Weakness Of Distal Limb Muscles Research Articles

SIGMAR1 targets AMPK/ULK1 pathway to inhibit SH-SY5Y cell apoptosis by regulating endoplasmic reticulum stress and autophagy.

Distal hereditary motor neuropathy (dHMN) is a progressive neurological disease characterized by distal limb muscle weakness and amyotrophy. Sigma 1 receptor (σ1R), a gene product of SIGMAR1, mutations have been reported to induce dHMN, but its mechanism remains unknown. This study aims to explore the effect of C238T and 31_50del mutations in σ1R on neuronal SH-SY5Y cell functions. The SH-SY5Y cells that overexpressed σ1R, C238T mutant σ1R (σ1RC238T) or 31_50del mutant σ1R (σ1R31_50del) were constructed by pEGFPN1 vectors. We used Western blot (WB) and immunofluorescence (IF) staining to detect the expression of σ1R and green fluorescent proteins (GFP). Then, we evaluated the impact of σ1R mutation on apoptosis, autophagy, endoplasmic reticulum stress, and the involvement of the unfolded protein response (UPR) pathway in SH-SY5Y cells. We found that σ1RC238T and σ1R31_50del downregulated σ1R and promoted the apoptosis of SH-SY5Y cells. σ1RC238T and σ1R31_50del increased p-PERK, p-eIF2α, p-JNK, BIP, ATF4, CHOP, ATF6, XBP1, Caspase3, Caspase12 expressions and Ca2+ concentration, whereas decreased ATP content in SH-SY5Y cells. Besides, the expressions of LC3B, Lamp1, ATG7, Beclin-1 and phosphorylation of AMPK and ULK1 were increased, while the p62 level decreased after C238T or 31_50del mutation of σ1R. Additionally, AMPK knockdown abolished the apoptosis mediated by σ1RC238T or σ1R31_50del in SH-SY5Y cells. Our results indicated that C238T or 31_50del mutation in σ1R promoted motor neuron apoptosis through the AMPK/ULK1 pathway in dHMN. This study shed light on a better understanding of the neurons pathological mechanisms mediated by σ1R C238T and σ1R 31-50del in dHMN.

A novel nonsense variant in the ATL3 gene is associated with disturbed pain sensitivity, numbness of distal limbs and muscle weakness.

Introduction Hereditary sensory neuropathy (HSN) describes as a heterogeneous group of peripheral neuropathies. HSN type 1 (HSN1) is one subtype characterized by distal sensory impairment that occurs in the form of numbness, tingling, or pain. To date, only two variants in the atlastin GTPase 3 (ATL3) gene have been identified that result in hereditary sensory neuropathy type 1F (HSN1F) with autosomal dominantinheritance. Methods We sudied and examined who present with sensory disturbances and muscle weakness in their lower limb. Patients underwent Whole Exome Sequencing and Sanger sequencing was performed in families for validation of detected variant. Results Here, we identified two Iranian families carrying the novel heterozygous stop variant NM_015459.5: c.16C>T, p.Arg6Ter in ATL3 that led to disturbed pain and touch sensitivity. This variant in the ATL3 gene was detected in both families (NM_015459.5: c.16C>T, p.Arg6Ter) by whole-exome sequencing and confirmed by Sanger sequencing. Conclusion In this study, the subjects manifested weakness of distal limb muscles and numbness of the lower extremities. In addition, some unusual features, including hearing problems and inability to sit and walk presented in one of the patients. Eventually, we provide a case-based review of the clinical features associated with HSN1F. Hitherto, only 11 patients with HSN1F have been reported. We compared our findings to previously reported cases, suggesting that the clinical features are generally variable in the HSN1F patients.

Oculopharyngodistal myopathy.

Oculopharyngodistal myopathy (OPDM) is a rare adolescent or adult-onset neuromuscular disease that is characterized by progressive ocular, facial, pharyngeal and distal limb muscle weakness. The rimmed vacuoles and intranuclear inclusions in myofibers constitute the pathological hallmark of OPDM. In this review, the latest findings related to the genetic, molecular and clinical features of OPDM, as well as the diagnosis and management are summarized. Four gene mutations, CGG repeats in the 5'-untranslated region of LRP12 , GIPC1 , NOTCH2NLC and RILPL1 have been reported to be disease-causing genes in OPDM, namely OPDM1, OPDM2, OPDM3 and OPDM4, accordingly. So far, limited studies have suggested that CGG repeat expansion within the pathogenic range may play a key role in the pathogenesis of OPDM with the gain-of-function mechanism at the RNA and/or protein level, while repeat expansion over a threshold limit may cause hypermethylation, leading to the transcriptional silencing of the CGG repeats in the expanded allele, which results in the existence of mild phenotype or asymptomatic carriers. Novel gene mutations, possible molecular mechanisms and the clinical features related to different causative genes are discussed in this review. More studies on the exact pathogenic mechanism are needed.

Juvenile-Onset Relapsing Chronic Inflammatory Demyelinating Polyradiculoneuropathy: A Case Report

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired, immune-mediated condition. It is a symmetric, motor-predominant neuropathy that results in both proximal and distal limb muscle weakness and is characterized by electrodiagnostic or pathologic features of demyelination. CIDP is a treatable disease that is known to be rare in the pediatric population. This case report describes a 12-year-old female who presented with gait disturbance and progressive upper and lower limb weakness. The electrophysiologic findings were compatible with demyelinating polyneuropathy. Combined with the clinical features, the diagnosis of CIDP was made and treatment was administered. The first-line immunomodulatory treatment seemed to be effective, as shown by improvements in electrophysiologic and clinical parameters, but the relapsing-remitting clinical course required additional immunomodulatory treatment. Herein, we describe the patient’s clinical and electrophysiologic course according to the treatment. Keywords: Child; Polyradiculoneuropathy, chronic inflammatory demyelinating; Electrodiagnosis

CONGENITAL MYOPATHIES: NEMALINE AND TITINOPATHIES: P.236Congenital fiber type disproportion with mutations in tropomyosin 3 (TPM3) gene presenting as respiratory failure

Congenital fiber type disproportion(CFTD) is a rare subtype of congenital myopathy. CFTD is clinically heterogenous and histologically marked by hypotrophy of type I fibers compared with type 2 fibers. CFTD has been related with mutations in ACTA1, SEPN1, RYR1 and TPM3 genes. Particularly, TPM3 mutation was identified to the most frequent cause of CFTD and was also detected in cap myopathy and nemaline myopathy. We report autosomal dominant TPM3 missense mutations with CFTD in a family over two-generations. The two patients, the brother and sister, experienced first symptoms of muscle weakness in infancy with delayed motor milestones and followed a slowly progressive course. They presented generalized muscular hypotrophy, neck flexor muscle and distal limb muscle weakness, elongated face, retrognathia, high arched palate and scoliosis. Respiratory function became critical in two patients despite relatively good limb strength. The brother presented in respiratory arrest during sleep. The sister did not complain of difficulty on walking and climbing stairs but presented in respiratory failure needing ventilator. The finding of electromyography was compatible with myopathy and muscle biopsy showed type 1 fiber atrophy with predominance in the absence of other notable pathological findings such as nemaline rods and cap structures. TPM3 missense mutation c.502C>T (p.R168C) in exon 5 was identified by a target NGS. We confirmed CFTD caused by TPM3 mutation in this family. CFTD patients with mutation in TPM3 have been previously reported that many patients required nocturnal noninvasive ventilatory support despite remaining ambulant and several patients of these abruptly presented in respiratory failure. All patients in our family also showed sudden respiratory failure with relatively spared limb weakness. Therefore, it is clinically important for monitoring respiratory function regularly in CFTD patients with TPM3 mutation.

Truncating SLC5A7 mutations underlie a spectrum of dominant hereditary motor neuropathies.

ObjectiveTo identify the genetic cause of disease in 2 previously unreported families with forms of distal hereditary motor neuropathies (dHMNs).MethodsThe first family comprises individuals affected by dHMN type V, which lacks the cardinal clinical feature of vocal cord paralysis characteristic of dHMN-VII observed in the second family. Next-generation sequencing was performed on the proband of each family. Variants were annotated and filtered, initially focusing on genes associated with neuropathy. Candidate variants were further investigated and confirmed by dideoxy sequence analysis and cosegregation studies. Thorough patient phenotyping was completed, comprising clinical history, examination, and neurologic investigation.ResultsdHMNs are a heterogeneous group of peripheral motor neuron disorders characterized by length-dependent neuropathy and progressive distal limb muscle weakness and wasting. We previously reported a dominant-negative frameshift mutation located in the concluding exon of the SLC5A7 gene encoding the choline transporter (CHT), leading to protein truncation, as the likely cause of dominantly-inherited dHMN-VII in an extended UK family. In this study, our genetic studies identified distinct heterozygous frameshift mutations located in the last coding exon of SLC5A7, predicted to result in the truncation of the CHT C-terminus, as the likely cause of the condition in each family.ConclusionsThis study corroborates C-terminal CHT truncation as a cause of autosomal dominant dHMN, confirming upper limb predominating over lower limb involvement, and broadening the clinical spectrum arising from CHT malfunction.

Observation of clinical and electrophysiological features in patients with distal myasthenia gravis

Objective: To explore the clinical and electrophysiological features and prognosis of distal myasthenia gravis (MG). Methods: Data of MG patients in Beijing Tiantan Hospital from October 2016 to March 2017 were reviewed, including thorough neurological examinations, nerve conduction studies, repetitive nerve stimulations (RNS) and needle electromyographies. Distal MG patients were included and were analyzed as to their clinical and electrophysiological features and response to treatments. Results: Four patients (7.7%) could be classified as distal type among 52 definitely diagnosed MG patients. They had initial symptoms at age 36 to 64 and developed distal limb muscle weakness in the first month to 6 years after the onset of this disease. Hand muscles were preferentially involved in a non-uniform way. And one patient also had leg weakness on his tibialis anterior muscles. RNS showed a more significant decrement at slow rates in distal muscles, compared with proximal muscles. The baseline compound muscle action potentials (CMAP) of the distal affected muscles presented with slightly decreased or fluctuating amplitudes. Their weakness of ocular, bulbar, proximal and distal limb muscles improved generally after administration of acetylcholinesterase inhibitors or steroids plus acetylcholinesterase inhibitors. Electrophysiological reexaminations revealed increased baseline CMAPs, reduced decrement on RNS, and relief of myogenic changes on needle electromyography. Conclusions: Relatively prominent distal limb muscle weakness can be found in a minority of MG patients. Besides profound decrement on slow rate RNS, the involved distal muscles may have a characteristic decreased baseline CMAP, sometimes with a diurnal fluctuation. Distal MG responds well to regular treatments. Its short-term prognosis seems similar to that of common MG with proximal predominance.

Characteristic involvement of muscle ultrasound in myotonic dystrophy type 1

Background: In myotonic dystrophy type 1 (DM1), predominant weakness of distal limb muscles affects quality of life. Non-invasive evaluation of muscular involvement by muscle sonography by ultrasound could be useful for characterizing muscle-specific involvement.

A novel missense variant (Gln220Arg) of GNB4 encoding guanine nucleotide-binding protein, subunit beta-4 in a Japanese family with autosomal dominant motor and sensory neuropathy

Dominant intermediate Charcot–Marie–Tooth disease F (CMTDIF) is an autosomal dominant hereditary form of Charcot–Marie–Tooth disease (CMT) caused by variations in the guanine nucleotide-binding protein, subunit beta-4 gene (GNB4). We examined two Japanese familial cases with CMT. Case 1 was a 49-year-old male whose chief complaint was slowly progressive gait disturbance and limb dysesthesia that appeared at the age of 47. On neurological examination, he showed hyporeflexia or areflexia, distal limb muscle weakness, and distal sensory impairment with lower dominancy. Nerve conduction studies demonstrated demyelinating sensorimotor neuropathy with reduced action potentials in the lower limbs. Case 2 was an 80-year-old man, Case 1's father, who reported difficulty in riding a bicycle at the age of 76. On neurological examination, he showed areflexia in the upper and lower limbs. Distal sensory impairment in the lower limbs was also observed. Nerve conduction studies revealed mainly axonal involvement. Exome sequencing identified a novel heterozygous nonsynonymous variant (NM_021629.3:c.659T > C [p.Gln220Arg]) in GNB4 exon 8, which is known to be responsible for CMT. Sanger sequencing confirmed that both patients are heterozygous for the variation, which causes an amino acid substitution, Gln220Arg, in the highly conserved region of the WD40 domain of GNB4. The frequency of this variant in the Exome Aggregation Consortium Database was 0.000008247, and we confirmed its absence in 502 Japanese control subjects. We conclude that this novel GNB4 variant is causative for CMTDIF in these patients, who represent the first record of the disease in the Japanese population.

A recurrent WARS mutation is a novel cause of autosomal dominant distal hereditary motor neuropathy.

Distal hereditary motor neuropathy is a heterogeneous group of inherited neuropathies characterized by distal limb muscle weakness and atrophy. Although at least 15 genes have been implicated in distal hereditary motor neuropathy, the genetic causes remain elusive in many families. To identify an additional causal gene for distal hereditary motor neuropathy, we performed exome sequencing for two affected individuals and two unaffected members in a Taiwanese family with an autosomal dominant distal hereditary motor neuropathy in which mutations in common distal hereditary motor neuropathy-implicated genes had been excluded. The exome sequencing revealed a heterozygous mutation, c.770A > G (p.His257Arg), in the cytoplasmic tryptophanyl-tRNA synthetase (TrpRS) gene (WARS) that co-segregates with the neuropathy in the family. Further analyses of WARS in an additional 79 Taiwanese pedigrees with inherited neuropathies and 163 index cases from Australian, European, and Korean distal hereditary motor neuropathy families identified the same mutation in another Taiwanese distal hereditary motor neuropathy pedigree with different ancestries and one additional Belgian distal hereditary motor neuropathy family of Caucasian origin. Cell transfection studies demonstrated a dominant-negative effect of the p.His257Arg mutation on aminoacylation activity of TrpRS, which subsequently compromised protein synthesis and reduced cell viability. His257Arg TrpRS also inhibited neurite outgrowth and led to neurite degeneration in the neuronal cell lines and rat motor neurons. Further in vitro analyses showed that the WARS mutation could potentiate the angiostatic activities of TrpRS by enhancing its interaction with vascular endothelial-cadherin. Taken together, these findings establish WARS as a gene whose mutations may cause distal hereditary motor neuropathy and alter canonical and non-canonical functions of TrpRS.

Preferential changes of skeletal muscle echogenicity in myotonic dystrophy type 1.

In myotonic dystrophy type 1 (DM1), weakness of distal limb muscles affects quality of life. Non-invasive evaluation of muscular involvement by muscle sonography could be useful for characterizing muscle-specific involvement. Sonography of the lower leg and forearm was performed in 19 patients with DM1 and 10 control subjects. The mean echo intensities (EIs) of seven limb muscles were obtained by computer-assisted histogram analysis and compared within DM1 according to the overall clinical severity. The EIs of the muscles were significantly higher in DM1 than in the controls (P < 0.01), except for the soleus (P = 0.4). Comparison of adjacent muscles showed the following: (i) greater EIs in flexor digitorum profundus than flexor carpi ulnaris (P < 0.01) and flexor digitorum superficialis (P = 0.02), and (ii) greater EIs in the medial head of the gastrocnemius than the soleus (P < 0.00001). In a subgroup analysis of DM1 according to the modified Rankin Scale (mRS), the more severe subgroup (mRS = 4-5) had lower mean EIs than the less severe subgroup (mRS from 1-3) (P = 0.01) in the flexor digitorum superficialis but not in other muscles. Preferential high echogenicity in the medial gastrocnemius and deep finger flexors is suggestive of DM1. Muscle echogenicity is not generally related to functional dysfunction in DM1.

EP 40. Gynecomastia – A sign of a neuromuscular disease?

Objective The aim of a neurological examination is to narrow down by signs and symptoms which components of the neurological system are affected. In neuromuscular diseases non-neurological signs such as gynecomastia can be a valuable hint. Gynecomastia is defined as excess glandular growth of breast tissue in males, pathologically associated e.g. with testicular neoplasms or gonadal dysfunction [1,2]. However there are also neuromuscular diseases such as spinal and bulbar muscular atrophy, myofibrillar myopathies and thyrotoxic hypokalemic periodic paralysispresenting with gynecomastia, we herby want to summarize. Methods A systematic PubMed literature search was carried out by application of the search terms “spinal and bulbar muscular atrophy”, “Kennedy’s disease”, “gynecomastia neuromuscular disease”, “myopathy gynecomastia”. Additionally, references in these articles were searched for further papers suitable to be included. Results Spinal and bulbar muscular atrophy (Kennedy’s disease, SBMA) is a slowly progressive adult onset neurodegenerative disorder, characterized by proximal muscle weakness and atrophy of the extremity and bulbar muscles, due to loss of lower motor neurons in the spinal cord and brainstem. It is caused by the expansion of a CAG repeat in the androgen receptor gene on the X Chromosome [3–6]. The length of the CAG expansion correlates inversely with age of disease onset and disease severity [7]. Up to 78% of patients present with gynecomastia due to partial androgen insensitivity [5,8]. Desminopathies and Alpha-B crystallinopathies belong to the myofibrillar myopathies (MFM), a group of neuromuscular disorders, characterized by desmin-positive protein aggregations in muscle fibres and myofibrillar degeneration. They are caused by mutations in genes encoding for extramyofibrillar proteins (desmin (DES) and αB-crystallin (CRYAB)) [9,10]. Desminopathiesdue to a variety of human desmin gene mutations on chromosome 2q35 cause different myopathy phenotypes, cardiac diseases and respiratory insufficiency [11,12]. DES mutation (R350P) leads to a variability of clinical manifestation ranging from scapuloperoneal, limb girdle and distal phenotypes. Gynecomastia can be observed [13]. Alpha-B crystallinopathy due to mutations in the CRYAB gene presents with proximal and distal limb muscle weakness often associated with neck, trunk, and palatopharyngeal muscle involvement, cardiomyopathy and pulmonary insufficiency. Alpha-B Crystallin is a chaperone stabilizing desmin molecule by preventing its aggregation [14,12]. Missense mutation p.Gly154Ser of CRYAB gene is associated with a late-onset distal vacuolar myopathy with protein aggregates. Mild gynecomastia can be present [15]. Thyrotoxic, hypokalemic periodic paralysis (THPP): Periodic paralysis associated with hyperthyroidism and hypokalemia is an uncommon disorder reported primarily in Asian males [1]. It is characterized by muscle paralysis and hypokalemia. Proximal muscles are more severely affected than distal muscles [17,18] Uni- or bilateral gynecomastia can be a symptom even prior to the onset of paralysis [18,19]. Conclusion There is a limited range of neuromuscular disease associated with gynecomastia. Looking carefully at your patient whilst examination and noticing symptoms other than neurological symptoms can speed up to find the correct diagnosis, especially SBMA. Finally, most important, breast cancer has to be excluded, as there is an incidence of up to 2% in men.

Clinical and muscle imaging findings in 14 mainland chinese patients with oculopharyngodistal myopathy.

Oculopharyngodistal myopathy (OPDM) is an extremely rare, adult-onset hereditary muscular disease characterized by progressive external ocular, pharyngeal, and distal muscle weakness and myopathological rimmed vacuole changes. The causative gene is currently unknown; therefore, diagnosis of OPDM is based on clinical and histopathological features and genetic exclusion of similar conditions. Moreover, variable manifestations of this disorder are reported in terms of muscle involvement and severity. We present the clinical profile and magnetic resonance imaging (MRI) changes of lower limb muscles in 14 mainland Chinese patients with OPDM, emphasizing the role of muscle MRI in disease identification and differential diagnosis. The patients came from 10 unrelated families and presented with progressive external ocular, laryngopharyngeal, facial, distal limb muscle weakness that had been present since early adulthood. Serum creatine kinase was mildly to moderately elevated. Electromyography revealed myogenic changes with inconsistent myotonic discharge. The respiratory function test revealed subclinical respiratory muscle involvement. Myopathological findings showed rimmed vacuoles with varying degrees of muscular dystrophic changes. All known genes responsible for distal and myofibrillar myopathies, vacuolar myopathies, and muscular dystrophies were excluded by PCR or targeted next-generation sequencing. Muscle MRI revealed that the distal lower legs had more severe fatty replacement than the thigh muscles. Serious involvement of the soleus and long head of the biceps femoris was observed in all patients, whereas the popliteus, gracilis and short head of biceps femoris were almost completely spared, even in advanced stages. Not only does our study widen the spectrum of OPDM in China, but it also demonstrates that OPDM has a specific pattern of muscle involvement that may provide valuable information for its differential diagnosis and show further evidence supporting the conclusion that OPDM is a unique disease phenotype.

P82 - Biomarkers research in neuromuscular disease Charcot-Marie-Tooth

Charcot-Marie-Tooth disease (CMT) (ORPHA166) is the most frequent hereditary neuropathy. CMT is a heterogeneous group of disorders which, despite some variability in their clinical features, share the same general phenotype, usually characterized by wasting and weakness of distal limb muscles, decreased to absent deep tendon reflexes, distal sensory loss, and frequent skeletal deformities. Despite the clinical and molecular description of this disease in the last 20 years, there is no effective drug or advanced therapy available. Here we have pretend the identification of metabolic and oxidative stress biomarkers in plasmas from patients with duplication at PMP22 gene, the most frequent mutation causing CMT, and clinically characterized as CMT1A. The samples were collected in the neuropathy units from “La Fe” Hospital of Valencia, “Bellvitge” Hospital of Barcelona, “La Paz” Hospital of Madrid, and “Virgen del Rocío” Hospital of Sevilla. The metabolic biomarkers research was performed using 2D-DIGE analysis (Typhoon TRIO, GE) and DeCyder software (GE). Protein identification was made by mass spectrometry by MALDI-TOF-TOF (ABSciex) and liquid Chromatography analysis (ABSciex). The oxidative stress biomarkers research consisted in carbonylated proteins analysis by reaction with DNPH and Dot-blot. Total antioxidant capacity and GSSG/GSH ratio were analyzed with Antioxidant Assay kit (Cayman) and Glutathione Fluorescent detection Kit (Arbor Assays), respectively. Finally now we are performing the MDA levels by HPLC-UV.We found 8, 13 and 36 proteins with differential expression in mild, moderate and severely affected patients, respectively compared with their own matched controls. Also we found differences on oxidative stress parameters between de different groups analyzed. Our results suggest differences in the oxidative stress profile between the studied phenotypes in CMT1A patients.

G.P.59: Muscle pathology as a diagnostic clue to Allgrove syndrome

Allgrove or triple A syndrome is an autosomal-recessive disorder caused by mutations in the AAAS gene, coding for the nucleoporin ALADIN. While the eponymous combination of Achalasia, Addisonianism and Alacrimia seems hard to miss, these cases are a diagnostic challenge when this trias is incomplete and other neurological signs from a broad range of associated symptoms predominate. This was the case with a 15year old boy from a consanguineous family suffering from progressive distal limb muscle weakness and atrophy as well as mild learning disability, whose muscle and sural nerve biopsy samples we received. No abnormalities of the sural nerve were found, but the gastrocnemius muscle sample showed considerable fatty replacement, increased endo- and perimysial connective tissue, rounded fibre profiles, increased fibre size variability, increased internalised myonuclei and nuclear clumps, numerous degenerating and some regenerating fibres, massive fibre splitting and many whirled fibres as well as some rimmed vacuoles, few target fibres, but more frequent targetoid/ core-like lesions. Conspicuous nuclear inclusions in electron microscopy and particularly reduced immunoreactivity with an antibody against lamin A/C led us to suspect a nuclear pathology. When he developed dysphagia due to achalasia, sequencing of the AAAS gene was initiated, revealing homozygous c.762delC mutations in exon 8 leading to a premature stop of translation due to frameshift (p.S255V fs ∗ 35). Adrenal deficiency and autonomic dysfunction can result in life threatening situations for these patients, but can be addressed by symptomatic medication. Thus making the diagnosis in time is important. Triple A syndrome with its variable, multi-system symptoms including optic atrophy, cerebellar ataxia, upper and lower motoneuron signs and various neuropathic presentations is a differential diagnosis for mixed pathologies with signs of nuclear changes that myopathologists need to be aware of.

Mitofusin 2 gene mutation causing early-onset CMT2A with different progressive courses

Charcot-Marie-Tooth disease Type 2A2 (CMT2A2), caused by mitofusin 2 (MFN2) genes, has been clinically classified into two types: severe early-onset and mild benign. Here we reported 3 early onset patients with different progressive courses. The 3 patients had mutations R94W, R364W and a novel W740R in the MFN2 gene. Two patients presented with progressive distal limb muscle weakness and wasting from the ages of 5 and 6 years, respectively. The disease developed slowly, with loss of ambulation after 35 years of age. The third patient presented with similar symptoms after birth, and has never been able to walk independently. Sural nerve biopsies revealed severe axonal neuropathy with mitochondrial aggregation in axons. Our data confirmed that early-onset CMT2A2 can present with different courses in Chinese patients. The novel mutation in MFN2 found in this study broadens the genotypic spectrum associated with MFN2 related CMT.

Oculopharyngodistal myopathy – A possible association with cardiomyopathy

Oculopharyngodistal myopathy is an uncommon myopathy characterised clinically by cranial and distal limb muscle weakness. Here we describe two siblings with autosomal dominant oculopharyngodistal myopathy apparently associated with dilated cardiomyopathy, which in one case progressed to ventricular hypertrabeculation/non-compaction. Electrocardiographic screening was normal and the cardiomyopathy was detected only with echocardiography. Our findings suggest that patients with oculopharyngodistal myopathy should be screened for cardiomyopathy (with both electrocardiography and echocardiography).

P2.15 Oculopharyngodistal myopathy – a possible association with cardiomyopathy

Oculopharyngodistal myopathy (OPDM) is an uncommon myopathy characterised clinically by cranial and distal limb muscle weakness. Here we describe two siblings with autosomal dominant OPDM apparently associated with dilated cardiomyopathy, which in one case progressed to ventricular hypertrabeculation/non-compaction. Electrocardiographic screening was normal and the cardiomyopathy was detected only with echocardiography. Our findings suggest that patients with OPDM should be screened for cardiomyopathy (with both electrocardiography and echocardiography). Consideration should also be given to screening asymptomatic relatives.

ABNORMAL EYE MOVEMENTS IN KENNEDY DISEASE

Kennedy disease, also known as spinal and bulbar muscular atrophy, is a neurodegenerative disease affecting lower motor neurons.1 The underlying genetic abnormality, a triplet (CAG) repeat expansion in the androgen receptor gene on the X chromosome, produces a toxic polyglutamine expansion in the androgen receptor protein.2 The disease is characterized by slowly progressive proximal muscle atrophy, weakness, and fasciculations, with prominent bulbar involvement, tremor, and, reportedly, sparing of eye movements.1,3,4 Stigmata of androgen insufficiency, such as gynecomastia, may be present.3 We report a patient with genetically confirmed Kennedy disease who had abnormal eye movements. ### Case report. A 58-year-old Caucasian man with a history of dyslipidemia and bilateral retinal detachments presented with progressive onset of proximal muscle atrophy, weakness, fasciculations, and tremor over 20 years. He also reported a progressive decline in mobility and fine motor control, as well as dysarthria and dysphagia. He denied sensory symptoms, sphincter disturbance, or visual symptoms, such as diplopia. On examination, there was atrophy of facial, bulbar, and limb muscles. Perioral, tongue, and limb muscle fasciculations were noted. There was moderate weakness of facial, palatal, tongue, and proximal limb muscles, with milder weakness of distal limb muscles. The reflexes were depressed and the plantar responses flexor. There were no cerebellar signs. Mild distal sensory loss was noted in the lower limbs. Visual acuity and color vision were within normal limits. Visual fields were full to confrontation. There was no optic atrophy, and his pupillary responses were normal. Ocular motor examination revealed a small exophoria, no …

Myofibrillar myopathies

The aim of this communication is to provide an up-to-date overview of myofibrillar myopathies. The most important recent advance in the myofibrillar myopathies has been the discovery that mutations in Z band alternatively spliced PDZ-containing protein and filamin C, as well as in desmin, alphaB-crystallin and myotilin, result in similar pathologic alterations in skeletal muscle that are typical of myofibrillar myopathy. Despite the increasing genetic heterogeneity, the clinical and morphologic phenotypes are remarkably homogeneous. The typical clinical manifestation is slowly progressive proximal, distal or both proximal and distal limb muscle weakness. Cardiomyopathy can be associated and is sometimes the presenting finding. Peripheral neuropathy also occurs in some patients. In every myofibrillar myopathy, there is abnormal accumulation of an array of proteins at ectopic sites as well as accumulation of degraded myofibrillar proteins forming large aggregates. The key issue now is to analyze the molecular mechanisms underlying the cascade of events that destroy the myofibrillar architecture and trigger the aberrant expression of multiple proteins. Several disease genes have recently been recognized in myofibrillar myopathies. So far, the disease proteins identified are components of or chaperone for the Z-disk. In each case, the molecular defect leads to a stereotyped cascade of structural events in the muscle fiber.