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Background and purpose: Juvenile- or adult-onset forms of severe 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency manifesting as complicated hereditary spastic paraplegia have rarely been described. Methods: Two siblings with mental retardation developed a progressive spastic paraparesis in their late teens. Their diagnostic assessment included extensive neurophysiologic, neuroimaging and metabolic studies. Results: Brain magnetic resonance imaging showed occipital white matter alterations, and electromyography documented a mixed polyneuropathy. Severe hyperhomocisteinemia (>150 Î1⁄4mol/L) associated with the characteristic amino acid profile suggested a diagnosis of severe MTHFR deficiency, confirmed by MTHFR direct sequencing. Treatment with betaine and vitamins benefitted patients' symptoms and diagnostic features. Conclusions: Severe MTHFR deficiency can be a rare, treatable cause of autosomal recessive complicated hereditary spastic paraplegia. Its screening should be part of the diagnostic flowchart for these disorders.

Purpose: To investigate whether prefrontal cortex (PFC) functioning during ataxic gait is linked to compensatory mechanisms or to the typical intra-subject variability of the ataxic gait. Methods: Nineteen patients with chronic ataxia and fifteen healthy subjects were evaluated. The subjects were requested to walk along a straight distance of 10 meters while PFC oxygenation and gait parameters were assessed. PFC activity was evaluated by NIRO-200 while gait analysis was performed by the SMART-D500. To investigate the intra-subject variability of gait, we calculated the coefficient of multiple correlation (CMC) of the hip, knee and ankle kinematic waveforms furthermore, we evaluated the step width. Results: We observed a positive correlation between PFC bilateral oxygenation changes and the step width (r = 0.54; p = 0.02 for the right PFC, and r = 0.50; p = 0.03 for the left PFC). No correlation was found between PFC activity and CMC of the hip, knee and ankle waveforms. Conclusions: Our results suggest that PFC activity is linked to gait compensatory mechanisms more than to the variability of the joint kinematic parameters caused by a defective cerebellar control.

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IMPORTANCE Myotonic dystrophy type 1 (DM1), the most common muscular dystrophy observed in adults, is a genetic multisystem disorder affecting several other organs besides skeletal muscle, including the brain. Cognitive and personality abnormalities have been reported; however, no studies have investigated brain functional networks and their relationship with personality traits/disorders in patients with DM1. OBJECTIVE To use resting-state functional magnetic resonance imaging to assess the potential relationship between personality traits/disorders and changes to functional connectivity within the default mode network (DMN) in patients with DM1. DESIGN, SETTING, AND PARTICIPANTS We enrolled 27 patients with genetically confirmed DM1 and 16 matched healthy control individuals. Patients underwent personality assessment using clinical interview and Minnesota Multiphasic Personality Inventory-2 administration; all participants underwent resting-state functional magnetic resonance imaging. Investigations were conducted at the Istituto di Ricovero e Cura a Carattere Scientifico Santa Lucia Foundation, Catholic University of Sacred Heart, and Azienda Ospedaliera San Camillo Forlanini. INTERVENTION Resting-state functional magnetic resonance imaging. MAIN OUTCOMES AND MEASURES Measures of personality traits in patients and changes in functional connectivity within the DMN in patients and controls. Changes in functional connectivity and atypical personality traits in patients were correlated. RESULTS We combined results obtained from the Minnesota Multiphasic Personality Inventory-2 and clinical interview to identify a continuum of atypical personality profiles ranging from schizotypal personality traits to paranoid personality disorder within our DM1 patients. We also demonstrated an increase in functional connectivity in the bilateral posterior cingulate and left parietal DMN nodes in DM1 patients compared with controls. Moreover, patients with DM1 showed strong associati

Channelopathy mutations prove informative on disease causing mechanisms and channel gating dynamics. We have identified a novel heterozygous mutation in the KCNA1 gene of a young proband displaying typical signs and symptoms of Episodic Ataxia type 1 (EA1). This mutation is in the S4 helix of the voltage-sensing domain and results in the substitution of the highly conserved phenylalanine 303 by valine (p.F303V). The contributions of F303 towards K+ channel voltage gating are unclear and here have been assessed biophysically and by performing structural analysis using rat Kv1.2 coordinates. We observed significant positive shifts of voltage-dependence, changes in the activation, deactivation and slow inactivation kinetics, reduced window currents, and decreased current amplitudes of both Kv1.1 and Kv1.1/1.2 channels. Structural analysis revealed altered interactions between F303V and L339 and I335 of the S5 helix of a neighboring subunit. The substitution of an aromatic phenylalanine with an aliphatic valine within the voltage-sensor destabilizes the open state of the channel. Thus, F303 fine-Tunes the Kv1.1 gating properties and contributes to the interactions between the S4 segment and neighboring alpha helices. The resulting channel's loss of function validates the clinical relevance of the mutation for EA1 pathogenesis.

OBJECTIVE: Idiopathic brachial plexopathy is a non-progressive disorder characterized by the sudden onset of shoulder pain associated with weakness and sometimes paraesthesia of the arm. Clinical and electrophysiological examinations are the primary diagnostic tools and allow physicians to localize the site of damage. MRI neurography is rarely performed in this setting. METHODS: We herein describe the cases of eight consecutive patients suffering from idiopathic brachial plexopathy. All patients underwent clinical visits, neurophysiological evaluations and MRI neurography. RESULTS: We confirmed the primary role of clinical and neurophysiological evaluations in the diagnosis of idiopathic brachial plexopathy and demonstrate the usefulness of brachial plexus MRI neurography for confirming the presence of inflammatory changes. CONCLUSION: In patients with idiopathic brachial plexopathy, MR neurography is a helpful tool for excluding different aetiologies, such as compression or tumour formation, and/or confirming inflammatory changes.

Myotonic dystrophy type 1 (DM1), the most common muscular dystrophy in adults, is characterized by a multisystem involvement. Cognitive involvement predominantly affecting frono-temporal functions is an established clinical feature in this disorder. Brain imaging and metabolic studies showed a predominant involvement of fronto-temporal regions in DM1 patients, yet correlation studies among these findings and neuropsychological data gave contrasting results. In order to contribute to clarify the relationship between the metabolic changes documented in the frontal cortex of DM1 patients and a related cognitive task, we applied the functional near-infrared spectroscopy (fNIRS) during the execution of a phonemic verbal fluency task (pVFT).

The objective of this article is to describe an atypical, remitting-relapsing presentation of carbamazepine toxicity due to its interaction with nebivolol. The method we use is a case report of an elderly epileptic patient in treatment with antiepileptic drugs (AEDs) and antihypertensive drugs, manifesting transient neurological symptoms in association with high blood pressure values. The case report is of a 72-year-old male by forty years of age had tonic-clonic seizures related to the presence of a cerebral arteriovenous malformation. Seizures had been successfully controlled for many years by the same dosage of carbamazepine and lamotrigine, and recently total serum carbamazepine levels resulted within the “therapeutic range.” He had also a history of controlled essential hypertension, but lately he manifested a scarce control of his blood pressure values. Few days after a modification of his antihypertensive therapy, the patient had two transient episodes of dysarthria, ataxia, and dizziness. At the emergency department, his blood pressure values were 190/110 mmHg, ECG and routine blood tests were normal, and a brain CT did not show acute lesions; about two hours later, his neurological examination was normal. Morning fasting carbamazepine serum levels were “normal” too; therefore, his symptoms were initially interpreted as vertebrobasilar transient ischemic attacks. However, the recurrence of similar episodes despite the normalization of his blood pressure suggested a carbamazepine intoxication. Indeed, its dosage resulted too high just in occasion of one of his attacks. A moderate reduction of carbamazepine was followed by cessation of toxicity. This case reminds us to be aware of adverse consequences of other drugs in patients assuming carbamazepine: in this case, its toxicity was consequential to a likely metabolic interaction with nebivolol.

INSR, one of those genes aberrantly expressed in myotonic dystrophy type 1 (DM1) and type 2 (DM2) due to a toxic RNA effect, encodes for the insulin receptor (IR). Its expression is regulated by alternative splicing generating two isoforms: IR-A, which predominates in embryonic tissue, and IR-B, which is highly expressed in adult, insulin-responsive tissues (skeletal muscle, liver, and adipose tissue). The aberrant INSR expression detected in DM1 and DM2 muscles tissues, characterized by a relative increase of IR-A versus IR-B, was pathogenically related to the insulin resistance occurring in DM patients. To assess if differences in the aberrant splicing of INSR could underlie the distinct fiber type involvement observed in DM1 and DM2 muscle tissues, we have used laser capture microdissection (LCM) and RT-PCR, comparing the alternative splicing of INSR in type I and type II muscle fibers isolated from muscle biopsies of DM1, DM2 patients and controls. In the controls, the relative amounts of IR-A and IR-B showed no obvious differences between type I and type II fibers, as in the whole muscle tissue. In DM1 and DM2 patients, both fiber types showed a similar, relative increase of IR-A versus IR-B, as also evident in the whole muscle tissue. Our data suggest that the distinct fiber type involvement in DM1 and DM2 muscle tissues would not be related to qualitative differences in the expression of INSR. LCM can represent a powerful tool to give a better understanding of the pathogenesis of myotonic dystrophies, as well as other myopathies.

Here we describe the first case of myotonic dystrophy type 1 (DM1) associated with facio–scapulo–humeral dystrophy (FSHD). From a clinical point of view, the patient displayed a pattern of muscle involvement reminiscent of both disorders, including hand-grip myotonia, facial, axial and distal limbs muscle weakness as well as a bilateral winged scapula associated with atrophy of the pectoralis major muscle and lumbar lordosis; pelvic muscles were mostly spared. An extensive muscle MRI assessment including neck, shoulder, abdominal, pelvic and lower limb muscles documented radiological features typical of DM1 and FSDH. Molecular genetic studies confirmed that the proband carried both a pathologically expanded DMPK allele, inherited from his father, and a de novo shortened D4Z4 repeat fragment at 4q35 locus.

We assessed clinical, molecular and muscle histopathological features in five unrelated Italian DM1 patients carrying novel variant pathological expansions containing CCG interruptions within the 3'-end of the CTG array at the DMPK locus, detected by bidirectional triplet primed PCR (TP-PCR) and sequencing. Three patients had a negative DM1 testing by routine long-range PCR; the other two patients were identified among 100 unrelated DM1 cases and re-evaluated to estimate the prevalence of variant expansions. The overall prevalence was 4.8 % in our study cohort. There were no major clinical differences between variant and non-variant DM1 patients, except for cognitive involvement. Muscle RNA-FISH, immunofluorescence for MBNL1 and RT-PCR analysis documented the presence of ribonuclear inclusions, their co-localization with MBNL1, and an aberrant splicing pattern involved in DM1 pathogenesis, without any obvious differences between variant and non-variant DM1 patients. Therefore, this study shows that the CCG interruptions at the 3'-end of expanded DMPK alleles do not produce qualitative effects on the RNA-mediated toxic gain-of-function in DM1 muscle tissues. Finally, our results support the conclusion that different patterns of CCG interruptions within the CTG array could modulate the DM1 clinical phenotype, variably affecting the mutational dynamics of the variant repeat.

Autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS) is an early-onset, slowly progressive spastic ataxia associated with axonal-demyelinating polyneuropathy, hypermyelinated retinal fibers, and, sometimes, with an IQ in the lower normal range [1]. MRI studies typically show vermian, cervical, and dorsal spinal cord atrophy, and T2 and FLAIR linear hypointensities in the pons [2]. So far, over 70 mutations in SACS have been described, but the significant clinical variability amongst patients – especially in atypical cases described outside Quebec [1] – limits easy genotype– phenotype correlations. Here, we describe two unrelated ARSACS patients from central Italy carrying two novel mutations in SACS

Purpose: 1) to verify if prefrontal cortex (PFC) is activated during over ground walking in ataxic patients, 2) to correlate the clinical parameters of gait with the PFC activation patterns. Methods: Fourteen patients and 20 healthy subjects were studied. Ataxia was assessed by the Scale for the Assessment and Rating of Ataxia (SARA). A 2-channel near-infrared system was used to investigate the changes in oxygenated ([O2Hb]t) and deoxygenated ([HHb]t) hemoglobin concentrations on the PFC during gait. [O2Hb] baseline-corrected activation values ([O2Hb]c) were calculated by the difference between [O2Hb]t and [O2Hb] during upright posture ([O2Hb]b). Results: [O2Hb]t was increased for both channels (respectively p < 0.01 and p = 0.01) only in the patients. No variation was observed in [HHB]t. The correlation coefficient between [O2Hb]c and the SARA gait score was respectively r: 0.878 (p < 0.01) and r: 0.839 (p < 0.01) for the right and left PFC, between [O2Hb]c and the SARA stance score respectively r: 0.893 (p < 0.01) and r: 0.832 (p < 0.01). Conclusions: During over ground gait PFC is bilaterally activated in patients with severe chronic ataxia. These findings may be associated with compensatory mechanisms which are involved in severe conditions when other nervous centers controlling balance are functionally not efficient.

It has been recently reported that a large proportion of patients with familial and sporadic amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD) carries the hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72. We describe a patient with a complex phenotype characterized by behavioural variant of FTD, Parkinsonism and ALS with predominant lower motor neuron involvement in which the C9ORF72 expansion was detected

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.

BACKGROUND AND PURPOSE: Duchenne muscular dystrophy carriers represent a rare condition that needs to be recognized because of the possible implications for prenatal diagnosis. Muscle biopsy is currently the diagnostic instrument of choice in sporadic patients. We wanted to verify whether muscle magnetic resonance imaging (MRI) could identify a pattern of involvement suggestive of this condition and whether it was similar to that reported in Duchenne and Becker muscular dystrophy. METHODS: Evaluation of pelvic and lower limb MRI scans of 12 dystrophinopathy carriers was performed. RESULTS: We found a frequent involvement of the quadratus femoris, gluteus maximus and medius, biceps femoris long head, adductor magnus, vasti and paraspinal muscles, whilst the popliteus, iliopsoas, recti abdominis, sartorius, and gracilis were relatively spared. Asymmetry was a major feature on MRI; it could be detected significantly more often than with sole clinical examination and even in patients without weakness. CONCLUSIONS: The pattern we describe here is similar to that reported in Duchenne and Becker muscular dystrophy, although asymmetry represents a major distinctive feature. Muscle MRI was more sensitive than clinical examination for detecting single muscle involvement and asymmetry. Further studies are needed to verify the consistency of this pattern in larger cohorts and to assess whether muscle MRI can improve diagnostic accuracy in carriers with normal dystrophin staining on muscle biopsy.

Transitory depression of the compound muscle action potential during repetitive nerve stimulation is a well-documented neurophysiologic finding in recessive myotonia congenita. It represents the neurophysiologic counterpart of the transitory weakness often impairing patients at the beginning of a movement after rest, and it is usually better induced using high-rate nerve stimulations. The authors examined 30 patients with recessive myotonia congenita and carried out a 3 Hz nerve stimulation study to ascertain to what extent this protocol was able to detect the occurrence of transitory depression. Their findings were compared with the results obtained by 12 patients affected by dominant myotonia congenita and 12 patients affected by nondystrophic myotonia due to SCN4A mutations. Molecular genetic analysis of the CLCN1 and SCN4A genes was also performed. The 3 Hz nerve stimulation protocol was well tolerated and showed high sensitivity, resulting positive in 66% of recessive case and good reproducibility, if performed after an adequate period of rest. All dominant cases and all patients affected by myotonia due to SCN4A mutations showed negative results. Molecular studies identified 26 different CLCN1 mutations, 16 of which were novel. Transitory depression confirmed to vary in accordance to CLCN1 mutations. The 3 Hz protocol was well tolerated and showed good sensitivity and reproducibility. Furthermore, this test might be suitable for genotype-phenotype correlation studies.

We want to report on the positive outcome of a low-dosage zinc regimen in a woman affected byneurologic Wilson’sdisease(WD)during pregnancy.

BACKGROUND: Autosomal recessive hereditary spastic paraplegia with thin corpus callosum is a neurodegenerative disorder characterized by spastic paraparesis, cognitive impairment, and peripheral neuropathy. The neuroradiologic hallmarks are thin corpus callosum and periventricular white matter changes. Mutations in the SPG11 gene have been identified to be a major cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum and recently also proven to be responsible for juvenile parkinsonism associated with spastic paraplegia. METHODS: We describe one Italian autosomal recessive hereditary spastic paraplegia with thin corpus callosum patient who unusually presented at onset, 16 years, with parkinsonism-like features, responsive to dopaminergic therapy. Then the clinical picture evolved and became more complex. A brain magnetic resonance imaging scan showed thin corpus callosum and hyperintense T(2)-weighted lesions in periventricular regions, and the (123)I-ioflupane single-photon emission coupled tomography was abnormal. RESULTS: Genetic analysis detected two novel mutations, a c.3664insT variant in compound heterozygosity with a c.6331insG mutation, in SPG11. DISCUSSION: This case confirms the high genetic and clinical heterogeneity associated with SPG11 mutations. It also offers further evidence that parkinsonism may initiate autosomal recessive hereditary spastic paraplegia with thin corpus callosum and that parkinsonian symptoms can have variable dopaminergic response in these patients.

GM2 gangliosidosis type Sandhoff is caused by a defect of beta-hexosaminidase, an enzyme involved in the catabolism of gangliosides. It has been proposed that substrate reduction therapy using N-butyl-deoxynojirimycin (miglustat) may delay neurological progression, at least in late-onset forms of GM2 gangliosidosis. We report the results of a 3-year treatment with miglustat (100 mg t.i.d) in a patient with chronic Sandhoff disease manifesting with an atypical, spinal muscular atrophy phenotype. The follow-up included serial neurological examinations, blood tests, abdominal ultrasound, and neurophysiologic, cognitive, brain, and muscle MRI studies. We document some minor effects on neurological progression in chronic Sandhoff disease by miglustat treatment, confirming the necessity of phase II therapeutic trials including early-stage patients in order to assess its putative efficacy in chronic Sandhoff disease.

Charcot-Marie-Tooth disease (CMT) is a group of clinically and genetically heterogeneous neuropathies classically divided into demyelinating (CMT1) and axonal forms (CMT2). The most common demyelinating form is CMT1A, due to a duplication in the gene encoding the peripheral myelin protein 22 (PMP22). Less frequently, mutations in the myelin protein zero gene (MPZ/P0) account for demyelinating CMT1B. Herein, we report a patient presenting with an isolated hyperCKemia in whom electrophysiological and pathological findings revealed a demyelinating and axonal neuropathy. Sequencing of the MPZ gene revealed a 306delA at codon 102 in the proband and in two relatives. This mutation has been already described in association with paucisymptomatic CMT without hyperCKemia.

OBJECTIVE: To describe a case of acute nonherpetic limbic encephalitis (LE) with negative testing for antibodies directed against onconeuronal and cell membrane antigens, including voltage-gated potassium channels and N-methyl-D-aspartate receptor, that showed a dramatic response to immune therapy. MATERIALS AND METHODS: A 30-year-old woman manifested generalized seizures, altered consciousness, and memory impairment shortly after a prodromal viral illness. Few days later the patient developed a drug-resistant epileptic status. RESULTS: Electroencephalograph showed bitemporal slowing and paroxysmal slow wave bursts. Brain magnetic resonance imaging showed bilateral swelling in the medial temporal lobes. Cerebrospinal fluid analysis ruled out viral etiologies. A diagnostic search for cancer, including serum testing for known onconeuronal antibodies proved negative. Screening for cell membrane antigen antibodies, including voltage-gated potassium channels and N-methyl-D-aspartate receptor, was also negative. Suspecting an autoimmune etiology, we started an immunomodulatory treatment with intravenous immunoglobulin followed by a short course of oral prednisone, obtaining a full clinical recovery. CONCLUSIONS: Our report confirms previous observations of "seronegative" autoimmune LE, suggesting the presence of other, still unknown central nervous system antigens representing a target of a postinfectious, autoimmune response in these patients. Moreover, it emphasizes the importance of early recognition and treatment of acute autoimmune LE, to reduce the risk of intensive care unit-related complications and the occurrence of permanent cognitive or behavioral defects.