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| ORIGINAL ARTICLE |
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| Year : 2013 | Volume
: 61
| Issue : 4 | Page : 371-374 |
GNE myopathy in India
Atchayaram Nalini1, Narayanappa Gayathri2, Ischizo Nishino3, Yukiko K Hayashi3
1 Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, Karnataka, India
2 Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bangalore, Karnataka, India
3 Department of Neuromuscular Research, National Institute of Neuroscience; Department of Clinical Development, Translational Medical Center, National Center of Neurology and Psychiatry, Tokyo, Japan
| Date of Submission | 04-Jun-2013 |
| Date of Decision | 06-Jul-2013 |
| Date of Acceptance | 21-Jul-2013 |
| Date of Web Publication | 4-Sep-2013 |
Correspondence Address:
Atchayaram Nalini
Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore - 560 029, Karnataka
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/0028-3886.117609
Background: GNE myopathy is a clinicopathologically distinct distal myopathy with autosomal-recessive inheritance. The GNE gene mutations are known to cause this form of distal myopathy Materials and Methods: Over the last 6 years, a total of 54 patients from 48 families were diagnosed to have GNE myopathy based on the clinical and histopathological findings. We have reported on 23 cases earlier and from this cohort 12 patients from 11 families underwent genetic testing for GNE mutation. Results: Nine patients belonging to eight families were confirmed as GNE myopathy by genetic analysis. There were six women and three men. Mean age of onset was 26.7 ± 5.47 years (20-36 years) and mean age at clinical examination was 32.3 ± 4.2 years (28-39 years). Mean duration of the illness was 5.7 ± 4.7 years (1-14 years). All had characteristic clinical features of progressive weakness and wasting of the anterior part of leg muscles, adductors of thighs and hamstrings with relative sparing of the quadriceps muscles. Biopsy from the tibialis anterior muscles revealed the presence of rimmed vacuoles. Mutation analysis of the GNE gene revealed that c. 2086G > A (p.Val696Met) change was common in our series like Thailand and six of eight families carried this mutation, heterozygously. Conclusion: These results show the presence of a common mutation in GNE gene in Southeast Asia.
Keywords: c. 2086G > A (p.Val696Met), GNE myopathy, mutation analysis
How to cite this article:
Nalini A, Gayathri N, Nishino I, Hayashi YK. GNE myopathy in India. Neurol India 2013;61:371-4 |
| » Introduction | |  |
GNE myopathy also called as distal myopathy with rimmed vacuoles (DMRV), hereditary inclusion body myopathy (hIBM), quadriceps-sparing myopathy or Nonaka myopathy is a clinicopathologically distinct distal myopathy with autosomal-recessive inheritance. It is clinically characterized by preferential involvement of anterior tibial muscles and sparing of quadriceps and pathologically by the presence of rimmed vacuoles (RV) on muscle biopsy. [1],[2],[3] The age of onset ranges from 15 to 40 years. [4] Patients generally become wheelchair bound between 26 and 57 years of age, on an average 12 years after the onset of symptoms. [4] Serum creatine kinase (CK) level is normal or mildly elevated.
The GNE gene mutations are known to cause this form of distal myopathy. [5],[6] GNE encodes a bifunctional enzyme, uridine diphosphate-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase, which plays a critical role in the production of sialic acid. [7] GNE mutations are reported to be responsible for a lower level of sialic acid in skeletal muscles, which is postulated to be causative of the diseases. [8] Recently, limb girdle phenotype is reported to be frequent presentation in patients with myopathy associated with GNE mutations. [9] In the present report, we describe 9 patients with GNE myopathy who underwent GNE mutation studies.
| » Materials and Methods | | |
Institutional ethical approval was obtained for the study. Muscle biopsies are routinely performed for diagnostic purpose. Written informed consent was obtained from all patients who approached for genetic analysis. Nine adult patients who belonged to the original cohort of 23 cases were included in the present study. [10] All these patients were recruited from the Neuromuscular Disorders clinic at National Institute of Mental Health and Neurosciences, Bangalore, India. All patients attending the clinic undergo a thorough phenotypic characterization. An exhaustive proforma is completed for the topography of muscle involvement. GNE myopathy was diagnosed based on the following proposed findings (i) autosomal-recessive inheritance, but may be sporadic, (ii) onset of symptoms in early adulthood (iii) weakness beginning in the distal leg muscles, typically in the anterior tibialis muscles, with the quadriceps muscles remaining relatively unaffected, (iv) myogenic changes on electromyography, (v) normal or mildly elevated serum CK, (vi) muscle biopsies displaying RV without obvious dystrophic features. [1],[11],[12]
Genetic analysis
Genomic DNA was extracted from peripheral blood lymphocytes using the standard techniques. All exons and their flanking intronic regions of GNE were sequenced directly using an ABI PRISM 3130 automated sequencer (PE Applied Biosystems). The primer sequences used in this study are available on request. We used the GenBank NM_001190383 for the description of the mutations.
| » Results | | |
Clinical features
We examined nine patients (six women and three men) who had weakness and atrophy of peroneal muscles with relatively preserved to normal power in quadriceps muscles. Onset of the disease was in the second or third decade in the majority and the mean age of onset was 26.7 ± 5.4 (20-36) years. Mean age at clinical examination was 32.3 ± 4.2 years (28-39). Mean duration of illness was 5.6 ± 4.7 (1-14) years. Details of the clinical manifestations, investigations and mutation findings are represented in [Table 1]. The initial symptom in the majority of the patients was altered gait. Muscle weakness was particularly prominent in tibialis anterior, hip adductors and hamstrings in the lower limbs with foot drop. Neck flexors were weak in majority. In upper limbs, distal and shoulder girdle muscles were more affected than arm muscles. The long finger flexors were particularly weak. Within months to a few years, the patients developed muscle weakness of the proximal lower and the distal upper limbs. All patients had minimal or no involvement in quadriceps muscles and was ambulant at the time of evaluation except for three severely disabled patients (case three, four, five and seven). Serum CK levels were normal to only slightly elevated. | Table 1: Clinical characteristics and investigation findings in the nine cases with GNE mutation analyses
Click here to view |
Mutation analysis of GNE
We identified mutations in GNE in all 8 families examined. One consanguineous family (F1) had a homozygousc. 484C > T (p.Arg162Cys) mutation, which is previously reported. [13] Four had a compound heterozygous mutations including two novel missense mutations of c. 910G > A (p.Gly304Arg) and c. 1703G > T (p.Gly568Val) and two previously reported nonsense mutations of c. 1258C > T (p.Arg420X) andc. 1539G > A (p.Trp513X). [14] A c. 2086G > A (p.Val696Met) mutation was commonly seen in our series and identified in the six of eight families (75%), heterozygously. Four patients in three families (F6-8) had only one heterozygous reported mutation.
| » Discussion | | |
Familial vacuolar myopathy with autosomal-recessive inheritance characterized clinically by progressive distal and proximal muscle wasting and weakness beginning in early adulthood and almost always sparing the quadriceps femoris even in advanced stages was reported to occur in Jews of Persian origin. [15],[16] The familial myopathy in Persian Jews has been considered to be an autosomal-recessive form of hIBM, which is now called as GNE myopathy. [17],[18],[19] Our patients all had the classical clinical and histopathological features of GNE myopathy.
Over the last 6 years, we have diagnosed 54 patients phenotypically having the classical features of GNE myopathy and muscle biopsy confirming the diagnosis of rimmed vacuolar myopathy. Our earlier report on 23 cases was based on the clinical and histopathological features. [10] The initial and preferential peroneal muscle involvement appears in the second or third decade of life in most patients and the disease is progressive, usually leading to a non-ambulant state within 10 years after the onset. [1],[2],[3]
Nonaka et al., for the first time described three patients from two families of Japanese origin with autosomal-recessive inheritance and presence of RV in muscle biopsies. [11] DMRV or now termed as GNE myopathy is a distinct clinical entity inherited through an autosomal-recessive trait with female preponderance. [3] The mean age of onset in our group was 26.7 years and the initial symptoms of muscle weakness of the legs appeared in the majority in the second or third decade. In a review of 37 Japanese patients, the mean age of onset was 26.1 and onset in the third decade was noted in 64% of the patients. [20] Clinically in seven of their nine patients in whom duration of illness was more than 10 years, five of them became non-ambulatory. Serum CK was mildly elevated or within the normal limits among the 37 Japanese patients. CK levels in our cohort were normal or minimally elevated.
In the present study, genetic analysis identified a homozygous c. 484C > T (p.Arg162Cys) mutation in one family. This mutation was previously reported in an Italian family. [13] Four families had a compound heterozygous mutations including 2 novel missense mutations c. 910G > A (p.Gly304Arg) and c. 1703G > T (p.Gly568Val). Both these amino acids are well-preserved among species and a missense mutation p.Gly568Ser was also recently identified in a Japanese GNE myopathy patient. [21] The c. 2086G > A (p.Val696Met) mutation was common in this series and identified in the six of eight families (75%), heterozygously. This mutation was reported previously among patients from Thailand. [7],[21]
In GNE myopathy, presence of the common mutation is known to occur in different ethnic backgrounds, i.e. p.Val572 Leu mutation in Japanese and Korean patients and p.Met712Thr in the Jewish population. Findings in the present study and earlier studies, p.Val696Met substitution appears to be the most common mutation in both India and Thailand. [22] In this study, four patients from three families had only one heterozygous mutation in GNE gene. The second mutation may not be detectable using the present method, which detects only large deletions in the GNE gene. In a previous study from Japan, patients with a nonsense mutation in one allele showed relatively severe clinical features. [21] However, in this series, one patient (case 3) of 34 years of age harboring p.Arg420X/Val696Met mutation was ambulant, but had illness onset at 33 years of age while case 4 (30 years of age) with p.Try513X/Val696Met was wheel chair-bound after 10 years of illness duration. From the predicted structure models reported by Kurochkina, et al., p.Arg420X can preserve its epimerase activity and the enzyme hexameric state, whereas p.Try513X causes its conformational change on glucose binding if these proteins are produced. [23] This study confirms that GNE myopathy may be indeed one among the common inherited myopathies among Indians. Further analysis in a larger cohort is required to clarify the genotype-phenotype correlations of GNE myopathy among Indian population.
| » References | | |
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[Table 1]
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