Homozygosity for c 6325T>G transition in the ATM gene causes an atypical, late-onset variant form of ataxia-telangiectasia

Abstract

Dear Sirs,Ataxia-telangiectasia (A-T) is an inherited neurodegener-ative disorder caused by mutations in the ATM (A-TMutated) gene encoding the protein kinase ATM, a keyplayer in the cellular response to double-stranded DNAdamage [1, 2].Classical A-T patients manifest an early-onset of thedisease, severely disabling cerebellar ataxia, dysarthricspeech,oculocutaneoustelangiectasias,oculomotorapraxia,chorea and dystonia, endocrine dysfunctions, immunodefi-ciency and cancer. Brain MRI shows cerebellar atrophy.Laboratory tests reveal raised serum a-fetum protein (AFP)levels and chromosomal instability [1, 2]. Biochemicalstudies on cultured cells document a complete lack offunctional ATM protein. Accordingly, genetic studies usu-allyrevealhomozygousorheterozygous‘‘null’’mutationsinthe ATM gene [1–3].On the other hand, variant A-T forms show a relativelymild neurological phenotype, often normal brain MRI, andless frequently extra-neurological features. These forms areusually caused by missense mutations leaving somedetectable amount of functional ATM protein [2–4].We describe the peculiar clinical and biochemical fea-tures of two related variant A-T Italian patients carrying ahomozygous c.6325T[G transition in the ATM gene.Pt IV-1 (supplementary fig. 1), a 39 year-old woman,developed head and limb tremor and progressive gaitimbalance at around age 13. There was no history ofrecurrent infections or malignancies. Neurological exami-nation at age 28 showed resting and postural tremor, cer-ebellar dysarthria, severe gait ataxia, steppage with distallimb atrophy and areflexia. Eye movements were normal;ocular telangiectasias were noted. Brain MRI showedvermian atrophy. EMG studies documented an axonalsensory-motor polineuropathy. Laboratory tests showed amoderate increase of serum AFP levels (23 ng/ml, normalvalues \9), and normal Ig levels; a radiosensitivity assayon cultured lymphocytes was positive. She became wheel-chair bound at age 35.Pt IV-2 (supplementary fig. 1), a 44 year-old male, whois a third degree cousin of pt IV-1, from age 35 manifestedsome gait difficulties, progressive muscle weakness andcramps. At age 39 he presented a sensory-ataxic gait,weakness and atrophy of distal limb muscles and areflexia.Cerebellar and oculomotor signs were absent; mild con-junctival telangectasias were present. EMG studies docu-mented a sensory-motor axonal neuropathy. Two yearslater he manifested a mild cerebellar limb incoordination; abrain MRI showed cerebellar atrophy (Fig. 1). Serum AFPlevels were increased (82 ng/ml), while Ig levels werenormal and a radiosensitivity test was negative. He cur-rently walks using leg orthoses; until now, neither recurrentrespiratory infections nor malignancies occurred. An ocu-lographic study resulted normal.Immunoblotting [5] showed the absence of ATM proteinin both patients (Fig. 2a), confirmed by phosphorylationstudies (Fig. 2b), while the levels of Mre11, p95 and APTX