Mapa epidemiológico transversal de las ataxias y paraparesias espásticas hereditarias en España / Epidemiology of ataxia and hereditary spastic paraplegia in Spain: a cross-sectional study

Introducción: Las ataxias (AT) y paraparesias espásticas hereditarias (PEH) son síndromes neu-rodegenerativos raros. Nos proponemos conocer la prevalencia de las AT y PEH en Espa˜na en2019.Pacientes y métodos: Estudio transversal, multicéntrico, descriptivo y retrospectivo de lospacientes con AT y PEH, desde marzo de 2018 a diciembre de 2019 en toda Espa˜na.Resultados: Se obtuvo información de 1933 pacientes procedentes de 11 Comunidades Autóno-mas, de 47 neurólogos o genetistas. Edad media: 53,64 a˜nos ± 20,51 desviación estándar (DE);938 varones (48,5%), 995 mujeres (51,5%). En 920 pacientes (47,6%) no se conoce el defectogenético. Por patologías, 1.371 pacientes (70,9%) diagnosticados de AT, 562 diagnosticados dePEH (29,1%). La prevalencia estimada de AT es 5,48/100.000 habitantes, y la de PEH es 2,24casos/100.000 habitantes. La AT dominante más frecuente es la SCA3. La AT recesiva más fre-cuente es la ataxia de Friedreich (FRDA). La PEH dominante más frecuente es la SPG4, y la PEHrecesiva más frecuente es la SPG7.Conclusiones: La prevalencia estimada de AT y PEH en nuestra serie es de 7,73 casos/100.000habitantes. Estas frecuencias son similares a las del resto del mundo. En el 47,6% no se haconseguido un diagnóstico genético. A pesar de las limitaciones, este estudio puede contribuira estimar los recursos, visibilizar estas enfermedades, detectar las mutaciones más frecuentespara hacer los screenings por comunidades, y favorecer los ensayos clínicos.(AU)

Introduction: Ataxia and hereditary spastic paraplegia are rare neurodegenerative syndromes.We aimed to determine the prevalence of these disorders in Spain in 2019.Patients and methods: We conducted a cross-sectional, multicentre, retrospective, descrip-tive study of patients with ataxia and hereditary spastic paraplegia in Spain between March2018 and December 2019. Results: We gathered data from a total of 1933 patients from 11 autonomous communities,provided by 47 neurologists or geneticists. Mean (SD) age in our sample was 53.64 (20.51)years; 938 patients were men (48.5%) and 995 were women (51.5%). The genetic defect wasunidentified in 920 patients (47.6%). A total of 1371 patients (70.9%) had ataxia and 562 (29.1%)had hereditary spastic paraplegia. Prevalence rates for ataxia and hereditary spastic paraplegiawere estimated at 5.48 and 2.24 cases per 100 000 population, respectively. The most frequenttype of dominant ataxia in our sample was SCA3, and the most frequent recessive ataxia wasFriedreich ataxia. The most frequent type of dominant hereditary spastic paraplegia in oursample was SPG4, and the most frequent recessive type was SPG7.Conclusions: In our sample, the estimated prevalence of ataxia and hereditary spastic para-plegia was 7.73 cases per 100 000 population. This rate is similar to those reported for othercountries. Genetic diagnosis was not available in 47.6% of cases. Despite these limitations, ourstudy provides useful data for estimating the necessary healthcare resources for these patients,raising awareness of these diseases, determining the most frequent causal mutations for localscreening programmes, and promoting the development of clinical trials.(AU)

Revisiting Konzo Risk Factors in Three Areas Differently Affected by Spastic Paraparesis in Eastern Democratic Republic of the Congo Discloses a Prominent Role of the Nutritional Status-A Comparative Cross-Sectional Study.

This comparative cross-sectional study aimed to better understand the respective contributions of protein malnutrition and cassava-derived cyanide poisoning in the development of konzo. We compared data on nutritional status and cyanide exposure of school-age adolescent konzo-diseased patients to those of non-konzo subjects of similar age from three areas in the Eastern Democratic Republic of the Congo. Our results show that konzo patients had a high prevalence of both wasting (54.5%) and stunting (72.7%), as well as of cyanide poisoning (81.8%). Controls from Burhinyi and those from Idjwi showed a similar profile with a low prevalence of wasting (3.3% and 6.5%, respectively) and intermediate prevalence of stunting (26.7% and 23.9%, respectively). They both had a high prevalence of cyanide poisoning (50.0% and 63.0%, respectively), similar to konzo-patients. On the other hand, controls from Bukavu showed the lowest prevalence of both risk factors, namely chronic malnutrition (12.1%) and cyanide poisoning (27.6%). In conclusion, cassava-derived cyanide poisoning does not necessarily coexist with konzo outbreaks. The only factor differentiating konzo patients from healthy individuals exposed to cyanide poisoning appeared to be their worse nutritional status. This further suggests that, besides the known role of cyanide poisoning in the pathogenesis of konzo, malnutrition may be a key factor for the disease occurrence.

Konzo outbreak in the Western Province of Zambia.

OBJECTIVE: To identify the etiology of an outbreak of spastic paraparesis among women and children in the Western Province of Zambia suspected to be konzo. METHODS: We conducted an outbreak investigation of individuals from Mongu District, Western Province, Zambia, who previously developed lower extremity weakness. Cases were classified with the World Health Organization definition of konzo. Active case finding was conducted through door-to-door evaluation in affected villages and sensitization at local health clinics. Demographic, medical, and dietary history was used to identify common exposures in all cases. Urine and blood specimens were taken to evaluate for konzo and alternative etiologies. RESULTS: We identified 32 cases of konzo exclusively affecting children 6 to 14 years of age and predominantly females >14 years of age. Fourteen of 15 (93%) cases ≥15 years of age were female, 11 (73%) of whom were breastfeeding at the time of symptom onset. Cassava was the most commonly consumed food (median [range] 14 [4-21] times per week), while protein-rich foods were consumed <1 time per week for all cases. Of the 30 patients providing urine specimens, median thiocyanate level was 281 (interquartile range 149-522) µmol/L, and 73% of urine samples had thiocyanate levels >136 µmol/L, the 95th percentile of the US population in 2013 to 2014. CONCLUSION: This investigation revealed the first documented cases of konzo in Zambia, occurring in poor communities with diets high in cassava and low in protein, consistent with previous descriptions from neighboring countries.

An epidemic of spastic paraparesis of unknown aetiology in Northern Mozambique.

This case study is based on a real-life outbreak investigation undertaken in Mozambique in 1981. This case study describes and promotes one particular approach to unknown disease outbreak investigation. Investigational procedures, however, may vary depending on location and outbreak. It is anticipated that the epidemiologist investigating an unknown disease outbreak will work within the framework of a "multidisciplinary investigation team". It is through the collaborative efforts of this team, with each member playing a critical role, that outbreak investigations are successfully completed. Some aspects of the original outbreak and investigation have, however, been altered to assist in meeting the desired teaching objectives and to allow completion of the case study in less than 3 hours.

Traducción y validación de la escala Individualized Neuromuscular quality of life para la población española: evaluación de la calidad de vida para personas afectas de enfermedades neuromusculares / Translation and validation of the Individualised Neuromuscular Quality of Life scale for the Spanish population: quality of life assessment for persons with neuromuscular diseases

Introducción. La escala Individualized Neuromuscular Quality of Life (INQoL) es un cuestionario que valora la calidad de vida relacionada con la salud de personas adultas con enfermedades neuromusculares. Objetivo. Validar y analizar la fiabilidad de la versión española de la INQoL, como instrumento de medición de la calidad de vida relacionada con la salud en individuos con enfermedades neuromusculares. Pacientes y métodos. Se realiza una traducción-retrotraducción de la INQoL en la población española y, posteriormente, para el análisis de fiabilidad se llevan a cabo dos mediciones, test-retest, a 50 pacientes de 19 a 67 años. De este modo se evalúa la concordancia intraobservador y se evalúa la consistencia interna de la escala. Resultados. El estudio de la fiabilidad del índice de concordancia intraobservador tiene un valor de excelente en siete de las diez subdimensiones y en la puntuación total de la calidad de vida; de buena, en dos; y de moderada, en una. El análisis del alfa de Cronbach para las subdimensiones de la INQoL tiene un valor de excelente (> 0,818) en siete de ellas, así como en la puntuación total de la calidad de vida relacionada con la salud (0,928), un valor de buena consistencia interna en tres de las subdimensiones y de moderada en una. Conclusiones. La versión española de la INQoL es un instrumento válido y fiable como herramienta de medición de la calidad de vida en individuos adultos con enfermedades neuromusculares (AU)

Introduction. The Individualized Neuromuscular Quality of Life (INQoL) is a questionnaire that evaluates the quality of life related to the health of adults with neuromuscular diseases. Aim. To validate and analyze the reliability of the Spanish version of the INQoL scale as an instrument for measuring quality of life related to health in individuals with neuromuscular diseases. Patients and methods. A translation-back translation of the INQoL in the Spanish population is performed and, subsequently, for the analysis of reliability, two measurements are carried out; test retest, with 50 patients aged between 19 and 67 years. In this way we assess the intraobserver concordance and assess the internal consistency of the scale. Results. The study of the reliability of the intraobserver concordance index has a value of excellent in seven of the ten subdimensions as well as in the total score of the quality of life. It has a value of good in two and of moderate in one subdimension. The analysis of Cronbach’s alpha for the subdimensions of the INQoL has a value of excellent (> 0.818) in seven of them, as well as in the total score of the quality of life related to health (0.928), a value of good internal consistency in three of the subdimensions, and of moderate in one. Conclusions. The Spanish version of the INQoL is a valid and reliable instrument as a tool for measuring quality of life in adult patients with neuromuscular diseases (AU)

Health survey of adults with hereditary spastic paraparesis compared to population study controls.

BACKGROUND: Hereditary spastic paraparesis (HSP) is a rare neurodegenerative condition characterized by slowly progressive spastic weakness of the lower limbs and urinary sphincter dysfunction. Complex HSP involves additional neurologic symptoms and signs like ataxia, extra pyramidal signs, polyneuropathy, and cognitive decline. Little is known about the disease burden for adults with HSP beyond the described core symptoms. METHODS: A cross-sectional survey of 108 adults aged 30 years and older (Mage = 57.7 years, SD = 11.5, range 30 to 81; 54.2 % females) recruited from a national center of expertise for rare disorders and a patient advocacy organization in Norway. Self-report data from the HSP sample was compared to self-report data from a large Norwegian population study, HUNT3 (N = 46,293), covering health-related variables such as overall life satisfaction, mental wellbeing, memory function, perceived pain, and co-morbid diseases. In addition, the HSP sample reported specific items developed for this study in co-operation with the patient advocacy organization. RESULTS: The HSP sample more frequently lived alone. Overall, the HSP sample reported lower life satisfaction, lower mental wellbeing and lower social support, as well as poorer memory and sleep, compared to controls. Furthermore, the HSP sample more frequently reported musculoskeletal pain, constipation, and urinary incontinence compared to controls. There was no difference between samples in frequency of physical activity and alcohol and tobacco use. Men with HSP reported higher impact of HSP, lower life satisfaction, and less ability to perform activities of daily living compared to women with HSP. CONCLUSIONS: Adults with HSP experience disease burden on a larger number of areas than previously documented, and men with HSP may represent a particularly vulnerable group.

Paraparesia espástica progresiva y siringomielia estática: síndrome de Silver/SPG17 / Progressive spastic paraparesis and static syringomyelia: Silver syndrome/SPG17

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Evaluation of prognostic factors in medically treated patients of spinal tuberculosis.

This study was aimed to determine the prognostic factors in medically treated patients of spinal tuberculosis. In this longitudinal observational study, from July 2010 to December 2011, 70 consecutive patients (40 males and 30 females) spinal tuberculosis were enrolled. Diagnosis of spinal tuberculosis was based on characteristic clinical and neuroimaging features. Diagnosis was histopathologically and/or bacteriologically verified. Patients received antituberculous treatment as per World Health Organization guidelines and were followed for 6 months. Disability was evaluated with modified Barthel index (MBI). Outcome was defined as good (MBI > 12) and poor (MBI ≤ 12). Various clinical and neuroimaging parameters, likely to affect the outcome, were analyzed using univariate and multivariate analysis. After 6 months, 45 patients had a good outcome, while 25 patients had a poor outcome. On univariate analysis, duration of illness >6 months (OR 0.062, CI 0.018-0.212), bladder involvement (OR 0.102, CI 0.033-0.317), spinal deformity (OR 0.050, CI 0.013-0.196), spastic paraparesis (OR 0.572, CI 0.190-1.723), and flexor spasms (OR 0.077, CI 0.021-0.280) were found as important clinical predictors of poor outcome. Involvement of more than 2 vertebrae (OR 0.095, CI 0.028-0.328), complete collapse (OR 0.072, CI 0.022-0.241), cord compression (OR 0.025, CI 0.003-0.204), spinal extension of the abscess (OR 0.044, CI 0.005-0.350), and thick/septate abscess wall (OR 0.062, CI 0.016-0.240) were the neuroimaging parameters associated with poor prognosis. However, on multivariate analysis, duration of illness >6 months (Exp-b 0.086, CI 0.019-0.378), cord compression (Exp-b 0.035, CI 0.003-0348), and spinal extension of the abscess (Exp-b 0.109, CI 0.017-0.91) were significant. Medical management results in clinical improvement in a majority of the patients of spinal tuberculosis. Duration of illness >6 months, cord compression, and spinal extension of abscess are associated with poor outcome.

Appearance of konzo in South-Kivu, a wartorn area in the Democratic Republic of Congo.

Konzo is an upper motor neuron disease characterized by sudden-onset and irreversible spastic paraparesis occurring in nutritionally compromised people. It is associated with consumption of insufficiently processed cyanogenic-toxic cassava. Cassava, the main caloric source in the Democratic Republic of Congo, has been safely consumed for decades in the Eastern Province of South-Kivu. However, in the context of long-lasting war and violent conflicts, cases of spastic paraparesis resembling konzo appeared in a populous area (Burhinyi). Two field surveys (2003 and 2005) identified 41 subjects meeting clinical criteria of konzo and suffering from (chronic) malnutrition. Their urinary thiocyanate concentrations (median 129, range 20-688, SD 146 µg/L), and cyanogen levels (median 20 ppm, range 5-300 ppm, SD 73 ppm) in cassava roots from their household stocks were high. The source of cyanogenic-toxicity was unprocessed fresh cassava roots during harvest period, but probably also insufficiently processed roots. This first report of konzo in South-Kivu concludes that occurrence of konzo was triggered by food shortages because of the longstanding state of insecurity. Contributory factors included the introduction of new varieties of (bitter) cassava, but konzo may actually be caused by a combination of factors that are yet to be understood.

Idiopathic ventral spinal cord herniation: a rare presentation of tethered cord.

Idiopathic ventral spinal cord herniation is a rare condition that has been increasingly reported in the last decade. The natural history and optimal management have yet to be defined. Therefore, debate exists regarding the pathogenesis and surgical management of this condition. The purpose of this review article is to further educate neurosurgeons about the surgical techniques and outcomes associated with treating this rare and often misdiagnosed condition.

[Japan spastic paraplegia research consortium (JASPAC)].

Japan Spastic Paraplegia Research Consortium (JASPAC), a nationwide clinical and genetic survey of patients with HSP in Japan, was started from 2006 as a project of the Research Committee for Ataxic Diseases of the Ministry of Health, Labor and Welfare, Japan. To date (October 4, 2010), 321 index patients with HSP have been registered from 40 prefectures in Japan. We are now performing molecular testing for the HSP patients using direct sequencing (SPG4, SPG31, and ARSACS), comparative genomic hybridization (CGH) array (SPG1/2/3A/4/5/6/7/8/10/11/13/15/17/20/21/31/33/39/42/ABCD1/alsin/SACS), and resequencing microarray (SPG1/2/3A/4/5/6/7/8/10/11/13/17/20/21/31/33/ABCD1). In 144 Japanese ADHSP families, SPG4 was the most common form, accounting for 47%, followed by SPG31 (4%), SPG3A (3%), SPG8 (1%), and SPG10 (1%). The results of molecular testing will be applicable to patients in terms of improved positive diagnosis, follow-up, and genetic counseling. Since approximately 40% of ADHSP remain unknown, we will perform high-throughput linkage analyses using SNP HiTLink (SNP High Throughput Linkage analysis system) for the identification of loci for disease-associated genes. Meanwhile, preliminary data showed that SPG11 and ARSACS were common in Japanese ARHSP families. JASPAC will contribute to elucidate the spectrum of clinical features and mutations, genotype/phenotype correlations, pathophisiology in various HSP phenotypes.

Are acquired hepatocerebral degeneration and hepatic myelopathy reversible?

BACKGROUND: Acquired hepatocerebral degeneration (AHD) and hepatic myelopathy (HM) are rare complications of chronic liver disease and are usually resistant to medical therapy. MATERIALS AND METHODS: The clinical and laboratory findings of 14 male and 2 female patients with AHD or HM were evaluated. RESULTS: The prevalence of AHD and HM was 2% inpatient case series in the last 10 years. The median age of the patients (5 Child's B and 11 Child's C) was 48.7 years (28 to 66 y), and the mean known duration of the liver disease was 75 months (24 to 194 mo). The median time of onset of neurologic findings after diagnosis of the liver disease was 14.5 months. Eight patients who had marked spastic paraparesis or tetraparesis were included in the HM group and all others had AHD group. Sixty-nine percent of the patients had a spontaneous or surgical portosystemic shunts, and the remaining dense retroperitoneal collaterals. During the follow-up period of median 29 months (4 to 72 mo), 12 patients died while waiting for liver transplantation, and these patients suffered from the several complications of chronic liver disease more than the living patients. A marked improvement was observed in 2 of the patients (1 with AHD and the other with HM) at 6 and 8 months after the liver transplantation, respectively. CONCLUSIONS: Our data suggest that liver transplantation had an important effect on the improvement in these patients.

[Hereditary ataxias, spastic parapareses and neuropathies in Eastern Canada]. / Ataxies, paraparésies spastiques et neuropathies héréditaires fréquentes dans l'Est du Canada.

It has been demonstrated, for many inherited diseases, that historical events have shaped the various regional gene pools of Eastern Canada. In so doing, it has given rise to the increased prevalence of some rare diseases due, to founder effects. The following neurogenetic disorders were first identified in patients from Eastern Canada: AOA-2, Arsacs, HSN-2, Arca-1, HMSN/ACC and Arsal. The population of Eastern Canada, we are convinced, will still allow the identification of new rare forms of hereditary ataxias, spastic parapareses and neuropathies as well as contribute to the uncovering of their mutated genes. We have summarized our current knowledge of the various hereditary ataxias, spastic parapareses and neuropathies in Eastern Canada. The study of the more common and homogenous features of these diseases has been largely completed.

Restless legs syndrome in hereditary spastic paraparesis.

This study was designed to investigate the prevalence and determinants of the association of restless legs syndrome (RLS) and hereditary spastic paraparesis (HSP). Therefore, 132 patients with HSP were evaluated concerning the symptoms of RLS by a standardized questionnaire. RLS was supposed when patients met all of the established four essential criteria of RLS defined by the International RLS Study Group. In addition, we studied the relationship between RLS and age at HSP symptom onset and evaluated the severity of RLS symptoms. Out of 59 responses, RLS was found in 27 HSP patients (15 male, 12 female) so that RLS was more frequent in the total HSP group (20.5%; 27/132) than in previous population-based studies (about 11%). In all 27 patients, the diagnosis of RLS was established based on an additional personal interview. The probability to develop RLS did not increase with higher age. Age at onset of HSP symptoms in the HSP group with RLS (27.7 +/- 12.6 years) and the HSP group without RLS (37.0 +/- 16.9 years) differed significantly (p = 0.04). Most of the patients with RLS showed a moderate and severe grade on the RLS severity score. Only 8 patients had previously been diagnosed to have RLS and were on medication. The data of this screening for RLS provided evidence that patients with HSP are particularly susceptible to develop RLS. Consequently, special emphasis should be put on the diagnosis criteria of RLS in HSP patients.

Symptomatic ossification of the ligamentum flavum: a clinical series from the French Antilles.

STUDY DESIGN: A series of 14 patients from the French Antilles treated for ossification of the ligamentum flavum (OLF). OBJECTIVES: To describe the clinical and radiologic aspects, as well as disease course in a group of Caribbean patients. Also describe the use of sagittal computerized tomography (CT) reconstructions to distinguish OLF from calcification of the ligamenta flava. SUMMARY OF BACKGROUND DATA: OLF is a rare disease described almost exclusively in Japanese patients. Only rarely are patients of African descent affected. No series of OLF in African American or African Caribbean subjects has previously been published. METHODS: A retrospective study of 14 consecutive patients, including 7 men and 7 women (mean age, 66.8 years), was conducted from 1996 to 2003. Diagnosis in each case was established using CT. Magnetic resonance imaging was also performed in every case. For the 11 patients treated surgically, pathology studies were performed. RESULTS: Walking difficulties were the most common presenting complaint. A picture of spastic paraparesis associated with sphincter dysfunction was the most common finding on initial examination. In each case, CT provided sufficient information to establish a diagnosis of OLF, while magnetic resonance imaging was helpful for showing spinal cord involvement. In most of the patients, OLF was located in the lower thoracic spine. Surgical decompression through a posterior approach resulted in regression of symptoms in all 11 patients treated surgically. CONCLUSIONS: This study is the first reported series of OLF in a group of Caribbean patients. The disease appears to be underreported in the African Caribbean population. OLF can lead to debilitating thoracic myelopathy. Surgery is frequently indicated and achieves favorable results.

[The genetics of movement disorders--spinocerebellar degenerations]. / Genetikk ved bevegelsesforstyrrelser--spinocerebellaere lidelser.

BACKGROUND: Hereditary movement disorders include spinocerebellar disorders, a large and heterogeneous group of syndromes with ataxia or spasticity as the prominent symptom. In spite of the vast clinical and genetic heterogeneity, patterns of pathogenesis slowly emerge and help us understand these disorders. MATERIAL AND METHODS: This review is based on personal experience and recent literature. RESULTS: More than 20 types of hereditary spastic paraparesis have been reported. Dominant SPG4 and SPG3 with mutations in the spastin or the atlastin gene have been identified in many countries. The most prevalent type of recessive ataxia in Europe, Friedreich's ataxia, has become a model of integrated clinical-molecular-therapeutic research. More recessive ataxias (AOA1-2) have been described recently. More than 20 autosomal dominant ataxias have been reported, with 12 identified genes including the episodic ataxias, and 9 mapped. SCA7 appears to be the most frequent type in some Nordic countries. INTERPRETATION: A striking feature of many of these diseases is the involvement of very different genes for similar phenotypes. Conversely, very heterogeneous phenotypes are due to single-gene defects. Recently there has been considerable progress in the clinical description of movement disorders and the understanding of their genetic basis. Possible therapies are emerging.

Bovine spastic paresis: etiological hypotheses.

Bovine spastic paresis (BSP) is a rare and little-known disease of cattle. The etiology remains unknown. A pathogenesis close to the sub-acute transmissible spongiform encephalopathies (TSEs) has repeatedly been advanced. In order to confirm an infectious origin, intra- and inter-species transmission studies are proposed. A positive result would bring a major advance in knowledge.

Mutation analysis of the spastin gene (SPG4) in patients with hereditary spastic paraparesis.

BACKGROUND: Hereditary spastic paraparesis is a genetically heterogeneous condition. Recently, mutations in the spastin gene were reported in families linked to the common SPG4 locus on chromosome 2p21-22. OBJECTIVES: To study a population of patients with hereditary spastic paraparesis for mutations in the spastin gene (SPG4) on chromosome 2p21-22. METHODS: DNA from 32 patients (12 from families known to be linked to SPG4) was analysed for mutations in the spastin gene by single strand conformational polymorphism analysis and sequencing. All patients were also examined clinically. RESULTS: Thirteen SPG4 mutations were identified, 11 of which are novel. These mutations include missense, nonsense, frameshift, and splice site mutations, the majority of which affect the AAA cassette. We also describe a nucleotide substitution outside this conserved region which appears to behave as a recessive mutation. CONCLUSIONS: Recurrent mutations in the spastin gene are uncommon. This reduces the ease of mutation detection as a part of the diagnostic work up of patients with hereditary spastic paraparesis. Our findings have important implications for the presumed function of spastin and schemes for mutation detection in HSP patients.