325 IU/L) affected all of them (38/38). 39% had scoliosis (10/26) and 57% had atlantoaxial instability (8/14). Cardiac arrhythmias were detected in 57% (20/35) and 46% had ventricular tachycardia (16/35). Congenital pyloric stenosis was diagnosed in 39% (18/46), 9 had esophageal dysmotility and 19 had intestinal dysmotility. Four patients suffered from intestinal perforations. Seven patients died at mean age of 17 years (range: 2 months to 39 years). The cause of death in four patients was cardiac arrhythmia and sudden death, while others died of prematurity, gastrointestinal perforation, and infected foot ulcers leading to sepsis. Our study highlights high prevalence of myopathy, metabolic abnormalities, cardiac, and gastrointestinal problems in patients with CGL4. CGL4 patients are at high risk of early death mainly caused by cardiac arrhythmias.

Keywords: CAVIN1; congenital generalized lipodystrophy; gastrointestinal disease; metabolic abnormalities; myopathy; ventricular tachycardia.

Figure 1:. Phenotypic features and metabolic and organ complications in CGL4.

A. Patient pictures showing generalized fat loss; patient 7 (panel I) and patient 8 (panel II). B. Whole-body MRI (T1-weighted) demonstrating near total fat loss in a patient with CGL4 (patient 1; MRI performed at age of 16 years). Bone marrow fat is preserved along with orbital fat. Scalp fat is lost. Palms and soles show no significant fat signal. Reduced amounts of supraclavicular fat can be visualized. (I), whole body, coronal T1-weighted imaging; (II), whole body, coronal T2-weighted fat suppressed imaging; (III), orbital and scalp, axial T1-weighted imaging; (IV), shoulders, axial T1-weighted imaging; (V), breasts, axial T1-weighted imaging; (VI), visceral and retroperitoneal, axial T1-weighted imaging; (VII-VIII), external genital region and palms, axial T1-weighted imaging; (IX-XI), limbs, axial T1-weighted imaging. C. Kaplan Meier curves showing time to diabetes (panel I). A liver biopsy specimen (panel II) showing early changes of hepatic steatosis at age 1 in a patient with CGL4 (patient 3). Mild swelling of parenchymal cells. and macro- and microvesicular lipid depositions are shown (H&EX400). Kaplan Meier curves showing time to cardiac disease (panel III) and survival (panel IV) D. ECG showing Wolff-Parkinson-White syndrome (panel I) and an episode of ventricular tachycardia (panel II) in patient 8, and non-sustained polymorphic ventricular tachycardia (panel III) during treadmill exercise test in patient 2. E. Axial computerized tomography (CT) image showing air-fluid level due to intestinal perforation (panel I). Histopathology shows muscularis propria hypertrophy along with loss of orientation of circular and longitudinal layers of muscularis propria (panel II). Patient 1 had complaints of abdominal distention and pain that usually happened after meals (a feeling of fullness and early satiety and episodes of constipation and diarrhea when she first presented). Her symptoms were first treated with prokinetic agents, but no significant relief was observed. A small bowel follow-through study using barium showed slow transit time. At age 21, she presented with severe abdominal pain and tenderness. A CT showed colonic perforation and she underwent a colonic resection with colostomy. She did not have recurrent perforations but still lives with a colostomy bag.

Figure 2:. Pathogenic variants reported in the CAVIN1 gene.

A. Schematic drawing of the CAVIN1 gene and the pathogenic variants. Black rectangles are the coding regions of the exons and white rectangles indicate the non-coding regions. Solid line between the exons indicates the intronic region. CAVIN1 constitutes only two exons shown with numbers. The 5’ and 3’ ends are shown. Schematic is not drawn to scale. The numbering is as per the coding DNA. B. Schematic of the CAVIN1 protein and the pathogenic variants. CAVIN1 constitutes 390 amino acids. Modified from Nassar. International Review of Cell and Molecular Biology, Volume 320, 2015. The disordered regions are shown in light blue and helical regions in gray. The PEST (proline–glutamic acid–serine–threonine) domains are shown in black, and the Leucine zipper domains in green. The nuclear localization signals are shown in dark blue. Variants above the schematics are previously reported and those below are novel. Variants in orange color are reported in the paper and those in black color are not reported in the paper.