Adult-onset leukodystrophy with vanishing white matter: a case series of 19 patients.

BACKGROUND: Leukodystrophy with vanishing white matter (LVWM) is an autosomal recessive disease with typical pediatric-onset caused by mutations in one of the five EIF2B genes. Adult-onset (AO) cases are rare. METHODS: In this observational study, we reviewed clinical and laboratory information of the patients with AO-LVWM assessed at two referral centers in Italy and Portugal from Jan-2007 to Dec-2019. RESULTS: We identified 18 patients (13 females) with AO-LVWM caused by EIF2B5 or EIF2B3 mutations. Age of neurological onset ranged from 16 to 60 years, with follow-ups occurring from 2 to 37 years. Crucial symptoms were cognitive and motor decline. In three patients, stroke-like events were the first manifestation; in another, bladder dysfunction remained the main complaint across decades. Brain MRI showed white matter (WM) rarefaction in all cases, except two. Diffusion-weighted imaging documented focal hyperintensity in the acute stage of stroke-like events. 1H-spectroscopy primarily showed N-acetyl-aspartate reduction; 18fluorodeoxyglucose-PET revealed predominant frontoparietal hypometabolism; evoked potential studies demonstrated normal-to-reduced amplitudes; neuro-ophthalmological assessment showed neuroretinal thinning, and b-wave reduction on full-field electroretinogram. Interestingly, we found an additional patient with LVWM-compatible phenotype and monoallelic variants in two distinct eIF2B genes, EIF2B1 and EIF2B2. CONCLUSIONS: AO-LVWM presents varying clinical manifestations at onset, including stroke-like events. WM rarefaction is the most consistent diagnostic clue even in the latest onset cases. Spectroscopy and electrophysiological features are compatible with axon, rather than myelin, damage. Cerebral glucose metabolic abnormalities and retinal alterations can be present. LVWM might also be caused by a digenic inheritance affecting the eIF2B complex.

Early Parkinsonism in a Senegalese girl with Lafora disease.

We report the atypical presentation of Lafora disease in a Senegalese girl carrying the homozygous variant, c.560A>C, in the NHLRC1 gene. At 13 years, the patient developed myoclonic and visual seizures, progressive psychomotor slowing, and cognitive decline. At 14 years, a neurological examination showed severe hypomimia, bradykinesia, rigidity and low-amplitude myoclonic jerks. Flash-visual and somatosensory evoked potentials showed an increased amplitude of the cortical components, while an electroretinogram showed attenuated responses. An EEG showed diffuse polyspikes associated with positive-negative jerks as well as posterior slow waves and irregular spikes. The electroclinical picture suggested the diagnosis of Lafora disease regarding the association of visual seizures, cognitive deterioration, and action myoclonus, together with the EEG and evoked potential findings. Two uncommon findings were the prominence of extrapyramidal signs in the early stage of disease (which are rarely reported) and attenuation of electroretinal responses. We consider that Lafora disease should be included in the diagnostic work-up for juvenile Parkinsonism, when associated with epilepsy.

Expanding the spectrum of genes responsible for hereditary motor neuropathies.

BACKGROUND: Inherited peripheral neuropathies (IPNs) represent a broad group of genetically and clinically heterogeneous disorders, including axonal Charcot-Marie-Tooth type 2 (CMT2) and hereditary motor neuropathy (HMN). Approximately 60%-70% of cases with HMN/CMT2 still remain without a genetic diagnosis. Interestingly, mutations in HMN/CMT2 genes may also be responsible for motor neuron disorders or other neuromuscular diseases, suggesting a broad phenotypic spectrum of clinically and genetically related conditions. Thus, it is of paramount importance to identify novel causative variants in HMN/CMT2 patients to better predict clinical outcome and progression. METHODS: We designed a collaborative study for the identification of variants responsible for HMN/CMT2. We collected 15 HMN/CMT2 families with evidence for autosomal recessive inheritance, who had tested negative for mutations in 94 known IPN genes, who underwent whole-exome sequencing (WES) analyses. Candidate genes identified by WES were sequenced in an additional cohort of 167 familial or sporadic HMN/CMT2 patients using next-generation sequencing (NGS) panel analysis. RESULTS: Bioinformatic analyses led to the identification of novel or very rare variants in genes, which have not been previously associated with HMN/CMT2 (ARHGEF28, KBTBD13, AGRN and GNE); in genes previously associated with HMN/CMT2 but in combination with different clinical phenotypes (VRK1 and PNKP), and in the SIGMAR1 gene, which has been linked to HMN/CMT2 in only a few cases. These findings were further validated by Sanger sequencing, segregation analyses and functional studies. CONCLUSIONS: These results demonstrate the broad spectrum of clinical phenotypes that can be associated with a specific disease gene, as well as the complexity of the pathogenesis of neuromuscular disorders.

Movement-activated cortical myoclonus in Dravet syndrome.

PURPOSE: we characterized multifocal myoclonus in Dravet syndrome (DS) that was never systematically typified before. METHODS: we studied EEG-EMG recordings of 19 consecutive patients, aged 2-29 years, with DS associated with SCN1A gene mutations to detect and evaluate myoclonus based on the spectrum of EMG activity on antagonist muscle pairs and cortico-muscular coherence (CMC). RESULTS: multifocal action myoclonus was detected in all patients corresponding to brief EMG bursts, which occurred synchronously on antagonist muscles at a frequency peaking in beta band. There was significant CMC in beta band, and a cortico-muscular transfer time consistent with a cortical origin of the jerks. The somatosensory evoked potentials (SSEPs) were giant in only one patient who also showed exaggerated long-loop reflexes (LLRs). The nine patients who had experienced myoclonic seizures showed greater CMC. CONCLUSIONS: The cortical myoclonus consistently observed in patients with DS shows features that are similar to those characterizing progressive myoclonus epilepsy, but differs because it does not have a severely worsening course and is not commonly associated with increased SSEPs or enhanced LLRs. This kind of myoclonus is an intrinsic feature of DS associated with SCN1A mutations, and may be a cause of disability. SIGNIFICANCE: We hypothesize that myoclonus is generated in cortical motor areas by hyper-synchronous oscillations, which are possibly due to sodium channel dysfunction.

Spinal and bulbar muscular atrophy and Charcot-Marie-Tooth type 1A: Co-existence of two rare neuromuscular genetic diseases in the same patient.

Spinal and bulbar muscular atrophy is an X-linked neuromuscular disease caused by a trinucleotide CAG repeat expansion in the androgen receptor gene; it is clinically characterized by adult-onset, slowly progressive weakness and atrophy mainly affecting proximal limb and bulbar muscles. Charcot-Marie-Tooth disease type 1A is an autosomal dominant polyneuropathy due to peripheral myelin protein 22 gene duplication and characterized by slowly progressive distal limb muscle weakness, atrophy and sensory loss with foot deformities. Here we report the co-occurrence of both neuromuscular genetic diseases in the same male patient. Difficulties in climbing stairs and jaw weakness were presenting symptoms consistent with SBMA. However, predominant distal weakness and bilateral pes cavus were rather suggestive of a hereditary polyneuropathy. The combination of two diseases, even if extremely rare, should be considered in the presence of atypical symptoms; in the case of genetic diseases this event may have important implications on family members' counseling.

Electroclinical spectrum of the neuronal ceroid lipofuscinoses associated with CLN6 mutations.

OBJECTIVES: To describe the clinical and neurophysiologic patterns of patients with neuronal ceroid lipofuscinoses associated with CLN6 mutations. METHODS: We reviewed the features of 11 patients with different ages at onset. RESULTS: Clinical disease onset occurred within the first decade of life in 8 patients and in the second and third decades in 3. All children presented with progressive cognitive regression associated with ataxia and pyramidal and extrapyramidal signs. Recurrent seizures, visual loss, and myoclonus were mostly reported after a delay from onset; 7 children were chairbound and had severe dementia less than 4 years from onset. One child, with onset at 8 years, had a milder course. Three patients with a teenage/adult onset presented with a classic progressive myoclonic epilepsy phenotype that was preceded by learning disability in one. The EEG background was slow close to disease onset in 7 children, and later showed severe attenuation; a photoparoxysmal response (PPR) was present in all. The 3 teenage/adult patients had normal EEG background and an intense PPR. Early attenuation of the electroretinogram was seen only in children with onset younger than 5.5 years. Somatosensory evoked potentials were extremely enlarged in all patients. CONCLUSIONS: In all patients, multifocal myoclonic jerks and seizures were a key feature, but myoclonic seizures were an early and prominent sign in the teenage/adult form only. Conversely, the childhood-onset form was characterized by initial and severe cognitive impairment coupled with electroretinogram and EEG attenuation. Cortical hyperexcitability, shown by the PPR and enlarged somatosensory evoked potentials, was a universal feature.

A new mutation in GJC2 associated with subclinical leukodystrophy.

Recessive mutations in GJC2, the gene-encoding connexin 47 (Cx47), cause Pelizaeus-Merzbacher-like disease type 1, a severe dysmyelinating disorder. One recessive mutation (p.Ile33Met) has been associated with a much milder phenotype--hereditary spastic paraplegia type 44. Here, we present evidence that a novel Arg98Leu mutation causes an even milder phenotype--a subclinical leukodystrophy. The Arg98Leu mutant forms gap junction plaques in HeLa cells comparable to wild-type Cx47, but electrical coupling was 20-fold lower in cell pairs expressing Arg98Leu than for cell pairs expressing wild-type Cx47. On the other hand, coupling between Cx47Arg98Leu and Cx43WT expressing cells did not show such reductions. Single channel conductance and normalized steady-state junctional conductance-junctional voltage (G(j)-V(j)) relations differed only slightly from those for wild-type Cx47. Our data suggest that the minimal phenotype in this patient results from a reduced efficiency of opening of Cx47 channels between oligodendrocyte and oligodendrocyte with preserved coupling between oligodendrocyte and astrocyte, and support a partial loss of function model for the mild Cx47 associated disease phenotypes.

Recurrent generalized seizures, visual loss, and palinopsia as phenotypic features of neuronal ceroid lipofuscinosis due to progranulin gene mutation.

We detail the phenotype of a novel form of neuronal ceroid lipofuscinosis due to a homozygous progranulin gene mutation (c.813_816del; CLN11 MIM #614706). The symptoms appeared in two young adult siblings, and included progressive retinopathy, recurrent generalized seizures, moderate ataxia, and subtle cognitive dysfunction. Long-lasting episodes of palinopsia were a recurring symptom and associated with polyphasic visual-evoked potential waveform that suggested hyperexcitability of the occipital cortex. Electroencephalography showed rare spike-wave paroxysms, and magnetic resonance imaging revealed selective cerebellar atrophy. Skin biopsy revealed fingerprint storage and the absence of progranulin protein. Electron microscopy of peripheral blood leukocytes showed fingerprint profiles in 1/100 lymphocytes. These findings define a novel phenotype and provide clues for better understanding of progranulin function. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Tethered cord: natural history, surgical outcome and risk for Chiari malformation 1 (CM1): a review of 110 detethering.

The surgical results of this series of occult spina bifida seem better than the natural history registered in the long pre-operative period in terms of neurological deterioration. The major contribution to this result is attributed to neurophysiological monitoring that lowers the risks of permanent damage and increases the percentage of effective detethering. The present series of TCS, due to conus and filar lipoma, documents that CM1 is a really rare association occurring in less than 6% of the patients, despite the low position of conus. The detethering procedure did not influence the tonsillar position, thus excluding the correlation between the tethering and the tonsillar descent. The genetic alteration documented in a girl reinforces the hypothesis of a rare complex polymaformative picture deserving multiple procedures according to the prevailing clinical symptoms.

Characterization of severe action myoclonus in sialidoses.

To asses the characteristics of severe action myoclonus in three patients with progressive myoclonus epilepsy (PME) due to sialidosis. We assessed EEG-EMG coherence, relative power (RP) and bandwidth (BW) of the EMG-peak associated with myoclonus; we also evaluated somatosensory evoked potentials and long-loop reflexes (LLRs). We compared the findings with those obtained in ten Unverricht-Lundborg (UL) patients. The presentation of sialidosis included macular cherry-red spot, skeletal malformation and polyneuropathy in the infantile form and optic atrophy in the juvenile form. From its onset in adolescence myoclonus rapidly worsened, quickly leading to severe disability. In sialidosis patients, the EMG-peak was characterised by higher RP (p<0.01) and narrower BW (p<0.02) than in UL. EEG-EMG coherence values were higher (p<0.05) than in UL patients. Taking into account both sialidosis and UL patients, the coherence values and the RP of the EMG-peak were directly correlated with the severity of the myoclonus; while BW values were inversely correlated. All these measures showed extreme values in sialidosis patients. In the sialidosis patients, the strongly rhythmic recurrence of the jerks reflected on LLR, which included multiple components. Subtle differences indicate an especially high level of cortical motor synchronization in the sialidosis patients, which may account for their particularly severe motor impairment. Neurophysiological indexes indicating high EEG-EMG synchronization parallels the severity of the myoclonus.

Lower limb areflexia without central and peripheral conduction abnormalities is highly suggestive of Gerstmann-Sträussler-Scheinker disease Pro102Leu.

Gerstmann-Sträussler-Scheinker disease Pro102Leu (GSS102) is a rare autosomal dominant inherited prion disease due to a substitution of proline for leucine at codon 102 in the Prion Protein gene, and characterized by early walking difficulties and much later occurring dementia. We report clinical, electrophysiological and neuroradiological features of seven novel Italian cases of GSS102. The findings in our series support the thesis that early signs of GSS102 (including areflexia, ataxia, lower limb weakness, and painful dysesthesias) are likely due to a caudal myelopathic process, and suggest that GSS102 should be included among the causes of ataxia with areflexia. Moreover, our observations show that in patients with GSS102, as opposed to Friedreich's ataxia and other forms of ataxia with areflexia, nerve conduction studies and somato-sensory evoked potentials are normal, despite the presence of lower limb areflexia. Hence, in subjects with walking difficulties, the presence of lower limb areflexia without central and peripheral conduction abnormalities is highly suggestive or possibly pathognomonic of GSS102, and can easily guide the clinicians to make the diagnosis of this rare neurodegenerative disease.

Myoclonus in Creutzfeldt-Jakob disease: polygraphic and video-electroencephalography assessment of 109 patients.

We used electroencephalography (EEG)-polygraphic recordings to classify myoclonus in 109 patients with Creutzfeldt-Jakob disease (CJD) on the basis of its electromyography (EMG) pattern, time course, distribution, and EEG correlates. We recorded myoclonic jerks in 55 patients (50.4%), and we classified them as periodic myoclonus in 28, rhythmic in 13, and irregular in 20 (6 patients showed two types of myoclonus). Myoclonus occurred as a prominently negative event (interrupting the EMG discharge) in 10. Periodic sharp-wave complexes (PSWCs) were present in all but one patient with myoclonic jerks but were time-locked with EMG-bursts only in case of periodic myoclonus. Jerk-locked back averaging revealed a variable EEG-EMG transfer-time commonly exceeding that characterizing cortical myoclonus. Myoclonus was frequently associated with Met/Met polymorphism at codon 129 of the prion protein gene, but it was also observed in association with Met/Val or Val/Val polymorphisms provided that the EEG showed the presence of the PSWC pattern. The presence of enlarged somatosensory evoked potentials significantly correlated with the myoclonic presentation, as did MR signal hyperintensity involving the cortical mantle. Our observations on the basis of standard polygraphic criteria suggest that CJD associates with a remarkable variety of myoclonic jerks, and therefore different brain structures are probably involved as generators. The significant association between the presence of all myoclonus types with PSWCs suggests that hyperexcitable corticosubcortical loops are always required to generate (or allow) both myoclonus and the EEG complexes, either they are time locked or not.

A Multicentre Database for Normative Brainstem Auditory Evoked Potentials (BAEPs) in Children: Methodology for Data Collection and Evaluation.

BACKGROUND: The influence of physiological and methodological factors on recordings of brainstem auditory evoked potentials (BAEPs) is greater in children than in adults. OBJECTIVE: To collect and evaluate BAEP data in normal children, and measure intra- and inter-laboratory variability. METHODS: Seven hundred and fifty unselected BAEP recordings were collected and evaluated from children ranging from neonates to 14-year-olds by eight laboratories in Italy. RESULTS: In newborns, three laboratories showed satisfactory concordance; wave I was more broadly distributed than wave V and IPL I-V. The evaluation of pooled BAEP data from the older children showed that laboratories with age-matched data gave overlapping results; those with unmatched-age data differed significantly. The sound intensities of the laboratories did not significantly affect absolute BAEP latencies or IPLs. Females had shorter latencies than males; the difference was not significant. A single exponential regression model was an adequate but not the best predictor of normal data. CONCLUSIONS: The pooled data were consistent with the physiological maturation of the brainstem acoustic pathway. The BAEPs was reliably normalised using the natural logarithm of age. The differences between Centres were related to sample size, measurement accuracy, and inclusion and selection criteria. SIGNIFICANCE: The creation of multicentre common database from an unmatched data collection is feasible and reliable enough for clinical diagnosis and multicentre clinical research.

Systemic sagopilone (ZK-EPO) treatment of patients with recurrent malignant gliomas.

It has been demonstrated that sagopilone (ZK-EPO) has antitumor activity in human orthotopic glioma models in vitro and in vivo. The objective of this study was to evaluate the safety and efficacy of ZK-EPO in patients with pretreated, recurrent malignant gliomas. Fifteen patients with recurrent malignant gliomas who had received prior surgery, radiotherapy, and >or=2 lines of alkylating chemotherapy were recruited. ZK-EPO (16 mg/m(2)) was administered iv for 3 h every 21 days. The primary end point was six months progression-free survival (PFS-6); secondary end points were safety, toxicity, response rate, and median time to progression (TTP). Magnetic resonance imaging (MRI) evaluations were performed every two cycles and toxicity was evaluated at each cycle using common terminology criteria for adverse events (CTCAE 3.0). A median of four cycles was administered. The median TTP was 13 weeks. PFS-6 was achieved in five patients (33%), three with glioblastoma multiforme and two with anaplastic astrocytoma. The most common treatment-related adverse event was neuropathy, which occurred in 6/15 patients. ZK-EPO had an acceptable safety profile and clinically relevant activity in patients with pretreated, recurrent malignant gliomas.

Functional MRI/event-related potential study of sensory consonance and dissonance in musicians and nonmusicians.

Pleasurability of individual chords, known as sensory consonance, is widely regarded as physiologically determined and has been shown to be associated with differential activity in the auditory cortex and in several other regions. Here, we present results obtained contrasting isolated four-note chords classified as consonant or dissonant in tonal music. Using event-related functional MRI, consonant chords were found to elicit a larger haemodynamic response in the inferior and middle frontal gyri, premotor cortex and inferior parietal lobule. The effect was right lateralized for nonmusicians and less asymmetric for musicians. Using event-related potentials, the degree of sensory consonance was found to modulate the amplitude of the P1 in both groups and of the N2 in musicians only.