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C9orf72 gene repeat expansion (C9RE) is the most frequent gene variant associated with amyotrophic lateral sclerosis (ALS). We aimed to study the phenotype of motor neurone disease (MND) patients with C9RE in a Portuguese cohort. Demographical and clinical data of MND patients with (C9RE+) and without C9RE were compared. ALS al Rating Scale-Revised (ALSFRS-R) and Edinburgh Cognitive and Behavioural ALS Screen (ECAS) were used to evaluate functional and cognitive performance, respectively. Survival analysis was performed using Kaplan Meier log-rank test and Cox proportional hazards model. We included 761 patients of whom 61 (8.0 %) were C9RE+. C9RE+ patients had a higher frequency of ALS (95.1 vs 78.4 %, p = 0.002), and lower frequency of progressive muscular atrophy (3.3 vs 16.7 %, p = 0.006). C9RE+ was associated with earlier age of onset (58.1 vs 62.6 years, p = 0.003) and more frequent MND family history (65.5 vs 11.4 %, p < 0.001). Gender, ethnicity, onset site, diagnostic delay, disease progression rate until diagnosis (ΔF), ALSFRS-R and time until non-invasive ventilation did not differ between groups. Cognitive/behavioural symptoms and ECAS did not differ between groups, except a worse visuospatial score in C9RE+ group (p = 0.035). Death rate was 1.8 and 1.6 times higher in C9RE+ patients with MND and ALS, respectively. Significant survival prognostic factors in C9RE+ group were diagnosis delay (HR = 0.96, 95 %CI 0.92–0.99, p = 0.008) and ΔF (HR = 1.93, 95 %CI 1.26–2.96, p = 0.002). Our study corroborates most previous cohorts' findings, but harbours some singularities regarding onset site, phenotype, and cognitive profile, that contribute to a better understanding of C9RE epidemiology. • A retrospective Portuguese cohort study of MND patients with C9RE was performed. • MND patients with C9RE have an earlier disease onset and shorter survival. • Bulbar onset was not more frequent in patients with C9RE. • Progressive muscular atrophy was less prevalent in patients with C9RE. • Cognitive/behavioural abnormalities were not more frequent in patients with C9RE. [ABSTRACT FROM AUTHOR]

Rare diseases are characterized by substantial unmet need mostly because the majority have limited, or no treatment options and a large number also affect children. Since the inception of EU orphan regulation in 2000 the European Medicines Agency Committee for Orphan Medicinal Products has received several applications for paediatric rare neuromuscular diseases (PERAN) however treatment options remain limited. Here we discuss the results form an observational, retrospective, cross-sectional study to characterize the currently authorised orphan medicinal products (OMP) and orphan designations (OD) given to products for PERAN in the last two decades. In the EU about half of PERAN diseases have at least one active OD approved since 2000, and about half of these are for Duchenne muscular dystrophy (DMD). The large majority of PERAN diseases do not have an authorised medicine with only 6 OMP currently authorised for Spinal muscular atrophy (3); DMD (1) and Myasthenia gravis (2). One in five products have inactive or discontinued regulatory development but clinical trials are ongoing for the vast majority of PERAN diseases, and more than half are in the final stage of clinical research with significantly more products with medical plausibility based in clinical data reaching advanced stages in clinical development. • Overview of drug development for orphan products designated or approved for paediatric rare neuromuscular diseases (PERAN) • Majority of PERAN without approved medicines. More than half designated products are in the final stages of clinical trials • All PERAN have products with active development: orphan designated, clinical research phase, approval submission • A hight number of designations per disease, appears to have successfully translated into a hight number of drug approvals • Monitoring and resource provision to "Orphanage" of 1/5 products with inactive research, could improve regulatory development [ABSTRACT FROM AUTHOR]

Serum biomarkers that might detect clinical progression are currently lacking for Spinal and bulbar muscular atrophy (SBMA), thus limiting the effectiveness of possible future pharmacological trials. Elevation of cardiac troponin T (cTnT) unrelated to myocardial damage in a motor neuron (MN) disease as amyotrophic lateral sclerosis (ALS) was associated to disease severity. We enrolled 47 SBMA patients and 5 Spinal muscular atrophy (SMA) type 3 adult patients as control group; each SBMA patient was evaluated at baseline and at one-year follow-up visit. Demographic and clinical data including functional scores (SBMAFRS) were collected; serum was collected as standard of care and tested for cardiac troponins. Levels of cTnT but not cTnI were increased in SBMA with respect to reference values; unlike other neuromuscular diseases, SMA patients had overall normal cTnT values. Median cTnT concentrations did not change after one year and values were correlated to motor function, particularly with lower limb subdomain, at baseline only. Variations of cTnT and of SBMAFRS were unrelated. The cautiously promising results of cTnT as potential biomarker should undergo a more extensive clinical validation, including studies with longer follow-up period. When evaluating SBMA patients for a potential cardiac damage cTnI testing should be coupled or preferred to cTnT. • Concentrations of cardiac Troponin T in serum are increased in SBMA patients, while cardiac Troponin I is normal. • Concentrations of serum cardiac Troponin T do not fully correlate with functional impairment. • Serum Troponin T concentrations do not increase over one-year time in SBMA. • Cardiac Troponin I should be preferably tested when suspecting cardiac damage in SBMA patients. [ABSTRACT FROM AUTHOR]

Abstract Motor neuron disease (MND) includes both ALS and Progressive Muscular Atrophy (PMA) as variants. Abnormalities in brain excitability and upper motor neuron (UMN) function are characteristic of ALS, but by definition are absent in PMA. Transcranial magnetic stimulation (TMS) may be useful in demonstrating UMN pathology, but loss of muscle responsiveness with disease progression limits its usefulness in later stages of MND. We have developed a novel form of TMS comprised of 4 stimulating pulses that can enhance MEPs in target muscles already responding to traditional TMS inputs, in some cases even restoring MEPs in target muscles rendered unresponsive by the disease. An example of restored MEPs in response to this superconditioning TMS pattern (TMSsc) in a person with PMA is described, along with an unexpected finding. Despite a prolonged (> 5 year) history of movement paralysis in his right tibialis anterior (TA), immediately after cessation of TMSsc delivery the subject could now easily contract and relax this muscle; the presence of a latent pathway for voluntary innervation of his right TA was revealed. This modulation of central motor functional connectivity in response to TMSsc suggests a further, clinically-significant benefit of this form of noninvasive brain stimulation beyond its ability to enhance MEPs to traditional TMS inputs. Highlights • TMS is used to elicit motor evoked potentials (MEPs) in normal muscle. • MEPs from certain target muscles may fail in persons with MND. • We describe a novel 4-pulse TMS method that can restore MEPs in a subject with MND. • This TMS pattern unmasked voluntary movement in a muscle previously paralyzed. • This method may be useful for studies of brain plasticity, or neuromodulation. [ABSTRACT FROM AUTHOR]

Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by muscle weakness and atrophy resulting from progressive degeneration and loss of the anterior horn cells in the spinal cord and brain stem nuclei. The onset of weakness ranges from prenatal age to young adulthood. Thus, many female patients reach fertile age and may consider getting pregnant. However, only little information is available about outcomes and complications of pregnancy in women with SMA. In this review, we compared different studies on the subject, then we analyzed outcomes in the different stages of the pregnancy (preconceptional period, embryonal period, fetal period, delivery and post partum), with a special focus on maternal and fetal complications, prematurity, mode of delivery, anesthesiological risk, respiratory function and influence of pregnancy on the disease course. This is the first review focused exclusively on pregnancy in women affected by SMA. Our aim is to help clinicians who wish to understand the risks connected with pregnancy in SMA patients and to manage pregnancy course and delivery in an evidence-based and patient-oriented manner. [ABSTRACT FROM AUTHOR]

A dural arteriovenous fistula (DAVF) with spinal perimedullary venous drainage can cause progressive myelopathy, and it is sometimes incorrectly diagnosed as another spinal cord disease. Here we report the cases of three individuals with a DAVF (one craniocervical junction DAVF and two tentorial DAVFs) with progressive myelopathy showing unique magnetic resonance (MR) imaging findings. MR T2*WI or susceptibility-weighted imaging (SWI) demonstrated symmetrical dark signal intensity lesions predominantly in the dorsal aspect of medulla and the central gray matter of cervical spinal cord that showed the “black butterfly” silhouette. Cerebral angiography revealed DAVFs draining into anterior and posterior spinal veins. Dark signals on T2*WI and SWI were presumed to be hemorrhages, which were probably caused by prolonged venous congestion. Identifying this “black butterfly” sign can facilitate the diagnosis of DAVF, differentiating DAVF from other spinal cord diseases such as demyelinating lesions and neoplasms. [ABSTRACT FROM AUTHOR]

To investigate whether primary motor cortex (M1) volume measured with an automated approach in MRI reflects upper motor neuron dysfunction and whether it can serve as a potential diagnostic and/or disease-tracking biomarker for amyotrophic lateral sclerosis (ALS). In this retrospective study, we enrolled 95 subjects, including 33 possible or laboratory supported probable ALS, 26 probable or definite ALS (Prob/Def), 2 primary lateral sclerosis patients, 8 progressive muscular atrophy patients, 19 normal controls (NC) and 7 ALS patients having a second structural MRI scan. Some subjects also underwent functional MRI. We calculated M1, primary sensory cortex, precuneus volumes, and total gray matter volume (TGMV) with FreeSurfer. The sensorimotor network (SMN) was identified using independent component analysis. The M1/precuneus ratio showed a significant difference between the NC and Prob/Def groups (p < 0.05). The diagnostic accuracy of the M1/precuneus ratio was moderate for distinguishing Prob/Def from NC (cutoff = 1.00, sensitivity = 0.42, specificity = 0.90). Two of eight cases without upper motor neuron dysfunction could be diagnosed with ALS using M1/precuneus ratio as a surrogate marker. A negative correlation between M1/precuneus ratio and functional activity was found in Brodmann area 6 in the SMN in all subjects. TGMV tended to decrease with disease progression (p = 0.04). The M1/precuneus volume ratio, associated with the SMN, may have potential as a surrogate biomarker of upper motor neuron dysfunction in ALS. Furthermore, TGMV may serve as an ALS disease-tracking biomarker. • Upper motor neuron dysfunction is key for criteria in the diagnosis of ALS • We calculated M1 and precuneus volumes using an automated approach • M1/precuneus ratio was significantly decreased in probable or definite ALS • The AUC of the M1/precuneus ratio was 0.71 for diagnosis of probable or definite ALS • The M1/precuneus ratio may be a biomarker of upper motor neuron dysfunction [ABSTRACT FROM AUTHOR]

• Adult SMA cases may clinically and radiologically be misdiagnosed as myopathy. • EMG may provide valuable diagnostic information prior to genetic testing. • SMN1 testing should be considered in atypical presentations with neurogenic EMG. [ABSTRACT FROM AUTHOR]

Muscles are small in spinal muscular atrophy (SMA). It is not known if muscle size changes over time in SMA type 1. We quantified changes over time in muscle size and echointensity during two repeated ultrasound examinations of unilateral proximal (biceps brachii/brachialis and quadriceps) and distal (anterior forearm flexors and tibialis anterior) muscles in three children with SMA type 1. We compared muscle thickness (MT) to body weight-dependent normal reference values. Children were 1, 6, and 11 months old at baseline and had 2, 2 and 4 months between ultrasound examinations, respectively. At baseline, MT was normal for weight in all muscles except an atrophic quadriceps in the oldest child. MT decreased and echointensity increased (worsened) over time. At follow up, MT was below normal for weight in the quadriceps in all three children, in the biceps/brachioradialis in two, and in the anterior forearm in one. Tibialis anterior MT remained normal for weight in all three children. Muscle echointensity increased over time in all muscles and, on average, more than doubled in two children. In children with SMA type 1, muscle atrophies and becomes hyperechoic over time. Quantitative muscle ultrasound measures disease progression in SMA type 1 that warrants additional study in more children. [ABSTRACT FROM AUTHOR]

There is limited data on electromyography (EMG) findings in other motor neuron disorders than amyotrophic lateral sclerosis (ALS). We assessed whether the distribution of active denervation detected by EMG, i.e. fibrillations and fasciculations, differs between ALS and slowly progressive motor neuron disorders. We compared the initial EMG findings of 43 clinically confirmed, consecutive ALS patients with those of 41 genetically confirmed Late-onset Spinal Motor Neuronopathy and 14 Spinal and Bulbar Muscular Atrophy patients. Spontaneous activity was more frequently detected in the first dorsal interosseus and deltoid muscles of ALS patients than in patients with the slowly progressive motor neuron diseases. The most important observation was that absent fibrillations in the first dorsal interosseus muscle identified the benign forms with sensitivities of 66%–77% and a specificity of 93%. The distribution of active denervation may help to separate ALS from mimicking disorders at an early stage. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To investigate the association between SMN1 and SMN2 copy number variations (CNVs) and sporadic amyotrophic lateral sclerosis (SALS) by a meta-analysis. Methods: Through searching PubMed and EMBASE database (or manual searching) up to November 2013 using the following keywords: “survival motor neuron gene”, “SMN”, and “amyotrophic lateral sclerosis”, “ALS” or “motor neuron disease”. Nine studies were identified as eligible for this meta-analysis. The association between SMN genes and the SALS risk was investigated based on SMN1 and SMN2 CNVs. The heterogeneity across the studies was tested, as was publication bias. Results: The analysis showed significant association for SMN1 duplications in SALS risk: the risk estimates were OR=1.76, 95%CI=1.33–2.32, p<0.0001 (still significant when the p value was Bonferroni adjusted to 0.01). However, there was no significant association between SMN1 deletions and SALS risk after Bonferroni correction (OR=1.78, 95%CI=1.02–3.11, p=0.04). In addition, SMN2 copy number statuses were not associated with SALS in our pooled study. No evidence of publication bias was observed. Conclusion: Our meta-analysis suggested that SMN1 duplications are a genetic risk factor in SALS, while there was no modulator effect of the SMN2 gene. In addition, it was possible that SMN1 deletions in predisposition to SALS vary across different countries. More studies were required to warrant the findings of this study. [Copyright &y& Elsevier]

Motor neuron diseases (MNDs) are rare and frequently fatal neurological disorders in which motor neurons within the brainstem and spinal cord regions slowly die. MNDs are primarily caused by genetic mutations, and > 100 different mutant genes in humans have been discovered thus far. Given the fact that many more MND-related genes have yet to be discovered, the growing body of genetic evidence has offered new insights into the diverse cellular and molecular mechanisms involved in the aetiology and pathogenesis of MNDs. This search may aid in the selection of potential candidate genes for future investigation and, eventually, may open the door to novel interventions to slow down disease progression. In this review paper, we have summarized detailed existing research findings of different MNDs, such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), spinal bulbar muscle atrophy (SBMA) and hereditary spastic paraplegia (HSP) in relation to their complex genetic architecture. • MNDs are highly fatal neurodegenerative condition caused by the loss of MNs, which control diverse skeletal muscle activities. • Therapeutic interventions are limited due to the absence of clear insights into the pathophysiology of MNDs. • Multiple genetic elements working in tandem are believed to play a very crucial role in the pathogenesis of MNDs. • Understanding how genetic factors interplay will provide valuable insights into the cellular and molecular disease processes. • Investigating novel gene variants linked to MND using advanced sequencing techniques may result in new treatment strategies. [ABSTRACT FROM AUTHOR]

Abstract: Background: Vitamin B12 deficiency is a well recognized cause of posterolateral myelopathy. In Indian subcontinent, it may coexist with nutritional copper deficiency producing partial response of patients to B12 supplementation. Hence the study was planned to look for association of hypocupremia and B12 deficiency. Methods: Twenty-three patients with posterolateral myelopathy (Romberg sign positive) were enrolled and investigated for levels of vitamin B12, copper and zinc and followed up for six months. Result: In three patients, copper deficiency alone was found to be the cause. In another three, both copper and vitamin B12 were deficient. In all these six patients, ceruloplasmin and 24h urinary copper were found to be low suggesting dietary copper deficiency. Hyperzincemia was found in four of these patients. Magnetic resonance imaging of spine was normal in lone Cu deficient patients but showed T2 hyperintensity of posterior column in lone B12 or combined B12 and copper deficiency. Conclusion: In cases of B12 deficiency myelopathy not responding to supplementation, copper deficiency must be sought at the earliest to avoid and treat persistent neurological disability. [Copyright &y& Elsevier]

Abstract: Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by programmed motoneuron death. The survival motor neuron 1 (SMN1) gene is an SMA-determining gene and SMN2 represents an SMA-modifying gene. Here, we applied capillary electrophoresis to quantify the SMN gene dosage in 163 normal individuals, 94 SMA patients and 138 of their parents. We further quantified exons 7 and 8 in SMN1 and SMN2. We found that the SMA patients carried the highest SMN2 copies, which was inversely correlated with disease severity among its three subtypes. Increased SMN1 was significantly associated with decreased SMN2 in the normal group. We also observed that parents of type I SMA patients had significantly fewer SMN2 copies than those of types II and III patients. The hybrid SMN genes were detected in two normal individuals and one patient and her mother. These results imply that increased SMN2 copies in SMA patient group might be derived from SMN1-to-SMN2 conversion, whereas the trend that normal individuals with higher SMN1 copies simultaneously carry fewer SMN2 copies suggested a reverse conversion, SMN2-to-SMN1. Together with the identification of hybrid SMN genes, our data provided additional evidence to support that SMN1 and SMN2 gene loci are interchangeable between population groups. [Copyright &y& Elsevier]

Abstract: Childhood spinal muscular atrophy (SMA) is an autosomal recessive disorder characterised by loss of the alpha motor neurones of the spinal cord. SMA is cause by mutations in the survival motor neuron (SMN) gene. There are two copies of the SMN gene: SMN1 and SMN2. The two genes differ by only 11 nucleotides at the genomic level. One of these is a C to T single nucleotide polymorphism (SNP) at position 6 in exon 7. This change alters an exon splicing enhancer in exon 7, meaning that while SMN1 expresses exclusively full-length protein containing exon 7, SMN2 is predominantly alternatively spliced and expresses a truncated transcript lacking exon 7 (SMN∆7). As all SMA patients are effectively null for SMN1 but retain at least one copy of SMN2, patients express considerably lower levels of functional SMN protein compared with uneffected individuals. Therefore, SMA is triggered by a fall in the levels of expressed full-length protein, and the levels expressed by the retained SMN2 gene control the severity. As a result, RNA manipulation to suppress the alternative splicing event and thus increase SMN exon 7 inclusion has emerged as an attractive therapeutic approach. In this review we have discussed the current state of bifunctional RNAs as a viable therapy, concentrating on recent advances and overall implications of this research on SMA. [Copyright &y& Elsevier]

The amount of assistance required to perform daily activities for individuals with Type 2 and non-ambulant Type 3 spinal muscular atrophy (SMA) is often cited as meaningful for quality of life, and important to routinely assess. The SMA Independence Scale (SMAIS), a patient-reported outcome measure for individuals with SMA aged ≥12 years, and an observer-reported outcome measure for caregivers of individuals aged ≥2 years, was developed and evaluated in two phases. In Phase 1, 30 draft items were developed following review of the literature. Semi-structured interviews were then conducted with individuals with SMA and caregivers to establish content validity, resulting in a 29-item measure. In Phase 2, classical test theory and Rasch measurement theory methods were used to examine the cross-sectional and longitudinal measurement performance of the SMAIS in two independent datasets. Phase 1 qualitative findings supported the relevance, acceptability, and comprehensibility of 29 items. In Phase 2, psychometric analyses indicated that the five response options were poorly discriminated and were thus collapsed to three options for subsequent analyses. Items showed statistical misfit, implying that the SMAIS was not assessing a single underlying construct. Based on conceptual evaluation of the items, and assessment of item performance, a more targeted 22-item upper limb score was derived. Reliability and validity analyses confirmed acceptable measurement properties of this score. Qualitative and quantitative analyses support the use of the 22-item SMAIS–Upper Limb Module in individuals with Type 2 and non-ambulant Type 3 SMA, aged ≥2 years. [Display omitted] • Maintaining independence is critical for non-ambulant individuals with Type 2/3 SMA. • Psychometric analyses supported the development of the 22-item SMAIS–ULM. • The SMAIS–ULM measures the level of assistance required to complete upper limb ADLs. [ABSTRACT FROM AUTHOR]

Abstract: Background: Spinal muscular atrophy (SMA) is a degenerative motor neuron disease caused by homozygous mutations of the survival motor neuron 1 (SMN1) gene. Effective treatment for SMA is unavailable at present. The aim of this study was to investigate the effect of hydroxyurea (HU) in SMA cells and patients. Materials and methods: Fifteen SMA lymphoid and three fibroblast cell lines, 2 from SMA patients and 1 control, were treated with HU at different concentrations, and 33 patients (types II, III) randomized into three groups on different HU dosage, 20, 30, 40 mg/kg/day, were treated for 8 weeks and followed up for another drug-free 8 weeks. The effect of HU on SMN2 gene expression and clinical manifestations was evaluated. Results: After treatment, in vitro, full-length mRNA level and gems number increased significantly, and hnRNP A1 protein decreased. In vivo, there were slight increases in muscle strength scores at 4 weeks and full-length SMN mRNA at 8 weeks in 30 mg/kg/day subgroup. Conclusions: Treating with HU enhanced SMN2 gene expression in SMA cells and showed slight trend towards improvement in some clinical outcome measures in SMA patients which suggests HU may be safe to use in SMA patients but larger randomized, placebo-controlled, double-blind trials are needed to further investigate its efficacy. [Copyright &y& Elsevier]

Abstract: Background: Occurrence of nonprogressive juvenile-onset spinal muscular atrophy (SMA) predominantly in males suggests a possibility of X-linked disorder but there is no such report addressing this problem. Aims: To evaluate CAG repeat expansion of androgen receptor (AR) gene in patients with nonprogressive juvenile-onset SMA. Setting: Tertiary medical teaching institute. Subjects and methods: Patients fulfilling the diagnostic criteria of nonprogressive juvenile-onset SMA were included. Detailed clinical evaluation and pedigree charting were done in all. Nerve conduction study, electromyography and cervical spinal MRI were carried out. From peripheral venous blood, DNA was separated and AR gene CAG repeat exon polymorphism was assayed using polymerase chain reaction (PCR) in conjugation with genotyping and Gene scan soft ware. Number of CAG repeats was compared with normal controls. Results: 25 patients with nonprogressive juvenile-onset SMA from 24 families were included and their mean age was 22.2 years. Age at the time of disease onset ranged between 15 and 30 years with a mean duration of illness 2.6 years. None of the patients had testicular atrophy or gynecomastia. C7-T1 myotomal wasting and weakness although was unilateral to begin with but became bilateral in 16 and 4 more patients had evidences of subclinical involvement of the other side as revealed by EMG. Spinal MRI revealed cord atrophy at C6-8 vertebral level in 16 patients. CAG repeat study of AR gene was carried out in 16 patients. The number of CAG repeats in patients ranged between 15 and 39 (median 21) which were within the normal range. Conclusion: Abnormal CAG repeat expansion of AR gene is not found in patients with nonprogressive juvenile-onset SMA. [Copyright &y& Elsevier]

Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by low levels of full-length survival motor neuron (SMN) protein due to the loss of the survival motor neuron 1 (SMN1) gene and inefficient splicing of the survival motor neuron 2 (SMN2) gene, which mostly affects alpha motor neurons of the lower spinal cord. Despite the U.S. Food and Drug Administration (FDA) approved SMN-dependent therapies including Nusinersen, Zolgensma® and Evrysdi™, SMA is still a devastating disease as these existing expensive drugs may not be sufficient and thus, remains a need for additional therapies. The involvement of microRNAs (miRNAs) in SMA is expanding because miRNAs are important mediators of gene expression as each miRNA could target a number of genes. Hence, miRNA-based therapy could be utilized in treating this genetic disorder. However, the delivery of miRNAs into the target cells remains an obstacle in SMA, as there is no effective delivery system to date. This review highlights the potential strategies for intracellular miRNA delivery into target cells and current challenges in miRNA delivery. Furthermore, we provide the future prospects of miRNA-based therapeutic strategies in SMA. • Dysregulation of miRNAs may contribute to pathogenesis of spinal muscular atrophy. • miRNA could act as a potential biomarker for spinal muscular atrophy. • miRNA-based therapy may able to restore survival motor neuron function. • miRNA-based delivery faces off-target effects, safety and effectiveness issues. [ABSTRACT FROM AUTHOR]

Abstract: Background: Folate deficiency is known to be associated with subacute combined degeneration of the spinal cord; however, reports of long-standing cases are rare. Although neurological deficits due to folate deficiency have been reported to respond to folic acid supplementation, the functional outcomes have not been fully elucidated. Objective: The aim of the study was to evaluate the clinical features and response to folate supplementation in a patient with folate deficiency manifested over 10years as a slowly progressive myelopathy. Methods: We performed comprehensive clinical screening, electrophysiological testing, and posturography before and after folate supplementation. Results: A 49-year-old man had a slowly progressive gait disturbance for 10years. He had not eaten fresh green vegetables for more than 10years. Neurological examination revealed spastic paraplegia and absence of any vibration sense in the lower limbs accompanied by a positive Romberg's sign. Serum folate level was low, and plasma homocysteine level was elevated. Levels of blood thiamine and serum cobalamin were normal. We diagnosed the patient with myelopathy due to folate deficiency. Folic acid supplementation led to improvement of his symptoms; posturography and walking speed tests showed partial improvement, while the somatosensory-evoked potentials and central motor conduction time remained unchanged. Conclusions: Folate deficiency should be considered as a differential diagnosis of chronic slowly progressive myelopathy. The present case suggests the importance of early diagnosis and treatment before the adverse neurological manifestations of folate deficiency become irreversible. [Copyright &y& Elsevier]