Distal myopathy with rimmed vacuoles: Report on clinical characteristics in 23 cases
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.63804
Source of Support: None, Conflict of Interest: None
Background: Distal myopathy with rimmed vacuoles (DMRV) is an autosomal recessive (AR) myopathy characterized clinically by the preferential involvement of the tibialis anterior and has been reported predominantly in the Japanese population. Materials and Methods: A case series of DMRV patients seen over a period of 3 years at a tertiary national referral center for neurological disorders in south India. Results: We describe the clinical characteristics, muscle magnetic resonance imaging (MRI) findings and classical histopathological feature in 23 patients. There were 12 men and 11 women. Mean age of onset was 27.04 ± 6.35 years (10-39 years). Onset was in the second or third decade in a majority. Mean age at presentation was 33.95 ± 6.35 years (25-48 years). Mean duration of illness was 6.74 ± 4.8 years (1-18 years). Consanguinity was reported in eight (34.8%) patients. The predominant and initial manifestation was bilateral foot drop in all patients. Muscle MRI demonstrated classical involvement of the anterior compartment muscles of the lower legs and the posterior compartment muscles of the thighs and the quadriceps was normal in all. Muscle histopathology showed numerous fibers containing rimmed vacuoles. Necrotic fibers or phagocytosis or regenerating fibers were rarely noted or were absent. Conclusions: DMRV is a rare AR myopathy. The disorder presents as progressive foot drop and hence has many differential diagnoses. It is easily mistaken as neuropathy of hereditary nature and hence it is extremely important to recognize the preferential muscle involvement and characterize the phenotype. This is the first report from India with patients having characteristic phenotype of Nonaka's/AR hereditary inclusion body myopathy with quadriceps sparing, and all were confirmed by histopathology.
Keywords: Distal myopathy, DMRV, rimmed vacuoles
Distal myopathy with rimmed vacuoles (DMRV), originally described in 1981 by Nonaka et al., is an autosomal recessive (AR) disorder characterized clinically by the preferential involvement of the tibialis anterior muscle with sparing of the quadriceps muscles. ,, DMRV has been reported predominantly in the Japanese population, ,,,, with an estimated prevalence of 1 per million.  It is a slowly progressive and disabling myopathy due to mutations in the gene that regulates the synthesis of sialic acid. The disease begins in early adulthood with weakness of distal muscles in the lower limbs and presents with foot drop. ,, Serum creatine kinase (CK) levels are only mildly elevated or within normal limits. ,,,,, Characteristic histological features include presence of numerous rimmed vacuoles. ,,,,,, and eosinophilic inclusion bodies in muscle fibers. ,,, The vacuolated fibers show abnormal accumulation of amyloid beta protein.  and hyperphosphorylated tau protein.  Absence of inflammation in atrophic muscle fibers is another characteristic finding of DMRV. ,,,, The initial symptom is usually altered gait and patients attain a wheelchair-bound state between 26 and 57 years of age, on an average 12 years after the onset.  Hereditary inclusion body myopathy (HIBM), originally described in 1983 as "rimmed vacuolar myopathy" sparing the quadriceps, is an AR disorder very similar to DMRV, both clinically and pathologically. , Both disorders have been mapped to the same region on chromosome 9 , and recently HIBM was shown to be associated with mutations in the gene encoding a bifunctional enzyme, UDP-N-acetylglucosamine 2-epimerase/N-acetylmanosamine kinase (GNE).  Further, homozygous or compound heterozygous mutations in the GNE gene was demonstrated among patients with DMRV.  It is suggested that DMRV and HIBM are allelic disorders.  Distal myopathies, although reported to be common in Scandinavian countries, are relatively rare in other parts of the world. The sporadic and AR inherited distal myopathies are extremely rare and small series have been reported from many parts of the world. ,,,, In the present study, we report the clinical characteristics of DMRV and the muscle magnetic resonance imaging (MRI) findings from south India.
Twenty-three adult patients with clinical features of non-Miyoshi distal myopathy were included in this study. All patients were recruited from the Neuromuscular Disorders Clinic, National Institute of Mental Health and Neurosciences, Bangalore, India. All patients attending the clinic undergo a thorough and meticulous examination and phenotypic characterization. An exhaustive proforma is completed for the topography of muscle involvement. All these patients clinically had the classical features of Nonaka's distal myopathy/HIBM and pathologically demonstrated rimmed vacuoles in muscle biopsy. DMRV was diagnosed based on the following proposed findings: (i) AR inheritance and sporadic, (ii) onset of symptoms in early adulthood, (iii) weakness beginning in the distal leg muscles, typically in the anterior tibialis muscle, with the quadriceps muscle remaining relatively unaffected, (iv) mainly myogenic changes, with certain neurogenic features on electromyography (EMG), (v) normal or mildly elevated serum CK, (vi) muscle biopsies displaying rimmed vacuoles without obvious dystrophic features. ,,
Twenty-two of 23 patients underwent muscle biopsy after obtaining written informed consent. The other patient was the sister of one of the patients with typical clinical features. Muscle specimens were taken from the following muscles: tibialis anterior = 9; biceps = 9; and quadriceps =4. Sections were stained for enzyme and nonenzyme stains (Hematoxylin-Eosin, modified Gomori trichrome, periodic acid Schiff, NADH-TR, SDH, ATpase at pH 9.5 and 4.6). Immunostaining with monoclonal antibodies to dysferlin as primary and HRP-tagged LSAB as secondary antibody was carried out in all samples.
Seven patients underwent MRI studies of the leg and thigh muscles. Three had imaging on a 3T Philips Acheiva MR machine (Philips Medical Systems, DA Best, The Netherlands) manufactured by Philips, Holland and the remaining four on a 1.5 T Seimens Magnetom Vision (Seimens, Erlanger, Germany) manufactured by Seimens, Germany. Body coil was used in both the machines. The protocol followed is given in [Table 1].
The data were analyzed using descriptive statistics, such as mean standard deviation for continuous variables and frequency percentage for categorical variables.
Among the 23 patients, there were 12 men and 11 women. Mean age of onset was 27.04 ± 6.35 years (10-39 years). Onset was in the second or third decade in the majority. Mean age at presentation was 33.95 ± 6.35 years (25-48 years). Mean duration of illness was 6.74 ± 4.8 years (1-18 years). Consanguinity was reported in eight (34.8%) patients. Pedigree patterns were not available in five patients (43.5%). Details of clinical manifestations are presented in [Table 2] and [Table 3]. The predominant manifestation was bilateral foot drop in all the patients. The prominent initial symptom in a majority was altered gait (82.6%) and tendency to trip. Four patients reported onset as hand grip weakness but, as the disease evolved, foot drop was more pronounced compared to hand weakness [[Figure 1]a-c and [Figure 2] a and b]. Asymmetrical onset of weakness was noted in nine (39.1%) patients, and the time interval between the other limb involvement ranged from 1 to 3 years. Within months to a few years, patients developed weakness of the proximal lower limb and upper limb muscles. In advanced stages, upper limb proximal and distal muscles were affected significantly. All patients were ambulant at the time of evaluation except for four cases, three of whom were wheelchair bound and one required maximum support for ambulation. At the time of examination, a total of 14 patients (60.9%) were disabled and were dependent for most activities of daily living, particularly those that involved performing fine motor tasks with hands. Duration of illness equal to or more than 10 years at presentation was noted in five cases. The three patients in a wheelchair-bound state had duration of illness of 11, 10 and 3 years and they had attained this state after 8.5, 9 and 3 years of illness, respectively. Disability of individual patient is presented in [Table 4].
The weakness was particularly prominent in tibialis anterior, hip adductors and hamstrings in the lower limbs as compared to other groups, which were mild to moderately weak [Table 5]. Neck flexors were weak in a majority and anterior neck muscles were wasted in a few. In the upper limbs, distal and shoulder girdle muscles were more affected than arm muscles. The long finger flexors were particularly weak. Quadriceps was minimally weak or spared in the majority [Table 6]. The deep tendon reflexes in the upper limbs were diminished to absent in all the 23 patients. In the lower limbs, knee jerk was diminished to absent in 21 (91.3%) patients and normal to brisk in two (8.6%) patients. Ankle jerk was sluggish to absent in all the 23 patients. All ambulant patients had waddling gait, Gower's sign and foot drop. Seven patients had positive family history. In five families, a second sibling was affected while parents were normal. In the remaining two the mothers were affected. Among the affected siblings, only two could be examined, and one mother was evaluated.
Classically, the anterior compartment muscles of the lower legs and posterior compartment muscles of the thighs and, to a lesser degree, the posterior muscles of the legs were affected [Table 5]. The quadriceps was normal in all; adductors were affected in two patients only, in contrast to the severity of clinical involvement. Hamstrings were severely involved in the majority. Tibialis anterior was the most severely affected muscle while the peroneus longus were affected severely in three patients. Gastrocnemius and Soleus were mild to moderately affected in a few. The affected muscles showed severe involvement with atrophy and adipose tissue replacement. Interestingly, fibrosis of the involved muscle was not a prominent feature. The classical MRI findings are shown in [Figure 3] A-F and [Figure 4] A-D.
Muscle Biopsy Findings
The findings in the 22 patients were presence of a number of fibers with rimmed vacuoles, with no evidence of myositis or extensive changes of dystrophy. Numerous fibers contained rimmed vacuoles [Figure 5]. There was variation in fiber size, with atrophic fibers and grouping. Necrotic fibers or phagocytosis or regenerating fibers were rarely noted or absent. There were no differences between familial and sporadic cases with respect to clinical, laboratory or pathological findings. Immunohistochemistry with antidysferlin antibody was positive in all samples.
Distal myopathies, although reported to be common in Scandinavian countries, are relatively rare in other parts of the world. The sporadic and AR inherited distal myopathies are also extremely rare, although reported from different parts of the world. ,,,, DMRV is a distinct clinical entity inherited through an AR trait with female preponderance. ,, Our patients were diagnosed to have DMRV based on both clinical features and muscle pathology. In our series, female preponderance was not observed. Mean age at onset in our group was around 25 years and initial symptoms of muscle weakness of the legs appeared in a majority in the second or third decade. In the initial stages, distal muscles of the legs were more prominently affected and later the proximal muscles, the iliopsoas and the biceps femoris, were affected early and severely. Quadriceps was spared in a majority. Consanguinity was present in one-third of our patients and seven had a positive family history. In a review of 37 cases of Japanese origin, the mean age at onset was 26.1 years and onset in the third decade was noted in 64% of the cases. Consanguinity of parents was reported in about 40% of their cases and 12 patients in seven pedigrees had a family history. Initial symptom was muscle weakness of legs or gait disturbances in 33 (90%) patients. All had weakness, which was predominantly seen in the distal muscles of the legs or diffusely, but the quadriceps was spared or was mildly involved in a few cases.  Two patients reported by Kira et al. had high arched feet (aged 21 and 27 years).  Three of our patients with long duration of illness had high arched feet with hammer toes Clinically, in seven of the nine patients in whom duration of illness was more than 10 years, five were nonambulatory. In our series, three patients had attained a wheelchair-bound state by the end of 3-9 years of illness duration. Patients with DMRV may progress rapidly  or slowly.  Our case series also showed that the clinical course of DMRV can differ in patients from the same family and between families. 
Serum CK was mildly elevated or within normal limits in the 37 Japanese patients.  In our cases also the serum CK was normal or minimally elevated except in three where it was above five times the normal level. However, the dysferlin staining in these patients was positive. Patients of DMRV have been described to have high CK levels. In the study by Nonaka et al., EMG showed myopathic pattern in all and was associated with some spontaneous discharges in the form of positive sharp waves and fibrillation potentials.  Electrodiagnostic studies in our study also showed myopathic features with normal nerve conduction.
The inheritance and symptoms of Miyoshi myopathy (MM) resemble those of DMRV. The preferential involvement of the gastrocnemius rather than peroneal muscles and high CK levels in MM are the clinical findings crucial to differential diagnosis. The most outstanding morphological features in DMRV are myopathic changes and rimmed vacuole formation.  Such vacuoles are seen in various neuropathic and myopathic processes, ,, but the clinical manifestations are important to consider DMRV. Familial vacuolar myopathy with AR inheritance characterized clinically by progressive distal and proximal muscle weakness and wasting beginning in early adulthood but always sparing the quadriceps femoris even in advanced stages was reported to occur in Jews of Persian origin. [16, Askanas and Engel introduced the term HIBMs. , This encompasses several syndromes which can be inherited as an AR or autosomal dominant trait and the familial myopathy in Persian Jews has been considered to be an AR form of HIBM. ,, There is clinical, pathological and mode of inheritance similarities between the AR HIBMs in Persian Jews to those observed in DMRV in the Japanese population and are allelic diseases.  All our patients had the features of DMRV and probably had Nonaka's distal myopathy or AR HIBM. Four of them who had onset in the upper limb distal muscles with long flexor weakness probably had HIBM. In two families, the mother and child were affected. All our patients appeared to have an AR inheritance pattern. The similarity between the reported sporadic and inherited cases makes it likely that the sporadic cases belong to the recessively inherited group where only one member of a sibship has inherited disease.  Our patients with sporadic and familial forms had similar clinical manifestations. MRI of the lower limb muscles classically showed involvement of the anterior compartment of the leg and the hamstrings. Even in patients with severe weakness, the quadriceps were spared. Similar findings have been reported by others. ,, Muscle MRI can be a valuable tool for diagnosing inherited neuromuscular disorders. Each scan provides multiple images for each segment, enabling a precise evaluation of the bulk of individual muscles and their involvement. Pattern of muscle involvement is more important than severity of involvement of individual muscles.  Recently, it has been proposed that the myopathy is due to mutations in the gene that regulates the synthesis of sialic acid and this may have therapeutic importance.
Thus, this is the first report on DMRV from India. A majority of the patients hailed from southern states of India. We were unable to perform genetic studies on our patients.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]