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Year : 2013  |  Volume : 61  |  Issue : 6  |  Page : 622--626

New mutation of the desmin gene identified in an extended Indian pedigree presenting with distal myopathy and cardiac disease

Atchayaram Nalini1, Narayanappa Gayathri2, Pascale Richard3, Ana-Maria Cobo4, J Andoni Urtizberea4,  
1 Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India
2 Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India
3 Department of Genetics, Pitié-Salpêtrière Hospital, 75651 Paris, France
4 Department of Neurology, Neuromuscular Unit, Marin Hospital, 64700 Hendaye, France

Correspondence Address:
Atchayaram Nalini
Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka


In this report, we describe a new mutation located in the coiled 1B domain of desmin and associated with a predominant cardiac involvement and a high degree of cardiac sudden death in a large Indian pedigree with 12 affected members. The index cases was 38-year-old man who presented with progressive difficulty in gripping footwear of 5 years duration with the onset in the left lower limb followed by right lower limb in 6 months. 3 years from onset, he developed lower limb proximal and truncal muscle weakness. There was mild atrophy of the shoulder girdle muscles with grade 3 weakness, moderate wasting of thigh and anterior leg muscles with proximal muscle weakness and foot drop. At 40 years, he had a pacemaker implanted. The 9 exons and intronic boundaries of the desmin gene were sequenced and a heterozygous nucleotide change c. 734A > G in exon 3 was identified.

How to cite this article:
Nalini A, Gayathri N, Richard P, Cobo AM, Urtizberea J A. New mutation of the desmin gene identified in an extended Indian pedigree presenting with distal myopathy and cardiac disease.Neurol India 2013;61:622-626

How to cite this URL:
Nalini A, Gayathri N, Richard P, Cobo AM, Urtizberea J A. New mutation of the desmin gene identified in an extended Indian pedigree presenting with distal myopathy and cardiac disease. Neurol India [serial online] 2013 [cited 2022 Aug 17 ];61:622-626
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Full Text


Desminopathy is a genetically heterogeneous group of disorders named myofibrillar myopathies (MFMs) and are caused by mutations of desmin gene (DES), αB-crystallin (CRYAB), myotilin (MYOT), Z band alternatively spliced PDZ-containing protein (ZASP), filamin C (FLNC), or Bcl-2-associated athanogene-3 (BAG3). [1],[2] Human desmin is encoded by a single-copy gene (DES) on chromosome 2q35 and mutations in this gene were first shown in MFMs. [3],[4],[5],[6] DES encompasses nine exons within an 8.4-kb region and encodes 470 amino acids. [7] Desmin is composed of an α-helical rod containing 303 amino acid residues, flanked by globular N-and C-terminal structures. The rod is interrupted in several places, resulting in four consecutive α-helical segments, 1A, 1B, 2A and 2B, connected by short, non-helical linkers. This disorder is characterized by skeletal and cardiac myopathy with weakness in distal leg muscles spreading proximally and leading eventually to tetraparesis and wheelchair dependence. [8] Desmin is the main intermediate filament protein expressed in cardiac (2% of total protein), skeletal (0.35%) and smooth muscle. It is a major component of Purkinje fibers. [9] Clinical presentation is variable, often associated with cardiomyopathy and histopathologically characterized by aberrant desmin aggregation in abnormal muscle fibers. [4],[8],[10] It is important to identify these patients early as this would ensure prevention of sudden cardiac and other complications. [11] In the present report, we describe a family with a new mutation located in the coiled 1B domain of desmin.

 Case Report

The present case report is about a 38-year-old man, presented to our Institution in May 2010 with progressive asymmetrical onset lower limb distal muscle weakness of 5 years duration and proximal weakness of 2 years. Clinical details of summarized in [Table 1]. In 2012 due to persistent electrocardiogram (ECG) abnormalities and ectopic beats, he had a pacemaker implanted. Family history of similar illness in 12 members of the extended family was reported [Figure 1]. Father of the proband developed complete heart block at 42 years of age and had a pacemaker implanted. At 1 year later, he developed progressive lower limb weakness. At 51 years noticed upper limb weakness and also required help of a walking stick. At 63 years, he had a sudden cardiac death. Elder brother of the proband aged 40 years, developed arrhythmia with frequent ectopic and missed beats at 35 years and had a pacemaker implanted for 2:1 atrioventricular (AV) block. At 39 years, he developed lower limb weakness, serum creatine kinase (CK) 1,300 IU/l. Younger brother of the proband aged 33 years developed lower limb weakness at 27 years with no cardiac symptoms. Proband's paternal grandmother required a pacemaker at 60 years of age. She expired at age 69 years due to sudden cardiac arrest. Affected grandmother's elder brother had cardiac arrhythmias. His two sons had cardiac illness and one had a sudden death at 40 years. No further details are available.{Figure 1}{Table 1}

Examination of the proband's radial pulse revealed frequent missed beats. There was mild bifacial weakness, mild atrophy of shoulder girdles and moderate wasting of thighs and anterior leg muscles. Neck flexors and upper limbs were moderately weak. Motor power in lower limbs hips-grade 3/5; abductors and adductors 4/5; knee extensors 4 ± 5 and flexors 2/5, ankle and toe dorsiflexors 2/5 and plantar flexors 5/5. Deep tendon reflexes were normal. Gait was waddling with high steppage gait.

Investigations: Serum CK of 529 IU, myopathic electromyography and normal motor and sensory nerve conduction studies. Quadriceps muscle biopsy revealed dystrophic changes with the presence of vacuoles rimmed by red granular material. There were a significant number of atrophic fibers. Modified gomori trichrome (MGT) stained sections also revealed rimmed vacuoles and succinate dehydrogenase (SDH) enzyme staining showed a loss of reaction to oxidative enzyme stain in the fibers. There was no tissue available for ultrastructural studies or additional immunohistochemical staining [Figure 2].{Figure 2}

ECG showed complete right bundle branch block with occasional ventricular premature complexes. 2D Echocardiogram was normal. Magnetic resonance imaging (MRI) of the pelvis and thigh revealed severe involvement of the gluteus maximus, minimus and medius, vastus lateralis, intermedius and medius, rectus femoris, gracilis and sartorius. Semimembranosus, semitendinosus, adductor longus and brevis were moderately involved. Adductor magnus was well preserved [Figure 3]. MRI of leg muscles was not done.{Figure 3}

Genetic analysis

After written informed consent blood for genomic deoxyribonucleic acid was drawn from 9 members and transported to Paris, France for genetic analysis. The 9 exons and intronic boundaries of the DES were sequenced and a heterozygous nucleotide change c. 734A > G in exon 3 was found [Figure 4]. At the protein level, this substitution either introduces the missense mutation p.Glu245Gly or abolishes of 53% the adjacent donor splice site resulting in a putative in-frame skipping of exon 3 corresponding to the deletion of residues p.Asp214-Glu245. Nevertheless, in the absence of messenger ribonucleic acid (mRNA) analysis, we cannot speculate on the consequences of the variant at the protein level.{Figure 4}


This is the first report of genetically confirmed autosomal dominant desminopathy with cardioskeletal presentation from India. The common pathological pattern in myofibrillar myopathy is dissolution of myofibrils, aggregation of degraded myofibrillar products and ectopic expression of proteins is also well-described. [2] The clinical manifestations are remarkably variable. Progressive skeletal myopathy is one of the clinical variants of desminopathy [12] and is observed in almost a quarter of patients. [13] The illness generally starts at a later age than in individuals with other disease variants and the progression is commonly very slow. Skeletal muscle weakness is typically known to start in distal leg muscles and spreads to proximal muscles. In advanced disease, all four limbs are affected. [12] The disease course in our proband and other family members was relatively slow with involvement of both distal and proximal muscles. Phenotypic variability is reported to depend on the type of inheritance and the location of mutations within the relatively large and structurally and functionally complex desmin molecule. [4] Clinical features have been characterized as severe childhood-onset cardioskeletal myopathy adult-onset skeletal myopathy with cardiac involvement, pure skeletal myopathy, cardiomyopathy with distal weakness, pure dilated cardiomyopathy and distal myopathy with cardiac, respiratory, bulbar, facial and smooth muscle involvement. Distal, limb-girdle phenotypes and scapuloperoneal weakness with variable cardiac and respiratory involvement have been seen within a set of kindreds segregating with the p.Arg350Pro desmin mutation. [14] Our family had the early adult onset form, with the onset before age 40 and distal limb girdle phenotype with arrythmogenic cardiomyopathy requiring pacemaker implantation. About 80% of desminopathy families show classic autosomal dominant pattern of inheritance, most with full penetrance. [4],[13] Our family had this inheritance pattern with members affected in four generations. In the earliest generation the affected members survived for long years after the onset of illness.

Muscle involvement on imaging in desminopathy range from mild to severe. [10] In pelvic muscles: the gluteus maximus muscle is significantly more involved than the gluteus medius and minimus muscles. In our patient, all three muscles were equally and severely affected. In thigh: Semitendinosus, sartorius and gracilis are the most affected muscles exceeding the involvement of the adductor magnus, biceps femoris and semimembranosus. Similarly in our patient, sartorius and gracilis were more severely affected as compared to adductor magnus, biceps femoris and semimembranosus. However, there was no difference in affection of semimembranosus and semitendinosus. In the anterior compartment, rectus femoris, vastus lateralis, intermedius and medialis are reported to be relatively spared in most patients. [10] However, in our patient all these muscles were severely affected. In lower legs: the peroneal muscles are known to display significantly more lipomatous changes than the tibialis anterior and muscles of the posterior compartment (soleus, medial and lateral gastrocnemius).

The most consistent finding in muscle-biopsy specimen has been reported to be the presence of bluish accumulations in subsarcolemmal or centrally located areas immunoreactive on staining with antibodies against desmin. Rimmed vacuoles and small aggregates of rods are also reported. In our patient many rimmed vacuoles were noted. Dark-blue inclusions have also been reportedly identified on trichrome (MGT) staining. We did not detect these dark-blue inclusions. Multiple nuclei, atrophic fibers and cytoplasmic bodies are reported to be common. Our patients had plenty of atrophic fibers, but no cytoplasmic bodies. SDH staining had revealed loss of reaction to oxidative enzyme stain in the fibers. On electron microscopy (EM), myofibrillar disruption, fragments of thin and thick filaments, streaming Z bands and deposits of dense, amorphous material are known to be prominent. [15] In our patient, muscle tissue was insufficient to perform EM study.

Genetically, the substitution of the nucleotide c. 734A > G involved the last codon of exon 3, it may have several putative consequences on the mRNA and thus the protein. It can be responsible for a missense substitution p.Glu245Gly acting as a peptide poison with a dominant negative effect or for a truncating mutation resulting in the skipping of exon 3 and the deletion of residue 214-245 due to the partial (53%) abolition of the splice donor site. Nevertheless, this defect affects the end of the heli × 1B of the core domain of the protein. The heli × 1B of desmin is described to have an important role responsible for the polymerization of the protein. This mutation was identified for the 1 st time in this family, but a similar p.Glu245Asp (c. 735G > T) mutation that causes muscle weakness and cardiomyopathy in humans [16] has been studied at the functional level in vitro on cultured cardiomyocytes. The consequences of the p.Gly245Asp mutation was an alteration of the binding of desmin with nebulin, a loss of Z disk localization and an enhancement in the formation of cytoplasmic aggregates and finally an abnormal actin organization and lengths in myofilaments. All these results suggest that the coiled 1B region of desmin was the most efficient at localizing to the Z-discs cardiac and skeletal myocytes, in agreement with its interaction with C-terminal nebulin and although most of the missense mutations causing desminopathy were clustered at the carboxy-terminal part of the desmin rod domain within the heli × 2B subdomain, mutations in the helix IB are associated with severe forms of cardiomyopathy with rhythm disturbances at the young age and a moderate degree of skeletal myopathy.

MFMs with arrythmogenic cardiac involvement requiring pacemeker implantation and early adult onset before the age of 40 years are more likely to have desminopathy. AV conduction abnormalities requiring urgent pacemaker implantation of a permanent pacemaker is a frequent feature. Hence, early detection of this disorder and elective pacemaker implantation would be life saving. Clinical findings in addition to MR imaging of lower limbs and pathological findings are useful in differentiating distinct forms of MFMs and could guide in specific molecular genetic testing.


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