A novel homozygous missense mutation in the GNE gene of a patient with quadriceps-sparing hereditary inclusion body myopathy associated with muscle inflammation

An adult-onset hereditary inclusion body myopathy with sparing of the quadriceps muscle was originally described in Iranian Jews and assigned to a locus on chromosome 9p12–p13. Recently, mutations of the UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE) gene were reported to cause hereditary inclusion body myopathy and one type of distal myopathy in a world-wide distribution. Importantly, the lack of muscle inflammation was used to distinguish hereditary inclusion body myopathy from the sporadic form of inclusion body myopathy. We report a case of a quadriceps-sparing myopathy in a non-Jewish, Iranian patient with a high degree of muscle inflammation. A novel homozygous G-to-A mutation (128933G→A) in exon 7 changing a valine to isoleucine (V367I) in the epimerase domain of the GNE gene was found. We conclude that muscle inflammation is not sufficient to exclude the diagnosis of hereditary inclusion body myopathy.     

Nonaka肌病伴面部肌肉受累

目的 报道1个伴随面部肌肉受累及的Nonaka型远端性肌肉病家系的临床和病理特点，讨论其发病机制。方法 先证者在中年早期起病。主要临床表现为胫前肌为主的四肢远端肌无力和肌萎缩，伴随有面肌和胸锁乳突肌力弱以及眼睑下垂，股四头肌不受累。肌酶轻度升高。肌电图提示肌源性损害。对患者进行胫前肌活检，进行组织学，酶组织化学和超微结构检查。家族中其妹妹也具有相同的临床表现。出现下肢远端为主的肌无力和肌萎缩。结果 肌肉病理改变特点是出现肌纤维肥大和萎缩。伴随核内移和肌纤维分裂现象。在部分肌纤维内可见镶边空泡和胞浆体。电镜下可见肌纤维内和核内的管丝包涵体以及髓样小体，其中出现在膜下的管丝包涵体具有细胞核的轮廓，可以看到细胞核变性后形成致密破碎结构。结论 结合患者的家庭史，临床表现和病理学改变特点。此患者可以考虑为Nonaka肌病，我们证实此病可以伴随面部肌肉的受累及。其发病机制可能与肌核的变性有关。     

Late-onset distal myopathy with rimmed vacuoles without mutation in the GNE or dysferlin genes

We report two brothers from a Japanese family with a late-onset distal myopathy characterized by rimmed vacuoles and dysferlin deficiency with no inflammatory infiltration and dystrophic changes in muscle biopsy. Mutations in the GNE, dysferlin, caveolin 3, emerin, and lamin A/C genes were excluded. We speculate that dysferlin is involved in the pathogenesis of the myopathy in these patients, which may represent a new disease entity presenting as a distal myopathy.     

Hereditary inclusion-body myopathy associated with cardiomyopathy: report of two siblings

Hereditary inclusion-body myopathy (HIBM) or distal myopathy with rimmed vacuoles (DMRV) is an autosomal recessive disorder characterized by preferential involvement of distal muscles in the lower extremities, especially the anterior compartment of the legs, with relative preservation of the quadriceps.This is referred to as quadriceps-sparing myopathy. Previous reports have revealed exclusive involvement in skeletal muscles. Herein we describe two siblings with typical HIBM/DMRV. The patients developed exertional dyspnea 20-26 years after disease onset. Echocardiogram revealed a cardiomyopathy in both patients. This is the first report of the association between HIBM/DMRV and cardiomyopathy.     

Muscle imaging findings in GNE myopathy

GNE myopathy (MIM 600737) is an autosomal recessive muscle disease caused by mutations in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene. Besides the typical phenotype, characterized by the initial involvement of the distal leg muscles that eventually spreads proximally with sparing of the quadriceps, uncommon presentations with a non-canonical clinical phenotype, unusual muscle biopsy findings or both are increasingly recognized. The aim of our study was to characterize the imaging pattern of pelvic and lower limb muscles in GNE myopathy, thus providing additional diagnostic clues useful in the identification of patients with atypical features. We retrospectively evaluated muscle MRI and CT scans of a cohort of 13 patients heterogeneous for GNE mutations and degree of clinical severity. We found that severe involvement of the biceps femoris short head and, to a lesser extent, of the gluteus minimus, tibialis anterior, extensor hallucis and digitorum longus, soleus and gastrocnemius medialis was consistently present even in patients with early or atypical disease. The vastus lateralis, not the entire quadriceps, was the only muscle spared in advanced stages, while the rectus femoris, vastus intermedius and medialis showed variable signs of fatty replacement. Younger patients showed hyperintensities on T2-weighted sequences in muscles with a normal or, more often, abnormal T1-weighted signal. Our results define a pattern of muscle involvement that appears peculiar to GNE myopathy. Although these findings need to be further validated in a larger cohort, we believe that the recognition of this pattern may be instrumental in the initial clinical assessment of patients with possible GNE myopathy.     

有镶边空泡远端肌病一家系GNE基因突变分析

目的探讨有镶边空泡远端肌病(DMRV)基因突变型。方法回顾性分析了中国DMRV一家系姐妹患者的临床、病理资料及其家系调查结果,对其GNE基因进行序列分析。结果一家系2代7人中有2例(均为第二代)发病,均为女性,青年晚期起病,首发症状为步态异常,四肢远端受累明显,股四头肌受累相对较轻;病情缓慢进展,发病后10年左右不能行走。主要病理改变为镶边空泡形成,肌浆或肌核内可见细丝状包涵体。2例患者突变位点相同,均为T1574C和C1943T复合杂合子突变,患者父亲携带单一C1943T点突变,其母亲和胞兄、胞姐均携带T1574C单一杂合子突变。结论中国DMRV一家系与日本人比较,其临床和病理改变一致。中国人DMRV患者也存在GNE基因复合杂合子突变,1574T→C为我们首次发现的致病性突变。     

Nonaka肌病临床病理及肌肉磁共振特点分析

目的探讨Nonaka肌病的临床、肌肉病理及肌肉磁共振特点。方法入选2例患者,女性1例,男性1例,临床表现均以双下肢远端肌肉无力、萎缩为主,双上肢仅轻度受累。血清肌酸激酶轻度升高,肌电图提示肌源性损害,神经传导速度均正常。对患者完善大腿及小腿肌肉磁共振检查,并予以左上肢肱二头肌活检,进行组织学、酶组织化学及免疫组织化学染色,抽取外周静脉血2mL送基因公司进行遗传性肌肉病相关基因测序。结果肌肉病理提示,肌纤维肥大、萎缩、再生,肌纤维内可见镶边空泡,符合肌病样病理改变。肌肉MRI提示,大腿股四头肌脂肪化程度较轻,尤其是股外侧肌未受累及,大腿后组肌群及小腿胫前肌、胫后肌脂肪化程度严重。基因结果均提示GNE基因突变。结论 Nonaka肌病是一种与GNE基因突变相关的常染色体隐性遗传性远端肌病,临床表现特点为胫前肌首先受累,而股四头肌早期不受累。病理改变特点为肌纤维内镶边空泡形成。肌肉MRI可提示肌肉脂肪化的程度及分布规律,为诊断提供依据。     

Oculopharyngeal muscular dystrophy and distal myopathy

A family is reported which included a patient with a variant form of oculopharyngeal muscular dystrophy. The patient's son suffered from infantile muscular dystrophy with a distal distribution in the lower extremities and no oculopharyngeal symptoms. Case 1, the father, showed blepharoptosis, but no limitation of ocular movements. Case 2, the son, showed early onset of weakness and more rapid progression of muscle involvement than the father. In both patients EMG, muscle biopsies and elevated serum CPK indicated the myopathic nature of the disorder. A muscle biopsy specimen in Case 2 showed abundant rimmed vacuoles and abnormal filaments 13–19 nm in diameter in the sarcoplasm, usually reported to occur in inclusion body myositis. The findings indicate that oculopharyngeal muscular dystrophy and distal myopathy are related in their etiology and distal myopathy and inclusion body myositis are regarded as variant forms of the same disease.     

Distal myopathy with rimmed vacuoles: clinical and muscle morphological characteristics and spectrum of GNE gene mutations in 53 Chinese patients

Abstract

Objectives: Distal myopathy with rimmed vacuoles (DMRV) is a typical autosomal recessive hereditary inclusion body myopathy, characterized by slowly progressive distal muscle weakness with relative sparing of the quadriceps. This study aimed to investigate the variability of clinical and morphological presentation and the spectrum of Glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase (GNE) mutations in Chinese DMRV patients.

Methods: We retrospectively reviewed the medical records of 37 patients with DMRV in PLA General Hospital from 1986 to 2011, and further conducted a review of 16 reported Chinese DMRV patients from other hospitals. We systematically analyzed the clinical, muscle morphological features and GNE gene mutation status of all DMRV patients.

Results: A total of 53 DMRV patients were studied. Fourteen cases had family history and other 39 cases were sporadic. Fifteen cases showed atypical pathological presentation as mononuclear cell invasion into necrotic or non-necrotic muscle fibers. Rare initial symptom, earlier age of onset and more dysmorphic presentations were shown in sporadic patients. Eighteen mutations in GNE gene were identified. c.317T>C (p.I106T) was a novel GNE gene mutation. c.1892C>T (p.A631V), c.527A>T (p.D176V) and c.1523T>C (p.L508S) were the common GNE mutations in Chinese DMRV patients.

Discussion: The clinical, pathological and genetic characteristics of DMRV are distinct in Chinese patients.     

Sarcoplasmic body myopathy--a rare hereditary myopathy with characteristic inclusions

OBJECTIVES: To characterise a Swedish family with a rare hereditary myopathy with unique sarcoplasmic inclusion bodies in the muscle biopsy. MATERIALS AND METHODS: Part of the pedigree was described in 1980. Nine new members of the included and the phenotype further characterised through clinical, neurophysiological and radiological investigations. RESULTS: Six of the nine subjects displayed clinical and/or laboratory evidence of myopathy with sarcoplasmic inclusions. CONCLUSIONS: Sarcoplasmic body myopathy is distinguished from other distal myopathies by a more malignant course and early involvement of thenar muscles and hand flexors. Five to ten years after onset the affected subjects develop distal, as well as proximal, weakness and atrophy and the majority require a wheelchair after ten to fifteen years of disease. The disorder is manifested through elevated creatine kinase levels and the presence of the pathognomonic sarcoplasmic inclusions prior to clinical signs and symptoms.     

Novel dysferlin mutations and characteristic muscle atrophy in late-onset Miyoshi myopathy

Miyoshi myopathy is characterized by weakness of the calf muscles during early adulthood. We report a case of late-onset Miyoshi myopathy presenting at 48 years of age, with novel mutations in the dysferlin gene. Muscle computed tomography clearly revealed severe atrophy in the soleus and medial gastrocnemius muscles. Even older patients with atrophy in the posterior compartment of the distal lower extremities and a relatively high serum creatine kinase level should be examined for the dysferlin gene.     

A novel mutation in PNPLA2 causes neutral lipid storage disease with myopathy and triglyceride deposit cardiomyovasculopathy: A case report and literature review

Mutations in PNPLA2 cause neutral lipid storage disease with myopathy (NLSDM) or triglyceride deposit cardiomyovasculopathy (TGCV). We report a 59-year-old patient with NLSDM/TGCV presenting marked asymmetric skeletal myopathy and cardiomyovasculopathy. Skeletal muscle and endomyocardial biopsies showed cytoplasmic vacuoles containing neutral lipid. Gene analysis revealed a novel homozygous mutation (c.576delC) in PNPLA2. We reviewed 37 genetically-proven NLSDM/TGCV cases; median age was 30 years; distribution of myopathy was proximal (69%) and distal predominant (16%); asymmetric myopathy (right > left) was reported in 41% of the patients. Frequently-affected muscles were posterior compartment of leg (75%), shoulder girdle to upper arm (50%), and paraspinal (33%). Skeletal muscle biopsies showed lipid accumulation in 100% and rimmed vacuoles in 22%. Frequent comorbidities were cardiomyopathy (44%), hyperlipidemia (23%), diabetes mellitus (24%), and pancreatitis (14%). PNPLA2 mutations concentrated in Exon 4–7 without apparent genotype-phenotype correlations. To know the characteristic features is essential for the early diagnosis of NLSDM/TGCV.     

GNE myopathy: A prospective natural history study of disease progression

Mutations in the glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase gene cause GNE myopathy, a mildly progressive autosomal recessive myopathy. We performed a prospective natural history study in 24 patients with GNE myopathy to select evaluation tools for use in upcoming clinical trials. Patient clinical conditions were evaluated at study entry and one-year follow-up. Of the 24 patients, eight (33.3%) completed a standard 6-min walk test without assistance. No cardiac events were observed. Summed manual muscle testing of 17 muscles, grip power, and percent force vital capacity (%FVC) were significantly reduced (p < 0.05), and scores for 6-min walk test and gross motor function measure were decreased (p < 0.1) after one year. The decrement in %FVC was significant among non-ambulant patients, whereas the decrement in grip power tended to be greater among ambulant patients. The 6-min walk test, gross motor function measure, manual muscle testing, grip power, and %FVC reflect annual changes and are thus considered good evaluation tools for clinical trials.     

Juvenile muscular atrophy of distal upper extremity associated with airway allergy: two cases successfully treated by plasma exchange

Juvenile muscular atrophy of the distal upper extremity (JMADUE) is postulated to be a type of flexion myelopathy. However, patients with typical clinical features of JMADUE but without evidence of flexion myelopathy have been reported. We recently reported a significant association of JMADUE with airway allergy. Here we report the successful treatment by plasma exchange (PE) of two patients with both airway allergy and JMADUE without evidence of flexion myelopathy. Patient 1 had a 5-year history of allergic rhinitis and high titers of mite antigen-specific IgE, and patient 2 had an 8-year history of pollinosis and high titers of cedar pollen-specific IgE. Both patients noted progressive distal muscle atrophy and weakness of the upper extremities: patient 1 for 3 months and patient 2 for 3 years. Neurologically, both showed asymmetric intrinsic hand muscle atrophy, oblique atrophy of the forearm muscles, and weakness and contraction fasciculation (minipolymyoclonus) of these muscles without any sensory impairment. Neither had any evidence of flexion myelopathy on magnetic resonance imaging (MRI) in a flexed position. Both were subjected to PE three times. Soon after the PEs, both showed improvement of distal muscle weakness of the upper extremities and marked reduction of contraction fasciculation of the forearm muscles. Patient 1 showed marked reduction in ongoing denervation potentials in the distal muscles on needle electromyography, while patient 2 showed marked improvement of F wave persistence of bilateral median and ulnar nerves. Serum total and allergen-specific IgE decreased after PEs in both patients. PE was thus considered to be effective in these two patients having JMADUE without evidence of flexion myelopathy. These observations may suggest the involvement of an immune-mediated process in the neural damage of JMADUE without evidence of flexion myelopathy, especially in patients with atopic diathesis, and may support the notion that JMADUE is etiologically heterogeneous.     

肌原纤维肌病的临床与病理学特征(附1例报告)

目的研究肌原纤维肌病的临床与病理学特征。方法回顾性分析1例肌原纤维肌病患者的临床和病理学资料。结果本例患者中年起病,表现为进行性四肢近端肌无力,有轻度肌萎缩。肌电图示:双下肢神经源性损害。病理检查示:大量肌纤维内含有胞浆体,偶见镶边空泡,含有胞浆体的肌纤维内,出现肌原纤维网结构紊乱及结蛋白异常沉积。结论肌原纤维肌病在临床表现上缺乏特异性,肌纤维内肌原纤维网结构紊乱,出现大量胞浆体及结蛋白异常沉积是其特征性病理改变。     

Novel GNE mutations in two phenotypically distinct HIBM2 patients

Homozygous mutations in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene cause hereditary inclusion body myopathy type 2 (HIBM2). We describe two unrelated American patients with novel GNE mutations. While one patient followed a typical disease course for HIBM2 with an onset at age 25 and rimmed vacuole pathology on muscle biopsy, the second patient had several features atypical for HIBM2. This patient’s onset was at age 55, included distal weakness, quadriceps sparing and respiratory insufficiency. His muscle biopsy showed prominent necrosis without rimmed vacuoles. This study expands the phenotype and illustrates the clinical spectrum of HIBM2 identified in a U.S. based neuromuscular clinic.     

The clinical and myopathological features of oculopharyngodistal myopathy in a Chinese family

Oculopharyngodistal myopathy is a rare type of hereditary myopathy characterised pathologically by the changes of muscular dystrophy with rimmed vacuoles and intra‐muscular tubulofilamentous inclusions. Here we report the clinical and myopathological changes in a Chinese family with oculopharyngodistal myopathy. The proband showed external ophthalmoplegia, dysphagia, distal weakness and atrophy in all extremities. Serum creatine kinase level was mildly elevated and a myopathic pattern with myotonic discharge was demonstrated by electromyography (EMG). Molecular genetic analysis showed that the number of trinucleotide repeat expansions in the polyadenylate‐binding protein nuclear 1 gene was within the normal limit. No mutations were indentified in the GNE gene. Five other persons with similar symptoms were found in the same generation. Muscle biopsy was performed on the tibialis anterior muscle in the proband. Muscular dystrophy changes with rimmed vacuoles were the main histopathological changes. Ultrastructural examination revealed numerous tubulofilamentous inclusions in both sarcoplasm and nucleus. EMG showed myotonic discharges in oculopharyngodistal myopathy. In addition to the sarcoplasm inclusions, we confirmed that tubulofilamentous inclusions appeared also in the nucleus.     

GNE myopathy in a Chinese male with a novel homozygous mutation

GNE myopathy is a rare autosomal recessive inheritance disease due to the mutation of GNE gene. To date, 107 mutations have been reported in different populations worldwide in GNE gene(HGMD Professional 2016.2). Here we report a patient of novel homozygous GNE gene mutation from China.     

A Case of GNE Myopathy Presenting a Rapid Deterioration during Pregnancy

Background

GNE myopathy is characterized by early-adult-onset distal myopathy sparing quadriceps caused by mutations in the GNE gene encoding UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase, an enzyme in the sialic-acid synthesis pathway.

Case Report

A 27-year-old Korean woman presented a rapid deterioration in strength of the distal lower limbs during her first pregnancy. She was diagnosed with GNE myopathy and carrying the compound heterozygous mutations of the GNE gene (D208N/M29T).

Conclusions

This is a representative case implying that an increased requirement of sialic acid during pregnancy might trigger a clinical worsening of GNE myopathy.     

Mutation analysis of the GNE gene in distal myopathy with rimmed vacuoles (DMRV) patients in Thailand

Distal myopathy with rimmed vacuoles (DMRV) is an early-adult-onset, distal myopathy caused by a mutation of the UDP-N-acetylglucosamine 2 epimerase/N-acetylmannosamine kinase (GNE) gene. We herein report four Thai patients with DMRV who carried compound heterozygous mutations of the GNE gene including three novel (p.G89R, p.P511T, and p.I656N) and two known mutations (p.A524V and p.V696M). All patients shared p.V696M in one allele. Our study demonstrates the mutation spectrum of the GNE gene in Thai patients with DMRV.