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Sep 2021;36(9):2017-2025. doi:10.1002/mds.28663 54]]>17/56 16 16 0 1 34 56 - - 2/2 - 0 0 2/2 0 2 0 2/2 2 0 1 2 - - 1/1 - 0 0 - - - - 1/1 0 0 1 1 1/1 1/1 0/1 0/1 0 0 1/1 0 1 0 1/1 0 0 0 1 1/1 1/1 1/1 - 0 0 1/1 0 1 0 1/1 0 0 0 1 1/1 1/1 1/1 1/1 0 0 - - - - 1/1 0 0 1 1 1/1 - 1/1 0/1 1 0 1/1 1 0 0 0/1 0 0 0 0 6/6 - 9/13 0/5 18 2 18/ 13 5 0 17/23 14 0 0 5 23 2/2 3/3 2/2 0/1 0 3 7/7 4 3 0 1/7 0 1 0 0 2/2 1/1 - 1/1 0 0 - - - - 1/2 0 0 0 1 and DGCR2, h mild phenylalanine hydroxylase deficit with compound heterozygosity for two missense variants, i HTRA2 (2 patients), 45,X[3]/46,XX] mosaic Turner syndrome, j PRKN, k PRKN, l TAF1 (mosaicism): “XDP-disease-specific change 3”. - = unknown. 69]]>3.0.co;2-f 38. Fujiyama J, Kuriyama M, Yoshidome H, et al. Parkinsonism in cerebrotendinous xanthomatosis. Jpn J Med. Mar-Apr 1991;30(2):189-92. doi:10.2169/internalmedicine1962.30.189 39. Grandas F, Martin-Moro M, Garcia-Munozguren S, Anaya F. Early-onset parkinsonism in cerebrotendinous xanthomatosis. 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Journal of the American Geriatrics Society. 2018;66(Supplement 2):S187. 2018 Annual Scientific Meeting of the American Geriatrics Society, AGS 2018. United States. doi:http://dx.doi. org/10.1111/jgs.15376 102]]>3.3.co;2-q 54. Sedel F, Ribeiro MJ, Remy P, Blau N, Saudubray JM, Agid Y. Dihydropteridine reductase deficiency: levodopa’s long-term effectiveness without dyskinesia. Neurology. Dec 26 2006;67(12):2243-5. doi:10.1212/01.wnl.0000249335.35585.3e 55. Takahashi Y, Manabe Y, Nakano Y, et al. Parkinsonism in Association with Dihydropteridine Reductase Deficiency. Case Rep Neurol. Jan-Apr 2017;9(1):17-21. doi:10.1159/000456610 56. Porta F, Mussa A, Concolino D, Spada M, Ponzone A. Dopamine agonists in dihydropteridine reductase deficiency. Mol Genet Metab. Apr 2012;105(4):582-4. doi:10.1016/j. ymgme.2012.01.013 57. Straniero L, Guella I, Cilia R, et al. DNAJC12 and dopa-responsive nonprogressive parkinsonism. Ann Neurol. Oct 2017;82(4):640-646. doi:10.1002/ana.25048 58. Anikster Y, Haack TB, Vilboux T, et al. Biallelic Mutations in DNAJC12 Cause Hyperphenylalaninemia, Dystonia, and Intellectual Disability. Am J Hum Genet. Feb 2 2017;100(2):257-266. doi:10.1016/j.ajhg.2017.01.002 59. Koroglu C, Baysal L, Cetinkaya M, Karasoy H, Tolun A. DNAJC6 is responsible for juvenile parkinsonism with phenotypic variability. Parkinsonism Relat Disord. Mar 2013;19(3):320-4. doi:10.1016/j.parkreldis.2012.11.006 60. Ng J, Cortes-Saladelafont E, Abela L, et al. DNAJC6 Mutations Disrupt Dopamine Homeostasis in Juvenile Parkinsonism-Dystonia. Mov Disord. May 30 2020;doi:10.1002/mds.28063 61. Termsarasab P, Pearson TS. Juvenile Parkinsonism and epilepsy due to homozygous mutations in DNAJC6. Movement Disorders. 2015;30(SUPPL. 1):S459-S460. 19th International Congress of Parkinson’s Disease and Movement Disorders. San Diego, CA United States. (var. pagings). doi:http://dx.doi.org/10.1002/mds.26295 62. Edvardson S, Cinnamon Y, Ta-Shma A, et al. A deleterious mutation in DNAJC6 encoding the neuronal-specific clathrin-uncoating co-chaperone auxilin, is associated with juvenile parkinsonism. PLoS One. 2012;7(5):e36458. doi:10.1371/journal.pone.0036458 63. Elsayed LE, Drouet V, Usenko T, et al. A Novel Nonsense Mutation in DNAJC6 Expands the Phenotype of Autosomal-Recessive Juvenile-Onset Parkinson’s Disease. Ann Neurol. Feb 2016;79(2):335-7. doi:10.1002/ana.24591 64. Tassin J, Durr A, Bonnet AM, et al. Levodopa-responsive dystonia. GTP cyclohydrolase I or parkin mutations? Brain. Jun 2000;123 ( Pt 6):1112-21. doi:10.1093/brain/123.6.1112 65. Kikuchi A, Takeda A, Fujihara K, et al. Arg(184)His mutant GTP cyclohydrolase I, causing recessive hyperphenylalaninemia, is responsible for dopa-responsive dystonia with parkinsonism: a case report. Mov Disord. May 2004;19(5):590-3. doi:10.1002/mds.10712 66. Wirth T, Mariani LL, Bergant G, et al. Loss-of-Function Mutations in NR4A2 Cause Dopa- Responsive Dystonia Parkinsonism. Mov Disord. May 2020;35(5):880-885. doi:10.1002/ mds.27982 67. Zielonka M, Makhseed N, Blau N, Bettendorf M, Hoffmann GF, Opladen T. Dopamine-Responsive Growth-Hormone Deficiency and Central Hypothyroidism in Sepiapterin Reductase Deficiency. JIMD Rep. 2015;24:109-13. doi:10.1007/8904_2015_450 68. Bodhireddy S, Dickson DW, Mattiace L, Weidenheim KM. A case of Down’s syndrome with diffuse Lewy body disease and Alzheimer’s disease. Neurology. Jan 1994;44(1):159-61. doi:10.1212/wnl.44.1.159 69. Brandel JP, Marconi R, Serdaru M, Vidailhet M, Agid Y. Down’s syndrome and Parkinson’s disease. Neurology. Dec 1994;44(12):2419-20. doi:10.1212/wnl.44.12.2419-c 70. Agarwal P, Griffith AF, Borromeo-Wesner M. Case report and literature review of levodopa- reponsive young onset Parkinson’s disease in a patient with Down’s syndrome. Movement Disorders. 2010;25(SUPPL. 2):S499-S500. 14th International Congress of Parkinson’s Disease and Movement Disorders. Buenos Aires Argentina. (var.pagings). doi:http://dx.doi. org/10.1002/mds.23162 71. Marui W, Iseki E, Kosaka K, Kato M, Adachi Y, Ueda K. An autopsied case of Down syndrome with Alzheimer pathology and alpha-synuclein immunoreactivity. Neuropathology. 1999;19(4):410- 416. doi:http://dx.doi.org/10.1046/j.1440-1789.1999.00265.x 2 103]]>T mutation in MTFMT. Neurology: Genetics. 2018;4(6):e298. doi:http://dx.doi.org/10.1212/NXG.0000000000000298 91. Martikainen MH, Kytovuori L, Majamaa K. Juvenile parkinsonism, hypogonadism and Leigh- like MRI changes in a patient with m.4296G>A mutation in mitochondrial DNA. Mitochondrion. Mar 2013;13(2):83-6. doi:10.1016/j.mito.2013.01.012 92. Zyss J, Vlaicu M, Gerber S, Rodallec M, Gauthier C, Zuber M. Movement disorders in mevalonic aciduria. Movement Disorders. 2011;26(SUPPL. 2):S256. 15th International Congress of Parkinson’s Disease and Movement Disorders. Toronto, ON Canada. (var.pagings). doi:http:// dx.doi.org/10.1002/mds.23764 93. 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Periodic neurological evaluation, preferably by a movement disorder specialist, is warranted in all adults with 22q11.2DS aged 40 years and older, in order to enable early diagnosis and treatment. 114]]>20 dB HL Mild (2a) >20 ≤40 dB HL Moderate (2b) >40 ≤60 dB HL Severe (2c) >60 dB HL Loss, corrigible with hearing aids (3) <4 kHz >20 dB HL Mild (3a) >20 ≤ 40 dB HL Moderate (3b) >40 ≤ 60 dB HL Severe (3c) >60 dB HL 135]]>15 dB averaged over 0.5, 1, 2 and 4 kHz BC thresholds >20 dB HL and ABG <15 dB HL averaged over 0.5, 1, 2 and 4 kHz BC thresholds >20 dB HL and ABG >15 dB averaged over 0.5, 1, 2 and 4 kHz Audiometric configuration b Low-frequency ascending Mid-frequency n-shaped High-frequency Gently sloping Steeply sloping Flat >15 dB HL difference between the worst low frequency thresholds and the better high frequency thresholds >15 dB HL difference between the worst mid frequency thresholds and the better low and high frequency thresholds 15-29 dB HL difference between the mean of 0.5 and 1 kHz and the mean of 4 and 8 kHz, or 15 -29 dB HL between 4 and 8 kHz ≥30 dB HL difference between the above frequencies or ≥30 dB HL between 4 kHz and 8 kHz <15 dB HL difference between the mean of 0.25 and 1 kHz, the mean of 1 and 2 kHz, and the mean of 4 and 8 kHz Frequency ranges Low frequencies ≤0.5 kHz Mid frequencies High frequencies >0.5 kHz and ≤2 kHz >2 kHz and ≤8 kHz Symmetry of hearing impairment Unilateral Bilateral symmetrical Bilateral asymmetrical >10 dB HL difference between the ears in at least two frequencies <20 dB HL average over 0.5, 1, 2 and 4 kHz of the better ear <10 dB HL difference between the ears in at least two frequencies. Average over 0.5, 1, 2 and 4 kHz of both ears >20 dB >10 dB HL difference between the ears in at least two frequencies >20 dB HL average over 0.5, 1 ,2 and 4 kHz of the better ear a=increasing severity of hearing loss according to the Muenster classification,12 b=of the better- hearing ear. Adapted from the definitions by the European Working Group on the Genetics of Hearing Impairment (See methods section for details),13 HL=hearing level, kHz=kilo Hertz, ABG=air- bone gap, BC=bone-conduction. 136]]>20 dB HL from 0.5-1-2 kHz.16 Conductive hearing loss was the most common type (54%), sensorineural (4%) or mixed (2%) were found less often.16 In line with results from our study, they did find high- frequency hearing loss in the majority of individuals, which was assumed to be of sensorineural origin. Potential contributors to hearing loss in 22q11.2DS There are several potential contributors to hearing loss in adults with 22q11DS.7, 17 First, chronic otitis media, with or without congenital inner ear abnormalities,18 may result in the cochlea being more vulnerable in individuals with 22q11.2DS compared to the general population.7, 16 Second, early physiological degeneration and other medical conditions and their treatment, may lead to hearing loss.19 Age-related disorders such as Parkinson’s disease 142]]>0.30 – <0.50 LogMAR), moderate (≥0.50 – <1.0 LogMAR) or severely impaired (≥1.0 LogMAR) according to criteria of the World Health organization.11 Dutch multicenter cross-sectional study Study design and setting The study was approved by the institutional ethical committees of the University Medical Center Utrecht (UMCU, #18-510/C), Máxima Medical Center Veldhoven (MMCV, #L20.044), and Maastricht University Medical Center+ (MUMC+, #2019-1321). Through a review of medical records, we systematically compiled data of 22q11.2DS patients that visited the ophthalmological outpatient clinic of UMCU, MMCV, and/or MUMC+ between January 1992 and January 2021. All centers are multidisciplinary outpatient clinics for 22q11.2DS. Ophthalmic screening was carried out as regular screening after diagnosis or referral in all clinics and only in a minority of cases upon clinical indication. 152]]>2.0D and <4.0D and severe in case of ≥4.0D. Finally, astigmatism with cylindrical errors of ≤ -2.0D were extracted and considered high. Astigmatism was classified as with-the-rule, against-the-rule and oblique as described before.12 5 Statistical analysis Categorical data are presented as frequencies with percentage (%) and continuous data are presented as median with ranges. For prevalence rates in our cross-sectional study, 95% confidence intervals were calculated. We used Spearman’s Rank-Order correlation for studying the degree of association between age and refractive errors, given the asymmetric data distribution. We used Chi-square tests to compare ophthalmic findings, such as retinal vascular tortuosity, between men and women and between those with and without congenital heart defects. All analyses were two- tailed, with statistical significance defined as P < 0.05, using IBM SPSS software (Statistics 25; SPSS, Inc., Chicago, IL). 153]]>2D) 37 Belgium 36 7 3-14 78 41 0 36 6 NR 67 (≥2D) Turkey 16 M:7 4m-37 56 50 6 25 NR 6 50 (>2D) 28 48 6 Prevalence rates were based on the total number of patients except for the prevalence of refractive errors which was based on the number of eyes examined. Abbreviations: y=year, m=months, wk= weeks, M=median, D=diopters, NR=not reported, CD=cannot determine because cylinder error was reported for 2 cases only (both >1D and less than 2D), U.S.A.= United states of America. a Ages are reported as mean (SD), unless indicated otherwise. b Cut-off values for refractive errors were not defined. Midbari Kufert et al., 2016 Forbes et al., 2007 Prospective cohort Casteels et al., 2008 Gokturk et al., 2016 Prospective cohort Prospective cohort 10 6 3 3 5 Ocular findings in 22q11.2DS]]>