Antibody- and macrophage-mediated segmental demyelination in chronic inflammatory demyelinating polyneuropathy: clinical, electrophysiological, immunological and pathological correlates.

BACKGROUND AND PURPOSE: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a heterogeneous autoimmune disorder critically lacking diagnostic biomarkers. Autoantibodies to nodal and paranodal components have recently been described in a small subset of patients. Here, the diagnostic value of immune reactivity toward the myelin compartment was investigated. METHODS: Ninety-four French CIDP patients were retrospectively studied. The reactivity toward the peripheral nerve was investigated. Sural nerve biopsies were examined by electron microscopy and immunofluorescence. RESULTS: Twenty-one patients (22%) and three patients (3%) presented with a strong immunoglobulin G or immunoglobulin M reactivity respectively against the myelin compartment. The clinical, electrophysiological and morphological features were examined in nine of these patients for whom sural nerve biopsies were available. Seven patients were electrodiagnosed with definite CIDP, one with possible CIDP and one was unclassifiable but sural nerve biopsy argued for CIDP diagnosis. Electron microscopy of sural nerve biopsies demonstrated the presence of macrophage-mediated demyelination restricted to the internode in all nine patients. Immunolabelling for voltage-gated sodium channels, myelin and axonal markers confirmed the presence of segmental demyelination and of remyelination. The nodal and paranodal regions, however, were unaffected in these patients. Nerve conduction studies corroborated the multifocal and segmental profile, and seven patients showed increased duration of proximal (1.5-5.1 times) and/or distal (1.2-3.4 times) compound muscle action potential in at least two nerves. CONCLUSION: Antibody- and macrophage-mediated demyelination appears responsible for conduction alterations in CIDP patients and nerve immunostaining assays may serve as a supportive diagnostic biomarker.

Correlations between cervical spinal cord magnetic resonance diffusion tensor and diffusion kurtosis imaging metrics and motor performance in patients with chronic ischemic brain lesions of the corticospinal tract.

PURPOSE: To investigate modifications of Magnetic Resonance Diffusion Tensor Imaging (DTI) and Diffusion Kurtosis Imaging (DKI) metrics in lateral white matter (WM) bundles of the cervical spinal cord in patients with previous stroke in the vascular territory of the middle cerebral artery (MCA). METHODS: Twenty consecutive patients with a previous ischemic stroke of the MCA territory and a varying degree of upper motor impairment were enrolled. DKI was centered at the C3C4 and C5C6 intervertebral level. RESULTS: The fractional anisotropy (FA) values in C3C4 and C5C6 were found to be significantly lower in the lateral WM bundles contralateral to the ischemic lesion and thus, in the WM bundle including the affected corticospinal tract (CST) (p = 0.005 and p = 0.008, respectively), as well as mean kurtosis (MK) and axonal water fraction (AWF) values (p = 0.004 and p = 0.04. respectively). FA values correlated significantly with the Global Motor Index (GMI) both for C3C4 (ρ = 0.61, p = 0.004) and C5C6 (ρ = 0.69, p = 0.002). At C3C4, AWF correlated significantly with GMI (ρ = 0.54, p = 0.03). No correlations were found between lateral WM bundle volumes and GMI. CONCLUSION: A reduction of anisotropy and microstructural complexity in the affected lateral WM bundle of the cervical spinal cord was observed in patients with previous ischemic stroke involving the CST. The correlations between these metrics and motor performance were statistically significant.

Clinical and nerve conduction features in Guillain-Barré syndrome associated with Zika virus infection in Cúcuta, Colombia.

BACKGROUND AND PURPOSE: Zika virus (ZIKV) infection has been associated with an increased incidence of Guillain-Barré syndrome (GBS) but the relative frequency of acute inflammatory demyelinating polyradiculoneuropathy (AIDP) and axonal GBS subtypes is controversial. METHODS: Twenty GBS patients diagnosed according to the Brighton criteria during the ZIKV outbreak in Cúcuta, Colombia, were evaluated clinically and electrophysiologically. The electrodiagnosis of GBS subtypes was made according to a recently described criteria set that demonstrated a high diagnostic accuracy on the basis of a single test. The electrophysiological features of 34 Italian AIDP patients were used as control. RESULTS: All patients had symptoms compatible with ZIKV infection before the onset of GBS and ZIKV infection was laboratory confirmed through a plaque reduction neutralization test (PRNT90 ) in 100% of patients. The median time from onset of ZIKV infection symptoms to GBS was 5 days (interquartile range 1-6 days). Cranial nerve palsy was present in 85% of patients (facial palsy in 75%, bulbar nerve involvement in 60%), autonomic dysfunction in 85%, and 50% of patients required invasive mechanical ventilation. AIDP was diagnosed in 70% of patients. 40% of nerves of AIDP patients showed a prevalent distal demyelinating involvement but this pattern was not different from the Italian AIDP patients without ZIKV infection. CONCLUSIONS: Guillain-Barré syndrome associated with ZIKV infection in Cúcuta is characterized by a high frequency of cranial nerve involvement, autonomic dysfunction and requirement of mechanical ventilation indicating an aggressive and severe course. AIDP is the most frequent electrophysiological subtype. Demyelination is prevalent distally but this pattern is not specific for ZIKV infection.

Spinal cord microstructure integrating phase-sensitive inversion recovery and diffusional kurtosis imaging.

PURPOSE: The aim of this prospective study was to determine the feasibility in terms of repeatability and reproducibility of diffusional kurtosis imaging (DKI) for microstructural assessment of the normal cervical spinal cord (cSC) using a phase-sensitive inversion recovery (PSIR) sequence as the anatomical reference for accurately defining white-matter (WM) and gray-matter (GM) regions of interests (ROIs). METHODS: Thirteen young healthy subjects were enrolled to undergo DKI and PSIR sequences in the cSC. The repeatability and reproducibility of kurtosis metrics and fractional anisotropy (FA) were calculated in GM, WM, and cerebral-spinal-fluid (CSF) ROIs drawn by two independent readers on PSIR images of three different levels (C1-C4). The presence of statistically significant differences in DKI metrics for levels, ROIs (GM, WM, and CSF) repeatability, reproducibility, and inter-reader agreement was evaluated. RESULTS: Intra-class correlation coefficients between the two readers ranged from good to excellent (0.75 to 0.90). The inferior level consistently had the highest concordance. The lower values of scan-rescan variability for all DKI parameters were found for the inferior level. Statistically significant differences in kurtosis values were not found in the lateral white-matter bundles of the spinal cord. CONCLUSION: The integration of DKI and PSIR sequences in a clinical MR acquisition to explore the regional microstructure of the cSC in healthy subjects is feasible, and the results obtainable are reproducible. Further investigation will be required to verify the possibility to translate this method to a clinical setting to study patients with SC involvement especially in the absence of MRI abnormalities on standard sequences.

Guillain-Barré syndrome: What have we learnt during one century? A personal historical perspective.

We are approaching the centenary of the first description of Guillain-Barré syndrome. The past 30 years had witnessed an amazing progress in the understanding of the immunological and pathological mechanisms of this disorder. We now recognize that Guillain-Barré syndrome is remarkably heterogeneous and under this umbrella term are several variants and subtypes with distinct clinical, electrophysiological and immunopathological features. This review is a historical journey, through a personal perspective, following the milestones that led to the current substantial knowledge of Guillain-Barré syndrome.

The effects of prolonged cathodal direct current stimulation on the excitatory and inhibitory circuits of the ipsilateral and contralateral motor cortex.

Weak cathodal transcranial direct current stimulation (tDCS) of the human hand area modulates corticospinal excitability with a suppression of motor-evoked potentials (MEPs) evoked by transcranial magnetic stimulation (TMS). The changes in excitability persist beyond the time of stimulation if tDCS is given for several minutes and can remain stable for an hour or more. The aim of present study was to evaluate whether a long-lasting suppression of cortical excitability could be induced by prolonged cathodal tDCS (20 min of stimulation). We also explored the impact of brain-derived neurotrophic factor (BDNF) gene polymorphisms, on tDCS after-effects. Cortical excitability to single and paired-pulse TMS was evaluated both for the stimulated and contralateral hemisphere, before and up to 24 h after 20 min of cathodal tDCS. We evaluated threshold and amplitude of MEPs, short interval intracortical inhibition (SICI), and intracortical facilitation (ICF). tDCS produced a pronounced suppression of MEP amplitude that was still significant at 3 h after the end of stimulation. The BDNF genotype had not influence on tDCS after-effects. Thresholds for MEPs, SICI and ICF were not affected. No significant effect was observed in the contralateral hemisphere. Twenty minutes of cathodal tDCS is capable of inducing a long-lasting suppression of the excitability of the human motor cortex.

CD1A and CD1E gene polymorphisms are associated with susceptibility to multiple sclerosis.

Multiple sclerosis (MS) is thought to be an autoimmune T-cell-mediated disease directed at myelin antigens of the central nervous system. Besides myelin proteins, lipid components of CNS are supposed to play a role as antigens for T cells in MS. CD1 is a family of MHC-like glycoproteins specialized in capturing and presenting a variety of microbial and self lipids and glycolipids to antigen-specific T cells. CD1-restricted T cells specific for gangliosides and sulfatide have been isolated from subjects with MS and in mice with experimental allergic encephalopathy. We genotyped exon 2 of CD1A and CD1E in 205 MS patients and 223 unrelated healthy controls and determined their association with the presence of anti-ganglioside and anti-sulfatide antibodies. CD1E 01-01 is associated with a reduced risk of MS (OR 0.54, p=0.001); CD1A 02-02 (OR 1.99, p=0.012) or CD1E 02-02 (OR 2.45, p=0.000) with an increased risk. The combination of the genotypes CD1A 02-02 and CD1E 02-02 is present in 90.7% of patients but in only 9.4% controls (OR 94.16, p= 0.000). CD1A and CD1E polymorphisms contribute to the polygenic susceptibility to MS. The functional effects of CD1 polymorphisms are unknown, however changes in CD1 alleles may affect numerous immunological functions.

Antibodies to ganglioside complexes in Guillain-Barré syndrome: clinical correlates, fine specificity and complement activation.

In the Schwann cells and neuronal plasma membranes the gangliosides are organized in clusters forming complexes of gangliosides in the microdomains termed lipid rafts. We investigated frequency, clinical correlates, fine specificity and pro-inflammatory properties of antibodies to ganglioside complexes (GSCs) in a Guillain Barre syndrome (GBS) population. In 63 patients with different GBS variants we performed an ELISA for antibodies to Campylobacter Jejuni (C. jejuni), gangliosides and GSCs. We studied the fine specificity of antibodies to GSCs by immunoabsorption study and performed a complement activation assay. Twenty-seven percent of patients had antibodies to GSCs and 71 percent had antibodies either to single gangliosides or to GSCs. Patients with antibodies to GSCs had more frequent involvement of cranial nerves but did not present more frequent antecedent respiratory, gastrointestinal or C. jejuni infection, did not have a preferential demyelinating or primary axonal GBS variant and did not develop greater disability at six months. The absorption study showed in 2 sera that antibodies to the complex GD1a/GD1b did not react with the gangliosides forming the complex or other single gangliosides, suggesting that antibodies to GSCs are targeted to new conformational glycoepitopes different from the ones displayed by the single gangliosides. Antibody anti-GSCs activated the complement more frequently than antibodies to single gangliosides. Complement activation indicates that antibodies to GSCs have high avidity, pro-inflammatory properties and may exert a pathogenic role in GBS.

T cell response in acute motor axonal neuropathy.

There is evidence that in the acute axonal motor neuropathy (AMAN) subtype of Guillain-Barré syndrome antibodies to gangliosides, produced through molecular mimicry by antecedent Campylobacter jejuni (C. jejuni) infection, attack gangliosides expressed in human peripheral nerve axolemma, inducing a primary axonal damage. The aim of this study is to investigate whether the T cell response has a role in AMAN pathogenesis. We isolated monocytes from 4 healthy subjects and 5 AMAN patients with antecedent C. jejuni infection and antibodies to GM1 and/or GD1a gangliosides. Immature dendritic cells expressing CD1 molecules cultured with autologous T cells were stimulated with 2 lipopolysaccharides (LPSs) extracted from C. jejuni strains containing GM1 and GD1a-like structures and with GM1 and GD1a. The T cell response to LPSs and to gangliosides was determined by measuring the release of IFN-gamma and TNF-alpha. We observed a T cell response to both LPSs in controls and AMAN patients, whereas only AMAN patients showed T cell reactivity to gangliosides GM1 and GD1a with a tight correlation between T cell reactivity to the ganglioside and individual antibody responses to the same ganglioside. T cells responding to gangliosides were CD1c-restricted CD8 positive and CD27 negative. These findings indicate a contribution of cellular immunity in the pathogenesis of AMAN. A possible role for ganglioside-reactive T cells might be to facilitate the production of antibodies against gangliosides.

Efficacy of a soft hand brace and a wrist splint for carpal tunnel syndrome: a randomized controlled study.

OBJECTIVE: To examine, in a randomized, controlled, single blinded trial, the efficacy of a soft hand brace and a wrist splint for carpal tunnel syndrome (CTS). METHODS: We randomized 120 patients with CTS into a group wearing the soft hand brace MANU and into another group wearing the wrist splint CAMP TIELLE at night for 3 months. We re-evaluated the patients after 3 (T1) and 9 months (T2). The primary efficacy measures were changes in scores of Boston Carpal Tunnel Questionnaire (BCTQ) and in Visual Analogical Scale (VAS) for pain and paresthesias. RESULTS: At T1, both groups showed a significant reduction in symptomatic and functional BCTQ (T0-T1 differences: MANU BCTQ sympt: 0.88 (0.68-1.08), funct: 0.45 (0.19-0.72); TIELLE BCTQ sympt: 0.78 (0.55-1.01), funct: 0.41 (0.22-0.59). At T2, a less evident benefit on symptoms persisted in both groups, except for pain VAS score that was significantly reduced only in the CAMP TIELLE group. No significant functional benefits persisted in either group. There were no differences in BCTQ and VAS scores between the two groups at T1 and T2 compared with that at baseline. CONCLUSIONS: A 3-month treatment with either the hand brace or the wrist splint induces a symptomatic and functional benefit in patients with CTS.

Functional MRI study of diencephalic amnesia in Wernicke-Korsakoff syndrome.

Anterograde amnesia in Wernicke-Korsakoff syndrome is associated with diencephalic lesions, mainly in the anterior thalamic nuclei. Whether diencephalic and temporal lobe amnesias are distinct entities is still not clear. We investigated episodic memory for faces using functional MRI (fMRI) in eight controls and in a 34-year-old man with Wernicke-Korsakoff syndrome and diencephalic lesions but without medial temporal lobe (MTL) involvement at MRI. fMRI was performed with a 1.5 tesla unit. Three dual-choice tasks were employed: (i) face encoding (18 faces were randomly presented three times and subjects were asked to memorize the faces); (ii) face perception (subjects indicated which of two faces matched a third face); and (iii) face recognition (subjects indicated which of two faces belonged to the group they had been asked to memorize during encoding). All activation was greater in the right hemisphere. In controls both the encoding and recognition tasks activated two hippocampal regions (anterior and posterior). The anterior hippocampal region was more activated during recognition. Activation in the prefrontal cortex was greater during recognition. In the subject with Wernicke-Korsakoff syndrome, fMRI did not show hippocampal activation during either encoding or recognition. During recognition, although behavioural data showed defective retrieval, the prefrontal regions were activated as in controls, except for the ventrolateral prefrontal cortex. fMRI activation of the visual cortices and the behavioural score on the perception task indicated that the subject with Wernicke-Korsakoff syndrome perceived the faces, paid attention to the task and demonstrated accurate judgement. In the subject with Wernicke-Korsakoff syndrome, although the anatomical damage does not involve the MTL, the hippocampal memory encoding has been lost, possibly as a consequence of the hippocampal-anterior thalamic axis involvement. Anterograde amnesia could therefore be the expression of damage to an extended hippocampal system, and the distinction between temporal lobe and diencephalic amnesia has limited value. In the subject with Wernicke-Korsakoff syndrome, the preserved dorsolateral prefrontal cortex activation during incorrect recognition suggests that this region is more involved in either the orientation or attention at retrieval than in retrieval. The lack of activation of the prefrontal ventrolateral cortex confirms the role of this area in episodic memory formation.

Cutaneous electromyographic silent period findings in brachial dystonia.

In this study we investigated the physiologic mechanisms in primary brachial dystonia by analyzing the cutaneous EMG silent period during isometric contraction of the opponens pollicis muscle. Results from the affected and unaffected arms of 11 patients with dystonia were compared to 7 patients with Parkinson's disease and 16 age-matched normal individuals (controls). The silent period onset latency, degree of EMG suppression during the silent period, and EMG rebound at the end of the silent period did not differ significantly between patients with dystonia and any other group. The duration of the silent period (the S-X interval), however, was significantly prolonged in dystonia (p<0.005) and in Parkinson's disease (p<0.001) in both affected and unaffected arms compared with controls. These findings suggest that mechanisms responsible for the initiation of the cutaneously induced silent period and the subsequent suppression depth of EMG activity are not affected in brachial dystonia, but the abnormally prolonged S-X intervals may reflect dysfunctional basal ganglia timing influences over spinal circuitry common to both dystonia and Parkinson's disease.

GCG genetic expansions in Italian patients with oculopharyngeal muscular dystrophy.

OBJECTIVE: To screen Italian patients with oculopharyngeal muscular dystrophy (OPMD) for GCG repeat expansions in the Poly(A) binding-protein 2 (PABP2) gene. BACKGROUND: Oculopharyngeal muscular dystrophy is an adult-onset autosomal dominant muscle disease linked to 14q11 pathologically characterized by unique 8.5 nm intranuclear filaments in skeletal muscle fibers. Short expansions of a (GCG)6 repeat located in exon 1 of the newly isolated PABP2 gene have been demonstrated in a large number of OPMD families. METHODS: We studied 18 patients diagnosed with OPMD. A muscle biopsy was performed in 16 patients. Screening for the pathologic expansion was performed on a PCR amplified DNA fragment encompassing the GCG repeat. RESULTS: Heterozygous (GCG)-repeat expansions were detected in 13 patients in association with (GCG)6 normal allele or (GCG)7 polymorphic allele. All the patients whose muscle biopsy showed typical 8.5 nm intranuclear filaments had a mutated PABP2 allele. Five patients with no intranuclear filaments were homozygous for the normal (GCG)6 allele. The pathologic expansion appeared to be stable with no variation among family members and between different tissues as blood and skeletal muscle in the same individual. CONCLUSIONS: These data 1) further confirm PABP2 gene analysis as a valuable tool in OPMD diagnosis; 2) indicate that PABP2 gene mutations are always present among Italian patients with morphologically proven OPMD, suggesting genetic homogeneity of the disease; and 3) strengthen the putative role of mutated PABP2 protein in filamentous inclusions accumulation.

Multifocal motor neuropathy with conduction block: is it a distinct clinical entity?

We studied 169 patients with motor neuron disease. Seventeen showed abnormal amplitude reduction of the compound muscle action potential. Ten had focal loss of both amplitude and area across a specific segment (conduction block). Eight of the 10 had slowing of conduction across that segment. Nine were men and had prominent hand involvement. Six had probable or definite upper motor neuron signs. Five of the 10 showed immunologic abnormalities (elevated GM1 antibody titers or paraproteinemia), and eight had had symptoms for more than 4 years. Seven of the 17 patients showed loss of amplitude without corresponding loss of area and focal slowing of conduction (temporal dispersion). Five of the seven were men, five had prominent hand involvement, and five had definite or probable upper motor neuron signs. Two had immunologic abnormalities, and ony one had had symptoms for longer than 4 years. Among 152 patients with no abnormality of conduction, 64% wee men, hands were dominantly involved in 34%, upper motor neuron signs were definite or probable in 72%, and 3% had immunologic abnormalities. None had symptoms for more than 4 years. Because there were so many exceptions, we could not define a unique syndrome by criteria involving conduction block, GM1 antibodies, or lack of upper motor neuron signs. The clinical syndrome associated with multifocal conduction block seemed uniform, however, and patients with conduction block had slower progression if there were no upper motor neuron signs.

A late-onset mitochondrial myopathy is associated with a novel mitochondrial DNA (mtDNA) point mutation in the tRNA(Trp) gene.

We detected a novel pathogenic mutation, a G-->A transition at position 5521 of mitochondrial tRNA(Trp) gene, in association with familial late-onset mitochondrial myopathy. The mutation was detected in muscle but not in leukocytes from the family's proband. Morphological and biochemical studies documented a severe defect of muscle cytochrome c oxidase (COX) activity. RFLP analysis of single muscle fibers demonstrated segregation of higher percentages of mutated genomes in COX-negative ragged red fibres compared with normal fibers. A predominant impairment in synthesis of subunits I and III of complex IV due to their highest relative content of tryptophane might explain the greater susceptibility of complex IV to the pathogenic effect of this mutation. A progressive accumulation of mutated genomes in muscle can account for the late onset of symptoms observed in affected members.

Autosomal dominant distal spinal muscular atrophy: an Italian family not linked to 12q24 and 7p14.

Distal spinal muscular atrophy is genetically heterogeneous, as sporadic cases and both autosomal dominant and recessive inheritance have been described. An autosomal dominant distal spinal muscular atrophy with upper limb predominance has been mapped to chromosome 7p, and more recently, an autosomal dominant distal spinal muscular atrophy with lower limb predominance has been linked to chromosome 12q24. We describe a four generation Italian family with autosomal dominant distal spinal muscular atrophy starting between 8 and 30 years with weakness and atrophy of distal leg muscles. The older patients also presented sensorineural deafness. We performed genetic linkage analysis with microsatellite markers D12S366, D12S349, D12S86, D12S321, D12S1612, D12S1349, D12S342, PLA2A on chromosome 12q24 and D7S516, D7S2496, D7S632, D7S2252 on chromosome 7p14. No support for linkage to chromosome 12q24 and 7p14 was found in our family, confirming a genetic heterogeneity within autosomal dominant distal spinal muscular atrophy.

Hepatitis C virus infection and myositis: a virus localization study.

We report a case of myositis associated with chronic hepatitis C virus infection. Muscle biopsy and immunohistochemistry showed perifascicular atrophy, few necrotic and regenerating fibres, scarce perivascular infiltrates, deposits of immunoglobulin G, C3, fibrinogen and MAC in muscle vessel walls, and non-uniform expression of major histocompatibility complex-I antigens among muscle fibres. Hepatitis C virus NS3 antigen and hepatitis C virus RNA were detected in infiltrating cells but not within muscle fibres or endothelial cells. Our findings suggest that humoral-mediated immune mechanisms, not directly related to hepatitis C virus infection of muscle structures, may sustain the local inflammatory reaction in this patient.

Macrophagic myofasciitis: an infantile Italian case.

Macrophagic myofasciitis is a recently identified inflammatory myopathy mostly described in adult French patients complaining of arthro-myalgias and fatigue. It is probably due to intramuscular injection of aluminium-containing vaccines and is characterized by a typical muscular infiltrate of large macrophages with aluminium inclusions. We report a 1-year-old Italian child presenting irritability, delayed motor development, hyperCKemia (up to 10 times the normal value), and typical features of macrophagic myofasciitis on muscle biopsy. The child recovered fully after steroid therapy. Macrophagic myofasciitis is a new treatable cause of motor retardation and hyperCKemia in children, and is probably more common than reported. Diagnosis requires a high index of suspicion and can be missed if biopsy is performed outside the vaccination site.

Becker muscular dystrophy or spinal muscular atrophy?--Dystrophin studies resolve conflicting results of electromyography and muscle biopsy.

We studied a 29-year-old man with slowly progressive proximal leg weakness, calf hypertrophy, and high serum levels of creatine kinase activity. Clinically, it was not possible to identify his as a sporadic instance of Becker muscular dystrophy (BMD) or one of spinal muscular atrophy. The problem arose because electromyography and elevated creatine kinase suggested a myopathy whereas changes in the muscle biopsy resembled a neurogenic disorder. The diagnosis of BMD was made by DNA analysis which detected a deletion at Xp21 and by immunoelectrophoresis and immunohistochemical tests that identified an abnormal form of gene product, dystrophin. These studies were important for genetic counselling, identifying an X-linked disease instead of one that is autosomal recessive.

Facioscapulohumeral muscular dystrophy presenting isolated monomelic lower limb atrophy. Report of two patients with and without 4q35 rearrangement.

Facioscapulohumeral muscular dystrophy has a distinctive regional distribution but variable clinical expression and may be markedly asymmetrical. We report two patients presenting weakness and wasting confined to a single lower limb. Creatine kinase was slightly increased, electromyogram and muscle biopsy were myopathic. Muscle computed tomography showed normal shoulder, mid-arm, pelvic and mid-thigh scans but involvement of calf muscles. In both cases, weakness of facial and periscapular muscles was found in other family members unaware of the disease. Molecular analysis showed 4q35 deletion in one family. These cases broaden the presentation of facioscapulohumeral muscular dystrophy to include isolated monomelic atrophy of lower limb with calf muscle involvement.