Progressive Spastic Paraparesis Research Articles

Delineation of C12orf65-related phenotypes: a genotype–phenotype relationship

C12orf65 participates in the process of mitochondrial translation and has been shown to be associated with a spectrum of phenotypes, including early onset optic atrophy, progressive encephalomyopathy, peripheral neuropathy, and spastic paraparesis.We used whole-genome homozygosity mapping as well as exome sequencing and targeted gene sequencing to identify novel C12orf65 disease-causing mutations in seven affected individuals originating from two consanguineous families. In four family members affected with childhood-onset optic atrophy accompanied by slowly progressive peripheral neuropathy and spastic paraparesis, we identified a homozygous frame shift mutation c.413_417 delAACAA, which predicts a truncated protein lacking the C-terminal portion. In the second family, we studied three affected individuals who presented with early onset optic atrophy, peripheral neuropathy, and spastic gait in addition to moderate intellectual disability. Muscle biopsy in two of the patients revealed decreased activities of the mitochondrial respiratory chain complexes I and IV. In these patients, we identified a homozygous splice mutation, g.21043 T>A (c.282+2 T>A) which leads to skipping of exon 2. Our study broadens the phenotypic spectrum of C12orf65 defects and highlights the triad of optic atrophy, axonal neuropathy and spastic paraparesis as its key clinical features. In addition, a clear genotype-phenotype correlation is anticipated in which deleterious mutations which disrupt the GGQ-containing domain in the first coding exon are expected to result in a more severe phenotype, whereas down-stream C-terminal mutations may result in a more favorable phenotype, typically lacking cognitive impairment.

Ganglioneuroblastoma Epidural Espinhal Torácico: Relato de Caso e Desafio Diagnóstico

Ganglioneuroblastomas are rare tumors of the central nervous system (CNS), especially in the spinal region. Their presentation often result from compressive symptoms caused by mass effect. The standard treatment is surgical resection. We report a case of a young patient with low back pain associated with progressive spastic paraparesis which revealed a homogeneous epidural mass lesion in the posterior region of T5-T6 submitted to partial microsurgical resection of the lesion, progressing satisfactorily. Given this context, the diversity of diagnostic hypotheses was discussed, including their challenges and difficulties in histologic appearance and immunohistochemical current forms of aid in order to guide and complete the pathological report.

Giant invasive spinal schwannoma in children: a case report and review of the literature

IntroductionGiant invasive spinal schwannoma is defined as a tumor that extends over two or more vertebral levels, erodes vertebral bodies, and extends into the extraspinal space disrupting myofascial planes. Because of its rarity, there have been few published reports describing clinical features and surgical outcomes, especially in the pediatric patient population.Case presentationWe analyzed the medical record, pathologic findings, and radiographic studies of a 14-year-old Hispanic boy who presented to Texas Children’s Hospital with a three-month history of progressive spastic paraparesis. Preoperative computed tomography and magnetic resonance imaging reports showed a large mass lesion centered at the left T7-8 neural foramen with intra- and extraspinal extension, resulting in severe spinal cord compression and vertebral body erosion, and protrusion into the retropleural space and descending aorta. Our patient underwent a single-stage posterior approach for complete resection of the tumor with reconstruction and stabilization of the vertebral column. The pathological examination was consistent with schwannoma. At the six-month follow-up, our patient had resolution of preoperative symptoms and remains neurologically intact without any radiographic evidence of recurrent tumor.ConclusionTo the best of our knowledge, our case represents the fourth child with giant invasive spinal schwannoma reported in the literature. We describe our case and review the literature to discuss the aggregate clinical features, surgical strategies, and operative outcomes for giant invasive spinal schwannoma in the pediatric age group.

Defective autophagy in spastizin mutated patients with hereditary spastic paraparesis type 15

Hereditary spastic paraparesis type 15 is a recessive complicated form of the disease clinically characterized by slowly progressive spastic paraparesis and mental deterioration with onset between the first and second decade of life. Thinning of corpus callosum is the neuroradiological distinctive sign frequently associated with white matter abnormalities. The causative gene, ZFYVE26, encodes a large protein of 2539 amino acid residues, termed spastizin, containing three recognizable domains: a zinc finger, a leucine zipper and a FYVE domain. Spastizin protein has a diffuse cytoplasmic distribution and co-localizes partially with early endosomes, the endoplasmic reticulum, microtubules and vesicles involved in protein trafficking. In addition, spastizin localizes to the mid-body during the final step of mitosis and contributes to successful cytokinesis. Spastizin interacts with Beclin 1, a protein required for cytokinesis and autophagy, which is the major lysosome-mediated degradation process in the cell. In view of the Beclin 1-spastizin interaction, we investigated the possible role of spastizin in autophagy. We carried out this analysis by using lymphoblast and fibroblast cells derived from four different spastizin mutated patients (p.I508N, p.L243P, p.R1209fsX, p.S1312X) and from control subjects. Of note, the truncating p.R1209fsX and p.S1312X mutations lead to loss of spastizin protein. The results obtained indicate that spastizin interacts with the autophagy related Beclin 1-UVRAG-Rubicon multiprotein complex and is required for autophagosome maturation. In cells lacking spastizin or with mutated forms of the protein, spastizin interaction with Beclin 1 is lost although the formation of the Beclin 1-UVRAG-Rubicon complex can still be observed. However, in these cells we demonstrate an impairment of autophagosome maturation and an accumulation of immature autophagosomes. Autophagy defects with autophagosome accumulation can be observed also in neuronal cells upon spastizin silencing. These results indicate that autophagy is a central process in the pathogenesis of complicated forms of hereditary spastic paraparesis with thin corpus callosum.

Hepatic myelopathy with spastic paraparesis: report of two cases and review of the literature

The present report illustrates two men aged for 59 and 43 years, respectively, who presented with slowly progressive spastic paraparesis. Two case reports and review of literature. The patent's history, clinical examination, biology, magnetic resonance imaging (MRI) findings and treatment are reported. We also discuss the pathogenesis and various treatment options. Neurologic examination showed spastic paraparesis without other neurological disorders. MRI of the spinal cord and brain were normal. Cytologic examination of cerebrospinal fluid from each patient was normal. Hemogram disclosed a pancytopenia. Partial thromboplastin time was prolonged. Liver function tests revealed raised serum bilirubin, normal alanine aminotransferase and aspartate aminotransferase, reduced total protein and albumin. Plasma ammonia was elevated. Blood vitamin B12 and folate values were in normal ranges. Serum antibodies to human T cell lymphotropic virus, human immunodeficiency virus, syphilis and hepatitis C virus were absent. Hepatitis B virus antibody assay was positive. The electromyographic evaluation for second motor neuron involvement was also normal. Endoscopy revealed esophageal varices and a spleno-renal shunt. Hepatic myelopathy remains a default diagnosis assigned only after the exclusion of other causes of spastic paraparesis and partial transverse myelopathy. An accurate history, along with appropriate imaging and laboratory findings, is crucial.

Further genotype–phenotype correlation emerging from two families with PLP1 exon 4 skipping

Proteolipid protein 1 (PLP1) gene-related disorders due to mutations in the PLP1 include a wide spectrum of X-linked disorders ranging from severe connatal Pelizaeus-Merzbacher disease (PMD) to spastic paraplegia 2 (SPG2). Duplications, deletions or point mutations in coding and noncoding regions of the PLP1 gene may occur. We report the clinical, neuroradiologic and molecular findings in six patients from two unrelated families. The affected males showed severe mental retardation, spastic tetraparesis, inability of walking and pes cavus at onset in early infancy. Brain magnetic resonance imaging (MRI) showed hypomyelination and brain atrophy. Nystagmus was never observed. The affected females showed adult-onset progressive spastic paraparesis leading to wheel-chair dependency and subtle white matter changes on brain MRI. Molecular studies in the two families identified two different intronic mutations, the novel c.622+2T>C and the known c.622+1G>A, leading to the skipping of PLP1-exon 4. The clinical presentation of the affected males did not consistently fit in any of the PLP1-related disorder subtypes (i.e., connatal or classic PMD, SPG2 and 'PLP1 null syndrome'), and in addition, the carrier females were symptomatic despite the severe clinical picture of their respective probands. This study provides new insight into the genotype-phenotype correlations of patients with PLP1 splice-site mutations.

A rare family with Hereditary Spastic Paraplegia Type 35 due to novel FA2H mutations: A case report with literature review

BackgroundHereditary Spastic Paraplegia Type 35 is a complicated form of HSP characterized by progressive spastic paraparesis, dysarthria, and mild cognitive decline associated with leukodystrophy on brain imaging. Mutations in the fatty acid 2-hydroxylase (FA2H) gene have been associated SPG35. MethodsSequencing of FA2H gene was conducted in a Chinese non-consanguineous family with two affected siblings manifesting with typical clinical features of SPG 35. 100 healthy individuals were set for control. ResultTriple heterozygous mutations in FA2H gene (c.968C>A; c.976G>A; c.688G>A) were identified in the two affected siblings. All the mutations were not documented previously and were not detected among 100 healthy controls. ConclusionIn this study we identified the first SPG 35 family in Han population. Triple FA2H mutations seem to result in a severe phenotype while more patients are needed to establish the genotype–phenotype correlations.

Tropical spastic paraparesis treated with Combivir (lamivudine–zidovudine)

Tropical spastic paraparesis (TSP) or human T-cell leukemia virus–type 1 (HTLV–I)-associated myelopathy is caused by human T-lymphotropic virus type 1. It is a slow, progressive spastic paraparesis with significant morbidity and causing profound repercussions on quality of life. No therapies have been found to persistently improve the outcome in these patients. We present a patient with HTLV–1-associated myelopathy/TSP (HAM/TSP) who was treated with Combivir® (lamivudine–zidovudine, GlaxoSmithKline, London, UK). She was walker-dependent for several years but, soon after treatment with lamivudine–zidovudine, was able to walk using only a cane. The role of lamivudine–zidovudine should be investigated further in this patient population.

Effects of Danazol on Clinical Improvement of Patients with Human T-cell Lymphotropic Virus Type I Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP): A Placebo-Controlled Clinical Trial.

Human T-Cell Lymphotropic Virus Type I (HTLV-I) associated myelopathy/tropical spastic paraparesis (HAM/TSP) is an endemic disease observed in Japan, Africa, Caribbean basin, and north-east Iran. It is usually presented as a chronic and progressive spastic paraparesis. There are some options for treatment of HAM/TSP patients. The aim of this study was to compare the effects of danazol controlled with placebo in relieving the symptoms and signs of HAM/TSP patients. Among 77 patients with definite diagnosis of HAM/TSP based on clinical and para-clinical findings, 71 patients had the required criteria for entering the study. Severity of symptoms and the degree of motor disability were determined before the beginning of treatment based on motor disability grading (MDG) in both groups of patients and were followed during 6 months in 1 month intervals for changes in symptoms and their motor disabilities. Among 38 patients of the first group, after 6 months therapy with danazol, mean difference between MDG0 (before starting the treatment) and MDG6 (after six months), as an indicator of motor improvement in the patients, was 0.89. Meanwhile, among the 33 patients treated with identical appearing placebo, there was no significant difference between MDG0 and MDG6 (P< 0.001). Moreover, there was a significant difference in improvement of symptoms between two study groups. This study showed that danazol provides relative effects on improving motor disabilities and symptoms of HAM/TSP patients that can be considered according to its lower side effects compared to other suggested treatments such as corticosteroids, and its lower costs in particular patients.

Pigmented Villonodular Synovitis of the Thoracic Vertebra Presenting with Progressive Spastic Paraparesis

Pigmented villonodular synovitis (PVNS) is a proliferative benign lesion originating from the synovium and commonly affects large joints of the extremities. PVNS can arise from any synovium in the whole body and rarely affects the zygapophyseal joints of the spine. Spinal PVNS is diagnosed mostly after resection of the mass. In our case we present a 22-year-old male patient showing progressive spastic paraparesis with insidious onset of back pain and difficulty of walking in a relatively short period of 1 month. After gross excision of the mass, diagnosis was established through histopathology. Two years of follow-up period reveals complete resolution of the patient's complaints and no recurrence on radiologic images.

Hepatic myelopathy in a patient with decompensated liver disease: An unusual complication

Hepatic myelopathy (HM) is a rare neurological complication of the chronic liver disease usually seen in adults and presents as a disabling progressive pure motor spastic paraparesis, which is almost always associated with overt liver failure. We report a case of a 45-year-old male who presented with rapidly progressive spastic paraparesis due to HM and features of hepatic decompensation (postnecrotic cirrhosis), who presented with the second episode of hepatic encephalopathy. Patient had not undergone any shunt procedure.

Adrenomyeloneuropathy Presenting With Adrenal Insufficiency

Adrenomyeloneuropathy (AMN), one of the variants of X-linked adrenoleukodystrophy (ALD), is inherited peroxisomal disorder associated with the accumulation of very long chain fatty acids (VLCFA). AMN is characterized primarily by involvements of long ascending and descending tracts of the spinal cord and peripheral neuropathy, which leads to spastic paraparesis and urinary and erectile dysfunction. We experienced the AMN case of a 33-year-old man presenting bilateral progressive spastic paraparesis, impotence and urge incontinence with primary adrenal failures, as confirmed by increased serum of VLCFA concentrations. Considering that somatosensory evoked potentials in posterior tibial nerve was the only abnormal finding in electrophysiologic findings when compared with the severe spastic gait pattern shown, it is necessary to follow up with electrophysiologic studies.

Teaching Neuro Images : Oculodentodigital dysplasia

A 44-year-old woman presented to our department with an 8-year history of slowly progressive spastic paraparesis, urinary and bowel incontinence, depression, and forgetfulness. The patient was born with syndactyly of the fourth and fifth fingers ([figure][1], C). Cranial MRI revealed a distinct

P4. A patient with familiar Amyotrophic Lateral Sclerosis (ALS) carrying the C9orf72 repeat expansion: Clinical picture and review of literature

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder of upper and lower motor neuron disorder and is associated with frontotemporal dementia in about 14% of cases. Recently identified C9orf72 expansion in familiar and apparently sporadic cases of ALS seems to present a peculiar and recognisable phenotype. We describe a case of 50-years old patient who developed rapidly progressive spastic paraparesis, followed by appearance of generalized symptoms and signs of the first and second motor neuron disorder, fulfilling clinical and electrophysiological diagnostic criteria of ALS. The cerebral MRI showed marked hyperintensity of pyramidal tracts. In the following months cognitive, especially executive changes appeared. The clinical course was extremely rapid, with consecutively bulbar and respiratory involvement within 6 month after onset. The patient refused both non invasive and invasive ventilation and percutaneous gastrostomy and died 1 year after diagnosis. As in family history his father died at the age of 60 from define ALS after 2 years since onset, an extensive genetic testing for familiar ALS forms has been performed. Mutation in Superoxide Dismutase 1 (SOD 1) gene was firstly excluded. Mutations in Angiogenin gene (ANG), Fused In Sarcoma gene (FUS), Tar DNA binding Protein (TARDPB) gene and optineurin (OPTN) gene were also excluded. However the patient carried C9orf72 hexanucleotide repeat expansion. The expansion of C9orf72 has been recently described in patients from different geographical regions. The clinical picture is not homogeneous but patients share some common characteristic as younger age at onset, autosomal dominant inheritance, rapid progression and presence of cognitive and behavioural changes similar to frontotemporal dementia. The radiological picture may show, together with pyramidal tracts hyperintensity, also grey matter volume loss.

Extraosseous multiple myeloma mimicking spinal epidural metastasis

A 42-year-old man presented with a one-month history of upper back pain and a two-week history of progressive spastic paraparesis. Thoracic spinal MRI showed an epidural mass with spinal cord compression at T6–8 but no bony involvement. The patient underwent T6–8 laminectomy for decompression. Lumbosacral MRI and CT scans revealed bony abnormalities on the sacrum and left posterior iliac bone. Immunohistochemical studies confirmed the diagnosis of multiple myeloma (MM). Thus, this patient suffered from extraosseous MM without adjacent bony involvement or distant skeletal involvement.

Neurotransmitter abnormalities and response to supplementation in SPG11

Objective: To report the detection of secondary neurotransmitter abnormalities in a group of SPG11 patients and describe treatment with l-dopa/carbidopa and sapropterin.Design: Case reports.Setting: National Institutes of Health in the Undiagnosed Disease Program; Children's National Medical Center in the Myelin Disorders Bioregistry Program.Patients: Four SPG11 patients with a clinical picture of progressive spastic paraparesis complicated by extrapyramidal symptoms and maculopathy.Interventions: l-Dopa/carbidopa and sapropterin.Results: 3/4 patients presented secondary neurotransmitter abnormalities; 4/4 partially responded to l-dopa as well as sapropterin.Conclusions: In the SPG11 patient with extrapyramidal symptoms, a trial of l-dopa/carbidopa and sapropterin and/or evaluation of cerebrospinal fluid neurotransmitters should be considered.

Erdheim–Chester disease presenting with an intramedullary spinal cord lesion

Erdheim–Chester disease (ECD) is a rare form of nonLangerhans histiocytosis characterized by multi-systemic xanthogranulomatous infiltration. The disease commonly affects the skeleton, but may also involve the skin, viscera including the cardiovascular system and lungs, as well as the central nervous system [1–4]. Diagnosis is based on histopathology typically showing infiltration by histiocytes expressing CD68, but not CD1a [3]. In the nervous system, ECD commonly affects the neurohypophysis resulting in diabetes insipidus. Extrahypophyseal nervous system involvement is seen in about a third of ECD patients and includes intra-axial infiltrative lesions, meningioma-like masses, and periarterial infiltration [3, 5, 6]. Spinal cord involvement may occur due to extramedullary masses [3, 7, 8] but intra-axial cord lesions are rare and only a single patient has been described [9]. We report a case of ECD presenting with progressive spastic paraparesis caused by an intramedullary cord tumor. A 31-year-old female was referred to our clinic with a 10-year history of slowly progressive gait difficulties due to a spinal cord mass. She also complained of polydipsia, polyuria, and irregular menstruation. Clinical examination revealed spastic paraparesis with extensor plantar responses and normal sensory function. There was saccadic smooth pursuit in all directions and horizontal nystagmus on lateral gaze, but no other signs of cerebellar dysfunction. She had multiple periorbital xanthelasma-like lesions (Fig. 1). She did not complain of skeletal pain. MRI of the brain revealed symmetrical high T2 signal in the cerebellar white matter, sparing the dentate nuclei. There was calcification of the dentates and globus pallidus (Fig. 1). MRI of the spine showed diffuse, non-contrast enhancing, low T1 and T2 signal changes in multiple cervical and thoracic vertebrae. There was a fusiform masslesion of the thoracic cord showing inhomogeneously high T2 signal intensity and partial contrast enhancement (Fig. 2). Scintigraphy with technetium 99 and fluorodeoxyglucose positron-emission tomography (FDG-PET) showed pathological tracer uptake in the epiphyses of long bones, several cervical and thoracic vertebra (corresponding to signal changes on the MRI) and parts of the facial skeleton. Skeleton radiograms showed moderate hyperostosis of the skull and sclerotic changes in the epiphyses of the long bones (Fig. 1). A computed tomography (CT)-guided biopsy of the 9th thoracic vertebra was performed. Histology revealed a hypercellular bone marrow with focal fibrosis and infiltration C. Tzoulis (&) I. O. Gjerde Department of Neurology, Haukeland University Hospital, 5021 Bergen, Norway e-mail: chtzoulis@yahoo.com; charalampos.tzoulis@helsebergen.no

Development and Validation of a Neurological Disability Scale for Patients with HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP): The IPEC-1 Scale (P03.258)

Objective: To create and validate a neurological disability scale (NDS) for patients with Human T-cell Lymphotropic Virus Type 1 (HTLV-1) associated myelopathy / tropical spastic paraparesis (HAM/TSP). Background HAM/TSP is a chronic disorder which is an important cause of disability among relatively young persons. It is characterized by a progressive spastic paraparesis, neurogenic bladder, pain, and minor sensory signs. Many aspects about the disease progression, disability profile and response to therapeutic approaches are yet to be defined. The current scales used to measure neurological disability (ND) in HAM/TSP are incomplete, measuring only motor disability as the Osame9s scale or the Disability Status Score (DSS), or are of difficult application and not created for this specific disease, as the Expanded Disability Status Score (EDSS), that was created for patients with Multiple Sclerosis. Design/Methods: The IPEC-1 scale was created based on a extensive literature review about the clinical aspects of the disease and our clinical experience acquired by evaluation of a large cohort of patients with HAM/TSP (about 1000 patients) in our out-patient clnic in Fiocruz, Rio de Janeiro, Brazil. It is a multidimentional scale that assesses more than one aspect of the disease. Fifty-nine HAM/TSP patients were submitted to the IPEC scale, DSS, Osame9s scale. Its internal consistency, inter-rater agreement and face and content validity were evaluated. Results: The score distribution shows good variability, and no floor or ceiling effects were detected. The internal consistency of the IPEC scale varied from 0.43 to 0.92, and the inter-rater agreement was 96%. The scale showed good face and content validity, and the instrument was able to distinguish significantly groups of patients with distinct deambulation independence levels. The administrative and respondent burdens were very low. Conclusions: The IPEC-1 scale provides a useful and objective tool to assess the ND in this group of individuals. Disclosure: Dr. Schmidt has nothing to disclose. Dr. Oliveira has nothing to disclose. Dr. Araujo has nothing to disclose.

Adult-Onset Progressive Spastic Paraparesis Due to a Novel, Heteroplasmic Mitochondrial tRNAGlu (m.14685A&gt;G) Gene Mutation (IN7-1.010)

Objective: We report a 45 year old lady with a five year history of progressive spastic paraparesis and ataxia. Background There was visual impairment – cataracts aged 8 and primary photo–receptor retinopathy, bilateral sensory–neural deafness as a teenager and stroke–like episodes as an adult. She was initially believed to have Usher9s syndrome and then congenital rubella following evidence of bilateral basal ganglia calcification on MRI brain. Family history was unremarkable, a male sibling had spina–bifida whilst her maternal grandmother had multiple sclerosis. Design/Methods: Investigations revealed elevated plasma lactate, with no evidence of CSF abnormalities, or CSF rubella RNA and rubella specific intrathecal antibodies. Brain MRI demonstrated progressive atrophy of the cerebral hemispheres and spinal cord, and the existing basal ganglia and thalamic calcifications. Muscle biopsy revealed numerous COX-deficient fibres, some of which showed “ragged-red” changes. Results: Having excluded common mtDNA mutations, sequencing of the entire mitochondrial genome was undertaken, identifying a novel, heteroplasmic m.14685G>A tRNAGlu (MTTE) variant affecting an evolutionary conserved nucleotide within the TψC arm of the mt-tRNAGlu molecule. Single fibre PCR analysis revealed segregation of m.14685G>A mutation with the COX deficiency, confirming pathogenicity of this novel mt-tRNA mutation. She died of broncho-pneumonia. Autopsy revealed generalised cerebral atrophy with dense calcification of the lentiform nuclei with neuronal loss and gliosis. Mutation analysis of post-mortem skeletal and cardiac muscle tissues confirmed the m.14685G>A MTTE gene mutation at intermediate levels of heteroplasmy (42% and 68% respectively) whilst genetic analysis of the family indicated that the mutation had arisen sporadically. Conclusions: This is an unusual presentation of adult–onset spastic paraparesis related to mitochondrial dysfunction, due to a novel, pathogenic mtDNA mutation. Mitochondrial diseases are an important differential of Usher9s syndrome which can manifest into adulthood, and of perinatal infections (TORCH complex) which can involve the eye and CNS with focal cerebral calcification. Disclosure: Dr. Gnanapavan has nothing to disclose. Dr. Alston has nothing to disclose. Dr. Lax has nothing to disclose. Dr. Yarham has nothing to disclose. Dr. Everett has nothing to disclose. Dr. Hewazy has nothing to disclose. Dr. O9Donovan has nothing to disclose. Dr. Dean has nothing to disclose. Dr. Taylor has nothing to disclose.

Adult-Onset Progressive Spastic Paraparesis Due to a Novel, Heteroplasmic Mitochondrial tRNAGlu (m.14685A&gt;G) Gene Mutation (P02.022)

Adult-Onset Progressive Spastic Paraparesis Due to a Novel, Heteroplasmic Mitochondrial tRNAGlu (m.14685A&gt;G) Gene Mutation (P02.022)