Cerebellar ataxia with neuropathy and elevated serum AFP: SETX mutations are a frequent genetic cause of juvenile and adult onset disease


Oculomotor apraxia ( OMA ) associated with cerebellar ataxia was first noted by Boder and Sedgwick in patients with ataxia-telangiectasia ( A-T ). This abnormality of eye movements consists of an impairment in the generation of horizontal saccades with patients performing compensatory head thrusts.

OMA has been described in four genetically distinct forms of inherited neurodegenerative ataxias, classified as autosomal recessive cerebellar ataxias ( ARCA ) : ataxia-telangectasia ( A-T ), A-T like disorder ( A-TLD ), ataxia with oculomotor apraxia type 1 ( AOA1 ) and ataxia with oculomotor apraxia type 2 ( AOA2 ).

In addition to eye movement abnormalities, these recessive ataxias also share further clinical, biochemical and molecular features. All are characterized by early onset progressive cerebellar gait and limb ataxia, peripheral sensory neuropathy and cerebellar degeneration.
A-T, AOA2, and occasionally AOA1 present elevated serum levels of alpha-fetoprotein ( AFP ).

The proteins coded by the causative genes for these four ARCAs are all involved in DNA single or double-strand break repair mechanisms. A-T ( MIM 208900 ), the most prevalent of the four with an incidence of 1 in 300,000, is caused by mutation in the ATM ( A-T mutated ) gene encoding a phosphatidylinositol-3 kinase protein.

A-T patients lack ATM protein or its kinase activity, and present extra neurological signs, such as immunodeficiency and cancer susceptibility.

A-TLD ( MIM 604391 ) is extremely rare, has a milder clinical course than A-T, and is caused by mutations in the human meiotic recombination 11 gene ( hMRE11 ). Patients with A-TLD do not show telangiectasia, no immunodeficiency and have normal AFP serum concentrations.

AOA1 ( MIM 208920 ) is characterized by early onset cerebellar ataxia, neuropathy, mental retardation, hypoalbuminemia and hypercholesterolemia. This disease is caused by mutations in the APTX gene, which encodes for aprataxin, a nuclear histidine-triad protein involved in DNA single-strand break repair. AOA1 is particularly frequent in Portugal ( 1:20000 ) and in Japan.

AOA2 ( MIM 606002 ) has a worldwide distribution, and its prevalence is estimated around 1 in 900,000. This form is caused by mutations in the SETX gene encoding for a large DNA/RNA helicase protein involved in the defense against DNA damage and in processing RNAs.
SETX gene mutations have also been associated with the autosomal dominant juvenile amyotrophic lateral sclerosis type 4 ( ALS4 ), and with the dominant tremor-ataxia syndrome.

In a study, researchers have performed a mutational screening of ATM, APTX, SETX in a selected cohort of twenty-two Italian patients presenting cerebellar ataxia, sensorimotor axonal neuropathy, and elevated AFP.
Thirteen patients ( 12 families ) carried SETX mutations ( AOA2, 57% ), two were mutated in ATM ( A-T ), and three in APTX ( AOA1 ). In three remaining patients, no pathogenic mutations were found, and in one case investigators found, in homozygosis, the SETX p.K992R polymorphism ( population frequency 1-2% ).
In AOA2 cases, researchers identified 14 novel and three reported SETX mutations.
Signs at onset were gait ataxia and facial dyskinesia, and the age ranged between 11 and 18 years. None had obvious oculomotor apraxia at the latest examination ( age 14-45 years ).
The patient carrying the p.K992R SETX polymorphism had a phenotype similar to that of the diagnosed AOA2 patients, while the other three undiagnosed subjects had a very late onset and a few distinguishing clinical features. ( Xagena )

Nanetti L et al, Orphanet Journal of Rare Diseases 2013, 8:123

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