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Fatal cardiac arrhythmia and long-QT syndrome in a new form of congenital generalized lipodystrophy with muscle rippling (CGL4) due to PTRF-CAVIN mutations.

Rajab A, Straub V, McCann LJ, Seelow D, Varon R, Barresi R, Schulze A, Lucke B, Lützkendorf S, Karbasiyan M, Bachmann S, Spuler S, Schuelke M - PLoS Genet. (2010)

Bottom Line: Additionally, we found impaired bone formation with osteopenia, osteoporosis, and atlanto-axial instability.Absence of PTRF-CAVIN did not influence abundance of its binding partner caveolin-1 and caveolin-3.In patient fibroblasts, however, caveolin-1 failed to localize toward the cell surface and electron microscopy revealed reduction of caveolae to less than 3%.

View Article: PubMed Central - PubMed

Affiliation: Genetics Unit, Ministry of Health, Directorate General of Health Affairs, Royal Hospital, Muscat, Oman.

ABSTRACT
We investigated eight families with a novel subtype of congenital generalized lipodystrophy (CGL4) of whom five members had died from sudden cardiac death during their teenage years. ECG studies revealed features of long-QT syndrome, bradycardia, as well as supraventricular and ventricular tachycardias. Further symptoms comprised myopathy with muscle rippling, skeletal as well as smooth-muscle hypertrophy, leading to impaired gastrointestinal motility and hypertrophic pyloric stenosis in some children. Additionally, we found impaired bone formation with osteopenia, osteoporosis, and atlanto-axial instability. Homozygosity mapping located the gene within 2 Mbp on chromosome 17. Prioritization of 74 candidate genes with GeneDistiller for high expression in muscle and adipocytes suggested PTRF-CAVIN (Polymerase I and transcript release factor/Cavin) as the most probable candidate leading to the detection of homozygous mutations (c.160delG, c.362dupT). PTRF-CAVIN is essential for caveolae biogenesis. These cholesterol-rich plasmalemmal vesicles are involved in signal-transduction and vesicular trafficking and reside primarily on adipocytes, myocytes, and osteoblasts. Absence of PTRF-CAVIN did not influence abundance of its binding partner caveolin-1 and caveolin-3. In patient fibroblasts, however, caveolin-1 failed to localize toward the cell surface and electron microscopy revealed reduction of caveolae to less than 3%. Transfection of full-length PTRF-CAVIN reestablished the presence of caveolae. The loss of caveolae was confirmed by Atomic Force Microscopy (AFM) in combination with fluorescent imaging. PTRF-CAVIN deficiency thus presents the phenotypic spectrum caused by a quintessential lack of functional caveolae.

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Related in: MedlinePlus

Phenotype of patient FI:201 from Oman.(A) Patient at the age of 4 years with macroglossia, grossly reduced subcutaneous fat tissue and a protruding abdominal wall. (B) ECG of the patient with a QTc (Bazett) of 480 ms. (C) Sections of 24h ECG Holter-monitoring show a complex cardiac arrhythmia with intermittent sinus bradycardia, supraventricular (SVT) and ventricular tachycardia (VT). BPM, beats per minute (D) Percussion-induced, local prolonged contractions (“mounding”) at the quadriceps muscle persisting for 2–3 seconds. (E) Pedigree of the consanguineous family and genotypes of the family members. (F) X-ray radiograph of the knees at 9 months of age, showing broadening of the distal metaphyses (arrowheads) and osteopenia. (G) X-ray radiograph of the left hand at the age of 13.5 years showing osteoporosis and osteopenia. The metacarpo-phalangeal joint of the thumb shows arthritic changes and a partial dislocation with ulnar deviation (arrowhead).
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pgen-1000874-g001: Phenotype of patient FI:201 from Oman.(A) Patient at the age of 4 years with macroglossia, grossly reduced subcutaneous fat tissue and a protruding abdominal wall. (B) ECG of the patient with a QTc (Bazett) of 480 ms. (C) Sections of 24h ECG Holter-monitoring show a complex cardiac arrhythmia with intermittent sinus bradycardia, supraventricular (SVT) and ventricular tachycardia (VT). BPM, beats per minute (D) Percussion-induced, local prolonged contractions (“mounding”) at the quadriceps muscle persisting for 2–3 seconds. (E) Pedigree of the consanguineous family and genotypes of the family members. (F) X-ray radiograph of the knees at 9 months of age, showing broadening of the distal metaphyses (arrowheads) and osteopenia. (G) X-ray radiograph of the left hand at the age of 13.5 years showing osteoporosis and osteopenia. The metacarpo-phalangeal joint of the thumb shows arthritic changes and a partial dislocation with ulnar deviation (arrowhead).

Mentions: The now 14-year-old boy (FI:201, Figure 1E) was born to first degree cousins from Oman. His sister is healthy. After birth he presented with paucity of subcutaneous fat, increased amount of body hair, a protruding abdomen and a large tongue (Figure 1A). Congenital hypothyroidism was excluded. At 6 weeks a hypertrophic pyloric stenosis was treated by pyloromyotomy. He had poor appetite and failure to thrive, with weight 3SD below the mean. He had episodic hot flushes and cutis marmorata and suffered from frequent staphylococcal skin infections and severe pneumonias. At 10 years of age investigation of frequent palpitations and syncopes revealed both ventricular and supraventricular tachycardia and extrasystoles alternating with sinus bradycardia and post-tachycardic pauses of up to 2.2 sec (Figure 1C). A corrected QT-time (QTc with Bazett's correction) between 450–480 ms (Figure 1B) and T-wave abnormalities (alternating in V2,V3 and notched in V4) indicate an intermediate to high probability of long-QT syndrome [10]. Around the same time he had difficulties swallowing and a barium study revealed esophageal dysmotility. Presently, at 14 years of age, he often feels tired, weak, cannot walk for more than one kilometer and complains of back pain and joint stiffness. His mental development is normal, and he is a very good pupil. He has mild splenomegaly, a liver size at the 95th percentile with normal echogenicity on ultrasound but elevated transaminases (AST 120 U/l; N<23 and ALT 76 U/I; N<29). His bone phenotype comprises osteopenia with enlarged epiphyses (Figure 1F), a bone age retarded by 1.5 years, finger contractures with ulnar deviation (Figure 1G), spinal rigidity and a prominent hyperlordosis. Skin fold thickness was measured with a Holtain-T/W-Skinfold-Caliper (Holtain, Crymych, UK) over the triceps (2.5 mm); biceps (2.9 mm), subscapular region (3.6 mm), and iliac crest (2.8 mm) yielding 6.1% whole body fat (<3rd percentile) [11]. Muscular hypertrophy, especially of the thighs, is associated with limb girdle weakness. “Mounding” (Figure 1D) and Percussion Induced Rapid Contractions (PIRCs) can be elicited from all larger muscles. These events are silent on EMG thus excluding myotonia. Serum investigations revealed elevated creatine kinase levels (1,898 IU/l; N<169), dyslipidemia with elevated serum triglycerides (2.29 mmol/l; N 0.57–1.71), pre-β-lipoproteins (VLDL 39%; N<30) and reduced HDL-cholesterol (0.47 mmol/l; N>0.96), apolipoprotein A1 (0.72 g/l; N 1.00–1.50) and B (0.6 g/l; N 0.7–1.2). Serum leptin levels were reduced (0.9 µg/l; N 2.4–24.4, reference range for adult individuals with a BMI below the 25th percentile). Insulin resistance was increased with a HOMA-IR index of 3.2 (N 0.97–2.27) without any signs of acanthosis nigricans. Fasting glucose was 5.9 mmol/l and rose to 8.6 mmol/l (insulin 960 pmol/l) two hours after a standard glucose tolerance test with 1.75 g/kg BW [12].


Fatal cardiac arrhythmia and long-QT syndrome in a new form of congenital generalized lipodystrophy with muscle rippling (CGL4) due to PTRF-CAVIN mutations.

Rajab A, Straub V, McCann LJ, Seelow D, Varon R, Barresi R, Schulze A, Lucke B, Lützkendorf S, Karbasiyan M, Bachmann S, Spuler S, Schuelke M - PLoS Genet. (2010)

Phenotype of patient FI:201 from Oman.(A) Patient at the age of 4 years with macroglossia, grossly reduced subcutaneous fat tissue and a protruding abdominal wall. (B) ECG of the patient with a QTc (Bazett) of 480 ms. (C) Sections of 24h ECG Holter-monitoring show a complex cardiac arrhythmia with intermittent sinus bradycardia, supraventricular (SVT) and ventricular tachycardia (VT). BPM, beats per minute (D) Percussion-induced, local prolonged contractions (“mounding”) at the quadriceps muscle persisting for 2–3 seconds. (E) Pedigree of the consanguineous family and genotypes of the family members. (F) X-ray radiograph of the knees at 9 months of age, showing broadening of the distal metaphyses (arrowheads) and osteopenia. (G) X-ray radiograph of the left hand at the age of 13.5 years showing osteoporosis and osteopenia. The metacarpo-phalangeal joint of the thumb shows arthritic changes and a partial dislocation with ulnar deviation (arrowhead).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2837386&req=5

pgen-1000874-g001: Phenotype of patient FI:201 from Oman.(A) Patient at the age of 4 years with macroglossia, grossly reduced subcutaneous fat tissue and a protruding abdominal wall. (B) ECG of the patient with a QTc (Bazett) of 480 ms. (C) Sections of 24h ECG Holter-monitoring show a complex cardiac arrhythmia with intermittent sinus bradycardia, supraventricular (SVT) and ventricular tachycardia (VT). BPM, beats per minute (D) Percussion-induced, local prolonged contractions (“mounding”) at the quadriceps muscle persisting for 2–3 seconds. (E) Pedigree of the consanguineous family and genotypes of the family members. (F) X-ray radiograph of the knees at 9 months of age, showing broadening of the distal metaphyses (arrowheads) and osteopenia. (G) X-ray radiograph of the left hand at the age of 13.5 years showing osteoporosis and osteopenia. The metacarpo-phalangeal joint of the thumb shows arthritic changes and a partial dislocation with ulnar deviation (arrowhead).
Mentions: The now 14-year-old boy (FI:201, Figure 1E) was born to first degree cousins from Oman. His sister is healthy. After birth he presented with paucity of subcutaneous fat, increased amount of body hair, a protruding abdomen and a large tongue (Figure 1A). Congenital hypothyroidism was excluded. At 6 weeks a hypertrophic pyloric stenosis was treated by pyloromyotomy. He had poor appetite and failure to thrive, with weight 3SD below the mean. He had episodic hot flushes and cutis marmorata and suffered from frequent staphylococcal skin infections and severe pneumonias. At 10 years of age investigation of frequent palpitations and syncopes revealed both ventricular and supraventricular tachycardia and extrasystoles alternating with sinus bradycardia and post-tachycardic pauses of up to 2.2 sec (Figure 1C). A corrected QT-time (QTc with Bazett's correction) between 450–480 ms (Figure 1B) and T-wave abnormalities (alternating in V2,V3 and notched in V4) indicate an intermediate to high probability of long-QT syndrome [10]. Around the same time he had difficulties swallowing and a barium study revealed esophageal dysmotility. Presently, at 14 years of age, he often feels tired, weak, cannot walk for more than one kilometer and complains of back pain and joint stiffness. His mental development is normal, and he is a very good pupil. He has mild splenomegaly, a liver size at the 95th percentile with normal echogenicity on ultrasound but elevated transaminases (AST 120 U/l; N<23 and ALT 76 U/I; N<29). His bone phenotype comprises osteopenia with enlarged epiphyses (Figure 1F), a bone age retarded by 1.5 years, finger contractures with ulnar deviation (Figure 1G), spinal rigidity and a prominent hyperlordosis. Skin fold thickness was measured with a Holtain-T/W-Skinfold-Caliper (Holtain, Crymych, UK) over the triceps (2.5 mm); biceps (2.9 mm), subscapular region (3.6 mm), and iliac crest (2.8 mm) yielding 6.1% whole body fat (<3rd percentile) [11]. Muscular hypertrophy, especially of the thighs, is associated with limb girdle weakness. “Mounding” (Figure 1D) and Percussion Induced Rapid Contractions (PIRCs) can be elicited from all larger muscles. These events are silent on EMG thus excluding myotonia. Serum investigations revealed elevated creatine kinase levels (1,898 IU/l; N<169), dyslipidemia with elevated serum triglycerides (2.29 mmol/l; N 0.57–1.71), pre-β-lipoproteins (VLDL 39%; N<30) and reduced HDL-cholesterol (0.47 mmol/l; N>0.96), apolipoprotein A1 (0.72 g/l; N 1.00–1.50) and B (0.6 g/l; N 0.7–1.2). Serum leptin levels were reduced (0.9 µg/l; N 2.4–24.4, reference range for adult individuals with a BMI below the 25th percentile). Insulin resistance was increased with a HOMA-IR index of 3.2 (N 0.97–2.27) without any signs of acanthosis nigricans. Fasting glucose was 5.9 mmol/l and rose to 8.6 mmol/l (insulin 960 pmol/l) two hours after a standard glucose tolerance test with 1.75 g/kg BW [12].

Bottom Line: Additionally, we found impaired bone formation with osteopenia, osteoporosis, and atlanto-axial instability.Absence of PTRF-CAVIN did not influence abundance of its binding partner caveolin-1 and caveolin-3.In patient fibroblasts, however, caveolin-1 failed to localize toward the cell surface and electron microscopy revealed reduction of caveolae to less than 3%.

View Article: PubMed Central - PubMed

Affiliation: Genetics Unit, Ministry of Health, Directorate General of Health Affairs, Royal Hospital, Muscat, Oman.

ABSTRACT
We investigated eight families with a novel subtype of congenital generalized lipodystrophy (CGL4) of whom five members had died from sudden cardiac death during their teenage years. ECG studies revealed features of long-QT syndrome, bradycardia, as well as supraventricular and ventricular tachycardias. Further symptoms comprised myopathy with muscle rippling, skeletal as well as smooth-muscle hypertrophy, leading to impaired gastrointestinal motility and hypertrophic pyloric stenosis in some children. Additionally, we found impaired bone formation with osteopenia, osteoporosis, and atlanto-axial instability. Homozygosity mapping located the gene within 2 Mbp on chromosome 17. Prioritization of 74 candidate genes with GeneDistiller for high expression in muscle and adipocytes suggested PTRF-CAVIN (Polymerase I and transcript release factor/Cavin) as the most probable candidate leading to the detection of homozygous mutations (c.160delG, c.362dupT). PTRF-CAVIN is essential for caveolae biogenesis. These cholesterol-rich plasmalemmal vesicles are involved in signal-transduction and vesicular trafficking and reside primarily on adipocytes, myocytes, and osteoblasts. Absence of PTRF-CAVIN did not influence abundance of its binding partner caveolin-1 and caveolin-3. In patient fibroblasts, however, caveolin-1 failed to localize toward the cell surface and electron microscopy revealed reduction of caveolae to less than 3%. Transfection of full-length PTRF-CAVIN reestablished the presence of caveolae. The loss of caveolae was confirmed by Atomic Force Microscopy (AFM) in combination with fluorescent imaging. PTRF-CAVIN deficiency thus presents the phenotypic spectrum caused by a quintessential lack of functional caveolae.

Show MeSH
Related in: MedlinePlus