Clinical, neuroradiological and genetic findings in pontocerebellar hypoplasia.
Pontocerebellar hypoplasia is a group of autosomal recessive neurodegenerative disorders with prenatal onset. The common characteristics are cerebellar hypoplasia with variable atrophy of the cerebellum and the ventral pons. Supratentorial involvement is reflected by variable neocortical atrophy, ventriculomegaly and microcephaly. Mutations in the transfer RNA splicing endonuclease subunit genes (TSEN54, TSEN2, TSEN34) were found to be associated with pontocerebellar hypoplasia types 2 and 4. Mutations in the mitochondrial transfer RNA arginyl synthetase gene (RARS2) were associated with pontocerebellar hypoplasia type 6. We studied a cohort of 169 patients from 141 families for mutations in these genes, of whom 106 patients tested positive for mutations in one of the TSEN genes or the RARS2 gene. In order to delineate the neuroradiological and clinical phenotype of patients with mutations in these genes, we compared this group with 63 patients suspected of pontocerebellar hypoplasia who were negative on mutation analysis. We found a strong correlation (P < 0.0005) between TSEN54 mutations and a dragonfly-like cerebellar pattern on magnetic resonance imaging, in which the cerebellar hemispheres are flat and severely reduced in size and the vermis is relatively spared. Mutations in TSEN54 are clinically associated with dyskinesia and/or dystonia and variable degrees of spasticity, in some cases with pure generalized spasticity. Nonsense or splice site mutations in TSEN54 are associated with a more severe phenotype of more perinatal symptoms, ventilator dependency and early death. In addition, we present ten new mutations in TSEN54, TSEN2 and RARS2. Furthermore, we show that pontocerebellar hypoplasia type 1 together with elevated cerebrospinal fluid lactate may be caused by RARS2 mutations.
Namavar
Yasmin
Y
Department of Genome Analysis, Academic Medical Centre, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
Barth
Peter G
PG
Kasher
Paul R
PR
van Ruissen
Fred
F
Brockmann
Knut
K
Bernert
Günther
G
Writzl
Karin
K
Ventura
Karen
K
Cheng
Edith Y
EY
Ferriero
Donna M
DM
Basel-Vanagaite
Lina
L
Eggens
Veerle R C
VR
Krägeloh-Mann
Ingeborg
I
De Meirleir
Linda
L
King
Mary
M
Graham
John M
JM
von Moers
Arpad
A
Knoers
Nine
N
Sztriha
Laszlo
L
Korinthenberg
Rudolf
R
Dobyns
William B
WB
Baas
Frank
F
Poll-The
Bwee Tien
BT
D000293:Adolescent; D001126:Arginine-tRNA Ligase / Q000235:genetics*; D001921:Brain / Q000473:pathology*; D016009:Chi-Square Distribution; D002648:Child; D002675:Child, Preschool; D004722:Endoribonucleases / Q000235:genetics*; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation; D009849:Olivopontocerebellar Atrophies / Q000235:genetics / Q000473:pathology
D004722:Endoribonucleases; C051012:splicing endonuclease; D001126:Arginine-tRNA Ligase