Banfi S

CRISCUOLO, CHIARA

DE MICHELE, GIUSEPPE

FILLA, ALESSANDRO

MANCINI, PIETRO

Monticelli A

SACCA', FRANCESCO

SANTORO, LUCIO

SCARANO, VALENTINA

Archivio della ricerca - Università degli studi di Napoli Federico II

Ataxia with oculomotor apraxia type 1 inSouthern ItalyLate onset and variable phenotypeC. Criscuolo, MD*; P. Mancini, PhD*; F. Saccà, MS; G. De Michele, MD; A. Monticelli, MD; L. Santoro, MD;V. Scarano, MD; S. Banfi, MD; and A. Filla, MDAbstract—Ataxia with oculomotor apraxia type 1 (AOA1) is an autosomal recessive disorder characterized by early-onsetcerebellar ataxia, oculomotor apraxia, and peripheral neuropathy. The causative gene (APTX) has been recently identifiedin Portuguese and Japanese kindreds. Three patients with AOA1 were identified in an APTX mutation screening on 28Southern Italian patients with progressive ataxia and peripheral neuropathy. A novel homozygous missense mutation(H201Q) was found in one patient and a Japanese missense mutation (P206L) in two. AOA1 clinical heterogeneity andonset later than previously described are shown.NEUROLOGY 2004;63:2173–2175Ataxia with oculomotor apraxia type 1 (AOA1; MIM208920) is the most frequent cause of autosomal re-cessive ataxia in Japan and second to Friedreichataxia (FRDA) in Portugal.1 It is a neurodegenera-tive disorder characterized by early-onset, progres-sive ataxia, peripheral neuropathy, and lateroculomotor apraxia. The gene responsible for AOA1(APTX) is organized into seven exons and maps tochromosome 9q13, spanning 17 kbp of genomic DNA.The encoded protein, aprataxin, has been involved inDNA single-strand break repair, as it shares similar-ity with the amino terminus of the polynucleotidekinase 3'-phosphatase and the histidine triad (HIT)proteins.2 To date, several missense, nonsense, andframeshift mutations have been identified in Europeand Japan.2-6We report clinical and molecular findings of threeSouthern Italian patients with mutations in theAPTX gene.Patients and methods. Clinical study. Twenty-eight indexcases were selected among the ataxic patients followed at ourdepartment. The inclusion criteria were sporadic or autosomalrecessive progressive cerebellar ataxia, onset within 35 years,clinical (decreased or absent ankle reflexes and decreased vibra-tion sense) or neurophysiologic signs of peripheral neuropathy orboth, and exclusion of GAA expansion or point mutation withinthe X25 gene. Mean ! SD age at onset was 15 ! 13 years.Peripheral neurophysiologic examination was performed at me-dian and posterior tibial nerves with needle electrodes.Molecular study. Genomic DNA was extracted from periph-eral blood samples after informed consent. Primer pairs were de-signed to screen for the seven coding exons of the APTX gene.Oligonucleotide primer pairs and PCR conditions are available onthe Neurology Web site at www.neurology.org. PCR products wereanalyzed by denaturing high-performance liquid chromatography(DHPLC). DHPLC was performed on a WAVE Nucleic Acid Frag-ment Analysis System HSM (Transgenomic, Crewe, UK). Patientswith altered DHPLC elution profile were analyzed by direct se-quencing. PCR products were purified from agarose gels by theQiagen gel extraction kit and directly sequenced on an automatedsequencer (ABI 3100; Applied Biosystems, Foster City, CA) usingthe ABI-Prism Big-Dye Terminator Cycle Sequencing Ready Reac-tion Kit (Applied Biosystems).Results. Case reports. Patient 1 had disease onset atage 28 with gait imbalance and tendency to fall (table).The patient became wheelchair bound at age 34. Routinechemistry showed slight hypoalbuminemia (3.5 g/dL) andhypercholesterolemia (281 mg/dL). Peripheral nerve con-duction studies performed elsewhere showed sensory mo-tor axonal neuropathy, but quantitative data are notavailable. Brain MRI revealed cerebellar atrophy moremarked in the vermis.The parents of Patient 2 were first cousins. Onset of thedisease was at age 29 with mild dysarthria followed byprogressive gait imbalance at 32 years. At age 38, heneeded support for walking. Fasciculations were observedat the lower limbs. Serum creatine kinase level was ele-vated (462 U/L; normal 0 to 190 U/L). Sensory action po-tentials (SAPs) were undetectable at wrist and internalmalleolus. Motor conduction velocities (MCVs) wereslightly decreased at median (50 m/s in the elbow–wristAdditional material related to this article can be found on the NeurologyWeb site. Go to www.neurology.org and scroll down the Table of Con-tents for the December 14 issue to find the title link for this article.*These authors contributed equally to this article.From the Departments of Neurological Sciences (Drs. Criscuolo, Mancini, Saccà, Scarano, Santoro, De Michele, and Filla) and Molecular and Cellular Biologyand Pathology (Dr. Monticelli), Federico II University, and Telethon Institute of Genetics and Medicine (Drs. Criscuolo and Banfi), Naples, Italy.Supported in part by grants from Italian Ministry of Health and FIRB (A.F. and G. D.M.).Received March 29, 2004. Accepted in final form July 12, 2004.Address correspondence and reprint requests to Dr. C. Criscuolo, Dipartimento di Scienze Neurologiche, Università degli Studi di Napoli Federico II, ViaPansini 5, I-80131, Napoli, Italy; e-mail: sky569@libero.itCopyright © 2004 by AAN Enterprises, Inc. 2173 by FRANCESCO SACCA on March 25, 2010 www.neurology.orgDownloaded from segment; lower limit 54 m/s) and moderately at posteriortibial nerves (35 m/s in the popliteal fossa–internal malle-olus segment; lower limit 52 m/s). Brain MRI revealedmoderate cerebellar atrophy and multiple supratentorialwhite matter hyperintensities (figure).Patient 3 had onset at age 8 with progressive gait im-balance. Sensory conduction velocity was moderately de-creased at the median (37 m/s in the digit III–wristsegment; lower limit 51 m/s) and at the posterior tibialnerves (30 m/s in popliteal fossa–internal malleolus seg-ment; lower limit 38 m/s). SAP was slightly reduced at thewrist (5 "V; lower limit 6 "V) and normal at the internalmalleolus (0.6 "V; lower limit 0.2 "V). MCV was slightdecreased at median (48 m/s) and moderately at posteriortibial nerves (40 m/s) in the same segments explored inPatient 2. Sural nerve biopsy confirmed axonal neuropathywith rare onion bulbs. MRI revealed cerebellar atrophymore marked in the vermis. IQ score was in the lowerlimits (88). Wolff–Parkinson–White–like abnormalitieswere found at EKG.Molecular analysis. We identified a homozygousC-to-T transition at position 617 (we refer to the number-ing starting at the first ATG codon of the long mRNAform), leading to the substitution of proline for leucine atposition 206 of aprataxin (P206L). This mutation is one ofthe most frequent in Japan.2,4,7 Sequencing of the APTXgene in Patient 2 showed a new homozygous missensemutation 603T3A, which results in the substitution ofhistidine for glutamine at amino acid residue 201 (H201Q).This substitution was not found in 200 Italian control chro-mosomes. Patient 3 had compound heterozygosity forP206L and 593C3T, which produces an alanine-to-valinereplacement at residue 198 (A198V). Finally, one patientcarried the substitution 431C3A (S144Y), a polymor-phism with no detectable effect on the protein.8Discussion. The relative frequency of AOA1 was5.7% in a mixed European series of non-FRDA pa-tients with progressive cerebellar ataxia,5 7.5% in aPortuguese series of patients with a possible AOA1phenotype,2 and 11.1% in the current series of pa-tients with progressive non-FRDA and peripheralneuropathy.The most frequent AOA1 phenotype comprisesearly-onset (2 to 18 years) cerebellar ataxia with cer-ebellar atrophy at MRI and areflexia with sensori-motor axonal neuropathy.4-6 Choreic movements maybe prominent at onset (79%) and decrease in thecourse of the disease.5 The typical AOA1 oculomotorabnormality, frequent but not present in all patients(86%),5 consists of normal ocular saccade initiationand increased duration with a succession of multiplehypometric saccades. Head reaches the target beforethe eyes as in congenital oculomotor apraxia, whereinitiation of saccades is impaired.9 Thus, eyes–headlag may be a better definition.Figure. Patient 2. T1-weighted sagittal MRI showing cer-ebellar atrophy (A) and T2-weighted axial MRI showingwhite matter subcortical hyperintensities (B).Table Clinical and molecular findingsFindingPatient no.1 2 3Parental consanguinity No Yes NoSex F M MAge at onset, y 28 29 8Age at examination, y 34 45 18Gait and limb ataxia ### ## #Dysarthria ## ## #Nystagmus # # $Eyes–head lag $ $ #Tendon reflexes $ $ $Extensor plantar response $ $ $Muscle wasting ## ## #Impaired position/vibration sense # # #Choreiform movements $ $ #Scoliosis $ $ #Pes planus # $ #Cognitive impairment $ $ #Aprataxin mutations P206L/P206L H201Q/H201Q P206L/A198VPresence and severity of features: (#) % mild; (##) % moderate; (###) % severe; ($) % absent.2174 NEUROLOGY 63 December (1 of 2) 2004 by FRANCESCO SACCA on March 25, 2010 www.neurology.orgDownloaded from Other clinical features include hypoalbuminemiaand hypercholesterolemia in the late stage. Intelli-gence was normal in the Portuguese series,1 whereascognitive impairment was observed in the Japanese.4Recently, more detailed neuropsychological testshave shown in the European patients a subcorticalsyndrome probably due to disruption of frontocer-ebellar pathways.5 No immunologic impairment hasbeen reported. The patients become wheelchairbound after mean disease duration of 11.2 years.5Patient 1 is homozygous for P206L, not previouslydescribed in the Caucasian population. P206L is thesecond commonest Japanese mutation, and it is con-stantly associated with hypoalbuminemia, as in Pa-tient 1, and cognitive impairment, which is absent inPatient 1. Moreover, the onset (28 years) in this pa-tient is later than previously described.Patient 2 is homozygous for the novel H201Q mu-tation. The same codon is affected in the Japanesemutation H201R, suggesting a mutational hot spot.Japanese H201R patients show a typical phenotypewith cognitive impairment.3 Patient 2 shows amilder clinical presentation with late onset (29years), no wheelchair use after 16 years of diseaseduration, and no cognitive impairment. The less se-vere presentation in Patient 2 suggests that glu-tamine substitution at position 201 is lessdeleterious than arginine for the protein function.MRI of this patient showed multiple supratentorialwhite matter hyperintensities in the absence of riskfactors for cerebrovascular disease. White matterchanges have not been described previously in AOA1and may be coincidental. Presence of fasciculationssuggests loss of motor neurons. This may be of inter-est as mutations in the gene responsible for AOA2,senataxin, may also cause juvenile ALS.10Patient 3 is a compound heterozygote for A198V/P206L. A198V has been identified in a homozygousstate in one Caucasian patient with persistent andsevere chorea.5 Patient 3 had persistence of choreicmovements, suggesting that a single A198V dose issufficient to cause this feature.All the mutations (A198V, H201Q, P206L) are lo-calized in exon 5 and probably alter the function ofaprataxin, leading to changes in the HIT domain andin the secondary structure.Late onset in Patients 1 and 2 and presence offasciculations in Patient 2 suggest a wider clinicalpresentation and that AOA1 diagnosis should be alsoconsidered in ataxic patients with neuropathy andonset later than 20 years.References1. Barbot C, Coutinho P, Chorao R, et al. Recessive ataxia with ocularapraxia: review of 22 Portuguese patients. Arch Neurol 2001;58:201–205.2. Moreira MC, Barbot C, Tachi N, et al. The gene mutated in ataxia–ocular apraxia 1 encodes the new HIT/Zn-finger protein aprataxin. NatGenet 2001;29:189–193.3. Date H, Onodera O, Tanaka H, et al. Early-onset ataxia with ocularmotor apraxia and hypoalbuminemia is caused by mutations in a newHIT superfamily gene. Nat Genet 2001;29:184–188.4. Shimazaki H, Takiyama Y, Sakoe K, et al. Early-onset ataxia with ocularmotor apraxia and hypoalbuminemia. Neurology 2002;59:590–595.5. Le Ber I, Moreira MC, Rivaud-Pechoux S, et al. Cerebellar ataxia withoculomotor apraxia type 1: clinical and genetic studies. Brain 2003;126:2761–2772.6. Tranchant C, Fleury M, Moreira MC, et al. Phenotypic variability ofaprataxin gene mutations. Neurology 2003;60:868–870.7. Moreira MC, Barbot C, Tachi N, et al. Homozygosity mapping of Portu-guese and Japanese forms of ataxia–oculomotor apraxia to 9p13, andevidence for genetic heterogeneity. Am J Hum Genet 2000;68:501–508.8. Coutinho P, Barbot C, Moreira MC, Koenig M. Ataxia with oculomotorapraxia. In: GeneReviews at GeneTests: Medical Genetics InformationResource (database online). University of Washington, Seattle, 1997–2004 (http://www.genetests.org); accessed January 30, 2004.9. Cogan DG. A type of congenital ocular motor apraxia presenting jerkyhead movements. Am J Ophthalmol 1953;36:433–441.10. Chen YZ, Bennett CL, Huynh HM, et al. DNA/RNA helicase gene mu-tations in a form of juvenile amyotrophic lateral sclerosis (ALS4). Am JHum Genet 2004;74:1128–1135.December (1 of 2) 2004 NEUROLOGY 63 2175 by FRANCESCO SACCA on March 25, 2010 www.neurology.orgDownloaded from 

Ataxia with oculomotor apraxia type 1 in southern italy: late onset and variable phenotype.

C. Criscuolo

P. Mancini

F. Sacca

G. De Michele

A. Monticelli

L. Santoro

V. Scarano

S. Banfi

A. Filla

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Neurology

Ataxia with oculomotor apraxia type 1 in Southern Italy: Late onset and variable phenotype

Ataxia with oculomotor apraxia type 1 in southern italy: late onset and variable phenotype.

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Archivio della ricerca - Università degli studi di Napoli Federico II

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