Complete APTX deletion in a patient with ataxia with oculomotor apraxia type 1.
BACKGROUND
Ataxia with oculomotor apraxia type 1 is an autosomal-recessive neurodegenerative disorder characterized by a childhood onset of slowly progressive cerebellar ataxia, followed by oculomotor apraxia and a severe primary motor peripheral axonal motor neuropathy. Ataxia with oculomotor apraxia type 1 is caused by bi-allelic mutations in APTX (chromosome 9p21.1).


METHODS
Our patient has a clinical presentation that is typical for ataxia with oculomotor apraxia type 1 with no particularly severe phenotype. Multiplex Ligation-dependent Probe Amplification analysis resulted in the identification of a homozygous deletion of all coding APTX exons (3 to 9). SNP array analysis using the Illumina Infinium CytoSNP-850 K microarray indicated that the deletion was about 62 kb. Based on the SNP array results, the breakpoints were found using direct sequence analysis: c.-5 + 1225_*44991del67512, p.0?. Both parents were heterozygous for the deletion. Homozygous complete APTX deletions have been described in literature for two other patients. We obtained a sample from one of these two patients and characterized the deletion (156 kb) as c.-23729_*115366del155489, p.0?, including the non-coding exons 1A and 2 of APTX. The more severe phenotype reported for this patient is not observed in our patient. It remains unclear whether the larger size of the deletion (156 kb vs 62 kb) plays a role in the phenotype (no extra genes are deleted).


CONCLUSIONS
Here we described an ataxia with oculomotor apraxia type 1 patient who has a homozygous deletion of the complete coding region of APTX. In contrast to the patient with the large deletion, our patient does not have a severe phenotype. More patients with deletions of APTX are required to investigate a genotype-phenotype effect.
Department of Clinical Genetics, Erasmus Medical Center, P.O. Box 2040, Rotterdam, 3000 CA, The Netherlands. r.vanminkelen@erasmusmc.nl.
Rick
R
van Minkelen
Genetic Laboratory, UDIAT-Centre Diagnòstic, Neuropediatrics Unity, Corporació Sanitària Universitària Parc Taulí, Sabadell, Spain. MGuitart@tauli.cat.
Miriam
M
Guitart
Genetic Laboratory, UDIAT-Centre Diagnòstic, Neuropediatrics Unity, Corporació Sanitària Universitària Parc Taulí, Sabadell, Spain. CEscofet@tauli.cat.
Conxita
C
Escofet
Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children and University of Toronto, Toronto, Canada. grace.yoon@utoronto.ca.
Grace
G
Yoon
Department of Clinical Genetics, Erasmus Medical Center, P.O. Box 2040, Rotterdam, 3000 CA, The Netherlands. p.elfferich@erasmusmc.nl.
Peter
P
Elfferich
Department of Clinical Genetics, Erasmus Medical Center, P.O. Box 2040, Rotterdam, 3000 CA, The Netherlands. g.bolman@erasmusmc.nl.
Galhana M
GM
Bolman
Department of Clinical Genetics, Erasmus Medical Center, P.O. Box 2040, Rotterdam, 3000 CA, The Netherlands. r.vanderhelm@erasmusmc.nl.
Robert
R
van der Helm
Department of Clinical Genetics, Erasmus Medical Center, P.O. Box 2040, Rotterdam, 3000 CA, The Netherlands. r.vandegraaf@erasmusmc.nl.
Raoul
R
van de Graaf
Department of Clinical Genetics, Erasmus Medical Center, P.O. Box 2040, Rotterdam, 3000 CA, The Netherlands. a.vandenouweland@erasmusmc.nl.
Ans M W
AM
van den Ouweland
D001483:Base Sequence; D004268:DNA-Binding Proteins / Q000172:deficiency*; D004576:Electromyography; D017353:Gene Deletion; D006801:Humans; D008297:Male; D046228:Microarray Analysis; D008969:Molecular Sequence Data; D009018:Morocco; D009687:Nuclear Proteins / Q000172:deficiency*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017422:Sequence Analysis, DNA; D020754:Spinocerebellar Ataxias / Q000151:congenital; D013132:Spinocerebellar Degenerations / Q000235:genetics*
C438188:APTX protein, human; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins