Saccades and Eye–Head Coordination in Ataxia with Oculomotor Apraxia Type 2

Panouillères, Muriel; Frismand, Solène; Sillan, Olivier; Urquizar, Christian; Vighetto, Alain; Pélisson, Denis; Tilikete, Caroline

doi:10.1007/s12311-013-0463-1

Cited by 20 publications

(21 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…None had oculomotor apraxia (OMA), reported in half of the AOA2 cases. However, all had hypometric saccades with a staircase pattern, a sign recently suggested as more reliable for OMA [ 14 ].…”

Section: Discussionmentioning

confidence: 99%

An atypical form of AOA2 with myoclonus associated with mutations in SETX and AFG3L2

Mancini

Orsi²,

Guo

et al. 2015

BMC Med Genet

View full text Add to dashboard Cite

BackgroundHereditary ataxias are a heterogeneous group of neurodegenerative disorders, where exome sequencing may become an important diagnostic tool to solve clinically or genetically complex cases.MethodsWe describe an Italian family in which three sisters were affected by ataxia with postural/intentional myoclonus and involuntary movements at onset, which persisted during the disease. Oculomotor apraxia was absent. Clinical and genetic data did not allow us to exclude autosomal dominant or recessive inheritance and suggest a disease gene.ResultsExome sequencing identified a homozygous c.6292C > T (p.Arg2098*) mutation in SETX and a heterozygous c.346G > A (p.Gly116Arg) mutation in AFG3L2 shared by all three affected individuals. A fourth sister (II.7) had subclinical myoclonic jerks at proximal upper limbs and perioral district, confirmed by electrophysiology, and carried the p.Gly116Arg change. Three siblings were healthy.Pathogenicity prediction and a yeast-functional assay suggested p.Gly116Arg impaired m-AAA (ATPases associated with various cellular activities) complex function.ConclusionsExome sequencing is a powerful tool in identifying disease genes. We identified an atypical form of Ataxia with Oculoapraxia type 2 (AOA2) with myoclonus at onset associated with the c.6292C > T (p.Arg2098*) homozygous mutation. Because the same genotype was described in six cases from a Tunisian family with a typical AOA2 without myoclonus, we speculate this latter feature is associated with a second mutated gene, namely AFG3L2 (p.Gly116Arg variant).We suggest that variant phenotypes may be due to the combined effect of different mutated genes associated to ataxia or related disorders, that will become more apparent as the costs of exome sequencing progressively will reduce, amplifying its diagnostics use, and meanwhile proposing significant challenges in the interpretation of the data.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-015-0159-0) contains supplementary material, which is available to authorized users.

show abstract

Section: Discussionmentioning

confidence: 99%

An atypical form of AOA2 with myoclonus associated with mutations in SETX and AFG3L2

Mancini

Orsi²,

Guo

et al. 2015

BMC Med Genet

View full text Add to dashboard Cite

show abstract

“…Saccades are hypometric with a typical staircase pattern. The VOR in the form of head thrusts may be used as a compensatory mechanism [49, 50]. …”

Section: Differential Diagnosesmentioning

confidence: 99%

Central ocular motor disorders, including gaze palsy and nystagmus

et al. 2014

View full text Add to dashboard Cite

An impairment of eye movements, or nystagmus, is seen in many diseases of the central nervous system, in particular those affecting the brainstem and cerebellum, as well as in those of the vestibular system. The key to diagnosis is a systematic clinical examination of the different types of eye movements, including: eye position, range of eye movements, smooth pursuit, saccades, gaze-holding function and optokinetic nystagmus, as well as testing for the different types of nystagmus (e.g., central fixation nystagmus or peripheral vestibular nystagmus). Depending on the time course of the signs and symptoms, eye movements often indicate a specific underlying cause (e.g., stroke or neurodegenerative or metabolic disorders). A detailed knowledge of the anatomy and physiology of eye movements enables the physician to localize the disturbance to a specific area in the brainstem (midbrain, pons or medulla) or cerebellum (in particular the flocculus). For example, isolated dysfunction of vertical eye movements is due to a midbrain lesion affecting the rostral interstitial nucleus of the medial longitudinal fascicle, with impaired vertical saccades only, the interstitial nucleus of Cajal or the posterior commissure; common causes with an acute onset are an infarction or bleeding in the upper midbrain or in patients with chronic progressive supranuclear palsy (PSP) and Niemann–Pick type C (NP-C). Isolated dysfunction of horizontal saccades is due to a pontine lesion affecting the paramedian pontine reticular formation due, for instance, to brainstem bleeding, glioma or Gaucher disease type 3; an impairment of horizontal and vertical saccades is found in later stages of PSP, NP-C and Gaucher disease type 3. Gaze-evoked nystagmus (GEN) in all directions indicates a cerebellar dysfunction and can have multiple causes such as drugs, in particular antiepileptics, chronic alcohol abuse, neurodegenerative cerebellar disorders or cerebellar ataxias; purely vertical GEN is due to a midbrain lesion, while purely horizontal GEN is due to a pontomedullary lesion. The pathognomonic clinical sign of internuclear ophthalmoplegia is an impaired adduction while testing horizontal saccades on the side of the lesion in the ipsilateral medial longitudinal fascicule. The most common pathological types of central nystagmus are downbeat nystagmus (DBN) and upbeat nystagmus (UBN). DBN is generally due to cerebellar dysfunction affecting the flocculus bilaterally (e.g., due to a neurodegenerative disease). Treatment options exist for a few disorders: miglustat for NP-C and aminopyridines for DBN and UBN. It is therefore particularly important to identify treatable cases with these conditions.

show abstract

“…AOA1 and AOA2 and AT are considered to share several clinical and molecular characteristrics 1 even if their individual oculomotor features are not clearly elucidated. Apart from a few studies including oculographic recordings of a single ataxia 5 , 10 , 15 , 16 , specific oculomotor abnormalities of AOA1, AOA2 and AT have never been systematically compared and whether they may be distinguished through oculomotor findings is presently unknown just as whether video-oculography (VO) and biomarkers such as AFP and albumin serum level can assist diagnosis of AOA1, AOA2 and AT in clinical practice. Our aim was to assess whether AOA1, AOA2 and AT could be distinguished from one another by VO and to identify specific AFP thresholds in order to further evaluate the need for VO and AFP in diagnosis.…”

Section: Introductionmentioning

confidence: 99%

Comparing ataxias with oculomotor apraxia: a multimodal study of AOA1, AOA2 and AT focusing on video-oculography and alpha-fetoprotein

Mariani

Rivaud-Péchoux

Charles

et al. 2017

Sci Rep

View full text Add to dashboard Cite

Whether the recessive ataxias, Ataxia with oculomotor apraxia type 1 (AOA1) and 2 (AOA2) and Ataxia telangiectasia (AT), can be distinguished by video-oculography and alpha-fetoprotein level remains unknown. We compared 40 patients with AOA1, AOA2 and AT, consecutively referred between 2008 and 2015 with 17 healthy subjects. Video-oculography revealed constant impairments in patients such as cerebellar signs, altered fixation, impaired pursuit, hypometric saccades and abnormal antisaccades. Horizontal saccade latencies could be highly increased reflecting oculomotor apraxia in one third of patients. Specific distinctive alpha-fetoprotein thresholds were determined for AOA1 (7–15 µg/L), AOA2 (15–65 µg/L) and AT (>65 µg/L). Early age onset, severe walking disability, movement disorders, sensori-motor neuropathy and cerebellar atrophy were all shared. In conclusion, alpha-fetoprotein level seems to permit a distinction while video-oculography does not and therefore is not mandatory, even if an appropriate oculomotor examination remains crucial. Our findings are that AOA1, AOA2 and AT form a particular group characterized by ataxia with complex oculomotor disturbances and elevated AFP for which the final diagnosis is relying on genetic analysis. These findings could guide genetic analysis, assist reverse-phenotyping and provide background for the interpretation of the numerous variants of unknown significance provided by next-generation sequencing.

show abstract

Saccades and Eye–Head Coordination in Ataxia with Oculomotor Apraxia Type 2

Cited by 20 publications

References 37 publications

An atypical form of AOA2 with myoclonus associated with mutations in SETX and AFG3L2

An atypical form of AOA2 with myoclonus associated with mutations in SETX and AFG3L2

Central ocular motor disorders, including gaze palsy and nystagmus

Comparing ataxias with oculomotor apraxia: a multimodal study of AOA1, AOA2 and AT focusing on video-oculography and alpha-fetoprotein

Contact Info

Product

Resources

About