Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

Background: Disorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditions in 2015 and 2016, but these analyses did not include neurodevelopmental disorders, as defined by the International Classification of Diseases (ICD)-11, or a subset of cases of congenital, neonatal, and infectious conditions that cause neurological damage. Here, we estimate nervous system health loss caused by 37 unique conditions and their associated risk factors globally, regionally, and nationally from 1990 to 2021. Methods: We estimated mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs), with corresponding 95% uncertainty intervals (UIs), by age and sex in 204 countries and territories, from 1990 to 2021. We included morbidity and deaths due to neurological conditions, for which health loss is directly due to damage to the CNS or peripheral nervous system. We also isolated neurological health loss from conditions for which nervous system morbidity is a consequence, but not the primary feature, including a subset of congenital conditions (ie, chromosomal anomalies and congenital birth defects), neonatal conditions (ie, jaundice, preterm birth, and sepsis), infectious diseases (ie, COVID-19, cystic echinococcosis, malaria, syphilis, and Zika virus disease), and diabetic neuropathy. By conducting a sequela-level analysis of the health outcomes for these conditions, only cases where nervous system damage occurred were included, and YLDs were recalculated to isolate the non-fatal burden directly attributable to nervous system health loss. A comorbidity correction was used to calculate total prevalence of all conditions that affect the nervous system combined. Findings: Globally, the 37 conditions affecting the nervous system were collectively ranked as the leading group cause of DALYs in 2021 (443 million, 95% UI 378–521), affecting 3·40 billion (3·20–3·62) individuals (43·1%, 40·5–45·9 of the global population); global DALY counts attributed to these conditions increased by 18·2% (8·7–26·7) between 1990 and 2021. Age-standardised rates of deaths per 100 000 people attributed to these conditions decreased from 1990 to 2021 by 33·6% (27·6–38·8), and age-standardised rates of DALYs attributed to these conditions decreased by 27·0% (21·5–32·4). Age-standardised prevalence was almost stable, with a change of 1·5% (0·7–2·4). The ten conditions with the highest age-standardised DALYs in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer's disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications due to preterm birth, autism spectrum disorder, and nervous system cancer. Interpretation: As the leading cause of overall disease burden in the world, with increasing global DALY counts, effective prevention, treatment, and rehabilitation strategies for disorders affecting the nervous system are needed. Funding: Bill & Melinda Gates Foundation

Nonmotor And Extracerebellar Features In Machado-joseph Disease: A Review

Spinocerebellar ataxia type 3 or Machado-Joseph disease is the most common spinocerebellar ataxia worldwide, and the high frequency of nonmotor manifestations in Machado-Joseph disease demonstrates how variable is the clinical expression of this single genetic entity. Anatomical, physiological, clinical, and functional neuroimaging data reinforce the idea of a degenerative process involving extracerebellar regions of the nervous system in Machado-Joseph disease. Brain imaging and neuropathologic studies have revealed atrophy of the pons, basal ganglia, midbrain, medulla oblongata, multiple cranial nerve nuclei, and thalamus and of the frontal, parietal, temporal, occipital, and limbic lobes. This review provides relevant information about nonmotor manifestations and extracerebellar symptoms in Machado-Joseph disease. The main nonmotor manifestations of Machado-Joseph disease described in previous data and discussed in this article are: sleep disorders, cognitive and affective disturbances, psychiatric symptoms, olfactory dysfunction, peripheral neuropathy, pain, cramps, fatigue, nutritional problems, and dysautonomia. In addition, we conducted a brief discussion of noncerebellar motor manifestations, highlighting movement disorders. © 2013 Movement Disorder Society.28912001208Schos, L., Bauer, P., Schmidt, T., Schulte, T., Riess, O., Autosomal dominant cerebellar ataxias: clinical features, genetics, and pathogenesis (2004) Lancet Neurol, 3, pp. 291-304Jardim, L.B., Pereira, M.L., Silveira, I., Ferro, A., Sequeiros, J., Giugliani, R., Neurologic findings in Machado-Joseph disease: relation with disease duration, subtypes, and (CAG)n (2001) Arch Neurol, 58, pp. 899-904Nakano, K.K., Dawson, D.M., Spence, A., Machado disease. A hereditary ataxia in Portuguese emigrants to Massachusetts (1972) Neurology, 22, pp. 49-55Pedroso, J.L., Braga-Neto, P., Radavany, J., Barsottini, O.G., Machado-Joseph disease in Brazil: from the first descriptions to the emergence as the most common spinocerebellar ataxia (2012) Arq Neuropsiquiatr, 70, pp. 630-632Igarashi, S., Takiyama, Y., Cancel, G., Intergenerational instability of the CAG repeat of the gene for Machado-Joseph disease (MJD1) is affected by the genotype of the normal chromosome: implications for the molecular mechanisms of the instability of the CAG repeat (1996) Hum Mol Genet, 5, pp. 923-932D'Abreu, A., Franca Jr., M.C., Paulson, H.L., Lopes-Cendes, I., Caring for Machado-Joseph disease: current understanding and how to help patients (2010) Parkinsonism Relat Disord, 16, pp. 2-7Riess, O., Rub, U., Pastore, A., Bauer, P., Schols, L., SCA3: neurological features, pathogenesis and animal models (2008) Cerebellum, 7, pp. 125-137D'Abreu, A., Franca Jr., M.C., Yasuda, C.L., Campos, B.A., Lopes-Cendes, I., Cendes, F., Neocortical atrophy in Machado-Joseph disease: a longitudinal neuroimaging study (2012) J Neuroimaging, 22, pp. 285-291Grimaldi, G., Manto, M., Topography of cerebellar deficits in humans (2011) Cerebellum, 11, pp. 336-351Paulson, H.L., Das, S.S., Crino, P.B., Machado-Joseph disease gene product is a cytoplasmic protein widely expressed in brain (1997) Ann Neurol, 41, pp. 453-462Klockgether, T., Skalej, M., Wedekind, D., 1998. Autosomal dominant cerebellar ataxia type I, MRI-based volumetry of posterior fossa structures and basal ganglia in spinocerebellar ataxia types 1, 2 and 3 (1998) Brain, 121, pp. 1687-1693Rub, U., Brunt, E.R., Deller, T., New insights into the pathoanatomy of spinocerebellar ataxia type 3 (Machado-Joseph disease) (2008) Curr Opin Neurol, 21, pp. 111-116D'Abreu, A., Franca Jr., M.C., Yasuda, C.L., Souza, M.S., Lopes-Cendes, I., Cendes, F., Thalamic volume and dystonia in Machado-Joseph disease (2012) J Neuroimaging, 21, pp. e91-e93D'Abreu, A., Franca, M.J., Appenzeller, S., Lopes-Cendes, I., Cendes, F., Axonal dysfunction in the deep white matter in Machado-Joseph disease (2009) J Neuroimaging, 19, pp. 9-12Taniwaki, T., Sakai, T., Kobayashi, T., Positron emission tomography (PET) in Machado-Joseph disease (1997) J Neurol Sci, 145, pp. 63-67Braga-Neto, P., Felicio, A.C., Hoexter, M.Q., Cognitive and olfactory deficits in Machado-Joseph disease: a dopamine transporter study (2012) Parkinsonism Relat Disord, 18, pp. 854-858Schmidt, T., Landwehrmeyer, G.B., Schmitt, I., An isoform of ataxin-3 accumulates in the nucleus of neuronal cells in affected brain regions of SCA3 patients (1998) Brain Pathol, 8, pp. 669-679Rub, U., Seidel, K., Ozerden, I., Consistent affection of the central somatosensory system in spinocerebellar ataxia type 2 and type 3 and its significance for clinical symptoms and rehabilitative therapy (2007) Brain Res, 53, pp. 235-249Seidel, K., Den Dunnen, W.F., Schultz, C., Axonal inclusions in spinocerebellar ataxia type 3 (2010) Acta Neuropathol, 120, pp. 449-460Khan, L.A., Bauer, P.O., Miyazaki, H., Lindenberg, K.S., Landwehrmeyer, B.G., Nukina, N., Expanded polyglutamines impair synaptic transmission and ubiquitin-proteasome system in Caenorhabditis elegans (2006) J Neurochem, 98, pp. 576-587Chou, A.H., Yeh, T.H., Ouyang, P., Chen, Y.L., Chen, S.Y., Wang, H.L., Polyglutamine expanded ataxin-3 causes cerebellar dysfunction of SCA3 transgenic mice by inducing transcriptional dysregulation (2008) Neurobiol Dis, 31, pp. 89-101Raggi, A., Ferri, R., Sleep disorders in neurodegenerative diseases (2010) Eur J Neurol, 17, pp. 1326-1338D'Abreu, A., Franca Jr., M., Conz, L., Sleep symptoms and their clinical correlates in Machado-Joseph disease (2009) Acta Neurol Scand, 119, pp. 277-280Pedroso, J.L., Braga-Neto, P., Felicio, A.C., Sleep disorders in cerebellar ataxias (2011) Arq Neuropsiquiatr, 69, pp. 253-257Pedroso, J.L., Braga-Neto, P., Felicio, A.C., Sleep disorders in Machado-Joseph disease: frequency, discriminative thresholds, predictive values, and correlation with ataxia-related motor and non-motor features (2011) Cerebellum, 10, pp. 291-295Pedroso, J.L., Bezerra, M.L., Braga-Neto, P., Is neuropathy involved with restless legs syndrome in Machado-Joseph disease? (2011) Eur Neurol, 66, pp. 200-203Pedroso, J.L., Bor-Seng-Shu, E., Felicio, A.C., Braga-Neto, P., Teixeira, M.J., Barsottini, O.G., Transcranial sonography findings in spinocerebellar ataxia type 3 (Machado-Joseph disease): a cross-sectional study (2011) Neurosci Lett, 504, pp. 98-101Pedroso, J.L., Bor-Seng-Shu, E., Felicio, A.C., Severity of restless legs syndrome is inversely correlated with echogenicity of the substantia nigra in different neurodegenerative movement disorders. A preliminary observation (2012) J Neurol Sci, 319, pp. 59-62Schols, L., Haan, J., Riess, O., Amoiridis, G., Przuntek, H., Sleep disturbance in spinocerebellar ataxias: is the SCA3 mutation a cause of restless legs syndrome? (1998) Neurology, 51, pp. 1603-1607Reimold, M., Globas, C., Gleichmann, M., Spinocerebellar ataxia type 1, 2, and 3 and restless legs syndrome: striatal dopamine D2 receptor status investigated by [11C]raclopride positron emission tomography (2006) Mov Disord, 21, pp. 1667-1673Pedroso, J.L., Braga-Neto, P., Felicio, A.C., Sleep disorders in Machado-Joseph disease: a dopamine transporter imaging study (2013) J Neurol Sci, 324, pp. 90-93Iranzo, A., Munoz, E., Santamaria, J., Vilaseca, I., Mila, M., Tolosa, E., REM sleep behavior disorder and vocal cord paralysis in Machado-Joseph disease (2003) Mov Disord, 18, pp. 1179-1183D'Abreu, A., Friedman, J., Coskun, J., Non-movement disorder heralds symptoms of Machado-Joseph disease years before ataxia (2005) Mov Disord, 20, pp. 739-741Friedman, J.H., Fernandez, H.H., Sudarsky, L.R., REM behavior disorder and excessive daytime somnolence in Machado-Joseph disease (SCA-3) (2003) Mov Disord, 18, pp. 1520-1522Schmahmann, J.D., Caplan, D., Cognition, emotion and the cerebellum (2006) Brain, 129, pp. 288-292Stoodley, C.J., Schmahmann, J.D., Evidence for topographic organization in the cerebellum of motor control versus cognitive and affective processing (2010) Cortex, 46, pp. 831-844Radvany, J., Camargo, C.H.P., Costa, Z.M., Fonseca, N.C., Nascimento, E.D., Machado Joseph disease of Azorean ancestry in Brazil: the Catarina kindred. Neurological, neuroimaging, psychiatric and neuropsychological findings in the largest known family, the Catarina kindred (1993) Arq Neuropsiquiatr, 51, pp. 21-30Zawacki, T.M., Grace, J., Friedman, J.H., Sudarsky, L., Executive and emotional dysfunction in Machado-Joseph disease (2002) Mov Disord, 17, pp. 1004-1010Maruff, P., Tyler, P., Burt, T., Currie, B., Burns, C., Currie, J., Cognitive deficits in Machado-Joseph disease (1996) Ann Neurol, 40, pp. 421-427Kawai, Y., Takeda, A., Abe, Y., Washimi, Y., Tanaka, F., Sobue, G., Cognitive impairments in Machado-Joseph disease (2004) Arch Neurol, 61, pp. 1757-1760Braga-Neto, P., Pedroso, J.L., Alessi, H., Cerebellar cognitive affective syndrome in Machado Joseph disease: core clinical features (2011) Cerebellum, 11, pp. 549-556Manto, M., Lorivel, T., Cognitive repercussions of hereditary cerebellar disorders (2011) Cortex, 47, pp. 81-110Braga-Neto, P., Dutra, L.A., Pedroso, J.L., Cognitive deficits in Machado-Joseph disease correlate with hypoperfusion of visual system areas (2012) Cerebellum, 11, pp. 1037-1044Schmitz-Hubsch, T., Coudert, M., Giunti, P., Self-rated health status in spinocerebellar ataxia-results from a European multicenter study (2010) Mov Disord, 25, pp. 587-595Schmitz-Hubsch, T., Coudert, M., Tezenas Du Montcel, S., Depression comorbidity in spinocerebellar ataxia (2011) Mov Disord, 26, pp. 870-876Cecchin, C.R., Pires, A.P., Rieder, C.R., Depressive symptoms in Machado-Joseph disease (SCA3) patients and their relatives (2007) Commun Genet, 10, pp. 19-26Saute, J.A., da Silva, A.C., Donis, K.C., Vedolin, L., Saraiva-Pereira, M.L., Jardim, L.B., Depressive mood is associated with ataxic and non-ataxic neurological dysfunction in SCA3 patients (2010) Cerebellum, 9, pp. 603-605Rodrigues, C.S., de Oliveira, V.Z., Camargo, G., Presymptomatic testing for neurogenetic diseases in Brazil: assessing who seeks and who follows through with testing (2012) J Genet Couns, 21, pp. 101-112Wolf, U., Rapoport, M.J., Schweizer, T.A., Evaluating the affective component of the cerebellar cognitive affective syndrome (2009) J Neuropsychiatry Clin Neurosci, 21, pp. 245-253Monte, T.L., Rieder, C.R., Tort, A.B., Use of fluoxetine for treatment of Machado-Joseph disease: an open-label study (2003) Acta Neurol Scand, 107, pp. 207-210Silva, R.C., Saute, J.A., Silva, A.C., Coutinho, A.C., Saraiva-Pereira, M.L., Jardim, L.B., Occupational therapy in spinocerebellar ataxia type 3: an open-label trial (2010) Braz J Med Biol Res, 43, pp. 537-542Hawkes, C., Olfaction in neurodegenerative disorder (2003) Mov Disord, 18, pp. 364-372Fernandez-Ruiz, J., Diaz, R., Hall-Haro, C., Olfactory dysfunction in hereditary ataxia and basal ganglia disorders (2003) Neuroreport, 14, pp. 1339-1341Connelly, T., Farmer, J.M., Lynch, D.R., Doty, R.L., Olfactory dysfunction in degenerative ataxias (2003) J Neurol Neurosurg Psychiatr, 74, pp. 1435-1437Abele, M., Riet, A., Hummel, T., Klockgether, T., Wullner, U., Olfactory dysfunction in cerebellar ataxia and multiple system atrophy (2003) J Neurol, 250, pp. 1453-1455Velazquez-Perez, L., Fernandez-Ruiz, J., Diaz, R., Spinocerebellar ataxia type 2 olfactory impairment shows a pattern similar to other major neurodegenerative diseases (2006) J Neurol, 253, pp. 1165-1169Braga-Neto, P., Felicio, A.C., Pedroso, J.L., Clinical correlates of olfactory dysfunction in spinocerebellar ataxia type 3 (2011) Parkinsonism Relat Disord, 17, pp. 353-356Moscovich, M., Munhoz, R.P., Teive, H.A., Olfactory impairment in familial ataxias (2012) J Neurol Neurosurg Psychiatry, 83, pp. 970-974Kim, Y.T., Shin, S.M., Lee, W.Y., Kim, G.M., Jin, D.K., Expression of expanded polyglutamine protein induces behavioral changes in Drosophila (polyglutamine-induced changes in Drosophila) (2004) Cell Mol Neurobiol, 24, pp. 109-122Sobel, N., Prabhakaran, V., Hartley, C.A., Odorant-induced and sniff-induced activation in the cerebellum of the human (1998) J Neurosci, 18, pp. 8990-9001Coutinho, P., Guimaraes, A., Pires, M.M., Scaravilli, F., The peripheral neuropathy in Machado-Joseph disease (1986) Acta Neuropathol (Berl), 71, pp. 119-124Kinoshita, A., Hayashi, M., Oda, M., Tanabe, H., Clinicopathological study of the peripheral nervous system in Machado-Joseph disease (1995) J Neurol Sci, 130, pp. 48-58van de Warrenburg, B.P.C., Notermans, N.C., Schelhaas, H.J., Peripheral nerve involvement in spinocerebellar ataxias (2004) Arch Neurol, 61, pp. 257-261Franca Jr., M.C., D'Abreu, A., Nucci, A., Cendes, F., Lopes-Cendes, I., Prospective study of peripheral neuropathy in Machado-Joseph disease (2009) Muscle Nerve, 40, pp. 1012-1018Klockgether, T., Schols, L., Abele, M., Age related axonal neuropathy in spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) (1999) J Neurol Neurosurg Psychiatry, 66, pp. 222-224Friedman, J.H., Amick, M.M., Fatigue and daytime somnolence in Machado-Joseph disease (spinocerebellar ataxia type 3) (2008) Mov Disord, 23, pp. 1323-1324Franca Jr., M.C., D'Abreu, A., Nucci, A., Lopes-Cendes, I., Muscle excitability abnormalities in Machado-Joseph disease (2008) Arch Neurol, 65, pp. 525-529Kanai, K., Kuwabara, S., Arai, K., Sung, J.Y., Ogawara, K., Hattori, T., Muscle cramp in Machado-Joseph disease: altered motor axonal excitability properties and mexiletine treatment (2003) Brain, 126, pp. 965-973Franca Jr., M.C., D'Abreu, A., Friedman, J.H., Nucci, A., Lopes-Cendes, I., Chronic pain in Machado-Joseph disease: a frequent and disabling symptom (2007) Arch Neurol, 64, pp. 1767-1770Yeh, T.H., Lu, C.S., Chou, Y.H., Autonomic dysfunction in Machado-Joseph disease (2005) Arch Neurol, 62, pp. 630-636Franca Jr., M.C., D'Abreu, A., Nucci, A., Lopes-Cendes, I., Clinical correlates of autonomic dysfunction in patients with Machado-Joseph disease (2010) Acta Neurol Scand, 121, pp. 422-425Pradhan, C., Yashavantha, B.S., Pal, P.K., Sathyaprabha, T.N., Spinocerebellar ataxias type 1, 2 and 3: a study of heart rate variability (2008) Acta Neurol Scand, 117, pp. 337-342Yamanaka, Y., Asahina, M., Akaogi, Y., Cutaneous sympathetic dysfunction in patients with Machado-Joseph disease (2012) Cerebellum, 11, pp. 1057-1060Asahina, M., Katagiri, A., Yamanaka, Y., Spectral analysis of heart rate variability in patients with Machado-Joseph disease (2010) Auton Neurosci, 154, pp. 99-101Kazuta, T., Hayashi, M., Shimizu, T., Iwasaki, A., Nakamura, S., Hirai, S., Autonomic dysfunction in Machado-Joseph disease assessed by iodine123-labeled metaiodobenzylguanidine myocardial scintigraphy (2000) Clin Auton Res, 10, pp. 111-115Takiyama, Y., Sakoe, K., Nakano, I., Nishizawa, M., Machado-Joseph disease: cerebellar ataxia and autonomic dysfunction in a patient with the shortest known expanded allele (56 CAG repeat units) of the MJD1 gene (1997) Neurology, 49, pp. 604-606van Gaalen, J., Giunti, P., van de Warremburg, B.P., Movement disorders in spinocerebellar ataxias (2011) Mov Disord, 26, pp. 792-800Schols, L., Peters, S., Szymanski, S., Extrapyramidal motor signs in degenerative ataxias (2000) Arch Neurol, 57, pp. 1495-1500Schimitz-Hubsch, T., Coundert, M., Bauer, P., Spinocerebellar ataxia types 1, 2, and 6. Disease severity and nonataxia symptoms (2008) Neurology, 71, pp. 982-989Tuite, P.J., Rogaeva, E.A., St George-Hyslop, P.H., Lang, A.E., Dopa-responsive parkinsonism phenotype of Machado-Joseph disease: confirmation of 14q CAG expansion (1995) Ann Neurol, 38, pp. 684-687Bettencourt, C., Santos, C., Coutinho, P., Parkinsonism phenotype in Machado-Joseph disease (MJD/SCA3): a two-case report [serial online] (2011) BMC Neurol, 11, p. 131Socal, M.P., Emmel, V.E., Rieder, C.R., Hilbig, A., Saraiva-Pereira, M.L., Jardim, L.B., Intrafamilial variability of Parkinson phenotype in SCAs: novel cases due to SCA2 and SCA3 expansions (2009) Parkinsonism Relat Disord, 15, pp. 374-378Gwinn-Hardy, K., Singleton, A., O'Suilleabhain, P., Spinocerebellar ataxia type 3 phenotypically resembling Parkinson disease in a black family (2001) Arch Neurol, 58, pp. 296-299Subramony, S.H., Hernandez, D., Adam, A., Ethnic differences in the expression of neurodegenerative disease: Machado-Joseph disease in Africans and Caucasians (2002) Mov Disord, 17, pp. 1068-1071Lu, C.S., Chang, H.C., Kuo, P.C., The parkinsonian phenotype of spinocerebellar ataxia type 3 in a Taiwanese family (2004) Parkinsonism Relat Disord, 10, pp. 369-373Teive, H.A.G., Munhoz, R.P., Arruda, W.O., Spinocerebellar ataxias-Genotype-phenotype correlation in 104 Brazilian families (2012) Clinics (Sao Paulo), 67, pp. 443-449Pedroso, J.L., Bor-Seng-Shu, E., Braga-Neto, P., Teixeira, M.J., Barsottini, O.G., Transcranial sonography: Brazilian experience (2012) Arq Neuropsiquiatr, 70, pp. 313-314Siebert, M., Donis, K.C., Socal, M., Glucocerebrosidase gene variants in parkinsonism patients with Machado-Joseph/spinocerebellara ataxia 3 (2012) Parkinsonism Relat Disord, 18, pp. 185-190Lima, L., Coutinho, P., Clinical criteria for diagnosis of Machado-Joseph disease: report of a non-Azorean Portuguese family (1980) Neurology, 30, pp. 319-322Cardoso, F., de Oliveira, J.T., Puccioni-Sohler, M., Fernandes, A.R., de Mattos, J.P., Lopes-Cendes, I., Eyelid dystonia in Machado-Joseph disease (2000) Mov Disord, 15, pp. 1028-1030Pedroso, J.L., Braga-Neto, P., Felicio, A.C., Barsottini, O.G., Jardim, L.B., Saraiva-Pereira, M.L., Akathisia: an unusual movement disorder in Machado-Joseph disease (2011) Parkinsonism Relat Disord, 17, pp. 12-13Pedroso, J.L., Felicio, A.C., Braga-Neto, P., Barsottini, O.G., Movement disorders in spinocerebellar ataxias [letter] (2011) Mov Disord, 26, p. 2302Freeman, W., Wszolek, Z., Botulinum toxin type A for treatment of spasticity in spinocerebellar ataxia type 3 (Machado-Joseph disease) [letter] (2005) Mov Disord, 20, p. 644Saute, J.A., da Silva, A.C., Souza, G.N., Body mass index is inversely correlated with the expanded CAG repeat length in SCA3/MJD patients (2012) Cerebellum, 11, pp. 771-774Saute, J.A., da Silva, A.C., Muller, A.P., Serum insulin-like system alterations in patients with spinocerebellar ataxia type 3 (2011) Mov Disord, 26, pp. 731-735Boy, J., Schmidt, T., Wolburg, H., Reversibility of symptoms in a conditional mouse model of spinocerebellar ataxia type 3 (2009) Hum Mol Genet, 18, pp. 4282-429

Evidence-Based Consensus and Systematic Review on Reducing the Time to Diagnosis of Duchenne Muscular Dystrophy

Evidence-Based Consensus and Systematic Review on Reducing the Time to Diagnosis of Duchenne Muscular Dystroph

DNAJC6 Mutations Associated with Early-Onset Parkinson's Disease

_Objective_ DNAJC6 mutations were recently described in two families with autosomal recessive juvenile parkinsonism (onset age < 11), prominent atypical signs, poor or absent response to levodopa, and rapid progression (wheelchair-bound within ∼10 years from onset). Here, for the first time, we report DNAJC6 mutations in early-onset Parkinson's disease (PD). _Methods_ The DNAJC6 open reading frame was analyzed in 274 patients with early-onset sporadic or familial PD. Selected variants were followed up by cosegregation, homozygosity mapping, linkage analysis, whole-exome sequencing, and protein studies. _Results_ We identified two families with different novel homozygous DNAJC6 mutations segregating with PD. In each family, the DNAJC6 mutation was flanked by long runs of homozygosity within highest linkage peaks. Exome sequencing did not detect additional pathogenic variants within the linkage regions. In both families, patients showed severely decreased steady-state levels of the auxilin protein in fibroblasts. We also identified a sporadic patient carrying two rare noncoding DNAJC6 variants possibly effecting RNA splicing. All these cases fulfilled the criteria for a clinical diagnosis of early-onset PD, had symptoms onset in the third-to-fifth decade, and slow disease progression. Response to dopaminergic therapies was prominent, but, in some patients, limited by psychiatric side effects. The phenotype overlaps that of other monogenic forms of early-onset PD. _Interpretation_ Our findings delineate a novel form of hereditary early-onset PD. Screening of DNAJC6 is warranted in all patients with early-onset PD compatible with autosomal recessive inheritance. Our data provide further evidence for the involvement of synaptic vesicles endocytosis and trafficking in PD pathogenesis

Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the Global Burden of Disease Study 2019

Background Given the projected trends in population ageing and population growth, the number of people with dementia is expected to increase. In addition, strong evidence has emerged supporting the importance of potentially modifiable risk factors for dementia. Characterising the distribution and magnitude of anticipated growth is crucial for public health planning and resource prioritisation. This study aimed to improve on previous forecasts of dementia prevalence by producing country-level estimates and incorporating information on selected risk factors. Methods We forecasted the prevalence of dementia attributable to the three dementia risk factors included in the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 (high body-mass index, high fasting plasma glucose, and smoking) from 2019 to 2050, using relative risks and forecasted risk factor prevalence to predict GBD risk-attributable prevalence in 2050 globally and by world region and country. Using linear regression models with education included as an additional predictor, we then forecasted the prevalence of dementia not attributable to GBD risks. To assess the relative contribution of future trends in GBD risk factors, education, population growth, and population ageing, we did a decomposition analysis. Findings We estimated that the number of people with dementia would increase from 57·4 (95% uncertainty interval 50·4–65·1) million cases globally in 2019 to 152·8 (130·8–175·9) million cases in 2050. Despite large increases in the projected number of people living with dementia, age-standardised both-sex prevalence remained stable between 2019 and 2050 (global percentage change of 0·1% [–7·5 to 10·8]). We estimated that there were more women with dementia than men with dementia globally in 2019 (female-to-male ratio of 1·69 [1·64–1·73]), and we expect this pattern to continue to 2050 (female-to-male ratio of 1·67 [1·52–1·85]). There was geographical heterogeneity in the projected increases across countries and regions, with the smallest percentage changes in the number of projected dementia cases in high-income Asia Pacific (53% [41–67]) and western Europe (74% [58–90]), and the largest in north Africa and the Middle East (367% [329–403]) and eastern sub-Saharan Africa (357% [323–395]). Projected increases in cases could largely be attributed to population growth and population ageing, although their relative importance varied by world region, with population growth contributing most to the increases in sub-Saharan Africa and population ageing contributing most to the increases in east Asia. Interpretation Growth in the number of individuals living with dementia underscores the need for public health planning efforts and policy to address the needs of this group. Country-level estimates can be used to inform national planning efforts and decisions. Multifaceted approaches, including scaling up interventions to address modifiable risk factors and investing in research on biological mechanisms, will be key in addressing the expected increases in the number of individuals affected by dementia