Skip to main content
Erschienen in: neurogenetics 3-4/2013

01.11.2013 | Original Article

Diagnostic utility of whole exome sequencing in patients showing cerebellar and/or vermis atrophy in childhood

verfasst von: Chihiro Ohba, Hitoshi Osaka, Mizue Iai, Sumimasa Yamashita, Yume Suzuki, Noriko Aida, Nobuyuki Shimozawa, Ayumi Takamura, Hiroshi Doi, Atsuko Tomita-Katsumoto, Kiyomi Nishiyama, Yoshinori Tsurusaki, Mitsuko Nakashima, Noriko Miyake, Yoshikatsu Eto, Fumiaki Tanaka, Naomichi Matsumoto, Hirotomo Saitsu

Erschienen in: neurogenetics | Ausgabe 3-4/2013

Einloggen, um Zugang zu erhalten

Abstract

Cerebellar and/or vermis atrophy is recognized in various types of childhood disorders with clinical and genetic heterogeneity. Although careful evaluation of clinical features and neuroimaging can lead to correct diagnosis of disorders, their diagnosis is sometimes difficult because clinical features can overlap with each other. In this study, we performed family-based whole exome sequencing of 23 families including 25 patients with cerebellar and/or vermis atrophy in childhood, who were unable to be diagnosed solely by clinical examination. Pathological mutations of seven genes were found in ten patients from nine families (9/23, 39.1 %): compound heterozygous mutations in FOLR1, C5orf42, POLG, TPP1, PEX16, and de novo mutations in CACNA1A, and ITPR1. Patient 1A with FOLR1 mutations showed extremely low concentration of 5-methyltetrahydrofolate in the cerebrospinal fluid and serum, and Patient 6 with TPP1 mutations demonstrated markedly lowered tripeptidyl peptidase 1 activity in leukocytes. Furthermore, Patient 8 with PEX16 mutations presented a mild increase of very long chain fatty acids in the serum as supportive data for genetic diagnosis. The main clinical features of these ten patients were nonspecific and mixed, and included developmental delay, intellectual disability, ataxia, hypotonia, and epilepsy. Brain MRI revealed both cerebellar and vermis atrophy in eight patients (8/10, 80 %), vermis atrophy/hypoplasia in two patients (2/10, 20 %), and brainstem atrophy in one patient (1/10, 10 %). Our data clearly demonstrate the utility of whole exome sequencing for genetic diagnosis of childhood cerebellar and/or vermis atrophy.
Anhänge
Nur mit Berechtigung zugänglich
Literatur
3.
Zurück zum Zitat Schaefer AM, McFarland R, Blakely EL, He L, Whittaker RG, Taylor RW, Chinnery PF, Turnbull DM (2008) Prevalence of mitochondrial DNA disease in adults. Ann Neurol 63(1):35–39. doi:10.1002/ana.21217 PubMedCrossRef Schaefer AM, McFarland R, Blakely EL, He L, Whittaker RG, Taylor RW, Chinnery PF, Turnbull DM (2008) Prevalence of mitochondrial DNA disease in adults. Ann Neurol 63(1):35–39. doi:10.​1002/​ana.​21217 PubMedCrossRef
4.
Zurück zum Zitat Santorelli FM, Garavaglia B, Cardona F, Nardocci N, Bernardina BD, Sartori S, Suppiej A, Bertini E, Claps D, Battini R, Biancheri R, Filocamo M, Pezzini F, Simonati A (2013) Molecular epidemiology of childhood neuronal ceroid-lipofuscinosis in Italy. Orphanet J Rare Dis 8:19. doi:10.1186/1750-1172-8-19 PubMedCrossRef Santorelli FM, Garavaglia B, Cardona F, Nardocci N, Bernardina BD, Sartori S, Suppiej A, Bertini E, Claps D, Battini R, Biancheri R, Filocamo M, Pezzini F, Simonati A (2013) Molecular epidemiology of childhood neuronal ceroid-lipofuscinosis in Italy. Orphanet J Rare Dis 8:19. doi:10.​1186/​1750-1172-8-19 PubMedCrossRef
5.
Zurück zum Zitat Erichsen AK, Koht J, Stray-Pedersen A, Abdelnoor M, Tallaksen CM (2009) Prevalence of hereditary ataxia and spastic paraplegia in southeast Norway: a population-based study. Brain 132(Pt 6):1577–1588. doi:10.1093/brain/awp056 PubMedCrossRef Erichsen AK, Koht J, Stray-Pedersen A, Abdelnoor M, Tallaksen CM (2009) Prevalence of hereditary ataxia and spastic paraplegia in southeast Norway: a population-based study. Brain 132(Pt 6):1577–1588. doi:10.​1093/​brain/​awp056 PubMedCrossRef
7.
Zurück zum Zitat Valente EM, Brancati F, Boltshauser E, Dallapiccola B (2013) Clinical utility gene card for: Joubert syndrome—update 2013. Eur J Hum Genet. doi:10.1038/ejhg.2013.10 Valente EM, Brancati F, Boltshauser E, Dallapiccola B (2013) Clinical utility gene card for: Joubert syndrome—update 2013. Eur J Hum Genet. doi:10.​1038/​ejhg.​2013.​10
9.
Zurück zum Zitat Bamshad MJ, Ng SB, Bigham AW, Tabor HK, Emond MJ, Nickerson DA, Shendure J (2011) Exome sequencing as a tool for Mendelian disease gene discovery. Nat Rev Genet 12(11):745–755. doi:10.1038/nrg3031 PubMedCrossRef Bamshad MJ, Ng SB, Bigham AW, Tabor HK, Emond MJ, Nickerson DA, Shendure J (2011) Exome sequencing as a tool for Mendelian disease gene discovery. Nat Rev Genet 12(11):745–755. doi:10.​1038/​nrg3031 PubMedCrossRef
10.
Zurück zum Zitat Vissers LE, de Ligt J, Gilissen C, Janssen I, Steehouwer M, de Vries P, van Lier B, Arts P, Wieskamp N, del Rosario M, van Bon BW, Hoischen A, de Vries BB, Brunner HG, Veltman JA (2010) A de novo paradigm for mental retardation. Nat Genet 42(12):1109–1112. doi:10.1038/ng.712 PubMedCrossRef Vissers LE, de Ligt J, Gilissen C, Janssen I, Steehouwer M, de Vries P, van Lier B, Arts P, Wieskamp N, del Rosario M, van Bon BW, Hoischen A, de Vries BB, Brunner HG, Veltman JA (2010) A de novo paradigm for mental retardation. Nat Genet 42(12):1109–1112. doi:10.​1038/​ng.​712 PubMedCrossRef
11.
Zurück zum Zitat de Ligt J, Willemsen MH, van Bon BW, Kleefstra T, Yntema HG, Kroes T, Vulto-van Silfhout AT, Koolen DA, de Vries P, Gilissen C, del Rosario M, Hoischen A, Scheffer H, de Vries BB, Brunner HG, Veltman JA, Vissers LE (2012) Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med 367(20):1921–1929. doi:10.1056/NEJMoa1206524 PubMedCrossRef de Ligt J, Willemsen MH, van Bon BW, Kleefstra T, Yntema HG, Kroes T, Vulto-van Silfhout AT, Koolen DA, de Vries P, Gilissen C, del Rosario M, Hoischen A, Scheffer H, de Vries BB, Brunner HG, Veltman JA, Vissers LE (2012) Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med 367(20):1921–1929. doi:10.​1056/​NEJMoa1206524 PubMedCrossRef
12.
Zurück zum Zitat Saitsu H, Nishimura T, Muramatsu K, Kodera H, Kumada S, Sugai K, Kasai-Yoshida E, Sawaura N, Nishida H, Hoshino A, Ryujin F, Yoshioka S, Nishiyama K, Kondo Y, Tsurusaki Y, Nakashima M, Miyake N, Arakawa H, Kato M, Mizushima N, Matsumoto N (2013) De novo mutations in the autophagy gene WDR45 cause static encephalopathy of childhood with neurodegeneration in adulthood. Nat Genet. doi:10.1038/ng.2562 PubMed Saitsu H, Nishimura T, Muramatsu K, Kodera H, Kumada S, Sugai K, Kasai-Yoshida E, Sawaura N, Nishida H, Hoshino A, Ryujin F, Yoshioka S, Nishiyama K, Kondo Y, Tsurusaki Y, Nakashima M, Miyake N, Arakawa H, Kato M, Mizushima N, Matsumoto N (2013) De novo mutations in the autophagy gene WDR45 cause static encephalopathy of childhood with neurodegeneration in adulthood. Nat Genet. doi:10.​1038/​ng.​2562 PubMed
13.
Zurück zum Zitat Yamanaka H, Gatanaga H, Kosalaraksa P, Matsuoka-Aizawa S, Takahashi T, Kimura S, Oka S (2007) Novel mutation of human DNA polymerase gamma associated with mitochondrial toxicity induced by anti-HIV treatment. J Infect Dis 195(10):1419–1425. doi:10.1086/513872 PubMedCrossRef Yamanaka H, Gatanaga H, Kosalaraksa P, Matsuoka-Aizawa S, Takahashi T, Kimura S, Oka S (2007) Novel mutation of human DNA polymerase gamma associated with mitochondrial toxicity induced by anti-HIV treatment. J Infect Dis 195(10):1419–1425. doi:10.​1086/​513872 PubMedCrossRef
14.
Zurück zum Zitat Honsho M, Tamura S, Shimozawa N, Suzuki Y, Kondo N, Fujiki Y (1998) Mutation in PEX16 is causal in the peroxisome-deficient Zellweger syndrome of complementation group D. Am J Hum Genet 63(6):1622–1630. doi:10.1086/302161 PubMedCrossRef Honsho M, Tamura S, Shimozawa N, Suzuki Y, Kondo N, Fujiki Y (1998) Mutation in PEX16 is causal in the peroxisome-deficient Zellweger syndrome of complementation group D. Am J Hum Genet 63(6):1622–1630. doi:10.​1086/​302161 PubMedCrossRef
15.
Zurück zum Zitat Grapp M, Just IA, Linnankivi T, Wolf P, Lucke T, Hausler M, Gartner J, Steinfeld R (2012) Molecular characterization of folate receptor 1 mutations delineates cerebral folate transport deficiency. Brain 135(Pt 7):2022–2031. doi:10.1093/brain/aws122 PubMedCrossRef Grapp M, Just IA, Linnankivi T, Wolf P, Lucke T, Hausler M, Gartner J, Steinfeld R (2012) Molecular characterization of folate receptor 1 mutations delineates cerebral folate transport deficiency. Brain 135(Pt 7):2022–2031. doi:10.​1093/​brain/​aws122 PubMedCrossRef
16.
Zurück zum Zitat Steinfeld R, Grapp M, Kraetzner R, Dreha-Kulaczewski S, Helms G, Dechent P, Wevers R, Grosso S, Gartner J (2009) Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism. Am J Hum Genet 85(3):354–363. doi:10.1016/j.ajhg.2009.08.005 PubMedCrossRef Steinfeld R, Grapp M, Kraetzner R, Dreha-Kulaczewski S, Helms G, Dechent P, Wevers R, Grosso S, Gartner J (2009) Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism. Am J Hum Genet 85(3):354–363. doi:10.​1016/​j.​ajhg.​2009.​08.​005 PubMedCrossRef
17.
Zurück zum Zitat Lukacs Z, Santavuori P, Keil A, Steinfeld R, Kohlschutter A (2003) Rapid and simple assay for the determination of tripeptidyl peptidase and palmitoyl protein thioesterase activities in dried blood spots. Clin Chem 49(3):509–511PubMedCrossRef Lukacs Z, Santavuori P, Keil A, Steinfeld R, Kohlschutter A (2003) Rapid and simple assay for the determination of tripeptidyl peptidase and palmitoyl protein thioesterase activities in dried blood spots. Clin Chem 49(3):509–511PubMedCrossRef
18.
Zurück zum Zitat Sohar I, Lin L, Lobel P (2000) Enzyme-based diagnosis of classical late infantile neuronal ceroid lipofuscinosis: comparison of tripeptidyl peptidase I and pepstatin-insensitive protease assays. Clin Chem 46(7):1005–1008PubMed Sohar I, Lin L, Lobel P (2000) Enzyme-based diagnosis of classical late infantile neuronal ceroid lipofuscinosis: comparison of tripeptidyl peptidase I and pepstatin-insensitive protease assays. Clin Chem 46(7):1005–1008PubMed
19.
Zurück zum Zitat Ebberink MS, Csanyi B, Chong WK, Denis S, Sharp P, Mooijer PA, Dekker CJ, Spooner C, Ngu LH, De Sousa C, Wanders RJ, Fietz MJ, Clayton PT, Waterham HR, Ferdinandusse S (2010) Identification of an unusual variant peroxisome biogenesis disorder caused by mutations in the PEX16 gene. J Med Genet 47(9):608–615. doi:10.1136/jmg.2009.074302 PubMedCrossRef Ebberink MS, Csanyi B, Chong WK, Denis S, Sharp P, Mooijer PA, Dekker CJ, Spooner C, Ngu LH, De Sousa C, Wanders RJ, Fietz MJ, Clayton PT, Waterham HR, Ferdinandusse S (2010) Identification of an unusual variant peroxisome biogenesis disorder caused by mutations in the PEX16 gene. J Med Genet 47(9):608–615. doi:10.​1136/​jmg.​2009.​074302 PubMedCrossRef
20.
Zurück zum Zitat Shimozawa N, Nagase T, Takemoto Y, Suzuki Y, Fujiki Y, Wanders RJ, Kondo N (2002) A novel aberrant splicing mutation of the PEX16 gene in two patients with Zellweger syndrome. Biochem Biophys Res Commun 292(1):109–112PubMedCrossRef Shimozawa N, Nagase T, Takemoto Y, Suzuki Y, Fujiki Y, Wanders RJ, Kondo N (2002) A novel aberrant splicing mutation of the PEX16 gene in two patients with Zellweger syndrome. Biochem Biophys Res Commun 292(1):109–112PubMedCrossRef
22.
Zurück zum Zitat Kousi M, Lehesjoki AE, Mole SE (2012) Update of the mutation spectrum and clinical correlations of over 360 mutations in eight genes that underlie the neuronal ceroid lipofuscinoses. Hum Mutat 33(1):42–63. doi:10.1002/humu.21624 PubMedCrossRef Kousi M, Lehesjoki AE, Mole SE (2012) Update of the mutation spectrum and clinical correlations of over 360 mutations in eight genes that underlie the neuronal ceroid lipofuscinoses. Hum Mutat 33(1):42–63. doi:10.​1002/​humu.​21624 PubMedCrossRef
23.
Zurück zum Zitat Sun Y, Almomani R, Breedveld GJ, Santen GW, Aten E, Lefeber DJ, Hoff JI, Brusse E, Verheijen FW, Verdijk RM, Kriek M, Oostra B, Breuning MH, Losekoot M, den Dunnen JT, van de Warrenburg BP, Maat-Kievit AJ (2013) Autosomal recessive spinocerebellar ataxia 7 (SCAR7) is caused by variants in TPP1, the gene involved in classic late-infantile neuronal ceroid lipofuscinosis 2 disease (CLN2 disease). Hum Mutat 34(5):706–713. doi:10.1002/humu.22292 PubMedCrossRef Sun Y, Almomani R, Breedveld GJ, Santen GW, Aten E, Lefeber DJ, Hoff JI, Brusse E, Verheijen FW, Verdijk RM, Kriek M, Oostra B, Breuning MH, Losekoot M, den Dunnen JT, van de Warrenburg BP, Maat-Kievit AJ (2013) Autosomal recessive spinocerebellar ataxia 7 (SCAR7) is caused by variants in TPP1, the gene involved in classic late-infantile neuronal ceroid lipofuscinosis 2 disease (CLN2 disease). Hum Mutat 34(5):706–713. doi:10.​1002/​humu.​22292 PubMedCrossRef
25.
Zurück zum Zitat Roach JC, Glusman G, Smit AF, Huff CD, Hubley R, Shannon PT, Rowen L, Pant KP, Goodman N, Bamshad M, Shendure J, Drmanac R, Jorde LB, Hood L, Galas DJ (2010) Analysis of genetic inheritance in a family quartet by whole-genome sequencing. Science 328(5978):636–639. doi:10.1126/science.1186802 PubMedCrossRef Roach JC, Glusman G, Smit AF, Huff CD, Hubley R, Shannon PT, Rowen L, Pant KP, Goodman N, Bamshad M, Shendure J, Drmanac R, Jorde LB, Hood L, Galas DJ (2010) Analysis of genetic inheritance in a family quartet by whole-genome sequencing. Science 328(5978):636–639. doi:10.​1126/​science.​1186802 PubMedCrossRef
28.
Zurück zum Zitat Huang L, Chardon JW, Carter MT, Friend KL, Dudding TE, Schwartzentruber J, Zou R, Schofield PW, Douglas S, Bulman DE, Boycott KM (2012) Missense mutations in ITPR1 cause autosomal dominant congenital nonprogressive spinocerebellar ataxia. Orphanet J Rare Dis 7:67. doi:10.1186/1750-1172-7-67 PubMedCrossRef Huang L, Chardon JW, Carter MT, Friend KL, Dudding TE, Schwartzentruber J, Zou R, Schofield PW, Douglas S, Bulman DE, Boycott KM (2012) Missense mutations in ITPR1 cause autosomal dominant congenital nonprogressive spinocerebellar ataxia. Orphanet J Rare Dis 7:67. doi:10.​1186/​1750-1172-7-67 PubMedCrossRef
29.
Zurück zum Zitat Srour M, Schwartzentruber J, Hamdan FF, Ospina LH, Patry L, Labuda D, Massicotte C, Dobrzeniecka S, Capo-Chichi JM, Papillon-Cavanagh S, Samuels ME, Boycott KM, Shevell MI, Laframboise R, Desilets V, Maranda B, Rouleau GA, Majewski J, Michaud JL (2012) Mutations in C5ORF42 cause Joubert syndrome in the French Canadian population. Am J Hum Genet 90(4):693–700. doi:10.1016/j.ajhg.2012.02.011 PubMedCrossRef Srour M, Schwartzentruber J, Hamdan FF, Ospina LH, Patry L, Labuda D, Massicotte C, Dobrzeniecka S, Capo-Chichi JM, Papillon-Cavanagh S, Samuels ME, Boycott KM, Shevell MI, Laframboise R, Desilets V, Maranda B, Rouleau GA, Majewski J, Michaud JL (2012) Mutations in C5ORF42 cause Joubert syndrome in the French Canadian population. Am J Hum Genet 90(4):693–700. doi:10.​1016/​j.​ajhg.​2012.​02.​011 PubMedCrossRef
Metadaten
Titel
Diagnostic utility of whole exome sequencing in patients showing cerebellar and/or vermis atrophy in childhood
verfasst von
Chihiro Ohba
Hitoshi Osaka
Mizue Iai
Sumimasa Yamashita
Yume Suzuki
Noriko Aida
Nobuyuki Shimozawa
Ayumi Takamura
Hiroshi Doi
Atsuko Tomita-Katsumoto
Kiyomi Nishiyama
Yoshinori Tsurusaki
Mitsuko Nakashima
Noriko Miyake
Yoshikatsu Eto
Fumiaki Tanaka
Naomichi Matsumoto
Hirotomo Saitsu
Publikationsdatum
01.11.2013
Verlag
Springer Berlin Heidelberg
Erschienen in
neurogenetics / Ausgabe 3-4/2013
Print ISSN: 1364-6745
Elektronische ISSN: 1364-6753
DOI
https://doi.org/10.1007/s10048-013-0375-8

Weitere Artikel der Ausgabe 3-4/2013

neurogenetics 3-4/2013 Zur Ausgabe

Leitlinien kompakt für die Neurologie

Mit medbee Pocketcards sicher entscheiden.

Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag

Neu im Fachgebiet Neurologie

Update Neurologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.