Pyramidal Signs Research Articles

New spinocerebellar ataxia subtype caused by SAMD9L mutation triggering mitochondrial dysregulation (SCA49).

Spinocerebellar ataxias consist of a highly heterogeneous group of inherited movement disorders clinically characterized by progressive cerebellar ataxia variably associated with additional distinctive clinical signs. The genetic heterogeneity is evidenced by the myriad of associated genes and underlying genetic defects identified. In this study, we describe a new spinocerebellar ataxia subtype in nine members of a Spanish five-generation family from Menorca with affected individuals variably presenting with ataxia, nystagmus, dysarthria, polyneuropathy, pyramidal signs, cerebellar atrophy and distinctive cerebral demyelination. Affected individuals presented with horizontal and vertical gaze-evoked nystagmus and hyperreflexia as initial clinical signs, and a variable age of onset ranging from 12 to 60 years. Neurophysiological studies showed moderate axonal sensory polyneuropathy with altered sympathetic skin response predominantly in the lower limbs. We identified the c.1877C > T (p.Ser626Leu) pathogenic variant within the SAMD9L gene as the disease causative genetic defect with a significant log-odds score (Zmax = 3.43; θ = 0.00; P < 3.53 × 10−5). We demonstrate the mitochondrial location of human SAMD9L protein, and its decreased levels in patients’ fibroblasts in addition to mitochondrial perturbations. Furthermore, mutant SAMD9L in zebrafish impaired mobility and vestibular/sensory functions. This study describes a novel spinocerebellar ataxia subtype caused by SAMD9L mutation, SCA49, which triggers mitochondrial alterations pointing to a role of SAMD9L in neurological motor and sensory functions.

Technology to support autonomy in patients with Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis is a neurodegenerative pathology, which selectively affects motor neurons of the motor cortex, brain stem and spinal cord, which involves progressive muscle atrophy and weakening of skeletal muscles, spasticity and pyramidal signs, dysarthria, dysphagia and dyspnea. The routine, the normal daily life is completely altered and the impact does not only concern the patient, but the entire personal environment of the patient. In fact, the problems that arise gradually lead the patient to not be able to make any movement in an active and voluntary way and to no longer be able to express himself through verbal communication. Inevitably these deficit aspects also involve the participation and autonomy of the subject, which are increasingly limited in time. The aim of the following study is to demonstrate the validity of the technology as a useful tool for maintaining autonomy in ALS patients. The evaluation, choice and supply of technological devices customized according to the individual needs of the user and his physical and social environment is, in most cases, the most useful and functional solution to improve the quality of life of the patient and those around him. Tools such as electronic wheelchairs and/or eye-controlled communicators can increase the autonomy and participation of the individual, reducing the care burden and allowing the expression of needs, thoughts, social roles and future wills.

Technology to support autonomy in patients with Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis is a neurodegenerative pathology, which selectively affects motor neurons of the motor cortex, brain stem and spinal cord, which involves progressive muscle atrophy and weakening of skeletal muscles, spasticity and pyramidal signs, dysarthria, dysphagia and dyspnea. The routine, the normal daily life is completely altered and the impact does not only concern the patient, but the entire personal environment of the patient. In fact, the problems that arise gradually lead the patient to not be able to make any movement in an active and voluntary way and to no longer be able to express himself through verbal communication. Inevitably these deficit aspects also involve the participation and autonomy of the subject, which are increasingly limited in time. The aim of the following study is to demonstrate the validity of the technology as a useful tool for maintaining autonomy in ALS patients. The evaluation, choice and supply of technological devices customized according to the individual needs of the user and his physical and social environment is, in most cases, the most useful and functional solution to improve the quality of life of the patient and those around him. Tools such as electronic wheelchairs and/or eye-controlled communicators can increase the autonomy and participation of the individual, reducing the care burden and allowing the expression of needs, thoughts, social roles and future wills.

Update on the Pathogenesis, Clinical Diagnosis, and Treatment of Hirayama Disease.

Hirayama disease (HD) is characterized by the juvenile onset of unilateral or asymmetric weakness and amyotrophy of the hand and ulnar forearm and is most common in males in Asia. A perception of compliance with previous standards of diagnosis and treatment appears to be challenged, so the review is to update on HD. First, based on existing theory, the factors related to HD includes, (1) cervical cord compression during cervical flexion, (2) immunological factors, and (3) other musculoskeletal dynamic factors. Then, we review the clinical manifestations: typically, (1) distal weakness and wasting in one or both upper extremities, (2) insidious onset and initial progression for 3–5 years, (3) coarse tremors in the fingers, (4) cold paralysis, and (5) absence of objective sensory loss; and atypically, (1) positive pyramidal signs, (2) atrophy of the muscles of the proximal upper extremity, (3) long progression, and (4) sensory deficits. Next, updated manifestations of imaging are reviewed, (1) asymmetric spinal cord flattening, and localized lower cervical spinal cord atrophy, (2) loss of attachment between the posterior dural sac and the subjacent lamina, (3) forward displacement of the posterior wall of the cervical dural sac, (4) intramedullary high signal intensity in the anterior horn cells on T2-weighted imaging, and (5) straight alignment or kyphosis of cervical spine. Thus, the main manifestations of eletrophysiological examinations in HD include segmental neurogenic damages of anterior horn cells or anterior roots of the spinal nerve located in the lower cervical spinal cord, without disorder of the sensory nerves. In addition, definite HD needs three-dimensional diagnostic framework above, while probable HD needs to exclude other diseases via “clinical manifestations” and “electrophysiological examinations”. Finally, the main purpose of treatment is to avoid neck flexion. Cervical collar is the first-line treatment for HD, while several surgical methods are available and have achieved satisfactory results. This review aimed to improve the awareness of HD in clinicians to enable early diagnosis and treatment, which will enable patients to achieve a better prognosis.

Bypassing conventional anaesthetics: Dexmedetomidine sedation in MEGDEL syndrome

Sir, 3-Methylglutaconic aciduria (MEG) with sensori-neural deafness (D), encephalopathy (E), and neuroradiological evidence of Leigh-like disease (L) (MEGDEL) syndrome is one of the rare mitochondrial disorders with a prevalence of 0.09:100,000. Clinical features include progressive myopathy, hypoglycaemia, feeding difficulty, developmental delay, failure to thrive, acute liver failure, arrhythmias and cardiac failure.[1] We report a case of a 1-year-old female child, weighing 8 kg, scheduled for magnetic resonance imaging (MRI) and computerised tomography (CT) under anaesthesia. The child was diagnosed to have MEGDEL syndrome on the basis of genetic and biochemical testing in the neonatal period. She presented with global developmental delay, bilateral profound hearing loss and bilateral pyramidal signs. There was no history of seizure disorder. A careful anaesthesia plan was chalked out considering the concerns of using conventional anaesthetic agents like propofol and sevoflurane for sedation. Since both these agents are contraindicated in a child with mitochondrial dysfunction, we planned to use dexmedetomidine infusion to maintain sedation during the MRI procedure. The child was admitted on the morning of the procedure and was kept fasting as per American Society of Anesthesiologists guidelines. Intravenous (IV) maintenance fluid with dextrose normal saline at the rate of 25 ml/hour was started 2 hours prior to the procedure and administered till the induction of anaesthesia. Pre-induction blood glucose level was 70 mg/dl and a bolus of 15 ml of dextrose normal saline was also administered prior to induction. Sedation was induced with IV ketamine 0.25 mg/kg, IV dexmedetomidine 0.5 μg/kg and IV midazolam 0.1 mg/kg, in titrated bolus doses. Maintenance of sedation was done with IV dexmedetomidine infusion at the rate of 0.5 μg/kg/hour. The baseline core temperature was 36.4°C and the child was carefully wrapped in warm clothes prior to shifting inside the MR gantry. The imaging period was uneventful and was completed in 35 minutes. The child was next shifted to the CT room with ongoing sedation and the scan was completed in 4 minutes duration. The vital signs of heart rate, respiratory rate, and saturation were continuously monitored and were within normal limits. Following the completion of MRI and CT, dexmedetomidine infusion was discontinued, and the child was monitored for awakening, vital signs, temperature and glucose. The child woke up after 15 minutes and vital signs remained stable during the recovery period. Post-procedure period in the ward was uneventful and the child was discharged the next day. In this report, we want to highlight the use of dexmedetomidine in a patient with MEGDEL syndrome. Dexmedetomidine was used instead of propofol or sevoflurane based anaesthesia, to avoid the development of malignant hyperthermia due to inhaled anaesthetics or mitochondrial dysfunction due to propofol infusion and inhaled anaesthetics. The reduced ability to generate adenosine triphosphate and use oxygen can result in these patients being at more risk of developing rhabdomyolysis and anaesthesia induced malignant hyperthermia. Propofol, though considered safe in malignant hyperthermia, has the same risk as inhaled anaesthetics in causing mitochondrial dysfunction.[2] Centrally acting alpha-adrenergic agonists like dexmedetomidine can be used for sedation as an alternative to propofol. Dexmedetomidine does not depress respiration, protects airway reflexes, provides good anxiolysis and sedation.[3] It has been reported to be safe in patients with mitochondrial disease since the mechanism of action in the central nervous system differs from commonly used general anaesthetics. Successful trials have been conducted using non-triggering anaesthesia with dexmedetomidine in patients with mitochondrial disease.[45] We also made efforts to reduce the metabolic burden of the patient which includes avoidance of prolonged fasting and hypoglycaemia, prevention of hypovolaemia and maintenance of normothermia.[6] In remote location anaesthesia like an MRI suite, dexmedetomidine is a safer alternative to propofol or sevoflurane for children with mitochondrial dysfunction undergoing sedation. In addition, strategies to decrease the metabolic burden in the perioperative period should be stringently employed. Post-anaesthesia monitoring in a hospital setting is prudent for the first 24 hours. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

An NEFH founder mutation causes broad phenotypic spectrum in multiple Japanese families.

Mutations in neurofilament genes have been linked to several neuromuscular disorders. The neurofilament heavy (NEFH) gene was identified as the causative gene of Charcot-Marie-Tooth disease type 2CC (CMT2CC) in 2016, with a toxic gain of function mechanism caused by the translation and aggregation of cryptic amyloidogenic element (CAE) in the 3' untranslated region (UTR). But the NEFH-related clinical and genetic spectrums are still unclear in Japan. We analyzed all variants in the NEFH gene from our in-house whole-exome sequencing data, established from Japanese nationwide patients with neuromuscular disorders, including Charcot-Marie-Tooth (CMT) disease and spinal muscular atrophy (SMA). We identified a c.3017dup (p.Pro1007Alafs*56) variant in NEFH from three families clinically diagnosed with CMT, and one family with SMA. In addition to the patients presented with typical peripheral neuropathies, pyramidal signs were observed from one CMT patient. Whereas the SMA patients showed severe characteristic weakness of triceps brachii and quadriceps femoris. All of these four families reside in Kagoshima Prefecture of Japan, and a following haplotype analysis strongly suggests a founder effect. This is the original report referring to a founder mutation in NEFH. The clinical diversity in our study, comprising CMT, with or without pyramidal signs, and SMA, suggest an extensive involvement of peripheral nerve, anterior horn cells, or both. Our findings broaden the phenotypic spectrum of NEFH-related disorders.

A novel variant in SMG9 causes intellectual disability, confirming a role for nonsense-mediated decay components in neurocognitive development

Biallelic loss-of-function variants in the SMG9 gene, encoding a regulatory subunit of the mRNA nonsense-mediated decay (NMD) machinery, are reported to cause heart and brain malformation syndrome. Here we report five patients from three unrelated families with intellectual disability (ID) and a novel pathogenic SMG9 c.551 T > C p.(Val184Ala) homozygous missense variant, identified using exome sequencing. Sanger sequencing confirmed recessive segregation in each family. SMG9 c.551T > C p.(Val184Ala) is most likely an autozygous variant identical by descent. Characteristic clinical findings in patients were mild to moderate ID, intention tremor, pyramidal signs, dyspraxia, and ocular manifestations. We used RNA sequencing of patients and age- and sex-matched healthy controls to assess the effect of the variant. RNA sequencing revealed that the SMG9 c.551T > C variant did not affect the splicing or expression level of SMG9 gene products, and allele-specific expression analysis did not provide evidence that the nonsense mRNA-induced NMD was affected. Differential gene expression analysis identified prevalent upregulation of genes in patients, including the genes SMOX, OSBP2, GPX3, and ZNF155. These findings suggest that normal SMG9 function may be involved in transcriptional regulation without affecting nonsense mRNA-induced NMD. In conclusion, we demonstrate that the SMG9 c.551T > C missense variant causes a neurodevelopmental disorder and impacts gene expression. NMD components have roles beyond aberrant mRNA degradation that are crucial for neurocognitive development.

Efficacy and safety of intravenous high-dose immunoglobulin in treatment of the severe form of Japanese encephalitis

To explore the efficacy and safety of intravenous immunoglobulin (IVIG) in the treatment of severe Japanese encephalitis (JE). A retrospective study of 124 children diagnosed with the severe or very severe form of JE was undertaken. There were 62 cases in the IVIG group and control group. The efficacy, safety, and tolerability of IVIG were evaluated 3days, as well as 1, 2, and 3weeks after IVIG, respectively, and the prognosis was assessed at 6months. Cox regression survival analysis suggested that the IVIG group reached the criteria for efficacious treatment faster than that in the control group. The duration of unconsciousness and the number of days of seizures, a dull response to light, the pyramidal sign, and meningeal-irritation sign in the IVIG group were shorter than those in the control group (p < 0.05). The number of complications occurring in the IVIG group (including gastrointestinal bleeding and pneumonia) was less than that in the control group (p < 0.05). Cox regression survival analysis suggested that age (p = 0.003) and imaging abnormalities (p = 0.042) had an effect on the efficacy of IVIG treatment. The Liverpool Outcome Score at 6months showed that the prognosis of the IVIG group was better than that of the control group (p < 0.05). IVIG treatment was safe and tolerable. IVIG showed good efficacy, safety, and tolerance for treatment of the severe form of JE. The age and imaging abnormalities of patients affect the efficacy of IVIG treatment.

Mast Syndrome Outside the Amish Community: SPG21 in Europe.

Background:Mast syndrome is a rare disorder belonging to the group of hereditary spastic paraplegias (HSPs). It is caused by bi-allelic mutations in the ACP33 gene, and is originally described in Old Order Amish. Outside this population, only one Japanese and one Italian family have been reported. Herein, we describe five subjects from the first three SPG21 families of German and Austrian descent.Methods:Five subjects with complicated HSP were referred to our centers. The workup consisted of neurological examination, neurophysiological and neuropsychological assessments, MRI, and genetic testing.Results:Onset varied from child- to adulthood. All patients exhibited predominant spastic para- or tetraparesis with positive pyramidal signs, pronounced cognitive impairment, ataxia, and extrapyramidal signs. Neurophysiological workup showed abnormal motor and sensory evoked potentials in all the patients. Sensorimotor axonal neuropathy was present in one patient. Imaging exhibited thin corpus callosum and global brain atrophy. Genetic testing revealed one heterozygous compound and two homozygous mutations in the ACP33 gene.Conclusion:Herein, we report the first three Austrian and two German patients with SPG21, presenting a detailed description of their clinical phenotype and disease course. Our report adds to the knowledge of this extremely rare disorder, and highlights that SPG21 must also be considered in the differential diagnosis of complicated HSP outside the Amish community.

Аcute transverse myelitis and Guillain – Barre overlap syndrome in a patient with СOVID-19

We report a case of transverse myelitis and Guillain–Barre syndrome (GBS) overlap in the 42-year-old patient with moderate course of Coronavirus disease 2019 (СOVID-19). Nasopharyngeal SARS-CoV 2 RT-PCR was positive. Severe neck pain developed in this patient on the 5-th day of СOVID-19. A few hours later weakness in the feet arised and then spread to the thighs and arms. Quadriparesis, arefl exia in all limbs, sensory loss below the level of T4 and bladder/bowel dysfunction were present. Pyramidal signs were negative. There was no increase of COVID-19 severity at the time of neurological signs development. Magnetic resonance imaging of the spinal cord showed the focal lesion in the C2-T1 segments, which was consistent with the features of longitudinally extensive transverse myelitis. Along with the myelitis, acute motor axonal polyneuropathy was diagnosed. This diagnosis of GBS was supported by ascending weakness with arefl exia, albumin-cytological dissociation in cerebrospinal fl uid and the data of neuroelectrophysiological examination. We proposed that both myelitis and GBS had disimmune nature associated with COVID-19. The other possible causes of damage to the spinal cord and peripheral nervous system were excluded.Immunotherapy with high dose of intravenous immunoglobulins was administered. Steroids also were used taking into account the myelitis. At the follow up in 4 months the motor functions were found to be improved nonsignifi cantly, the patient was still severe disabled.

Extensive spontaneous spinal epidural hematoma in infancy. Case report

Introduction: Spontaneous spinal epidural hematomas are a rare condition of spinal cord compression. We report a case of spontaneous spinal epidural hematoma in a child with neurological deficit. Case presentation: A 5-year-old male child with walking difficulty for 15 days. Clinical examination revealed spastic paraparesis and pyramidal signs. Magnetic resonance imaging of the cervical and thoracic spine showed extensive epidural hematoma (C7–T4) with significant medullary edema. Laminotomy was performed for decompression followed by drainage of the hematoma. Spontaneous spinal epidural hematoma usually occurs in the absence of identifiable etiology. The clinical presentation in children is nonspecific. The treatment is based on surgical decompression mainly by laminotomy performed within 48 hours of hematoma formation. Conclusion: In the case presented, the child remained paraparetic despite surgical decompression. The timing (&gt;48 hours) of the surgical procedure probably influenced the poor prognosis.

Spinocerebellar ataxia type 8 in Russian patients

To assess the incidence of spinocerebellar ataxia type 8 (SCA8) in patients with progressive cerebellar ataxia and describe the clinical features of the SCA8 phenotype in Russian patients. Genotyping of CTA/CTG repeats in ATXN8OS gene was carried out in 411 patients with degenerative ataxias using fragment analysis. SCA types 1, 2, 3 and 6 as well as Friedreich's ataxia were preliminarily excluded. All patients underwent brain MRI study. Scale for the Assessment and Rating of Ataxia (SARA), and the Montreal Cognitive Assessment Scale (MoCA) to screen for cognitive impairment were used. Six patients with SCA8 (1.5%) were identified as carriers of the expansion in the ATXN8OS gene (91-152 CTA/CTG repeats). All cases were sporadic. Age of onset ranged from 14 to 42 years. All patients had slowly progressive cerebellar ataxia, oculomotor disturbances, dysarthria, pyramidal signs, and two patients had cognitive impairment. In one patient the clinical presentation corresponded to multiple system atrophy cerebellar type (ataxia, orthostatic hypotension, cerebellum and brainstem atrophy). Brain MRI study in all patients revealed cerebellar atrophy. SCA8 is a rare form of autosomal dominant ataxia with a predominance of the classical phenotype. All identified cases of SCA8 were sporadic, which should be taken into account when planning genetic testing in patients with spinocerebellar ataxia.

Phenotypic Pleiotropy in Arginase Deficiency: A Single Center Cohort.

Arginase deficiency is considered a masquerader of diplegic cerebral palsy. The rarity of hyperammonemic crisis and the slowly progressive course has made it a unique entity among the urea cycle defects. The aim of our study is to describe the varied phenotypic spectrum of children with arginase deficiency. This retrospective study included children and adolescents aged <18 years with a biochemical or genetic diagnosis of arginase deficiency from May 2011 to May 2022. Data were collected from the hospital's electronic database. The clinical presentation, laboratory parameters at baseline and during metabolic decompensation, neuroimaging, electroencephalography findings, and molecular studies were analyzed. About 11 children from nine families with biochemically or genetically proven arginase deficiency were analyzed. The male: female ratio was 2.7:1. Consanguineous parentage was observed in all children. The median age at presentation was 36 months (Range: 5 months-18 years). All children with onset of symptoms in early childhood had a predominant delay in motor milestones of varying severity. Metabolic decompensation with encephalopathy occurred in all except two children (n = 9, 81.8%). Pyramidal signs were present in all patients and additional extrapyramidal signs in two children. Positive family history was present in four probands. Seizures occurred in all children. Epilepsy with electrical status in slow wave sleep and West syndrome was noted in three children. All children had elevated ammonia and arginine at the time of metabolic crisis. The spectrum of neuroimaging findings includes periventricular, subcortical, and deep white matter signal changes and diffusion restriction. The mean duration of follow-up was 38.6 ± 34.08 months. All patients were managed with an arginine-restricted diet and sodium benzoate with or without ornithine supplementation. Spastic diparesis, recurrent encephalopathy, presence of family history, and elevated serum arginine levels must alert the clinician to suspect arginase deficiency. Atypical presentations in our cohort include frequent metabolic crises and epileptic encephalopathy. Early identification and management will ensure a better neurodevelopmental outcome.

Genetic Spectrum of Inherited Neuropathies in India.

Background and Objectives:Charcot-Marie-Tooth (CMT) disease is the commonest inherited neuromuscular disorder and has heterogeneous manifestations. Data regarding genetic basis of CMT from India is limited. This study aims to report the variations by using high throughput sequencing in Indian CMT cohort.Methods:Fifty-five probands (M:F 29:26) with suspected inherited neuropathy underwent genetic testing (whole exome: 31, clinical exome: 17 and targeted panel: 7). Their clinical and genetic data were analysed.Results:Age at onset ranged from infancy to 54 years. Clinical features included early-onset neuropathy (n=23), skeletal deformities (n=45), impaired vision (n=8), impaired hearing (n=6), facial palsy (n=8), thickened nerves (n=4), impaired cognition (n=5), seizures (n=5), pyramidal signs (n=7), ataxia (n=8) and vocal cord palsy, slow tongue movements and psychosis in one patient each. Twenty-eight patients had demyelinating electrophysiology. Abnormal visual and auditory evoked potentials were noted in 60.60% and 37.5% respectively. Sixty two variants were identified in 37 genes including variants of uncertain significance (n=34) and novel variants (n=45). Eleven patients had additional variations in genes implicated in CMTs/ other neurological disorders. Ten patients did not have variations in neuropathy associated genes, but had variations in genes implicated in other neurological disorders. In seven patients, no variations were detected.Conclusion:In this single centre cohort study from India, genetic diagnosis could be established in 87% of patients with inherited neuropathy. The identified spectrum of genetic variations adds to the pool of existing data and provides a platform for validation studies in cell culture or animal model systems.

Creutzfeldt Jacob’s Disease: A Senegalese Observation

Creuzfelt-Jakob Disease is a rare and progressive neurodegenerative disease that results in fatal, transmissible, subacute, spongiform encephalopathy characterized by rapidly progressive dementia and movement disorder. We present a 62-year-old male with no medical history who was admitted to our hospital because of gait and balance disturbance, language impairment and progressive motor deficit of the four limbs. A neurological examination found frontal lobe syndrome signs, myoclonic movements, pyramidal and extra-pyramidal signs. Brain Magnetic Resonance Imaging detected high intensity areas in the basal ganglia. EEG showed generalized triphasic sharp-wave complexes. A Cerebro Spinal Fluid examination found protein 14-3-3. Death occurred six months after onset. This is the first known case of Creuzfelt-Jakob Disease documented in Senegal.

Global Rostral Midbrain Syndrome (GRMS) and Corpus callosum infarction in the context of shunt overdrainage

We report 3 cases of Global rostral midbrain syndrome (GRMS) and Corpus Callosum (CC) infarction, in the context of hydrocephalus followed by shunt dysfunction and slit ventricles. Prior shunt implantation had been indicated for adult-onset hydrocephalus secondary to aqueductal stenosis of varying causes. All three patients had been stable for months before developing repeated shunt dysfunctions, ultimately progressing to parkinsonism, Parinaud syndrome, akinetic mutism, pyramidal signs, cognitive impairment, CC infarction and slit ventricles, in the context of CSF overdrainage. Parkinsonism-related symptoms responded to dopa in all cases, but Parinaud syndrome and cognitive impairment persisted. Although GRMS has been described in the context of a transtentorial pressure gradient after shunt blockage, in these three cases with similar clinical presentation, reverse transtentorial pressure gradient and slit ventricles due to shunt overdrainage was the likely cause. The authors discuss the role of CC infarction and provide a detailed analysis after gathering previously described data, to unify information under a recognizable clinical entity and better understand the underlying pathophysiology, treatment options and outcome

De novo PSEN1 mutation (Pro436Gln) in a very early onset posterior variant of Alzheimer's disease is associated with pyramidal signs.

Alzheimer's disease (AD) is a common cause of dementia even in cases with very early onset, and implication of monogenic mutations in the PSEN1, PSEN2, and APP genes must be considered. Strong family history is the rule in autosomal dominant AD associated with mutations in these genes but, in rare cases, de novo mutations can occur. Case report of a sporadic AD case with onset in his twenties carrying the Pro436Gln mutation (exon 12, TM-9 region) in PSEN1. Comparison with a previously reported familial case carrying the same mutation. A 32 years old male consulted for a 10 years-long mild but slowly progressive learning difficulties, apathy and anxiety. There was no family history of neurologic diseases and both parents were cognitively preserved in their early 70s. The previous two years he had developed progressive visual disturbances including impaired reading, recognizing numbers, letters and faces and, more recently, he had experienced troubles with manual praxias. There were no specific complaints regarding episodic memory. Neuropsychological assessment showed severe visual agnosia and mild impairments in memory, speech, and executive functions. Neurologic examination showed brief distal myoclonus in upper limbs, markedly enhanced reflexes in lower limbs, as well as mild spasticiy. Blood tests, EEG, spinal MRI, and SSEP were normal. Brain MRI and FDG-PET revealed severe parieto-occipital atrophy/hypoperfusion (fig. 1-4). AD CSF biomarkers showed decrease in Ab1-42 and 1-42/1-40 ratio, increased pTau and normal total tau. Amyloid-PET was positive, identifying a high burden of amyloid plaques in posterior cortex. The pathogenic PSEN1 mutation was found in the patient but was absent in his parents. It is remarkable that the phenotype of the previously reported case with this mutation was almost identical as regards onset in the late twenties and associated pyramidalism. PSEN1 mutations should be considered in patients with sporadic very early onset dementia, as de novo mutations may occur. AD CSF biomarkers offer valuable diagnostic information in such cases. The specific mutation has a very strong impact in the clinical phenotype. Further, this case is another example that PSEN1 mutations affecting proline residues have the earliest age at onset.

Cerebral Folate Deficiency, Folate Receptor Alpha Autoantibodies and Leucovorin (Folinic Acid) Treatment in Autism Spectrum Disorders: A Systematic Review and Meta-Analysis.

The cerebral folate receptor alpha (FRα) transports 5-methyltetrahydrofolate (5-MTHF) into the brain; low 5-MTHF in the brain causes cerebral folate deficiency (CFD). CFD has been associated with autism spectrum disorders (ASD) and is treated with d,l-leucovorin (folinic acid). One cause of CFD is an autoantibody that interferes with the function of the FRα. FRα autoantibodies (FRAAs) have been reported in ASD. A systematic review was performed to identify studies reporting FRAAs in association with ASD, or the use of d,l-leucovorin in the treatment of ASD. A meta-analysis examined the prevalence of FRAAs in ASD. The pooled prevalence of ASD in individuals with CFD was 44%, while the pooled prevalence of CFD in ASD was 38% (with a significant variation across studies due to heterogeneity). The etiology of CFD in ASD was attributed to FRAAs in 83% of the cases (with consistency across studies) and mitochondrial dysfunction in 43%. A significant inverse correlation was found between higher FRAA serum titers and lower 5-MTHF CSF concentrations in two studies. The prevalence of FRAA in ASD was 71% without significant variation across studies. Children with ASD were 19.03-fold more likely to be positive for a FRAA compared to typically developing children without an ASD sibling. For individuals with ASD and CFD, meta-analysis also found improvements with d,l-leucovorin in overall ASD symptoms (67%), irritability (58%), ataxia (88%), pyramidal signs (76%), movement disorders (47%), and epilepsy (75%). Twenty-one studies (including four placebo-controlled and three prospective, controlled) treated individuals with ASD using d,l-leucovorin. d,l-Leucovorin was found to significantly improve communication with medium-to-large effect sizes and have a positive effect on core ASD symptoms and associated behaviors (attention and stereotypy) in individual studies with large effect sizes. Significant adverse effects across studies were generally mild but the most common were aggression (9.5%), excitement or agitation (11.7%), headache (4.9%), insomnia (8.5%), and increased tantrums (6.2%). Taken together, d,l-leucovorin is associated with improvements in core and associated symptoms of ASD and appears safe and generally well-tolerated, with the strongest evidence coming from the blinded, placebo-controlled studies. Further studies would be helpful to confirm and expand on these findings.

Acute disseminated encephalomyelitis: A retrospective study of 20 children in a pediatrics department in Tunisia

BackgroundAcute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating disorder of the central nervous system. Little information is available about the clinical and neuroradiological profile or the follow-up of this disease in Tunisian children. AimTo determine the clinical, laboratory, and radiological features and the outcome of ADEM in children admitted to the pediatrics department of a university hospital in Tunisia. MethodsAll children ≤ 18 years old presenting with ADEM and admitted to the tertiary referral center for pediatrics at Sahloul University Hospital from January 2000 to December 2020 were included in the study. The diagnosis of ADEM was confirmed according to the international pediatric multiple sclerosis study group criteria. ResultsA total of 20 patients (13 girls and 7 boys) fulfilled the diagnostic criteria for ADEM. The mean age at diagnosis was 5.6 years. The clinical presentation included polyfocal neurological signs such as cranial hypertension (45%), seizures (35%), and motor weaknesses (55%). Pyramidal tract signs and cranial nerve palsies were noted in 55% of cases. Brain magnetic resonance imaging showed particular features, namely, a relapsing tumor-like form in one case, and optic neuritis and demyelinating lesions of the white matter in the brain and the spinal cord with gadolinium cerebral ring-like enhancement in another case. The treatment consisted of intravenous immunoglobulin in 16 cases (80%) and corticosteroid in 19 cases (95%). Plasmapheresis was used for one patient. Complete recovery was observed in 12 patients (60%); 19 patients (95%) had a monophasic course of the disease while only one patient developed multiphasic ADEM. ConclusionsADEM remains a difficult diagnosis in children. Nevertheless, after prompt diagnosis and adequate treatment, most children with ADEM have a favorable outcome with restitutio ad integrum.

The Genotype and Phenotype Features in a Large Chinese MFN2 Mutation Cohort.

Introduction: Charcot–Marie–Tooth disease type 2A (CMT2A) is a group of clinically and genetically heterogeneous disorders, which is mostly caused by mutations of the mitofusin2 (MFN2) gene. As the genotype–phenotype characteristics of CMT2A were still incompletely understood, we further explored the spectrum of CMT2A variants in China and demonstrated their phenotypic diversities.Methods: A total of 402 index patients/families with CMT throughout Mainland China were enrolled in this study. Among them, we analyzed 20 unrelated index cases with CMT2A by Sanger sequencing, next-generation sequencing, or whole-exome sequencing. Detailed clinical and genetic features of CMT2A patients were collected and analyzed. Of note, de novo mutations were not rare in MFN2 gene; we compared the clinical features of patients from the de novo group with those from the non-de novo group.Results: We identified 20 MFN2 variants, occupying 5.0% of CMT. Most patients presented with early onset and moderate phenotype with abnormal gait and foot drop as the main complaints at onset. Pyramidal signs accounts for 31.6% (6/19) in all patients, which is not uncommon. Four novel variants (p.Tyr752*, c.475-2A>G, p.Val99Met, and p.Arg275_Gln276insArg) were identified in the cohort. Besides, de novo variants occupied 35.0% (7/20) in our study with a much earlier age at onset compared with those in the non-de novo group (p = 0.021).Conclusion: Chinese CMT2A is a predominant typical pure CMT2A, with early onset and mild to moderate phenotype. Given the high frequency of de novo MFN2 mutations, genetic study should be considered for patients with early onset and severe idiopathic axonal neuropathy.