Distal Lower Limb Weakness Research Articles

The most common European HINT1 neuropathy variant phenotype and its case studies.

HINT1 is an ubiquitous homodimeric purine phosphoramidase belonging to the histidine-triad superfamily. In neurons, HINT1 stabilizes the interaction of different receptors and regulates the effects of their signaling disturbances. Changes in HINT1 gene are associated with autosomal recessive axonal neuropathy with neuromyotonia. Aim of the study was detailed description of patients' phenotype with HINT1 homozygous NM_005340.7: c.110G>C (p.Arg37Pro) variant. Seven homozygous and three compound heterozygous patients were recruited and evaluated using standardized tests for CMT patients, in four patients' nerve ultrasonography was performed. The median age of symptom onset was 10 years (range 1-20), with initial complaints being distal lower limb weakness with gait impairment, combined with muscle stiffness, more pronounced in the hands than in the legs and worsened by cold. Arm muscles became involved later, presenting with distal weakness and hypotrophy. Neuromyotonia was present in all reported patients and is thus a diagnostic hallmark. Electrophysiological studies demonstrated axonal polyneuropathy. Impaired mental performance was observed in six out of ten cases. In all patients with HINT1 neuropathy, ultrasound examination showed significantly reduced muscle volume as well as spontaneous fasciculations and fibrillations. The nerve cross-sectional areas of the median and ulnar nerves were closer to the lower limits of the normal values. None of the investigated nerves had structural changes. Our findings broaden the phenotype of HINT1-neuropathy and have implications for diagnostics and ultrasonographic evaluation of HINT1-neuropathy patients.

Analysis of a pedigree with distal hereditary motor neuropathy type 2A caused by mutation in HSPB8 gene

To explore phenotypic and mutational characteristics of a pedigree with distal hereditary motor neuropathy (dHMN). Clinical data of the proband and her family members was collected. Electrophysiology, muscle biopsy and whole exome sequencing were carried out for the proband. Patients of the family mainly presented with distal lower limb weakness. Electrophysiological test of the proband revealed distal motor neuropathy and sensory nerves were normal. Muscle biopsy suggested neurogenic atrophy of muscle fibers. Genetic analysis revealed a heterozygous c.421A>G (p.K141E) mutation in exon 2 of the HSPB8 gene, which was a hot spot mutation. This family was the first reported HSPB8 related dHMN2A in Chinese population, and p.K141E was the causative mutation, which enriched the mutational spectrum of dHMN in China.

Charcot-Marie-Tooth disease secondary to biallelic mutations in SORD

IntroductionSORD is a newly described autosomal recessive gene that is emerging as the commonest cause of autosomal recessive CMT (Charcot-Marie-Tooth disease) and hereditary motor neuropathy (HMN).MethodsWe present nine cases of SORD-related neuropathy.ResultsNine unrelated patients were found to have biallelic mutations in SORD. Eight were male (89%) and median age of assessment was 34 years (range 18–55 years). Median age of symptom onset was 15 years (range 12–18 years) and all patients initially presented with difficulty walking and/or problems involving distal lower limbs. Only one patient (11%) had sensory symptoms. 5/9 (56%) had distal upper limb weakness and all had distal lower limb weakness. Sensory examination was abnormal to at least one modality in 7/9 cases (78%). The median CMT Examination and CMT Neuropathy Scores were 6 (range 2–12) and 7.5 (range 3–14) respectively. Neurophysiology showed conduction velocities in the axonal or intermediate ranges in all cases. Clinical diagnosis was distal HMN in 5/9 (56%), CMT2 in 2/9 (22%) and CMT intermediate in 2/9 (22%).ConclusionsThe SORD phenotype is typically a slowly progressive, length-dependent motor neuropathy of onset during the second decade. Sensory symptoms are rare and sensory signs minimal.chris.record@ucl.ac.uk

Genetic spectrum in a cohort of patients with distal hereditary motor neuropathy.

BackgroundDistal hereditary motor neuropathy (dHMN) is a heterogeneous group of diseases characterized by exclusive degeneration of peripheral motor nerves, while only 20.0–47.8% of dHMN patients are genetically identified. Recently, GGC expansion in the 5’UTR of NOTCH2NLC has been associated with dHMN. Accordingly, short tandem repeat (STR) should be further explored in genetically unsolved patients with dHMN.MethodsA total of 128 patients from 90 unrelated families were clinically diagnosed as dHMN, and underwent a comprehensively genetic screening. Skin biopsies were conducted with routine protocols.ResultsMost patients showed chronic distal weakness of lower limbs (121/128), while 20 patients initially had asymmetrical involvements, 14 had subclinical sensory abnormalities, 11 had pyramidal impairments, five had cerebellar disturbance, and four had hyperCKmia. The rate of genetic detection was achieved in 36.7% (33/90), and the rate increased to 46.7% (42/90) if patients with variants uncertain significance were included. The most common causative genes included chaperone‐related genes (8/33, 24.2%), tRNA synthetase genes (4/33, 12.1%), and cytoskeleton‐related genes (4/33, 12.1%). Additionally, two dominant inherited families were attributed to abnormal expansion of GGC repeats in the 5‘UTR of NOTCH2NLC; and a patient with dHMN and cerebellar symptoms had CAG repeat expansion in the ATXN2 gene. Skin biopsy from patients with GGC expansion in NOTCH2NLC revealed typical intranuclear inclusions on histological and ultrastructural examinations.InterpretationsThis study further extends the genetic heterogeneity of dHMN. Given some dHMN patients may be associated with nucleotides repeat expansion, STR screening is necessary to perform in genetically unsolved patients.

ORGANOPHOSPHATE INDUCED DELAYED NEUROPATHY-A CASE REPORT

Organophoshate induced delayed polyneuropathy (OPIDP) is a rare clinical condition associated with ingestion of organophosphate. Clinically the patient presents with distal lower limb weakness mainly along with paraesthesia and other symptoms of neuropathy. Nerve conduction study shows motor axonal neuropathy.Here, we are presenting a case of 23 years old INDIAN male who presented with pain and tingling sensations in lower limbs along with bilateral upper limb and lower limb paresis with difculty in getting up and walking. He had history of Dichlorvos based organophosphate ingestion around 45 days before. Electrophysiological study suggestive of Severe motor axonal polyneuropathy affecting all four limbs. No central nervous system signs were present.

VRK1 variants in two Portuguese unrelated patients with childhood-onset motor neuron disease

VRK1 encodes a serine/protein kinase possibly involved in pathways related to amyotrophic lateral sclerosis (ALS) pathogenesis. Pathogenic variants in VRK1 have been related to different phenotypes. We describe the clinical phenotype of two unrelated Portuguese patients with different VRK1 variants. Both patients presented a bilateral distal weakness in lower limbs beginning in childhood slowly progressing to upper limbs, associated with pyramidal signs, without bulbar, respiratory or cognitive involvement, according to probable ALS. Imaging and nerve conduction studies were unremarkable in both patients. Genetic testing in patient 1 identified two VRK1 variants in heterozygosity: c.265C > T, p.(Arg89*) and c.769G > A, p.(Gly257Ser), classified as pathogenic and variant of uncertain significance, respectively. In patient 2, two probably pathogenic variants in VRK1 were identified in heterozygosity: c.710-14T > C in intron 8 and c.721C > T, p.(Arg241Cys) in exon 9. We report two unrelated patients with different variants in VRK1 displaying a similar childhood-onset motor neuron disease/ALS, further expanding the phenotypic spectrum associated to VRK1 variants.

Analysis of a pedigree with autosomal dominant intermediate Charcot-Marie-Tooth disease type E and nephropathy

To explore phenotypic and mutational characteristics of a pedigree affected with autosomal dominant Charcot-Marie-Tooth disease (CMT) and nephropathy. Clinical data of the proband and his family members was collected. Electrophysiology, renal biopsy and next-generation sequencing were carried out for the proband. The proband presented with distal lower limb weakness and proteinuria in childhood. His mother and brother had similar symptoms. Electrophysiological test of the proband revealed demyelination and axonal changes in both motor and sensory nerves. Renal biopsy suggested focal segmental glomerulosclerosis. Genetic testing revealed a heterozygous c.341G>A (p.G114D) mutation in exon 2 of the INF2 gene. The phenotypic feature of the pedigree is autosomal dominant intermediate CMT and focal segmental glomerulosclerosis, which may be attributed to the c.341G>A mutation of the INF2 gene.

Clinical Features and Outcome of Guillain-Barré Syndrome in Children.

There are no reports about the clinical presentations and outcome of Guillain-Barré syndrome (GBS) in our region, therefore, we aimed to report some mentioned findings in children diagnosed with GBS in Isfahan, central Iran. In this retrospective study, pediatric diagnosed with GBS referred to Imam Hossein Hospital, the Pediatric Referral Center of Isfahan Province, central Iran were enrolled from 2011-2014. The following data were extracted from the medical files of patients; age, gender, early signs and symptoms of GBS, neurological features, sensory and motor and autonomic involvements, sphincter dysfunction, bulbar muscle involvement, respiratory failure, cranial nerve paralysis, delay time from onset to definite diagnosis and management of GBS and the outcome. Overall, 57 children with GBS aged 1-13 yr were evaluated. Frequency of GBS was significantly higher in boys than in girls (38.6% vs. 61.4%, P=0.01, OR=0.39). The most common clinical presentations were distal lower limb weakness (92.11%), reduced deep tendon reflex (DTR) (82.46%) and neuropathic pain (75.44%). 92.9% of patients had complete recovery. Distal lower limb weakness, reduced deep tendon reflex, and neuropathic pain are the main clinical presentation in children with GBS but in some patients, DTR may be normal or even exaggerated in early stage of disease. Revising the diagnostic criteria for GBS may be necessary. Most of our patients had complete recovery. The only death was due to autonomic involvement. Autonomic dysfunction could be associated with catastrophic outcome and patients with these clinical presentations need critical care.

Novel TCAP mutation c.32C>A causing limb girdle muscular dystrophy 2G.

TCAP encoded telethonin is a 19 kDa protein, which plays an important role in anchoring titin in Z disc of the sarcomere, and is known to cause LGMD2G, a rare muscle disorder characterised by proximal and distal lower limb weakness, calf hypertrophy and loss of ambulation. A total of 300 individuals with ARLGMD were recruited for this study. Among these we identified 8 clinically well characterised LGMD2G cases from 7 unrelated Dravidian families. Clinical examination revealed predominantly proximo - distal form of weakness, scapular winging, muscle atrophy, calf hypertrophy and foot drop, immunoblot showed either complete absence or severe reduction of telethonin. Genetic analysis revealed a novel nonsense homozygous mutation c.32C>A, p.(Ser11*) in three patients of a consanguineous family and an 8 bp homozygous duplication c.26_33dupAGGTGTCG, p.(Arg12fs31*) in another patient. Both mutations possibly lead to truncated protein or nonsense mediated decay. We could not find any functionally significant TCAP mutation in the remaining 6 samples, except for two other polymorphisms, c.453A>C, p.( = ) and c.-178G>T, which were found in cases and controls. This is the first report from India to demonstrate TCAP association with LGMD2G.

Two Novel GDAP1 Mutations with Intermediate Type Autosomal Recessive Charcot-Marie-Tooth Neuropathy (P05.145)

Objective: We report two different types of intermediate AR CMT patients with GDAP1 mutations: a His256Arg homozygous mutation, and two heterozygous Pro111His and Val219Gly mutations. Background Various phenotypes have been reported in Charcot-Marie-Tooth disease (CMT) patients carrying mutations in the GDAP1 gene, e.g. autosomal recessive (AR) axonal, AR demyelinating, AR intermediate, and autosomal dominant (AD) axonal neuropathies. Design/Methods: This study included two Korean autosomal recessive CMT families (FC316 and FC426) with GDAP1 mutations (totally 8 individuals: 2 patients, 4 carriers and 2 normals). Disease severities were measured by CMT neuropathy score (CMTNS) and functional disability scale (FDS). MNCVs were carried out on 6 individuals (2 patients, 3 carriers and 1normal). Leg MRI and sural nerve biopsy were performed on 2 patients. The mutation in the GDAP1 gene was screened by PCR amplification and subsequent sequencing of all exons. Results: Two patients showed an early-onset of severe neuropathy with prominent distal lower limb weakness within the first decade of life. The present patients are similar to those with other AR CMT.By neuropathological criteria, two patients showed well documented neuropathological findings consisting of mixed demyelinating and axonal neuropathies and the presence of abnormal mitochondria in nerve biopsy materials was suggestive of the regulatory role of GDAP1 in mitochondrial network dynamics. In addition, nerve conduction velocities of both patients fall in the intermediate range. The leg MRI features were predominantly involved anterolateral compartment muscles of the calf. But, deep and superficial posterior compartments of the low leg were nearly normal. Those findings were different from reported axonal CMT neuropathies with GDAP1 mutations, and similar to the demyelinating CMT1A neuropathies. Conclusions: The fatty replacements of leg muscles were different within the same GDAP1 gene mutations, and the leg MRI provides a valuable non-invasive method for phenotypic evaluation of muscular involvement in CMT neuropathies harboring GDAP1 mutations. Disclosure: Dr. Chung has nothing to disclose.

Functional muscle analysis of the Tcap knockout mouse

Autosomal recessive limb‐girdle muscular dystrophy type 2G (LGMD2G) is an adult‐onset myopathy characterized by distal lower limb weakness, calf hypertrophy, and progressive decline in ambulation. The disease is caused by mutations in Tcap, a z‐disc protein of skeletal muscle, although the precise mechanisms resulting in clinical symptoms are unknown. To provide a model for preclinical trials and for mechanistic studies, we generated knockout mice carrying a null mutation in the TCAP gene. Here we present the first report of a Tcap knockout mouse model for LGMD2G and the results of an investigation into the effects of Tcap deficiency on skeletal muscle function in 4‐month‐ and 12‐month‐old mice. Muscle histology of Tcap‐null mice revealed abnormal myofiber size variation with central nucleation, similar to findings in the muscles of LGMD2G patients. An analysis of a Tcap binding protein, myostatin, showed that deletion of TCAP was accompanied by increased protein levels of myostatin. Our Tcap‐null mice exhibited a decline in the ability to maintain balance on a rotating rod, relative to wild‐type controls. No differences were detected in force or fatigue assays of isolated extensor digitorum longus (EDL) and soleus muscles. Finally, a mechanical investigation of EDL and soleus indicated an increase in muscle stiffness in knockout animals. We are the first to establish a viable knockout mouse model of Tcap deficiency and our model mice demonstrate a dystrophic phenotype comparable to humans with LGMD2G.Support: M.K. Childers Laboratory Startup Fund

Functional muscle analysis of the Tcap knockout mouse

Autosomal recessive limb-girdle muscular dystrophy type 2G (LGMD2G) is an adult-onset myopathy characterized by distal lower limb weakness, calf hypertrophy and progressive decline in ambulation. The disease is caused by mutations in Tcap, a z-disc protein of skeletal muscle, although the precise mechanisms resulting in clinical symptoms are unknown. To provide a model for preclinical trials and for mechanistic studies, we generated knockout (KO) mice carrying a null mutation in the Tcap gene. Here we present the first report of a Tcap KO mouse model for LGMD2G and the results of an investigation into the effects of Tcap deficiency on skeletal muscle function in 4- and 12-month-old mice. Muscle histology of Tcap-null mice revealed abnormal myofiber size variation with central nucleation, similar to findings in the muscles of LGMD2G patients. An analysis of a Tcap binding protein, myostatin, showed that deletion of Tcap was accompanied by increased protein levels of myostatin. Our Tcap-null mice exhibited a decline in the ability to maintain balance on a rotating rod, relative to wild-type controls. No differences were detected in force or fatigue assays of isolated extensor digitorum longus (EDL) and soleus (SOL) muscles. Finally, a mechanical investigation of EDL and SOL indicated an increase in muscle stiffness in KO animals. We are the first to establish a viable KO mouse model of Tcap deficiency and our model mice demonstrate a dystrophic phenotype comparable to humans with LGMD2G.

Hip flexor fatigue limits walking in Charcot–Marie–Tooth disease

Charcot-Marie-Tooth (CMT) disease results in distal lower limb weakness that affects walking. In this study we assess the role of the hip flexors in compensating for distal weakness while walking and the effects of prolonged walking on these putative compensatory strategies. Eighteen subjects with CMT disease were compared with 14 matched controls while they walked on a treadmill to a predetermined point of perceived effort. A significant reduction was observed in peak hip flexor velocity during walking and hip flexor maximal voluntary contraction. In a second session following selective fatigue of the hip flexors, hip flexor velocity decreased immediately on walking, and walking duration was greatly reduced. This study suggests that hip flexors compensate for distal weakness and that fatigue in the hip flexors can limit walking duration. Treatments directed toward improving proximal muscle strength may therefore help to delay onset of hip flexor fatigue and thus prolong walking duration.

A Case of Central Core Disease with Distal Lower Limb Weakness - Case Report -

A Case of Central Core Disease with Distal Lower Limb Weakness - Case Report -

DIAGNOSTIC APPROACHES TO IMPORTED SCHISTOSOMAL MYELORADICULOPATHY IN TRAVELERS

Schistosomiasis affects more than 200 million people around the world.1 Schistosomal myeloradiculopathy (SMR) is an inflammation of the spinal cord (myelitis) or nervous roots (radiculitis) due to schistosomiasis, mostly reported with S mansoni or S hematobium .2 We describe three cases of SMR in travelers from France, defined as nonimmune patients, briefly exposed to schistosomiasis, and then discuss diagnosis approach in this population. ### Case reports. #### Patient 1. A 58-year-old man was hospitalized for subacute paraparesis. Four weeks after trekking in Madagascar, a dysenteric syndrome appeared with 5,214 eosinophils/mm3 and identification of S mansoni eggs in stool. Forty mg/kg of praziquantel was administered. Two days later, bilateral pain in the legs, gait instability, and dysuria appeared. Physical examination revealed distal weakness in lower limbs with stepping and right quadriceps fasciculation. Schistosomal serology was positive with hemagglutination (HA) and indirect immunofluorescence (IFI) at 1/320 (normal < 1/160). CSF showed seven cells/mm3 (70% lymphocytic and 30% eosinophils), normoglycorrhachia, and 0.57 g/dL proteins. Three praziquantel daily doses of 40 mg/kg and five daily prednisolone doses of 500 mg were administered, followed by 1 mg/kg oral prednisolone tapered within 1 month. Neurologic symptoms had completely reversed in 24 hours and MRI at 3 months had normalized. #### Patient 2. A 29-year-old man was hospitalized for progressive gait disorder 4 …

P13.1 Conduction block in Charcot–Marie–Tooth type 1B (CMT1B) neuropathy

Background: On neurophysiological studies the hereditary demyelinating motor and sensory neuropathies (CMT1) usually show uniform reduction in motor conduction velocities. On the other hand, conduction block (CB) far from compression sites is typical of acquired demyelinating neuropathies. Aims: To describe a patient with CMT1 in whom neurophysiological studies disclosed marked CB outside entrapment sites. Case report:A34-year-oldwomanwith afive-year history ofmuscle cramps, right hand and distal lower limbweakness after longstanding efforts. She only startedwalking at the age of 30months but had no other motor development problem. Her father had a history of disabling demyelinating motor– sensory neuropathy. On neurological examination, she had bilateral pes cavus, slight weakness on right thumb abduction, bilateral foot dorsiflexion and hallux extension weakness (4/5); there was a generalized areflexia and distal lower limb light touch and pinprick hypostesia and few errors on postural sense testing; walking on heels was impaired. Motor conduction studies showed low velocities with prolonged latencies, with absent motor responses in feet. Partial conduction blocks were present in the median and ulnar nerves at the forearm (below elbow), more severe aftermuscular fatigue. Sensory potentialswere absent (lower limbs) or small. Laboratorial evaluation includingCSFanalysis was unremarkable. The genetic study was positive for the 233C > T mutation at the MPZ gene. Conclusion: This case illustrates the electrophysiological heterogeneity of CMT1B and adds this entity to conduction block differential diagnosis.

CMT1A ASSOCIATED WITH 17p11.2 DUPLICATION AND ASYMMETRICAL LEG MUSCLE HYPERTROPHY

Charcot‐Marie‐Tooth disease (CMT) is the most common inherited disorder of the peripheral nervous system. It is characterized by distal muscle weakness and atrophy, first involving legs and particularly the peroneal muscles with the typical leg as “inverted champagne bottle”.The CMT1A is an autosomal dominant demyelinating sensorimotor neuropathy most often associated with a duplication of chromosome 17p11.2, a region that contains the gene for the peripheral protein 22 (PMP22). We describe two families with CMT1A, in which three of six members did not show the typical feature of leg atrophy. In fact, a patient belonging to the first family showed a bilateral symmetric hypertrophy of the calf. In the second family, a patient had an asymmetric bilateral calf hypertrophy, and his son showed a similar condition but the asymmetric hypertrophy involved the whole left limb. The other cardinal features in our family were distal weakness of lower limbs (5 of 6), pes cavus (3 of 6), and reduced or absent tendon reflexes (6 of 6).Motor and sensory conduction velocities showed, in all nerves explored, values at or below 38 m/sec. The computed tomography of lower limbs showed that leg enlargement was due to true muscle hypertrophy without concomitant increase of adipose or connective tissue.The pathophysiological mechanisms responsible for muscle enlargement are yet unclear. It is possible that one or more genetic factors, still unknown, may be linked genetically to the neuropathy in such pedigrees in which most or all affected members carry the trait.