Distal Leg Muscles Research Articles

Whole-Body muscle MRI in a series of patients with congenital myopathy related to TPM2 gene mutations

Beta-tropomyosin 2 (TPM2) gene mutations are a rare cause of congenital myopathy with variable clinical and histological features. We describe muscle involvement using Whole-Body muscle Magnetic Resonance Imaging (WBMRI) in 8 individuals with genetically proven TPM2 mutations and different clinical and histological features (nemaline myopathy, 'cap disease', Bethlem-like phenotype, arthrogryposis). Most patients shared a recognizable MRI pattern with the involvement of masticatory and distal lower leg muscles. The lower leg showed constant soleus muscle involvement, and often also involvement of peroneus, tibialis anterior, and toe flexor muscles. Pelvic and shoulder girdles, and upper limbs muscles were quite spared. Two adult subjects (a patient and a paucisymptomatic parent) had a more diffuse involvement with striking fat infiltration of the rectus femoris muscle. Two children showed variant findings: one presented with masseter involvement associated with severe axial fat infiltration, the second had masticatory and distal leg muscle involvement (soleus and gastrocnemius muscles). Our study suggests that, independently of the clinical and histological presentation, most patients with TPM2 mutations show a predominant involvement of masticatory and distal leg muscles with the other regions relatively spared. More spread involvement may be observed. This cephalic-distal MRI pattern is not frequent in other known myopathies.

G.P.86 X-linked Charcot–Marie–Tooth disease with c.22A>C missense mutation in the GJB1 gene in Koreans

<h2>Abstract</h2> X-linked Charcot–Marie–Tooth disease (CMT1X) is caused by gap junction beta 1 (GJB1) gene mutations, which encodes the connexin 32. Connexin 32 is an integral transmembrane protein expressed in peripheral nerve myelin. The frequency of CMT1X varies among different ethnic groups. The frequency in Koreans is low compared with those in Europeans. Herein we present one CMT1X patient with missense mutation in the GJB1 gene. The 27-year-old male presented with complaints of slowly progressive weakness beginning in the distal leg muscles. He had walked with waddling gait ever since he had started walking at 2years of age. He felt a weak hand grip around 8years of age. He could not run and have numbness on toe tips after 18years old. The family history revealed a more severe disease phenotype in affected males compared with affected females. Physical examination showed pes cavus, wasting of muscles below knee, and intrinsic hand muscle atrophy. Neurological examination demonstrated predominantly distal muscle weakness in the lower and upper limbs, decreased pinprick sensation in stocking-glove pattern, and areflexia. Electrophysiological study revealed sensori-motor polyneuropathy, but did not suggest sufficient evidence of demyelination or axonal degeneration. Gene analysis identified c.22A>C Missense Mutation in the GJB1 gene. We report a CMT1X patient having typical X-linked dominant inheritance and missense mutation in the GJB1 gene.

The first Italian patient with oculopharyngodistal myopathy: Case report and considerations on differential diagnosis

Oculopharyngodistal myopathy is a clinicopathologically distinct muscular disease. The underlying genetic defect has not been identified. We report here a 43-year old woman with asymmetric bilateral ptosis, dysphonia, swallowing difficulties, and weakness of the distal leg muscles. Serum creatine kinase was moderately increased. Electromyography revealed myopathic changes and myotonic discharges. Both cardiologic and pneumologic evaluation did not reveal abnormalities. Muscle computed tomography images showed adipose tissue replacement of abdominis rectus, lateral vastus, adductor magnus, and both the posterior and anterior compartment muscles below the knee, with prevalent involvement of medial gastrocnemius muscle. Muscle biopsy uncovered changes in fiber size and the presence of atrophic fibers with rimmed vacuoles of varying diameter, and core-like structures in type I fibers.Diagnosis was performed according to clinical and histopathologic findings, which were fully consistent with the other reported patients, and on the genetic exclusion of similar conditions such as oculopharyngeal muscular dystrophy, myotonic dystrophy type 1 and multi-minicore disease associated to RYR1 mutations. Differential diagnosis with mitochondrial myopathies, facioscapulohumeral muscular dystrophy and distal myopathies was also considered. This is the first Italian case of oculopharyngodistal myopathy, further suggesting the worldwide distribution of this rare neuromuscular disorder.

Aquaporin-4 expression in distal myopathy with rimmed vacuoles

BackgroundDistal myopathy with rimmed vacuoles/hereditary inclusion body myopathy is clinically characterized by the early involvement of distal leg muscles. The striking pathological features of the myopathy are muscle fibers with rimmed vacuoles. To date, the role of aquaporin-4 water channel in distal myopathy with rimmed vacuoles/hereditary inclusion body myopathy has not been studied.Case presentationHere, we studied the expression of aquaporin-4 in muscle fibers of a patient with distal myopathy with rimmed vacuoles/hereditary inclusion body myopathy. Immunohistochemical and immunofluorescence analyses showed that sarcolemmal aquaporin-4 immunoreactivity was reduced in many muscle fibers of the patient. However, the intensity of aquaporin-4 staining was markedly increased at rimmed vacuoles or its surrounding areas and in some muscle fibers. The fast-twitch type 2 fibers were predominantly involved with the strong aquaporin-4-positive rimmed vacuoles and TAR-DNA-binding protein-43 aggregations. Rimmed vacuoles with strong aquaporin-4 expression seen in the distal myopathy with rimmed vacuoles/hereditary inclusion body myopathy patient were not found in control muscles without evidence of neuromuscular disorders and the other disease-controls.ConclusionsAquaporin-4 might be crucial in determining the survival or degeneration of fast-twitch type 2 fibers in distal myopathy with rimmed vacuoles/hereditary inclusion body myopathy.

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.

P2.64 Muscle imaging in hereditary inclusion-body myopathy

Hereditary inclusion-body myopathy or distal myopathy with rimmed vacuoles (h-IBM/DMRV) is an autosomal recessive muscle disease caused by mutations in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene. Along with the typical phenotype, characterized by the involvement of distal leg muscles starting in early adulthood and quadriceps sparing, uncommon presentations with non-canonical phenotype and unusual muscle biopsy findings are increasingly recognized. The aim of our study was to characterize pelvic and lower limb muscle involvement in h-IBM, thus providing clues for the diagnosis especially in the presence of atypical clinical or pathological features.

Poster 75 The Importance of Electrodiagnostic Medicine in Diagnosing Compression Neuropathy of the Posterior Tibial Nerve Secondary to a Ganglion Cyst: A Case Report

treated with dilation and curettage. She had generalized weakness, which at the time contributed to dehydration and electrolyte imbalance. The patient was later readmitted for progressive generalized weakness and an inability to ambulate. Ultrasound revealed retained fetal products. Results of an initial physical examination revealed proximal lower extremity weakness and areflexia without sensory deficit. Setting: A tertiary hospital. Results: Initial nerve conduction studies revealed decreased motor amplitudes in the legs, with relatively preserved sensory responses. The motor and sensory studies in the arms were normal. Initial electromyography showed acute denervation and loss of motor units in proximal lower extremity muscles. Acute denervation was also seen in distal leg muscles. The upper extremities or lumbar paraspinals were electrically normal. Subsequent nerve conduction studies revealed a loss of motor and sensory responses in both arms and legs. Repeated electromyography reflected a similar denervation pattern in the upper extremities. She was diagnosed with acute motor and sensory axonal neuropathy subtype of Guillain-Barre syndrome (GBS). The patient had antecedent diarrheal illness but Campylobacter jejuni, antiganglioside GM1 antibodies, monoclonopathy, human immunodeficiency virus, West Nile serologies, and CSF studies were negative. Discussion: GBS is the most common cause of acute flaccid paralysis in the world. It is considered to be a postinfectious, immune-mediated disease targeting peripheral nerves though immune mimicry. There are several GBS subtypes: acute inflammatory demyelinating polyradiculoneuropathy, acute motor axonal neuropathy, and acute motor and sensory axonal neuropathy. The acute motor and sensory axonal neuropathy variant often presents with rapid and severe paralysis with delayed and poorer recovery. In several studies, C jejuni was the most commonly isolated pathogen associated with the axonal subtype. Conclusions: In the presence of multiple negative serologies, this would be the first case report that suggests a hyperimmune response to fetal demise and retained products as a potential etiology of GBS.

Distinct distal myopathy phenotype caused by VCP gene mutation in a Finnish family

Inclusion body myopathy with Paget disease and frontotemporal dementia (IBMPFD) is caused by mutations in the valosin-containing protein (VCP) gene. We report a new distal phenotype caused by VCP gene mutation in a Finnish family with nine affected members in three generations. Patients had onset of distal leg muscle weakness and atrophy in the anterior compartment muscles after age 35, which caused a foot drop at age 50. None of the siblings had scapular winging, proximal myopathy, cardiomyopathy or respiratory problems during long-term follow-up. Three distal myopathy patients developed rapidly progressive dementia, became bedridden and died of cachexia and pneumonia and VCP gene mutation P137L (c.410C>T) was then identified in the family. Late onset autosomal dominant distal myopathy with rimmed vacuolar muscle pathology was not sufficient for exact diagnosis in this family until late-occurring dementia provided the clue for molecular diagnosis. VCP needs to be considered in the differential diagnostic work-up in patients with distal myopathy phenotype.

Motor Cortical Representation of the Pelvic Floor Muscles

Pelvic floor muscle training involves rhythmical voluntary contractions of the external urethral sphincter and ancillary pelvic floor muscles. The representation of these muscles in the motor cortex has not been located precisely and unambiguously. We used functional magnetic resonance imaging to determine brain activity during slow and fast pelvic floor contractions. Cerebral responses were recorded in 17 healthy male volunteers, 21 to 47 years old, with normal bladder control. Functional magnetic resonance imaging was performed during metronome paced slow (0.25 Hertz) and fast (0.7 Hertz) contractions of the pelvic floor that mimicked the interruption of voiding. To study the somatotopy of the cortical representations, flexion-extension movements of the right toes were performed as a control task. Functional magnetic resonance imaging during pelvic floor contractions detected activity of the supplementary motor area in the medial wall and of the midcingulate cortex, insula, posterior parietal cortex, putamen, thalamus, cerebellar vermis and upper ventral pons. There were no significant differences in activation between slow and fast contractions. Toe movements involved significantly stronger activity of the paracentral lobule (ie the medial primary motor cortex) than did the pelvic floor contractions. Otherwise the areas active during pelvic floor and leg muscle contractions overlapped considerably. The motor cortical representation of pelvic floor muscles is located mostly in the supplementary motor area. It extends further ventrally and anteriorly than the representation of distal leg muscles.

Motor neuron disease due to neuropathy target esterase gene mutation: Clinical features of the index families

Recently, we reported that mutations in the neuropathy target esterase (NTE) gene cause autosomal recessive motor neuron disease (NTE-MND). We describe clinical, neurophysiologic, and neuroimaging features of affected subjects in the index families. NTE-MND subjects exhibited progressive lower extremity spastic weakness that began in childhood and was later associated with atrophy of distal leg and intrinsic hand muscles. NTE-MND resembles Troyer syndrome, except that short stature, cognitive impairment, and dysmorphic features, which often accompany Troyer syndrome, are not features of NTE-MND. Early onset, symmetry, and slow progression distinguish NTE-MND from typical amyotrophic lateral sclerosis. NTE is implicated in organophosphorus compound-induced delayed neurotoxicity (OPIDN). NTE-MND patients have upper and lower motor neuron deficits that are similar to OPIDN. Motor neuron degeneration in subjects with NTE mutations supports the role of NTE and its biochemical cascade in the molecular pathogenesis of OPIDN and possibly other degenerative neurologic disorders.

Non-invasive preoperative localization of primary motor cortex in epilepsy surgery by navigated transcranial magnetic stimulation

Navigated transcranial magnetic stimulation (nTMS) is a non-invasive method to localize the primary motor cortex (M1). To assess the safety and feasibility of nTMS as a non-invasive preoperative mode of functional localization of M1 in epilepsy surgery candidates with intractable focal epilepsy due to lesions in the vicinity of M1. We mapped the muscle representation areas of M1 with nTMS in 10 patients (age 2 to 55 years) with intractable epilepsy. The lesions were focal cortical dysplasia (n=6), ganglioglioma (n=2) polymicrogyria (n=1) or dysembryoblastic neuroepithelial tumour (n=1). The optimal stimulation sites and motor threshold (MT) of the distal hand or leg muscles were determined in both hemispheres. Cortical areas were mapped with stimulation intensities 100-120% of the MT to localize functional M1. Patients were on their stabile antiepileptic medication, and EEG was continuously monitored. The clinical benefit obtained with the preoperative nTMS mapping in the surgical decision making was scored as (1) essential, (2) beneficial, or (3) not beneficial, depending mainly on the difference between the functional and the presumed anatomic M1. The M1 was successfully assessed in all but the 2 youngest patients (aged 2 and 5 years), in whom nTMS was unable to elicit motor responses. nTMS was regarded as essential or beneficial in the localization of M1 in relation to the lesions in 6 out of 10 cases. The optimal motor representation areas were mainly located symmetrically on the precentral gyrus, and corresponded to the presumed location of M1 in MRI. No clinical or EEG evidence of acute epileptogenic adverse effects were observed during the localization procedure. None of the operated patients developed post-operative motor deficits. nTMS is a safe and feasible clinical tool for the non-invasive preoperative localization of motor cortex in patients with intractable epilepsy due to focal lesions adjacent or within the presumed M1 in MRI.

Balance control in patients with distal versus proximal muscle weakness

Muscle weakness is consistently associated with falls in the elderly people, typically when present along with other risk factors. However, it remains unknown whether and how muscle weakness alone affects balance. This hampers development of more effective fall prevention strategies. Clinical observations suggest that the amount and distribution of muscle weakness influences balance control. We therefore investigated balance corrections in patients with either predominantly proximal (limb girdle muscular dystrophy (LGMD); n=8) or distal (distal spinal muscular atrophy; n=5) leg weakness, and 27 matched healthy controls. Balance was perturbed using surface tilt rotations that were delivered randomly in eight directions. Balance measures were full body kinematics and surface electromyographic activity (EMG) of leg, arm, and trunk muscles. Both patient groups were more unstable than controls, as reflected by greater excursions of the centre of mass (COM), especially in the pitch (anterior–posterior (AP)) plane. COM displacements were greater in distal weakness patients. Patients with distal weakness had excessive and unstable trunk, knee and ankle movements, and this was present following both forward and backward directed balance perturbations, possibly reflecting the greater use of distal leg muscles in these directions. In contrast, the less weak proximal weakness patients demonstrated unstable trunk and ankle movements only for backward directed balance perturbations. Both patient groups used arm movements to compensate for their instability. We conclude that primarily distal but also proximal muscle weakness leads to significant postural instability. This observation, together with the retained ability of patients to use compensatory arm movements, provides targets that may be amenable to improvement with therapeutic intervention.

G.P.4.08 Flexor-dominant myopathic phenotype in patients with His46Arg substitution in the Cu/Zn superoxide dismutase gene

We present the cases of four patients with a histidine-to-arginine substitution at position 46 of the Cu/Zn superoxide dismutase gene. Consistent with previous reports, the initial symptom in each patient was unilateral weakness in the distal leg muscles. Remarkably, muscular atrophy in these patients during the early stage of the disease was more specific to the flexor muscle group, with the extensor muscle group remaining intact over long-term observation. Even in the advanced stage of the disease, the extensor muscle group was affected to a lesser extent than the flexor muscle group in the distal leg muscles.

Flexor-dominant myopathic phenotype in patients with His46Arg substitution in the Cu/Zn superoxide dismutase gene

We present the cases of 3 patients with a histidine-to-arginine substitution at position 46 of the Cu/Zn superoxide dismutase gene. Consistent with previous reports, the initial symptom in each patient was unilateral weakness in the distal leg muscles. Remarkably, muscular atrophy in these patients during the early stage of the disease was more specific to the flexor muscle group, with the extensor muscle group remaining intact over long-term observation. More interestingly, biopsy of the affected muscle in the early stage of the disease revealed necrotic and regenerative myofibers with infiltration of lymphocytes, resembling inflammatory myopathy. These novel findings might provide further insights into the pathophysiology of familial amyotrophic lateral sclerosis.

THE CROSSED EXTENSOR HALLUCIS RESPONSE IN NEUROLOGICAL DISORDERS; AN ELECTROMYOGRAPHIC ANALYSIS

The electromyographic activity in several leg muscles during the elicitation of "the crossed up-going toe sign" (CUT) was studied in patients and compared with that obtained in connection with the Babinski sign and in normal subjects. The results indicate that the patterns of activation and the responsible pathways are different for the CUT and Babinski signs. The difference between the normal subjects and the CUT positive patient is a matter of quantitative difference of coactivation of distal leg muscles during the test procedure rather than a change of reflex patterns.

EFFECTS OF MICROEMBOLIZATION ON THE SKELETAL MUSCLE BLOOD FLOW. A Critique of the Microvascular Occlusion Model of Duchenne Dystrophy

Muscle blood flow (MBF) during exercise was determined in both anterior tibial muscles of 12 rabbits by the local 133-Xe method before and after embolization of 20 to 80 mum dextran particles into the right femoral artery. With a relatively low dose of particles (dry weight: 8.7 mg), MBF was significantly decreased up to 4 days after each embolization, and mild histologic abnormalities were observed in the embolized muscles. A four-fold higher dose resulted in a marked and permanent decrease of the MBF, ischemic necrosis of the distal leg muscles and toe gangrene. In the light of these findings and the previously demonstrated normal MBF in Duchenne dystrophy, the validity of the assumption that Duchenne dystrophy is caused by small vessel occlusions is questioned.

The Lambert–Eaton myasthenic syndrome 1988–2008: A clinical picture in 97 patients

Background Neuromuscular symptoms in patients with Lambert–Eaton myasthenic syndrome (LEMS) and a small cell lung cancer (SCLC) develop more rapidly than in LEMS patients without a SCLC. We studied how this clinical information, which is readily available at the first consultation, can be used to predict the presence of SCLC. Patients and methods In our study we included 52 LEMS patients with SCLC and 45 non-tumor patients (NT-LEMS). We interviewed patients using a structured checklist and reviewed their clinical records. We compared frequency and onset of symptoms during the course of LEMS. Results In the first six months, over half the SCLC-LEMS patients had developed seven separate symptoms, while NT-LEMS patients developed only two symptoms. Proximal leg weakness and dry mouth were early symptoms in both groups. Rapid involvement of proximal arm muscles ( p = 0.0001), distal arm muscles ( p = 0.0037), distal leg muscles ( p = 0.0002), dysartria ( p = 0.0091) and the presence of erectile dysfunction ( p = 0.007) were found significantly more often in SCLC-LEMS patients in both cohorts. Cerebellar symptoms, although present in 9% of LEMS patients, were almost exclusively related to SCLC-LEMS. Conclusion A rapidly progressive course of disease from onset in LEMS patients should raise a high suspicion of SCLC. Special attention should be paid to involvement of upper extremities, involvement of distal arm and distal leg muscles, to erectile dysfunction and probably ataxia in order to discriminate between SCLC-LEMS and NT-LEMS.

Neurolymphomatose

We report on a 65-year-old patient with subacute painful sensorimotor polyneuropathy with distal leg muscle palsy and initially presenting with bilateral leg edema. Electrophysiologic testing showed an axonal lesion pattern with acute denervation. Nerve biopsy demonstrated neurolymphomatosis as an initial manifestation of a non-Hodgkin's B cell lymphoma.

Clinical and Genetic Analysis of Korean Patients with Facioscapulohumeral Muscular Dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominantly inherited muscular disorder, which is characterized by weakness of facial, shoulder and hip girdle, humeral, and anterior distal leg muscles. The FSHD gene has been mapped to 4q35 and a deletion of integral copies of a 3.3-kb DNA repeat motif named D4Z4 was known to be the genetic background of the disorder. Although FSHD is the second most common muscular dystrophy in adulthood, there were few reports on the genetically confirmed patients in Korea. Recently, we experienced four Korean patients with clinical features resembling FSHD. In order to confirm the diagnosis, conventional Southern blot (SB) analysis by using double digestion with EcoRI and BlnI and hybridization with p13E-11 probe was performed in three patients and newly developed long polymerase chain reaction (PCR) method was used for one patient because genomic DNA was not enough for conventional SB for this patient. All patients were demonstrated to have shortened D4Z4 repeats that were consistent with FSHD. Therefore, we could confirm the diagnosis of FSHD in four Korean patients and appropriate genetic counseling was done for the patients and their families. It is of note that long-PCR method could be a good alternative for conventional SB when D4Z4 repeats were less than 5.

RAGE, Diabetes, and the Nervous System

Longstanding diabetes mellitus targets kidney, retina, and blood vessels, but its impact upon the nervous system is another important source of disability. Diabetic peripheral neuropathy is a serious complication of inadequately treated diabetes leading to sensory loss, intractable neuropathic pain, loss of distal leg muscles, and impairment of balance and gait. Diabetes has been implicated as a cause of brain atrophy, white matter abnormalities, and cognitive impairment and a risk factor for dementia. Recent studies have incriminated advanced glycation end products (AGEs) and their receptor (RAGE) in the pathogenesis of diabetic nervous system complications. The availability of RAGE knockout mice and a competitive decoy for AGEs, soluble RAGE (sRAGE), has advanced our knowledge of the RAGE-mediated signalling pathways within the nervous system. They also provide hope for a future novel intervention for the prevention of diabetes-associated neurological complications. This review will discuss current knowledge of diabetes- and RAGE-mediated neurodegeneration, involving the distal-most level of epidermal nerve fibers in skin, major peripheral nerve trunks, dorsal root ganglia, spinal cord, and brain.