Adult-onset cerebellar ataxia due to mutations in CABC1/ADCK3.
OBJECTIVE
Inherited ataxias are heterogeneous disorders affecting both children and adults. The primary cause can be identified in about half of the patients and only very few can receive causative therapy.


METHODS
The authors performed sequencing of known Coenzyme Q10 (CoQ10) deficiency genes in 22 patients with unexplained recessive or sporadic ataxia.


RESULTS
CABC1/ADCK3 mutations were detected in four patients and two siblings presenting with cerebellar ataxia, epilepsy and muscle symptoms. Spasticity, dystonia, tremor and migraine were variably present; cognitive impairment was severe in early childhood cases, but was absent in adults. In contrast to previous reports, two of the patients had a later-onset, very mild phenotype and remained ambulatory in their late forties. Muscle biopsy revealed lipid accumulation, mitochondrial proliferation and cytochrome c oxidase-deficient fibres, but no typical ragged red fibres. Respiratory-chain enzyme activities and CoQ10 were decreased in severely affected patients but remained normal in a mildly affected patient at 46 years of age.


CONCLUSIONS
These observations highlight the importance of screening for a potentially treatable cause, CABC1/ADCK3 mutations, not only in severe childhood-onset ataxia, but also in patients with mild cerebellar ataxia in adult life.
Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK. rita.horvath@ncl.ac.uk
Rita
R
Horvath
Birgit
B
Czermin
Sweena
S
Gulati
Stephanie
S
Demuth
Gunnar
G
Houge
Angela
A
Pyle
Christine
C
Dineiger
Emma L
EL
Blakely
Adam
A
Hassani
Charlotte
C
Foley
Michael
M
Brodhun
Karin
K
Storm
Janbernd
J
Kirschner
Grainne S
GS
Gorman
Hanns
H
Lochmüller
Elke
E
Holinski-Feder
Robert W
RW
Taylor
Patrick F
PF
Chinnery
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D001706:Biopsy; D004252:DNA Mutational Analysis; D005260:Female; D017353:Gene Deletion; D006801:Humans; D008297:Male; D008875:Middle Aged; D008931:Mitochondria, Muscle / Q000201:enzymology / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics*; D018482:Muscle, Skeletal / Q000473:pathology; D009154:Mutation / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D013132:Spinocerebellar Degenerations / Q000235:genetics* / Q000473:pathology; D014451:Ubiquinone / Q000031:analogs & derivatives / Q000172:deficiency; D055815:Young Adult
C553453:COQ8A protein, human; D024101:Mitochondrial Proteins; D014451:Ubiquinone; C024989:coenzyme Q10