Ataxia with oculomotor apraxia type 2: not always an easy diagnosis

See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/273782512 Ataxia with oculomotor apraxia type 2: not always an easy diagnosis Article in Neurological Sciences · March 2015 DOI: 10.1007/s10072-015-2119-z · Source: PubMed CITATIONS READS 0 64 5 authors, including: Andrea Mignarri Alessandra Tessa 44 PUBLICATIONS 262 CITATIONS 154 PUBLICATIONS 2,098 CITATIONS Università degli Studi di Siena SEE PROFILE Università di Pisa SEE PROFILE Antonio Federico Università degli Studi di Siena 533 PUBLICATIONS 8,927 CITATIONS SEE PROFILE All content following this page was uploaded by Andrea Mignarri on 27 March 2015. The user has requested enhancement of the downloaded file. All in-text references underlined in blue are added to the original document and are linked to publications on ResearchGate, letting you access and read them immediately. Neurol Sci DOI 10.1007/s10072-015-2119-z LETTER TO THE EDITOR Ataxia with oculomotor apraxia type 2: not always an easy diagnosis A. Mignarri • A. Tessa • A. Federico • F. M. Santorelli • Maria Teresa Dotti Received: 24 December 2014 / Accepted: 19 February 2015 Ó Springer-Verlag Italia 2015 Dear Sirs, Autosomal recessive cerebellar ataxias (ARCAs) represent a large number of diseases, the most frequent being Friedreich’s ataxia (FRDA), autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), ataxia with vitamin E deficiency (AVED), mitochondrial ataxias, ataxia-telangiectasia (AT), and ataxia with oculomotor apraxia type 1 and 2. Ataxia with oculomotor apraxia type 2 (AOA2) is caused by mutations in SETX, which encodes a DNA/RNA helicase with multiple complex roles in DNA and RNA metabolism. Disease onset is usually between 7 and 25 years. AOA2 is characterized by ataxia, occasional oculomotor apraxia, cerebellar atrophy affecting predominantly the vermis, axonal sensory-motor neuropathy, and increased a-fetoprotein (AFP) serum level [1, 2]. Here, we describe two AOA2 patients presenting cerebellar atrophy in association with posterior fossa cystic malformations and mutations in SETX. Of note, both patients manifested AFP elevation and polyneuropathy 2 years after clinical onset. Two Italian siblings, a 12-year-old boy (FB) and a 10-year-old girl (CB) born to healthy non-consanguineous parents, were referred to us because of mild gait disturbances and incoordination since they were 9 years. Both siblings had developed normally with an unremarkable prenatal and perinatal clinical history. In both children, A. Mignarri
A. Federico
M. T. Dotti (&) Unit of Neurology and Neurometabolic Disorders, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy e-mail: dotti@unisi.it A. Tessa
F. M. Santorelli Unit of Molecular Medicine, IRCCS Stella Maris, Pisa, Italy neurological examination revealed cerebellar ataxia, oculomotor apraxia, slight limb dysmetria, hypotonus, and decreased deep tendon reflexes. Brain magnetic resonance imaging (MRI) showed cerebellar atrophy and cystic malformations of the posterior fossa, including retrocerebellar arachnoid cyst in one case (FB) and enlargement of cisterna magna and fourth ventricle in the other sib (CB) (Fig. 1). Electromyography (EMG) and nerve conduction study (NCS) were normal in both subjects. Routine blood tests were unremarkable. Serum assay of AFP (\7 ng/ml), immunoglobulins, vitamin E, and lactic acid was also normal. Molecular analyses for the expanded GAA tract in the first intron of FXN and for mutations in coding exons of the SACS and APTX genes were all normal. Patients underwent yearly clinical re-evaluation including brain MRI, EMG/ NCS, and AFP assessment. A slow progression of ataxia was clinically observed, while brain MRI did not detect changes over time. At 2-year follow-up, serum AFP dosage first revealed increased values (7.3 ng/ml in FB; 14.6 ng/ml in CB), and NCS documented mild sensory axonal neuropathy. Novel findings prompted us to reconsider clinical presentation and seek mutations in SETX; the two siblings harbored the heteroallelic c.839-2A[G and c.6461C[T on the paternal and maternal alleles, respectively. The c.839-2A[G affects an almost invariable AG consensus sequence at the donor splice site, it was absent in 200 Italian heathy chromosomes, and it is considered to be damaging in silico based on splicing site prediction tools (e.g., Splice Site Prediction, http://www.fruitfly.org/seq_tools/splice.html; HSF, http:// www.umd.be/HSF/; and Netgene2, http://www.cbs.dtu.dk/ services/NetGene2/). Unfortunately, no tissue was available to test experimentally effects on mRNA splicing in vitro. The c.6461C[T predicts a novel missense p.Thr2154Met, affecting a conserved residue in the AAA domain. In silico analyses (PolyPhen2, http://genetics.bwh.harvard. 123 Neurol Sci Fig. 1 a, b Brain MRI (a T1 sagittal, b FLAIR axial) of FB shows cerebellar atrophy and retrocerebellar (right [ left) arachnoid cyst in the posterior fossa. c, d Brain MRI (c T1 sagittal, d FLAIR axial) of CB reveals cerebellar atrophy, expanded cisterna magna, and mild enlargement of the fourth ventricle edu/pph2/; MutPred, http://mutpred.mutdb.org/) suggest that the p.Thr2154Met is probably damaging. The mutation was absent in 300 Italian control chromosomes and not listed in large collection of human exome studies (http://evs. gs.washington.edu/EVS/; http://exac.broadinstitute.org/). The expanding set of genes and the ever growing list of clinical phenotypes associated with new etiologies emerging in the clinical use of exome sequencing make differential diagnosis of ARCAs a diagnostic challenge. Clinical evaluation and family history are essential but brain MRI, EMG/NCS, and selected laboratory analyses are often required to get clues as for a specific diagnosis and prioritize gene testing. Measurement of serum AFP is considered a simple and reliable tool in the diagnostic workup: AFP is almost invariably increased in patients with AT (range 50–900 ng/ml) and AOA2 (range 10–100 ng/ml), and within the normal range in other ARCAs [3]. Results gathered in large cohorts of molecularly defined AOA2 patients [1, 2] have shown that AFP concentrations are elevated ([7 ng/ml) in 99 % of the cases, and levels are stable during the course of the disease. Moreover, cerebellar atrophy and peripheral neuropathy are almost invariable features of the clinical syndrome, occurring in 95–100 % of patients with AOA2 [1, 2]. In our patients, laboratory and instrumental data were initially misleading and caused a considerable diagnostic delay. Indeed, the contemporary absence of both AFP increase and peripheral neuropathy is to consider exceptional. Only during the follow-up, 2 years after neurological advice had been seeked, pathological serum AFP levels and NCS were disclosed. Thus, our experience suggests to re-evaluate laboratory parameters periodically during follow-up of ARCA patients when suggestive clinical manifestations are present. This could address the 123 Neurol Sci proper molecular diagnosis before embarking in more demanding deep sequencing studies. The late appearance of sensory axonal neuropathy occurred in our patients is intriguing: while marked cerebellar atrophy is present since onset and does not seem to undergo substantial changes over time, damage of peripheral axons may be time dependent, and NCS could be useful for monitoring the progression of the disease. One additional comment emerges by reconsidering the neuroimaging of our patients. MRI evidence of posterior fossa malformations has been reported in congenital cerebellar hypoplasias and ARSACS [4, 5]. Our neuroimages enlarge the spectrum of MRI findings associated with AOA2. Therefore, presence of posterior fossa malformations in addition to cerebellar atrophy should not lead to rule out SETX mutations. In conclusion, our case study suggests that AOA2 should not be excluded in patients with ataxia and cerebellar atrophy initially lacking AFP increase and/or polyneuropathy, since these alterations may emerge later as disease progresses. Conflict of interest of interest. The authors declare that they have no conflict References 1. Anheim M, Monga B, Fleury M et al (2009) Ataxia with oculomotor apraxia type 2: clinical, biological and genotype/ phenotype correlation study of a cohort of 90 patients. Brain 132:2688–2698 2. Nanetti L, Cavalieri S, Pensato V et al (2013) SETX mutations are a frequent genetic cause of juvenile and adult onset cerebellar ataxia with neuropathy and elevated serum alpha-fetoprotein. Orphanet J Rare Dis 8:123 3. Schieving JH, de Vries M, van Vugt JM et al (2014) Alphafetoprotein, a fascinating protein and biomarker in neurology. Eur J Paediatr Neurol 18:243–248 4. Steinlin M (1998) Non-progressive congenital ataxias. Brain Dev 20:199–208 5. Synofzik M, Soehn AS, Gburek-Augustat J et al (2013) Autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS): expanding the genetic, clinical and imaging spectrum. Orphanet J Rare Dis 8:41 123