Oculomotor apraxia (OMA) refers to a deficiency or absence of the ability to voluntarily initiate eye movements, particularly saccades (rapid eye movements).
First reported in 1953 by American ophthalmologist David Glendenning Cogan. Patients with OMA have difficulty consciously directing their gaze toward an attention-grabbing object. However, in other situations, they can freely look left and right. To bring an object into their field of view, they use compensatory movements such as vigorous head thrusting or blinking.
There is a notable point regarding the name. True “apraxia” refers to the inability to voluntarily initiate learned movements. Since eye movements are not considered learned movements, there is debate about whether OMA is a true apraxia. Additionally, OMA in juvenile Huntington disease is interpreted not as a disorder of motor planning but as a loss of voluntary saccade control6).
OMA is broadly classified into congenital OMA (Cogan type) and acquired OMA. Cogan’s initial report described it as a horizontal gaze disorder, but subsequent cases have reported diverse clinical presentations not necessarily limited to the horizontal direction.
QIs ocular motor apraxia a true "apraxia"?
A
True apraxia refers to the inability to voluntarily initiate “learned movements.” Since eye movements are not considered learned movements, there are objections to calling OMA a true apraxia. In juvenile Huntington disease, it is interpreted as a loss of voluntary saccade control6), and the term “apraxia” is used for historical reasons.
Difficulty with fixation: From infancy, it is difficult to fix the gaze on a target. Because normal tracking is poor, it may initially be mistaken for blindness or visual impairment.
Impulsive head movements: When trying to look at an object of interest, the head shakes violently. This becomes noticeable around 6 months of age when head control is established.
Symptoms of acquired OMA:
Difficulty shifting gaze: It becomes difficult to shift gaze to an object of interest. Diplopia is usually not present (due to conjugate disorder).
QWhy are children with congenital OMA sometimes mistaken for being "blind"?
A
In infancy, difficulty with fixation and poor visual tracking are prominent, making it hard to distinguish from visual impairment. However, eye movements using the vestibulo-ocular reflex (VOR) are preserved, so when the head is moved, the gaze can be maintained. As compensatory head movements develop with growth, the fixation difficulty becomes apparent, often leading to diagnosis.
Head thrust: When shifting gaze to a new target, the head is turned excessively in the direction of gaze, the eyes drag to catch the target, and then the head slowly returns while maintaining fixation. This uses the VOR to bring the target to the front.
VOR activation: The head is turned far enough to pass the target, and the rotation of endolymph in the semicircular canals induces eye movement.
Absence of the fast phase of optokinetic nystagmus and vestibular nystagmus: Because the fast phase does not function, “lock-up” occurs, and the slow phase is not suppressed, causing the eye to deviate to its mechanical limit.
Saccadic hypometria and low-gain pursuit eye movements: Both are observed. Vertical eye movements are usually preserved.
Acquired OMA
Selective impairment of voluntary saccades: Only voluntary saccadic eye movements are selectively impaired, and a dissociation phenomenon in which some eye movements remain is characteristic.
Vertical saccades are also impaired: Unlike congenital OMA, vertical saccadic eye movements are also impaired (an important distinguishing feature from congenital OMA).
Loss of pursuit movements: Pursuit movements may also be lost, but the vestibulo-ocular reflex is preserved.
Impulsive head movements: Similar to congenital cases, impulsive head movements may be observed.
In AOA (ataxia with oculomotor apraxia), the following findings are added:
AOA1: Loss of VOR suppression. Saccade initiation is normal but hypometric and consecutive.
AOA2: OMA is observed in approximately 51% of patients. Head shaking movements occur only in some patients.
AOA4 (new phenotype): Cases have been reported presenting with OMA, cerebellar dysarthria, dystonia, and gait ataxia, with independent walking possible into adulthood1).
Juvenile Huntington disease: Delayed saccade initiation (OMA) and upward gaze palsy appear, progressing to complete ophthalmoplegia6).
It is considered a genetic disorder, but the inheritance pattern is unknown and it is idiopathic. Illness during pregnancy or the perinatal period is cited as a risk factor. It may be accompanied by developmental delay, hypotonia, and speech disorders. Both horizontal saccadic and smooth pursuit eye movements are absent, suggesting an impairment in communication with the cerebrum.
Anoxic encephalopathy (after cardiac arrest or coronary artery bypass surgery)
Balint’s syndrome: A type of acquired OMA. Caused by damage to the parieto-occipital region, presenting with the triad of psychic paralysis of gaze, optic ataxia, and visual attention disorder.
Genetic causes (main disease groups associated with OMA)
The main clinical features of each type are shown below.
AOA1 (EOAH): Cerebellar ataxia, chorea, cognitive impairment, sensorimotor neuropathy. Low albumin, high cholesterol, elevated AFP. Frequent in Japan and Portugal.
AOA2 (ATX-SETX): Ataxia, sensorimotor neuropathy, OMA (51%), primary ovarian insufficiency, chorea, dystonia. Elevated AFP (98%, median 31 μg/L), hypercholesterolemia 2).
AOA4: Severe extrapyramidal symptoms, neuropathy, rapid progression, cerebellar atrophy. Second most common autosomal recessive ataxia in Portugal after Friedreich’s ataxia 1).
A-T: Ataxia, chorea, myoclonus, conjunctival telangiectasia. Horizontal and vertical OMA (about 1/3). Elevated AFP. Increased risk of leukemia and lymphoma.
Juvenile Huntington disease: OMA can be an initial symptom (about 20%). Parkinsonism, dystonia, progressive ophthalmoplegia 6).
Other related conditions include abetalipoproteinemia (vitamin E deficiency), Alagille syndrome, Cockayne syndrome, Gaucher disease, Niemann-Pick disease type C, and Wilson disease.
QHow are the different types of ataxia with oculomotor apraxia (AOA) distinguished?
A
They are differentiated by the combination of biomarker patterns of AFP, albumin, and cholesterol, age of onset, and presence of neuropathy. In AOA1, hypoalbuminemia is characteristic; in AOA2, AFP is elevated in 98% of cases and may be associated with ovarian failure 2). A-T is accompanied by low immunoglobulins and risk of malignancy. Genetic testing is required for definitive diagnosis.
OMA is primarily diagnosed clinically. In congenital cases, confirming characteristic impulsive head thrust and gaze shifting using the VOR is the first step in diagnosis. Confirmation of the disappearance of the fast phase of nystagmus induced by rotational testing is useful for diagnosis.
Neuroradiological findings may be normal. MRI is the most important imaging test, with focused evaluation of the posterior fossa and cerebellar vermis.
Cerebellar vermis atrophy/hypoplasia: Seen in many underlying diseases of OMA.
Corpus callosum abnormalities (less frequent) and fourth ventricle abnormalities have also been reported.
AOA4: MRI shows cerebellar atrophy in all cases1).
AOA2: MRI shows marked cerebellar atrophy of the vermis and hemispheres. The brainstem is preserved 2).
Genetic testing: Performed when AOA1 or AOA2 is suspected. Next-generation sequencing (NGS) panel testing is useful 5).
Western blot: In AOA2, a decrease in senataxin can be confirmed. Normal ATM protein and aprataxin can rule out A-T and AOA1 3).
Nerve conduction study: In AOA2, axonal sensorimotor neuropathy can be detected 2, 3).
Triplet repeat testing: If juvenile HD is in the differential, CAG repeat count testing is essential. It cannot be detected by exome testing or microarray, so separate testing is required 6).
The following are particularly important for differential diagnosis.
Childhood ataxia + OMA: A-T, AOA1, AOA2, Joubert syndrome, Niemann-Pick type C
OMA + Parkinsonism: Juvenile HD, AOA2, PLA2G6-related disorders
Compensatory impulsive head movements tend to naturally resolve and become less noticeable with growth due to improvement in saccades and acquisition of compensatory strategies. In congenital OMA, it is most important to check for comorbid conditions. Rehabilitation for visual-related central nervous system disorders may be effective.
AOA1: No specific treatment currently available. Rehabilitation therapy (physical therapy, occupational therapy, speech therapy) is the mainstay5).
AOA2: Provide supportive therapy including physical therapy, occupational therapy, and speech therapy. For osteoporosis risk, supplement calcium and vitamin D2). Genetic counseling is recommended2).
Epilepsy management in AOA4: A case has been reported with no seizure recurrence under management with levetiracetam (3 g/day) plus topiramate (200 mg/day)1). Management with phenobarbital (100 mg/day) has also been reported1).
Lipid management in AOA4: Atorvastatin 10 mg/day was used1).
Juvenile HD: There is no curative treatment; symptomatic therapy for epilepsy, dystonia, and spasticity is provided6).
Management by a multidisciplinary team including family, nurses, pediatricians, neurologists, physical therapists, genetic counselors, and educators is recommended.
QCan OMA be improved with treatment?
A
Congenital Cogan type tends to improve naturally with growth, and compensatory strategies for saccades are acquired. On the other hand, hereditary ataxias such as AOA1, AOA2, and AOA4 have no curative treatment, and symptomatic therapy and rehabilitation are the mainstays 5). In acquired OMA, appropriate treatment of the underlying disease is key to symptom improvement.
Developmental issues in the following neural structures involved in voluntary horizontal eye movements are suggested as causes.
Frontal Eye Fields (FEF): Located in Brodmann area 8, driving contralateral saccadic eye movements.
Superior colliculus: Involved in the control of visually guided saccades.
Paramedian pontine reticular formation (PPRF): Center for horizontal eye movements.
Medial longitudinal fasciculus (MLF): Connects the abducens nucleus and the oculomotor medial rectus nucleus, coordinating conjugate eye movements.
Damage to the posterior cranial fossa, particularly the cerebellar vermis, has also been suggested, and MRI evaluation is important. The fact that children’s ocular symptoms improve with growth supports this “developmental problem” hypothesis, but developmental delay often persists.
The main mechanism is disruption of cortical input due to damage to the descending pathways from the frontal and parietal eye fields to the superior colliculus and brainstem.
Information for saccadic eye movements travels from the frontal eye field (area 8) to the contralateral PPRF.
Information for smooth pursuit eye movements is transmitted from the occipital lobe area 19 to the ipsilateral PPRF.
The vestibulo-ocular reflex is preserved because it does not pass through the PPRF; instead, it travels from the semicircular canals via the vestibular nerve to the vestibular nuclei and then directly to the contralateral abducens nucleus.
This difference in pathways explains why the VOR is preserved in lesions above the PPRF.
Molecular pathology of AOA1: Aprataxin (histidine triad family) encoded by the APTX gene is involved in nucleotide excision repair and DNA single-strand break repair5). Instability of aprataxin leads to accumulation of DNA single-strand breaks, causing neurodegeneration5). The most common mutation in Japan is c.689-690insT, while in Portugal c.837G>A is frequent5).
Molecular pathology of AOA2: Senataxin (a 2,677-amino acid DNA/RNA helicase) encoded by the SETX gene is involved in transcriptional regulation, RNA processing, genome stability maintenance, DNA damage response, neurogenesis, and autophagy regulation3, 4). Most mutations are concentrated in the C-terminal DNA/RNA helicase domain (amino acids 1931-2456)3).
Loss-of-function mutations cause AOA2 (autosomal recessive). Gain-of-function mutations cause ALS4 (autosomal dominant), resulting in contrasting disease phenotypes 4). WGCNA (weighted gene co-expression network analysis) has shown that AOA2 and ALS4 have different gene expression profiles 4).
Molecular pathology of AOA4: The PNKP protein encoded by the PNKP gene is involved in DNA single-strand break (SSB) and double-strand break (DSB) repair pathways 1). Initially associated with early infantile epileptic encephalopathy type 10, it was later identified as causing ataxia with oculomotor apraxia 1). There is no clear correlation between the type/location of mutations and the phenotype, and gene-environment interactions may play a role 1).
Pathology of OMA in Huntington disease: Dysfunction of the descending input pathway from the frontal/parietal eye fields/cortex to the basal ganglia, superior colliculus, brainstem, and cerebellum is considered the main mechanism 6). The greater the number of CAG repeats, the earlier eye abnormalities tend to appear 6). Head-eye coordination impairment reflects cerebellar dysfunction, with eye movement latency being greater relative to head movement 6).
7. Latest Research and Future Perspectives (Reports at Research Stage)
Freitas et al. (2021) reported novel PNKP mutations (c.1029+2T>C and c.1221_1223del compound heterozygous) in a 52-year-old and 58-year-old sister pair 1). While all previously reported AOA4 patients became wheelchair-dependent in adolescence, these cases maintained independent walking into adulthood and had epilepsy. This finding indicates an expansion of the clinical spectrum of AOA4, and recognition of this disease in cases that progress into adulthood is important.
AOA2 and ovarian insufficiency/reproductive dysfunction
Kinkar et al. (2021) reported ovarian insufficiency with FSH 30.19 IU/L and LH 28.78 IU/L (equivalent to menopausal levels) in a 21-year-old woman with AOA2 carrying a heterozygous deletion of SETX exon 6 2). This report suggests a new role for the SETX gene in spermatogenesis and germ cell development, and recommends hormone testing and fertility evaluation in all AOA2 patients.
Variant interpretation and polymorphism determination in AOA2
Perry et al. (2021) identified two clear pathogenic mutations in SETX in a 16-year-old male 3). The additional sequence changes c.1807A>G and c.1957C>A were relatively frequent in gnomAD (691/143,320 and 916/143,216, respectively), suggesting they are likely benign polymorphisms. This report highlights the importance of interpreting polymorphisms and pathogenic mutations in gene panel testing.
Expansion of the SETX-related disease spectrum and functional diagnosis using RNA-seq
Hadjinicolaou et al. (2021) reported early-onset severe polyneuropathy in two unrelated patients with a de novo SETX p.Thr8Met mutation 4). Weighted gene co-expression network analysis (WGCNA) identified an ALS4-specific transcriptional signature, suggesting its potential as a functional diagnostic tool using RNA-seq.
Albaradie et al. (2022) reported that 18 pathogenic mutations in the APTX gene were identified in 39 families 5). The p.Pro206Leu/p.Val263Gly mutations were milder (mild gait impairment, mild OMA, no cognitive impairment) than the c.689-690insT mutation, which showed a higher rate of gait loss, earlier onset, and a more severe phenotype with hypoalbuminemia. This suggests that genotype may help predict prognosis.
OMA as an early indicator of juvenile Huntington disease
Innes et al. (2023) reported a case of a 14-year-old male in whom OMA was the initial symptom of juvenile Huntington disease (CAG 74) 6). This highlights the importance of actively considering juvenile HD in the differential diagnosis of adolescent patients presenting with OMA plus parkinsonism. Trinucleotide repeat testing is essential because it cannot be detected by microarray or exome sequencing.
Pathogenicity of synonymous variants in Joubert syndrome
Tuncel et al. (2021) reported a patient with Joubert syndrome carrying a homozygous synonymous variant c.2106G>A in AHI1 7). This suggests that synonymous variants may affect splicing and underscores the importance of not overlooking synonymous variants in the molecular diagnosis of ciliopathies.
Freitas E, Costa O, Rocha S. A New Phenotype of Ataxia With Oculomotor Apraxia Type 4. Cureus. 2021;13(2):e13601.
Kinkar JS, Jameel PZ, Kumawat BL, Kalbhor P. Heterozygous deletion in exon 6 of STEX gene causing ataxia with oculomotor apraxia type 2 (AOA2) with ovarian failure. BMJ Case Rep. 2021;14:e241767.
Perry MD, Evans MJ, Byrd PJ, Taylor MR. Biallelic Mutation of SETX and Additional Likely “In Cis” SETX Sequence Change in Ataxia with Oculomotor Apraxia Type 2. J Pediatr Genet. 2021;10:311-314.
Hadjinicolaou A, Ngo KJ, Conway DY, et al. De novo pathogenic variant in SETX causes a rapidly progressive neurodegenerative disorder of early childhood-onset with severe axonal polyneuropathy. Acta Neuropathol Commun. 2021;9:194.
Albaradie R, Alharbi A, Alsaffar G, Alhamad B, Bashir S. Ataxia with oculomotor apraxia type 1 associated with mutation in the APTX gene: A case study and literature review. Exp Ther Med. 2022;24:709.
Innes EA, Qiu J, Morales-Briceño H, Farrar MA, Mohammad SS. Oculomotor Apraxia as an Early Presenting Sign of Juvenile-Onset Huntington’s Disease. Mov Disord Clin Pract. 2023;10(S3):S12-S14.
Tuncel G, Kaymakamzade B, Engindereli Y, Temel SG, Ergoren MC. A Homozygous Synonymous Variant Likely Cause of Severe Ciliopathy Phenotype. Genes. 2021;12:945.
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