Lamin A/C mutations with lipodystrophy, cardiac abnormalities, and muscular dystrophy

Case reports.

The table shows the characteristics of the different cases/families. Patient 1, a 36-year-old woman, noticed rigidity of the neck during gymnastics at age 13. Around the age of 25, her muscle strength gradually diminished, and she showed lipo-atrophy of both upper and lower extremities, with atrophy of predominantly proximal arm muscles, but prominent calf muscles. There was fat accumulation in the neck (“buffalo” hump) and the face. She had a rigid neck and spine and a slight contracture of the right elbow ( figure 1). There was moderate limb girdle weakness. Serum creatine kinase activity was five times elevated. CT of the skeletal muscles is shown in figure 2. Muscle biopsy showed a mild dystrophy. During her pregnancy in 1999, she developed atrial fibrillation with a high ventricular frequency. Laboratory investigations showed normal cholesterol and glucose levels but elevated triglyceride level (3.28 mmol/L, normal <2.0 mmol/L). PCR/single-strand conformation polymorphism sequencing9 of the lamin A/C gene revealed a missense mutation in exon 9 (R527P).

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Figure 1. Patient 1. (A,B) Shown in this patient are lipo-atrophy of the extremities, fat accumulation in the neck, atrophy of proximal arm muscles, relatively prominent calves, and a rigid neck and spine.

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Figure 2. Patient 1. Muscle CT scans at lumbar (A), thigh (B), and lower leg (C) levels demonstrate minimal subcutaneous fat surrounding the muscles of thighs and lower legs (arrows), with fatty infiltration of the paraspinal muscles (P), hamstrings (H), quadriceps (Q), and gastrocnemius muscles (Ga). At the level of the fourth lumbar vertebra, abundant intra-abdominal visceral fat (asterisk) was found relative to subcutaneous fat (arrow), resulting in an increased ratio of visceral to total adipose tissue.

Patient 2, a 43-year-old woman (individual 5 of the EMD6 family1), presented with waddling gait and toe walking in childhood. She then developed progressive muscle weakness and wasting in her late twenties. The trunk and the extremities were extremely skinny with delineation of individual muscles. She had diffuse wasting, severe weakness of neck muscles, trunk extensors, elbow flexors, and shoulder girdle muscles, and moderate weakness of proximal leg muscles. There were contractures at the elbows, knees, ankles, and spine. Serum creatine kinase was five times above normal. A quadriceps muscle biopsy was dystrophic. Cardiac evaluation revealed atrial fibrillation. Echocardiography was normal. Muscle CT showed substitution of several muscles by fat and striking absence of subcutaneous adipose tissue at the level of shoulder, trunk, and lower limbs scans, with normal intra-abdominal fat. Serum glucose, glycosylated hemoglobin, insulin, C-peptide, cholesterol, triglycerides, and high-density lipoproteins were all normal.

Her son (individual 7 of EMD6 family1) had a typical EDMD phenotype with difficulty in walking from age 3 onward, followed by the development of contractures of elbows, hips, knees, ankles, and spine. Weakness was mild. Serum creatine kinase was three times above normal, and a quadriceps biopsy showed a myopathy. Rare ectopic supraventricular beats on Holter monitoring and mild ventricular dilatation with an ejection fraction of 59% were detected at age 24. On CT there was fatty infiltration of paravertebral and vasti muscles. Adipose tissue was normal at age 11 but scarce on shoulder, hip, abdominal, thigh, and leg sections at age 15.

Her father (individual 3 of EMD6 family1) presented in his forties with fatigue. He had required pacemaker implantation at age 55 because of an atrioventricular block. There was only mild weakness of quadriceps muscles and hamstrings, slight elbow contractures, and rigid spine at age 64. Serum creatine kinase was normal. A quadriceps muscle biopsy was dystrophic. CT revealed mild to moderate substitution of several muscles by fat and diminishment of subcutaneous adipose tissue in the legs. Analysis of LMNA gene revealed a R527P mutation in exon 9 in this family.1

Patient 3, a 44-year-old woman, had fat accumulation within the facial and neck regions together with a lack of adipose tissue in the limbs since adolescence. At age 35 hypertriglyceridemia was found and at age 41 diabetes mellitus. At that time, she also had ventricular arrhythmia. Congestive heart failure due to cardiomyopathy occurred at age 41. At that time, examination showed a Cushingoid face, “buffalo neck,” and four-limb lipo-atrophy but no muscle weakness or contractures. CT revealed only absence of subcutaneous fat. EKG disclosed intermittent atrial fibrillation and atrioventricular as well as left bundle-branch block. Echocardiography showed decreased ejection fraction (47%, normal 65 ± 5%) and an end-diastolic left ventricle diameter of 44 mm (normal <55 mm). Serum creatine kinase was normal. Blood glucose level was elevated (9.5 mmol/L), and glycosylated hemoglobin level was 6.8% (normal <5.6%) with an increased fasting insulin level (27 μmol/L, normal <20 μmol/L), indicating diabetes mellitus with insulin resistance. Triglyceride level was mildly elevated (2.85 mmol/L, normal <1.65 mmol/L). Muscle biopsy showed minimal nonspecific changes.

Family history revealed that the patient’s mother had presented with lipodystrophy, diabetes mellitus, hypertriglyceridemia, and cardiomyopathy associated with conduction disturbances. A pacemaker was implanted at age 42. The patient died in heart failure when she was 53 years old. At autopsy, the heart weight was 350 g, with a wall thickness of 1.8 cm (normal <1.3 cm) and fibrosis of the main branch of the conduction system. The lamin A/C gene showed a missense mutation (R60G) in exon 1 in the proband.

Discussion.

We identified a missense mutation (R527P) in exon 9 of the lamin A/C gene (LMNA) in a family and a sporadic case with a combination of muscular dystrophy, lipodystrophy, and cardiac rhythm disturbances. In addition, we report an LMNA exon 1 mutation (R60G) in a mother and her daughter showing Dunnigan lipodystrophy since adolescence and late-onset cardiac involvement with ventricular dysfunction, conduction defect, and arrhythmia.

LMNA is composed of 12 exons that code for the two lamins A and C by alternative splicing in exon 10. To date, a wide spectrum of mutations has been reported in this gene, resulting in four disease entities, one affecting adipose tissue, named familial partial or Dunnigan lipodystrophy (FPLD), and three others each affecting cardiac and/or skeletal muscles, namely, EDMD, LGMD1B, and DCM-CD.1-6⇓⇓⇓⇓⇓ In FPLD, mutations so far have been restricted to two specific locations in the globular C-terminal tail of lamins A/C. There is a major “hot spot” at R482, as 90% of the FPLD mutations affect this amino acid in exon 8. The remaining FPLD mutations have been localized in exons 8 and 11, also involving the tail domain.10 In contrast, mutations causing cardiac and skeletal disorders, namely, AD-EDMD, LGMD1B, and DCM-CD, are described in exons 1 to 11, implicating that no specific disease domain exists. Furthermore, two mutations were reported giving rise to different skeletal and cardiac phenotypes within the same family, namely, AD-EDMD and DCM-CD8 or a combination of EDMD, LGMD, and isolated DCM-CD.7

In our patients, no mutations were detected in exons 8 or 11. The R527P mutation in exon 9 was previously identified in another unrelated AD-EDMD family (Family EMD41,9⇓) and in a sporadic case of EDMD (Patient TB2), all demonstrating a typical EDMD phenotype of varying severity.1,2,9⇓⇓ In none of them was lipodystrophy described. The mutation detected in the French proband (R60G) has been previously reported4 in a family with isolated autosomal dominant cardiomyopathy associated with conduction system disease (Family D). It remains to be explained how the same mutation in the lamin A/C gene exerts a pleiotropic effect on muscle (cardiac and skeletal) and adipose tissue.

Our cases demonstrate that in patients with lipodystrophy due to lamin A/C mutations, careful cardiac evaluation is required because of the risk for concomitant cardiomyopathy with conduction disturbances resulting in heart failure and sudden death.8