Differential diagnosis between multiple sclerosis and leukodystrophies - A scoping review.

Multiple Sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS) characterized by damage to the myelin sheaths of oligodendrocytes. Currently, there is no specific biomarker to identify the disease; however, a diagnostic criterion has been established based on patient's clinical, laboratory, and imaging characteristics, which assists in identifying this condition. The primary method for diagnosing MS is the McDonald criteria, first described in 2001 and revised in the years 2005, 2012, and 2017. These criteria have been continuously reviewed to enhance specificity and sensitivity in the diagnosis of MS, thereby reducing errors in its differential diagnosis. An important differential diagnosis that shares overlapping features with MS, mainly the progressive forms, are leukodystrophies with demyelination as underlying pathology. Leukodystrophies comprise a rare group of genetically determined disorders that lead to either demyelination or hypomyelination of the central nervous system that can result neuroimaging changes as well as clinical findings similar to those observed in MS. Thus, systematic evaluation encompassing clinical presentation, neuroimaging findings, and laboratory metrics proves indispensable for a differential diagnosis. As such, this study aimed to establish, clearly and objectively, the similarities and differences between MS and the main demyelinating leukodystrophies. The study analyzed the parameters of the McDonald criteria, including clinical, laboratory, and magnetic resonance imaging aspects, as found in patients with leukodystrophies through scoping literature review. The data were compared with the determinations of the revised 2017 McDonald criteria to facilitate the differential diagnosis of these diseases in clinical practice.

Randomized Trial of Botulinum Toxin Type A in Hereditary Spastic Paraplegia - The SPASTOX Trial.

BACKGROUND: Hereditary spastic paraplegia presents spasticity as the main clinical manifestation, reducing gait quality and producing incapacity. Management with botulinum toxin type A (BoNT-A) is not well elucidated. The objective of the current study was to evaluate the efficacy and safety of BoNT-A in patients with hereditary spastic paraplegias. METHODS: This was a double-blind, randomized, placebo-controlled crossover trial. Each participant was randomly assigned to receive 1 injection session of either BoNT-A (100 IU/2 mL of Prosigne in each adductor magnus and each triceps surae) or saline 0.9% (2 mL). The primary outcome measure was change from baseline in maximal gait velocity, and secondary outcome measures included changes in gait at self-selected velocity, spasticity, muscle strength, Spastic Paraplegia Rating Scale, pain, fatigue, and subjective perception of improvement. We also looked at adverse events reported by the patients. RESULTS: We enrolled 55 patients, 36 of whom were men and 41 with the pure phenotype. Mean age was 43 ± 13.4 years (range, 19-72 years), mean age of onset waws 27 ± 13.1 years (range, <1 to 55 yars), and mean disease duration was 17 ± 12.7 years (range, 1-62 years). Compared with baseline, we did not find significant differences between groups in primary and secondary outcomes, except for reduction in adductor tone (P = 0.01). The adverse events were transient and tolerable, and their incidence did not significantly differ between treatments (P = 0.17). CONCLUSIONS: BoNT-A was safe in patients with hereditary spastic paraplegias and reduced the adductor tone, but it was not able to produce functional improvement considering the doses, injection protocol, measures, and instruments used. © 2021 International Parkinson and Movement Disorder Society.

Leading RNA Interference Therapeutics Part 1: Silencing Hereditary Transthyretin Amyloidosis, with a Focus on Patisiran.

In 2018, patisiran was the first-ever RNA interference (RNAi)-based drug approved by the US Food and Drug Administration. Now pharmacology textbooks may include a new drug class that results in the effect first described by Fire and Mello 2 decades ago: post-transcriptional gene silencing by a small-interfering RNA (siRNA). Patients with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) present with mutations in the transthyretin (TTR) gene that lead to the formation of amyloid deposits in peripheral nerves and heart. The disease may also affect the eye and central nervous system. The formulation of patisiran comprises the RNAi drug encapsulated into a nanoparticle especially developed to deliver the anti-TTR siRNA into the main TTR producer: the liver. Hepatic cells contain apolipoprotein E receptors that recognize ApoE proteins opsonized in the lipid carrier and internalize the drug by endocytosis. Lipid vesicles are disrupted in the cell cytoplasm, and siRNAs are free to trigger the RNAi-based TTR gene silencing. The silencing process involves the binding of siRNA guide strand to 3'-untranslated region sequence of both mutant and wild-type TTR messenger RNA, which culminates in the TTR mRNA cleavage by the RNA-induced silencing complex (RISC) as the first biochemical drug effect. Patisiran 0.3 mg/kg is administered intravenously every 3 weeks. Patients require premedication with anti-inflammatory drugs and antagonists of histamine H1 and H2 receptors to prevent infusion-related reactions and may require vitamin A supplementation. Following patisiran treatment, TTR knockdown remained stable for at least 2 years. Adverse effects were mild to moderate with unchanged hematological, renal, or hepatic parameters. No drug-related severe adverse effects occurred in a 24-month follow-up phase II open-label extension study. At the recommended dosage of patisiran, Cmax and AUC values (mean ± standard deviation) were 7.15 ± 2.14 µg/mL and 184 ± 159 µg·h/mL, respectively. The drug showed stability in circulation with > 95% encapsulated in lipid particles. Metabolization occurred by ribonuclease enzymes, with less than 1% excreted unchanged in the urine. Patisiran ameliorated neuropathy impairment according to the modified Neuropathy Impairment Score + 7 analysis of the phase III study. The Norfolk Quality of Life-Diabetic Neuropathy score and gait speed improved in 51% of the patisiran-treated group in 18 months. Additionally, the modified body mass index showed positive outcomes. Altogether, the data across phase I-III clinical trials points to patisiran as an effective and safe drug for the treatment of hATTR amyloidosis. It is hoped that real-world data from a larger number of patients treated with patisiran will confirm the effectiveness of this first-approved siRNA-based drug.

Sensory ataxia rating scale: Development and validation of a functional scale for patients with sensory neuronopathies.

Sensory neuronopathies (SN) result from dorsal root ganglia damage and manifest with a combination of sensory deficits and proprioceptive ataxia. Characterization of the natural history and development of therapeutic trials are hampered by the lack of clinical scales that capture the whole spectrum of SN-related manifestations. We propose and validate a rating instrument for SN. Three experienced neuromuscular specialists developed items to rate SN. The resultant instrument was later validated by the assessment of the intra-class correlation coefficient, for inter-rater validity in 48 SN patients, and later in a smaller subset of 16 patients to assess its intra-rater validity. Standardized Crombach's alpha and Oblimin rotation analysis were performed to verify internal consistency and items' relationship, respectively. Evaluation of Sensory Ataxia Rating Scale (SEARS)'s external validity was performed by comparison to: scale for the assessment and rating of ataxia (SARA), Beck balance scale (BBS), and INCAT sensory sum score (ISS). A 10-item scale with an intra-class correlation coefficient >0.95 for intra- and inter-rating measurements with a good internal consistency (standardized Cronbach's alpha of 0.83) were observed. There was a normal distribution of the scores without a floor or ceiling effect. A moderate to good correlation between SEARS and SARA, BBS, and ISS was observed. SEARS is a reliable, easy-to-perform and consistent instrument to rate SN. Larger cohorts and multicenter studies are needed to validate its usefulness towards possible treatment trials.

Autonomic dysfunction is frequent and disabling in non-paraneoplastic sensory neuronopathies.

INTRODUCTION: Sensory neuronopathies (SN) are characterized by asymmetric non-length dependent sensory deficits and sensory ataxia. Autonomic dysfunction in SN was not yet evaluated regarding its frequency, characteristics and relationship to sensory deficits. To address these issues, we performed a comprehensive clinical and neurophysiological evaluation of a large cohort of patients with non-paraneoplastic SN (np-SN). METHODS: We enrolled 50 consecutive patients with npSN and 32 age/sex-matched healthy controls. They were clinically evaluated (SCOPA-Aut scale) and underwent neurophysiological autonomic assessment (quantitative sudomotor axon reflex test, heart rate variability and sympathetic skin response). RESULTS: Mean age of patients was 50.9 ±â€¯10.3 years and there were 18 men. npSN patients had higher SCOPA-Aut scores than controls (26.63 ±â€¯12.72 vs. 12.66 ±â€¯9.11, p < .001). QSART was abnormal in 92% of the patients - sweat volumes in all examined sites were smaller among patients (p < .001). Cardiovascular autonomic neuropathy was more frequent in these patients as well (p < .001). CONCLUSION: Altogether our results suggest that autonomic dysfunction in distinct domains is frequent in npSN patients. These findings suggest that the clinical picture of npSN is related to a double neuronopathy: sensory and autonomic.

Clinical, ophthalmological, imaging and genetic features in Brazilian patients with ARSACS.

BACKGROUND: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an important form of inherited ataxia with a varied clinical spectrum. Detailed studies of phenotype and genotype are necessary to improve diagnosis and elucidate this disorder pathogenesis. OBJECTIVE AND METHODS: To investigate the clinical phenotype, retinal architecture, neuroimaging features and genetic profile of Brazilian patients with ARSACS, we performed neurological and ophthalmological evaluation in thirteen Brazilian patients with molecularly confirmed ARSACS, and examined their mutation profiles. Optical coherence tomography protocol (OCT) consisted in peripapillary retinal nerve fiber layer (RNFL) measurement and qualitative analysis of perifoveal scans. Neuroimaging protocol accessed the frequency of atrophy in cerebellum, corpus callosum and parietal lobe, brainstem signal abnormalities, and posterior fossa arachnoid cysts. We reviewed the literature to delineate the ARSACS phenotype in the largest series worldwide. RESULTS: All patients had ataxia and spasticity, and 11/13 had peripheral neuropathy. Macular microcysts were present in two patients. Peripapillary striations, dentate appearance of inner retina and papillomacular fold were found in eleven cases. All individuals exhibited thickening of RNFL in OCT. The most frequent radiological signs were cerebellar atrophy (13/13), biparietal atrophy (12/13), and linear pontine hypointensities (13/13). Genetic analysis revealed 14 different SACS variants, of which two are novel. CONCLUSION: Macular microcysts, inner retina dentate appearance and papillomacular fold are novel retinal imaging signs of ARSACS. Ophthalmological and neuroimaging changes are common findings in Brazilian patients. The core clinical features of ARSACS are ataxia, spasticity and peripheral neuropathy with onset predominantly in the first decade of life.

SPG11-related parkinsonism: Clinical profile, molecular imaging and l-dopa response.

BACKGROUND: Molecular imaging has proven to be a powerful tool to elucidate degenerated paths in a wide variety of neurological diseases and has not been systematically studied in hereditary spastic paraplegias. OBJECTIVES: To investigate dopaminergic degeneration in a cohort of 22 patients with hereditary spastic paraplegia attributed to SPG11 mutations and evaluate treatment response to l-dopa. METHODS: Patients and controls underwent single-photon emission computed tomography imaging utilizing 99m Tc-TRODAT-1 tracer. A single-blind trial with 600 mg of l-dopa was performed comparing UPDRS scores. RESULTS: Reduced dopamine transporter density was universal among patients. Nigral degeneration was symmetrical and correlated with disease duration and motor and cognitive handicap. No statistically significant benefit could be demonstrated with l-dopa intake during the trial. CONCLUSION: Disruption of presynaptic dopaminergic pathways is a widespread phenomenon in patients with SPG11 mutations, even in the absence of parkinsonism. Unresponsiveness to treatment could be related to postsynaptic damage that needs to be further investigated.

SPG11 mutations cause widespread white matter and basal ganglia abnormalities, but restricted cortical damage.

SPG11 mutations are the major cause of autosomal recessive Hereditary Spastic Paraplegia. The disease has a wide phenotypic variability indicating many regions of the nervous system besides the corticospinal tract are affected. Despite this, anatomical and phenotypic characterization is restricted. In the present study, we investigate the anatomical abnormalities related to SPG11 mutations and how they relate to clinical and cognitive measures. Moreover, we aim to depict how the disease course influences the regions affected, unraveling different susceptibility of specific neuronal populations. We performed clinical and paraclinical studies encompassing neuropsychological, neuroimaging, and neurophysiological tools in a cohort of twenty-five patients and age matched controls. We assessed cortical thickness (FreeSurfer software), deep grey matter volumes (T1-MultiAtlas tool), white matter microstructural damage (DTI-MultiAtlas) and spinal cord morphometry (Spineseg software) on a 3 T MRI scan. Mean age and disease duration were 29 and 13.2 years respectively. Sixty-four percent of the patients were wheelchair bound while 84% were demented. We were able to unfold a diffuse pattern of white matter integrity loss as well as basal ganglia and spinal cord atrophy. Such findings contrasted with a restricted pattern of cortical thinning (motor, limbic and parietal cortices). Electromyography revealed motor neuronopathy affecting 96% of the probands. Correlations with disease duration pointed towards a progressive degeneration of multiple grey matter structures and spinal cord, but not of the white matter. SPG11-related hereditary spastic paraplegia is characterized by selective neuronal vulnerability, in which a precocious and widespread white matter involvement is later followed by a restricted but clearly progressive grey matter degeneration.

Botulinum toxin for hereditary spastic paraplegia: effects on motor and non-motor manifestations.

Motor and non-motor manifestations are common and disabling features of hereditary spastic paraplegia (HSP). Botulinum toxin type A (Btx-A) is considered effective for spasticity and may improve gait in these patients. Little is known about the effects of Btx-A on non-motor symptoms in HSP patients. Objective To assess the efficacy of Btx-A on motor and non-motor manifestations in HSP patients. Methods Thirty-three adult patients with a clinical and molecular diagnosis of HSP were evaluated before and after Btx-A injections. Results Mean age was 41.7 ± 13.6 years and there were 18 women. Most patients had a pure phenotype and SPG4 was the most frequent genotype. The Btx-A injections resulted in a decrease in spasticity at the adductor muscles, and no other motor measure was significantly modified. In contrast, fatigue scores were significantly reduced after Btx-A injections. Conclusion Btx-A injections resulted in no significant functional motor improvement for HSP, but fatigue improved after treatment.

Botulinum toxin for hereditary spastic paraplegia: effects on motor and non-motor manifestations / Toxina botulínica nas paraplegias espásticas hereditárias: efeitos nas manifestações motoras e não-motoras

ABSTRACT Motor and non-motor manifestations are common and disabling features of hereditary spastic paraplegia (HSP). Botulinum toxin type A (Btx-A) is considered effective for spasticity and may improve gait in these patients. Little is known about the effects of Btx-A on non-motor symptoms in HSP patients. Objective To assess the efficacy of Btx-A on motor and non-motor manifestations in HSP patients. Methods Thirty-three adult patients with a clinical and molecular diagnosis of HSP were evaluated before and after Btx-A injections. Results Mean age was 41.7 ± 13.6 years and there were 18 women. Most patients had a pure phenotype and SPG4 was the most frequent genotype. The Btx-A injections resulted in a decrease in spasticity at the adductor muscles, and no other motor measure was significantly modified. In contrast, fatigue scores were significantly reduced after Btx-A injections. Conclusion Btx-A injections resulted in no significant functional motor improvement for HSP, but fatigue improved after treatment.

RESUMO Manifestações motoras e não motoras são comuns e incapacitantes nas paraparesias espásticas hereditárias (PEH). Toxina botulínica do tipo A (TB-A) é considerada eficaz no tratamento da espasticidade e pode melhorar a marcha nesses pacientes. Pouco se sabe sobre os efeitos da TB-A sobre sintomas não-motores. Objetivo avaliar a eficácia da TB-A sobre manifestações motoras e não-motoras nas PEH. Método trinta e três pacientes adultos com PEH foram avaliados antes e depois das aplicações de TB-A. Resultados A média de idade foi 41,7 ± 13,6 anos e havia 18 mulheres. A maioria dos pacientes portava a forma pura e o genótipo mais comum foi SPG4. Houve diminuição da espasticidade dos músculos adutores da coxa sem melhora da marcha. A pontuação da fadiga reduziu após as injeções. Conclusão As aplicações de TB-A não melhoraram a marcha nos pacientes mas a redução da fadiga foi significativa após o tratamento.

Hereditary spastic paraplegia from 1880 to 2017: an historical review.

The authors have constructed a brief timeline of major clinical research related to hereditary spastic paraplegia (HSP). This timeline summarizes the evolution of HSP research, from the first clinical descriptions by Adolf von Strümpell in 1880 to the present day, with the transformation of these diseases into a rapidly-growing and heterogeneous group of neurogenetic diseases.

Hereditary spastic paraplegia from 1880 to 2017: an historical review / Paraplegia espástica hereditária de 1880 a 2017: uma revisão histórica

ABSTRACT The authors have constructed a brief timeline of major clinical research related to hereditary spastic paraplegia (HSP). This timeline summarizes the evolution of HSP research, from the first clinical descriptions by Adolf von Strümpell in 1880 to the present day, with the transformation of these diseases into a rapidly-growing and heterogeneous group of neurogenetic diseases.

RESUMO Os autores constroem uma breve linha do tempo com as principais pesquisas clinicas relacionadas as paraplegias espásticas hereditárias. Desde a descrição clínica inicial em 1880, feita por Adolf von Strümpell, até os dias atuais com a transformação dessas doenças em um grupo de doenças neurogenéticas com grande variabilidade na apresentação fenotípica e genotípica.

Structural signature of classical versus late-onset friedreich's ataxia by Multimodality brain MRI.

INTRODUCTION: Friedreich's ataxia (FRDA) is the most common autosomal-recessive ataxia worldwide. It is characterized by early onset, sensory abnormalities, and slowly progressive ataxia. However, some individuals manifest the disease after the age of 25 years and are classified as late-onset FRDA (LOFA). Therefore, we propose a transversal multimodal MRI-based study to investigate which anatomical substrates are involved in classical (cFRDA) and LOFA. METHODS: We enrolled 36 patients (13 with LOFA) and 29 healthy controls. All subjects underwent magnetic resonance imaging in a 3 T device; three-dimensional high-resolution T1-weighted images and diffusion tensor images were used to assess gray and white matter, respectively. We used T1 multiatlas approach to assess deep gray matter and cortical thickness measures to evaluate cerebral cortex and DTI multiatlas approach to assess white matter. All analyses were corrected for multiple comparisons. RESULTS: Group comparison showed that both groups presented gray matter atrophy mostly in the motor cortex. Regarding white matter, we found abnormalities in the cerebellar peduncles, pyramidal tracts, midbrain, pons, and medulla oblongata for both groups, but the microstructural abnormalities in the cFRDA group were more widespread. In addition, we found that the corticospinal tract presented more severe microstructural damage in the LOFA group. Finally, the midbrain volume of the cFRDA, but not of the LOFA group, correlated with disease duration (R = -0.552, P = 0.012) and severity (R = -0.783, P < 0.001). CONCLUSION: The cFRDA and LOFA groups have similar, but not identical neuroimaging damage pattern. These structural differences might help to explain the phenotypic variability observed in FRDA. Hum Brain Mapp 38:4157-4168, 2017. © 2017 Wiley Periodicals, Inc.

Autoimmune neuropathies associated to rheumatic diseases.

Systemic manifestations are frequent in autoimmune rheumatic diseases and include peripheral nervous system damage. Neuron cell body, axons and myelin sheath may all be affected in this context. This involvement results in severe and sometimes disabling symptoms. Sensory, motor and autonomic features may be present in different patterns that emerge as peculiar clinical pictures. Prompt recognition of these neuropathies is pivotal to guide treatment and reduce the risks of long term disability. In this review, we aim to describe the main immune-mediated neuropathies associated to rheumatic diseases: sensory neuronopathies, multiple mononeuropathies and chronic inflammatory demyelinating polyradiculoneuropathy, with an emphasis on clinical features and therapeutic options.

Derek Denny-Brown: the man behind the ganglia.

The authors present an historical review about the main contributions of Professor Derek Denny-Brown to neurology. Some of his achievements include the first description of sensory neuronopathies, and some of the essential textbooks on the function and anatomy of the basal ganglia. In 2016, on the 35th anniversary of his death, modern neurologists are still strongly influenced by his legacy.

Derek Denny-Brown: the man behind the ganglia / Derek Denny-Brown: o homem por detrás dos gânglios

ABSTRACT The authors present an historical review about the main contributions of Professor Derek Denny-Brown to neurology. Some of his achievements include the first description of sensory neuronopathies, and some of the essential textbooks on the function and anatomy of the basal ganglia. In 2016, on the 35th anniversary of his death, modern neurologists are still strongly influenced by his legacy.

RESUMO Os autores apresentam uma revisão histórica sobre as principais contribuições do Professor Derek Denny-Brown à neurologia. Suas realizações incluem a primeira descrição da neuronopatia sensitiva e alguns dos livros fundamentais acerca da função e anatomia dos núcleos da base. Em 2016, ano do seu 35o aniversário de falecimento, os neurologistas atuais ainda são fortemente influenciados pelo seu legado.

Fatigue and Its Associated Factors in Spinocerebellar Ataxia Type 3/Machado-Joseph Disease.

Fatigue has been described in several neurodegenerative diseases, reducing quality of life. A systematic evaluation of this clinical feature is lacking in SCA3/MJD. The aim of this study was to evaluate the frequency and the factors associated with fatigue in SCA3/MJD. Patients with SCA3/MJD and matched healthy controls answered the Modified Fatigue Impact Scale (MFIS), Beck Inventory Depression (BDI) and Epworth Sleepiness Scale (ESS). Scale for the assessment and rating of ataxia (SARA) was used to determine ataxia severity. We used Mann-Whitney and Fisher exact tests to compare mean scores and proportions between groups. Linear regression analyses were employed to investigate factors associated with fatigue in SCA3/MJD. Seventy-four patients were included with a mean age and disease duration of 47.2 ± 12.8 and 9.5 ± 6.37 years, respectively. There were 38 men and 36 women. Mean (CAG)n was 72.2 ± 3.8. Mean MFIS score was higher in patients with SCA3/MJD (41.4 ± 16.2 vs 18.4 ± 12.9, p < 0.001). According to BDI scores, relevant depressive symptoms were found in 69.4 % of patients but only in 10.4 % of controls (p < 0.001). The proportion of patients with ESS scores indicating excessive daytime somnolence was also higher than controls (37.5 vs 22.3 %, p = 0.05). In the multiple regression analysis, both BDI and ESS scores were associated with fatigue (r = 0.67, p < 0.001 and p = 0.01). Fatigue is frequent and strongly associated with depression and excessive daytime somnolence in SCA3/MJD.

Nonneurological Involvement in Late-Onset Friedreich Ataxia (LOFA): Exploring the Phenotypes.

Friedreich's ataxia (FDRA) is the most common inherited ataxia worldwide, caused by homozygous GAA expansions in the FXN gene. Patients usually have early onset ataxia, areflexia, Babinski sign, scoliosis and pes cavus, but at least 25 % of cases have atypical phenotypes. Disease begins after the age of 25 in occasional patients (late-onset Friedreich ataxia (LOFA)). Little is known about the frequency and clinical profile of LOFA patients. One hundred six patients with molecular confirmation of FDRA and followed in three Brazilian outpatient centers were enrolled. General demographics, GAA expansion size, age at onset, cardiac, endocrine, and skeletal manifestations were evaluated and compared between LOFA and classic FDRA (cFDRA) groups. We used Mann-Whitney and Fisher tests to compare means and proportions between groups; p values <0.05 were considered significant. LOFA accounted for 17 % (18/106) and cFDRA for 83 % (88/106) of the patients. There were 13 and 48 women in each group, respectively. LOFA patients were significantly older and had smaller GAA expansions. Clinically, LOFA group had a tendency toward lower frequency of diabetes/impaired glucose tolerance (5.8 vs. 17 %, p = 0.29) and cardiomyopathy (16.6 vs. 28.4 %, p = 0.38). Skeletal abnormalities were significantly less frequent in LOFA (scoliosis 22 vs. 61 %, p = 0.003, and pes cavus 22 vs.75 %, p < 0.001) as were spasticity and sustained reflexes, found in 22 % of LOFA patients but in none of the cFDRA patients (p = 0.001). LOFA accounts for 17 % of Brazilian FDRA patients evaluated herein. Clinically, orthopedic features and spasticity with retained reflexes are helpful tips to differentiate LOFA from cFDRA patients.

Inflammatory demyelinating neuropathy heralding accelerated chediak-higashi syndrome.

INTRODUCTION: Chediak-Higashi syndrome (CHS) is a very rare autosomal recessive disorder (gene CHS1/LYST) characterized by partial albinism, recurrent infections, and easy bruising. Survivors develop a constellation of slowly progressive neurological manifestations. METHODS: We describe clinical, laboratory, electrophysiological, and genetic findings of a patient who developed an immune-mediated demyelinating neuropathy as the main clinical feature of CHS. RESULTS: The patient presented with subacute flaccid paraparesis, absent reflexes, and reduced vibration sense. Protein and immunoglobulins (Igs) were elevated in the cerebrospinal fluid. Electrodiagnostic tests indicated an acquired chronic demyelinating polyneuropathy. Intravenous Ig and immunosuppressant treatment resulted in neurological improvement. The patient later developed organomegaly and pancytopenia. Bone-marrow smear revealed giant azurophilic granules pathognomonic for CHS. Two novel mutations in the LYST gene were identified through whole exome sequencing [c.7786C>T and c.9106 + 1G>T]. CONCLUSIONS: This case expands the clinical phenotype of CHS and highlights inflammatory demyelinating neuropathy as a manifestation of the disease. Muscle Nerve 55: 756-760, 2017.