Autosomal-recessive cerebellar ataxia caused by a novel ADCK3 mutation that elongates the protein: clinical, genetic and biochemical characterisation.
BACKGROUND
The autosomal-recessive cerebellar ataxias (ARCA) are a clinically and genetically heterogeneous group of neurodegenerative disorders. The large number of ARCA genes leads to delay and difficulties obtaining an exact diagnosis in many patients and families. Ubiquinone (CoQ10) deficiency is one of the potentially treatable causes of ARCAs as some patients respond to CoQ10 supplementation. The AarF domain containing kinase 3 gene (ADCK3) is one of several genes associated with CoQ10 deficiency. ADCK3 encodes a mitochondrial protein which functions as an electron-transfer membrane protein complex in the mitochondrial respiratory chain (MRC).


METHODS
We report two siblings from a consanguineous Pakistani family who presented with cerebellar ataxia and severe myoclonus from adolescence. Whole exome sequencing and biochemical assessment of fibroblasts were performed in the index patient.


RESULTS
A novel homozygous frameshift mutation in ADCK3 (p.Ser616Leufs*114), was identified in both siblings. This frameshift mutation results in the loss of the stop codon, extending the coding protein by 81 amino acids. Significant CoQ10 deficiency and reduced MRC enzyme activities in the index patient's fibroblasts suggested that the mutant protein may reduce the efficiency of mitochondrial electron transfer. CoQ10 supplementation was initiated following these genetic and biochemical analyses. She gained substantial improvement in myoclonic movements, ataxic gait and dysarthric speech after treatment.


CONCLUSIONS
This study highlights the importance of diagnosing ADCK3 mutations and the potential benefit of treatment for patients. The identification of this new mutation broadens the phenotypic spectrum associated with ADCK3 mutations and provides further understanding of their pathogenic mechanism.
MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, , London, UK.
Yo-Tsen
YT
Liu
Joshua
J
Hersheson
Vincent
V
Plagnol
Katherine
K
Fawcett
Kate E C
KE
Duberley
Elisavet
E
Preza
Iain P
IP
Hargreaves
Annapurna
A
Chalasani
Matilde
M
Laurá
Nick W
NW
Wood
Mary M
MM
Reilly
Henry
H
Houlden
D000328:Adult; D002524:Cerebellar Ataxia / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D003241:Consanguinity; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics*; D006801:Humans; D024101:Mitochondrial Proteins / Q000235:genetics; D010375:Pedigree; D011494:Protein Kinases / Q000235:genetics*; D014451:Ubiquinone / Q000031:analogs & derivatives / Q000172:deficiency
D024101:Mitochondrial Proteins; D014451:Ubiquinone; D011494:Protein Kinases; C024989:coenzyme Q10
Cerebellar Ataxia; Mitochondrial Disorders; Movement Disorders; Myoclonus; Neurogenetics