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Table of Contents    
Year : 2012  |  Volume : 60  |  Issue : 6  |  Page : 631-634

Distal myopathy with rimmed vacuoles and inflammation: A genetically proven case

1 Department of Neurology, Nizam's Institute of Medical Sciences, Hyderabad, India
2 Department of Pathology, Nizam's Institute of Medical Sciences, Hyderabad, India
3 Institut de Myologie, Hôpital de la Salpêtrière, 75651 Paris Cedex, France

Date of Submission28-Sep-2012
Date of Decision25-Oct-2012
Date of Acceptance06-Nov-2012
Date of Web Publication29-Dec-2012

Correspondence Address:
Meena A Kannan
Department of Neurology, Nizam's Institute of Medical Sciences, Punjagutta, Hyderabad- 500 082
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.105199

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 » Abstract 

Distal myopathy with rimmed vacuoles (DMRV) is a major entity of distal myopathy. It is an autosomal recessive disorder and is due to mutations in the GNE gene that regulates the synthesis of sialic acid. Although reported predominantly from Japan, cases have been reported from other parts of the world. We report the first genetically proven case of DMRV from India in a 23-year-old male with gradual onset, progressive distal weakness of both lower limbs with features of inflammation in muscle biopsy.

Keywords: Distal myopathy, GNE gene, rimmed vacuoles

How to cite this article:
Kannan MA, Challa S, Urtizberea AJ, Krahn M, Jabeen A S, Borgohain R. Distal myopathy with rimmed vacuoles and inflammation: A genetically proven case. Neurol India 2012;60:631-4

How to cite this URL:
Kannan MA, Challa S, Urtizberea AJ, Krahn M, Jabeen A S, Borgohain R. Distal myopathy with rimmed vacuoles and inflammation: A genetically proven case. Neurol India [serial online] 2012 [cited 2021 Mar 9];60:631-4. Available from:

 » Introduction Top

Distal myopathy with rimmed vacuoles (DMRV), first described by Nonaka is one of the major entities of distal myopathy. [1] DMRV is an autosomal recessive or sporadic disease. Although reported mainly in the Japanese and Jewish population, [1],[2],[3],[4],[5],[6] it is evident from the genetic studies that these diseases are widely distributed in all ethnic groups. [7] Significant weakness in dorsiflexors of legs leading to foot drop is the presenting feature. Degree of progression varies among different populations and also within the families. [1],[5],[8],[9] Creatine kinase (CK) is usually slightly or moderately elevated (<51/2 times) but can be above 1000 IU/L in 23% of patients. [9] Muscle biopsies show presence of numerous rimmed vacuoles in affected muscles without inflammation. As the pathology is similar to sporadic inclusion body myositis (sIBM), the term "hereditary inclusion body myopathy (hIBM)" has been used. [10] DMRV and hIBM are genetically identical disorders caused by mutations in the GNE gene. GNE gene encodes a bifunctional protein with UDP-GlcNAc 2-epimerase and ManNAc kinase gene activities that catalyze rate-limiting step and succeeding step in the sialic acid biosynthetic pathway. In both, the gene abnormalities are located on Chromosome 9p1-q1. To date, several mutations have been reported in different populations worldwide in the DMRV GNE gene. [11],[12],[14] There is only a single clinico-pathological study published from India. [15] We report a patient of genetically confirmed DMRV with inflammation from India.

 » Case Report Top

A 23-year-old male presented with bilateral foot drop of three-year duration followed by difficulty in getting up from sitting position. He also gave history of wasting of legs bilaterally, especially in the anterior part. He had no symptoms referable to upper extremities. There was history of consanguinity in the family in two generations [Figure 1]. Neurological examination revealed wasting of both tibialis anterior (TA) muscle and weakness in sternocleidomastoid, hand muscles, TA (severe) and mild weakness in hamstrings, gluteus maximus and hip adductors. Quadriceps muscles were preserved. Deep tendon reflexes were diminished. Clinical examination of family members was normal. Serum CK was 615 IU/L (normal <200 IU/L). Nerve conduction study was normal and electromyogram was myopathic in TA and normal in quadriceps. Magnetic resonance imaging (MRI) of limbs showed generalized hyperintense signal in tibialis anterior and posterior, extensor hallucis longus, extensor digitorum longus, gluteus maximus, adductors of thigh, hamstrings, gastrocnemius, and right biceps brachialis. Quadriceps and peroneal muscles were spared [Figure 2].
Figure 1: Pedigree chart

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Figure 2: T1, T2, STIR (a, b, c respectively) weighted axial images of both thighs showing hyperintensities in hamstring muscles with atrophy (black arrows) sparing quadriceps (white arrowheads). T1, T2, STIR (d, e, f respectively) weighted axial images of both legs showing hyperintensities in tibialis anterior and posterior and gastro-soleous muscles on T2 and STIR

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Muscle biopsy showed normal fascicular architecture, marked variation in fiber size, hypertrophic fibers, split fibers and angulated atrophic fibers with significant degenerating and regenerating muscle fibers, with central nuclei. Prominent vacuoles rimmed by basophilic granular material in the periphery as well as in the centre of many muscle fibers were seen. These inclusions stained positive with modified Gomori trichrome (MGT) stain and negative with Congo red stain. There were distinct aggregates of lymphomononuclear infiltrations in the interstitium and perivascular region [Figure 3]. There was increase in interstitial adipose tissue and masson trichrome stain showed mild fibrosis. Vessels were unremarkable. Enzyme histochemistry with ATPase showed focal type grouping.
Figure 3: Hematoxylin and Eosin staining showing hypertrophic, and angulated atrophic fibers (a), H and E showing prominent vacuoles rimmed by basophilic granular material in the periphery as well as in the centre (b), Rimmed vacuoles staining positive with modified Gomori trichrome stain (c), H and E staining showing aggregates of lympho-mononuclear cells in the interstitium and around the blood vessels (d)

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Genetic study: Mutational analysis of GNE gene (NM_005476) was carried out using direct sequencing of GNE coding exons and flanking intronic boundaries (on a ABI3130 sequencer, Applied Biosystems, Foster City, CA, USA). A homozygous missense mutation was identified in the index case: c.878A > G, predicted to cause the replacement of a histidine residue by an arginine at position 293 of the protein. The same missense mutation was retrieved at a heterozygous state in the patient's parents and aunt.

 » Discussion Top

DMRV has a female preponderance but can occur in males too. Clinical spectrum of DMRV/hIBM seems to be more variable than previously thought. [16] Our patient was diagnosed as DMRV based on clinico-pathological features. Our patient had proximal weakness; although an uncommon feature at presentation, this has been reported in a few other studies. [17] Gastrocnemius, hamstrings, paraspinal and sternocleidomastoid are usually involved early in the course along with TA. As reported, the striking feature was relative sparing of the quadriceps despite progression of weakness in proximal muscles. Apart from the inflammatory cell infiltrates in muscle biopsy the other histopathological features were compatible with the diagnosis of DMRV. Inflammation was seen in the interstitial and perivascular connective tissue without endomysial involvement. Inflammatory infiltrates (endomysial and perivascular) are not common in DMRV but they have been reported in two earlier studies. [18],[19] Endomysial and perivascular inflammation is seen in familial inclusion body myositis. Usually, age of onset can differentiate DMRV from sIBM. The relationship between inflammatory changes and GNE mutations is not clearly understood.

DMRV and hIBM are allelic diseases caused by GNE gene mutations. GNE is bifunctional having epimerase activity in its N-terminal region and sugar kinase activity in its C-terminal region. Mutations associated with DMRV were localized in either or both the domains (epimerase and kinase). Almost all of the mutations associated with DMRV/hIBM are missense mutations scattered throughout the open reading frame. They can be found either in the epimerase domain only or kinase domain only, or heterozygous mutations on each domain. [11] The most common mutation 2186T-to-C (M712T) was initially reported from Middle Eastern Jews including a large proband family. [20] On the other hand, the most frequent mutation in Japanese DMRV patients was the 1714C-to-G (V572L) mutation which was found in more than 50% of patients. [11],[13] Genotype/phenotype correlation is still unclear and there is a phenotypic diversity associated with GNE mutations. Limb girdle phenotype is frequent in GNE-associated myopathy. [13],[17] Furthermore, an individual with a homozygous M721T mutation with no muscle symptom has been reported, suggesting an incomplete penetrance of the disease. [11] Recognizing a wider clinical spectrum of GNE mutations will benefit more patients with imminent new therapy. Studies on recombinant GNE demonstrate a loss-of-function nature of the missense mutations identified. Patients' cells show decreased sialylation status which can be recovered by adding GNE metabolites, such as ManNAc and NeuAc. This indicates the possibility of developing a therapy for DMRV/hIBM by giving these metabolites to patients. Our patient was homozygous for GNE mutation. The mutation was c.878 A > G (p. His293Arg) at exon 5. Patient's mother, father and maternal aunt who are asymptomatic clinically were heterozygous for the mutation. This sequence variation has not been reported previously, but bioinformatics analysis using PolyPhen2 [21] predicts a possibly damaging effect (PolyPhen2 score of 0.801); indicating this mutation as most likely disease-causing in this patient. This is the first genetically proven case of DMRV from India till date and the presence of this mutation needs to be looked for in the Indian patient population.

 » References Top

1.Nonaka I, Sunohara N, Ishiura S, Satoyoshi E. Familial distal myopathy with rimmed vacuole and lamellar (myeloid) body formation. J Neurol Sci 1981;51:141-55.  Back to cited text no. 1
2.Mizusawa H, Nakano I, Inoue K, Takagi A, Mannen T, Toyokura Y. Distal myopathy: a variety characterized by prominent vacuolar degeneration of muscle. Neurol Med (Tokyo) 1980;12:40-47.  Back to cited text no. 2
3.Mizusawa H, Kurisaki H, Takatsu M, Inoue K, Mannen T, Toyokura Y, et al. Rimmed vacuolar distal myopathy: A clinical, electrophysiological, histopathological and computed tomographic study of seven cases. J Neurol 1987;234:129-36.  Back to cited text no. 3
4.Sunohara N, Nonaka I, Kamei N, Satoyoshi E. Distal myopathy with rimmed vacuole formation. A follow-up study. Brain 1989;112:65-83.  Back to cited text no. 4
5.Markesbery WR, Griggs RC, Herr B. Distal myopathy: Electron microscopic and histochemical studies. Neurology 1977;27:727-35.  Back to cited text no. 5
6.Kuhn E, Schroder JM. A new type of distal myopathy in two brothers. J Neurol 1981;226:181-7.  Back to cited text no. 6
7.Nonaka I, Noguchi S, Nishino I. Distal myopathy with rimmed vacuoles and hereditary inclusion body myopathy. Curr Neurol Neurosci Rep 2005;5:61-5.  Back to cited text no. 7
8.Ro LS, Lee-Chen GJ, Wu YR, Lee M, Hsu PY, Chen CM. Phenotypic variability in a Chinese family with rimmed vacuolar distal myopathy. J Neurol Neurosurg Psychiatry 2005;76:752-5.  Back to cited text no. 8
9.Tomimitsu H, Ishikawa K, Shimizu J, Ohkoshi N, Kanazawa I, Mizusawa H. Distal myopathy with rimmed vacuoles: Novel mutations in the GNE gene. Neurology 2002;14:451-4.  Back to cited text no. 9
10.Askanas V, Engel WK. Sporadic inclusion-body myositis and hereditary inclusion-body myopathies: Current concepts of diagnosis and pathogenesis. Curr Opin Rheumatol 1998;10:543-7.  Back to cited text no. 10
11.Nishino I, Noguchi S, Murayama K, Driss A, Sugie K, Oya Y, et al. Distal myopathy with rimmed vacuoles is allelic to hereditary inclusion body myopathy. Neurology 2002;59:1689-93.  Back to cited text no. 11
12.Eisenberg I, Grabov-Nardini G, Hochner H, Korner M, Sadeh M, Bertorini T, et al. Mutations spectrum of GNE in hereditary inclusion body myopathy sparing the quadriceps. Hum Mutat 2003;21:99.  Back to cited text no. 12
13.Tomimitsu H, Shimizu J, Ishikawa K, Ohkoshi N, Kanazawa I, Mizusawa H. Distal myopathy with rimmed vacuoles (DMRV): New GNE mutations and splice variant. Neurology 2004;62:1607-10.  Back to cited text no. 13
14.Argov Z, Eisenberg I, Grabov-Nardini G, Sadeh M, Wirguin I, Soffer D, et al. Hereditary inclusion body myopathy: The middle eastern genetic cluster. Neurology 2003;60:1519-23.  Back to cited text no. 14
15.Nalini A, Gayathri N, Dawn R. Distal myopathy with rimmed vacuoles: Report on clinical characteristics in 23 cases. Neurol India 2010;58:235-41.  Back to cited text no. 15
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16.Nishino I, Noguchi S, Murayama K, Ohkuma A, Kasahata N, Malicdan MC, et al. Molecular pathomechanism of distal myopathy with rimmed vacuoles. Rinsho Shinkeigaku 2005;45:943-5.  Back to cited text no. 16
17.Park YE, Kim HS, Choi ES, Shin JH, Kim SY, Son EH, et al. Limb-girdle phenotype is frequent in patients with myopathy associated with GNE mutations. J Neurol Sci 2012;321:77-81.  Back to cited text no. 17
18.Yabe I, Higashi T, Kikuchi S, Sasaki H, Fukazawa T, Yoshida K, et al. GNE mutations causing distal myopathy with rimmed vacuoles with inflammation. Neurology 2003;61:384-6.  Back to cited text no. 18
19.Krause S, Schlotter-Weigel B, Walter MC, Najmabadi H, Wiendl H, Müller-Hfcker J, et al. A novel homozygous missense mutation in the GNE gene of a patient with quadriceps-sparing hereditary inclusion body myopathy associated with muscle inflammation. Neuromuscul Disord 2003;13:830-4.  Back to cited text no. 19
20.Eisenberg I, Avidan N, Potikha T, Hochner H, Chen M, Olender T, et al. The UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene is mutated in recessive hereditary inclusion body myopathy. Nat Genet 2001;29:83-7.  Back to cited text no. 20
21.Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, et al. A method and server for predicting damaging missense mutations. Nat Methods 2010;7:248-9.  Back to cited text no. 21


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