Congenital Ocular Motor Apraxia Research Articles

Visual Development in a Patient with Infantile-Onset Saccade Initiation Delay

Congenital ocular motor apraxia (COMA), also known as infantile-onset saccade initiation delay (ISID), is characterized by the inability to initiate volitional horizontal saccades. This five-month-old girl showed constant rapid movements to right or left one week after birth. After four months, she began thrusting her head from left to right when following target objects. She was diagnosed with COMA/ISID. At 4 years of age, head thrust became less evident. She first uttered meaningful words at 5 years of age, and spoke in sentences by 6 years of age. At 6 years of age, visual acuity was 1.0 in both eyes at 1 m. Head thrust disappeared at almost 6 years of age. She could not start crawling and sustaining a sitting position due to hypotonia. Clinicians should be aware of visual development in COMA/ISID and should look for them during the assessment of these children.

The genetic spectrum of congenital ocular motor apraxia type Cogan: an observational study, continued

BackgroundThe term congenital ocular motor apraxia (COMA), coined by Cogan in 1952, designates the incapacity to initiate voluntary eye movements performing rapid gaze shift, so called saccades. While regarded as a nosological entity by some authors, there is growing evidence that COMA designates merely a neurological symptom with etiologic heterogeneity. In 2016, we reported an observational study in a cohort of 21 patients diagnosed as having COMA. Thorough re-evaluation of the neuroimaging features of these 21 subjects revealed a previously not recognized molar tooth sign (MTS) in 11 of them, thus leading to a diagnostic reassignment as Joubert syndrome (JBTS). Specific MRI features in two further individuals indicated a Poretti–Boltshauser syndrome (PTBHS) and a tubulinopathy. In eight patients, a more precise diagnosis was not achieved. We pursued this cohort aiming at clarification of the definite genetic basis of COMA in each patient.ResultsUsing a candidate gene approach, molecular genetic panels or exome sequencing, we detected causative molecular genetic variants in 17 of 21 patients with COMA. In nine of those 11 subjects diagnosed with JBTS due to newly recognized MTS on neuroimaging, we found pathogenic mutations in five different genes known to be associated with JBTS, including KIAA0586, NPHP1, CC2D2A, MKS1, and TMEM67. In two individuals without MTS on MRI, pathogenic variants were detected in NPHP1 and KIAA0586, arriving at a diagnosis of JBTS type 4 and 23, respectively. Three patients carried heterozygous truncating variants in SUFU, representing the first description of a newly identified forme fruste of JBTS. The clinical diagnoses of PTBHS and tubulinopathy were confirmed by detection of causative variants in LAMA1 and TUBA1A, respectively. In one patient with normal MRI, biallelic pathogenic variants in ATM indicated variant ataxia telangiectasia. Exome sequencing failed to reveal causative genetic variants in the remaining four subjects, two of them with clear MTS on MRI.ConclusionsOur findings indicate marked etiologic heterogeneity in COMA with detection of causative mutations in 81% (17/21) in our cohort and nine different genes being affected, mostly genes associated with JBTS. We provide a diagnostic algorithm for COMA.

SUFU haploinsufficiency causes a recognisable neurodevelopmental phenotype at the mild end of the Joubert syndrome spectrum

BackgroundJoubert syndrome (JS) is a recessively inherited ciliopathy characterised by congenital ocular motor apraxia (COMA), developmental delay (DD), intellectual disability, ataxia, multiorgan involvement, and a unique cerebellar and brainstem malformation....

Heterozygous truncating variants in SUFU cause congenital ocular motor apraxia

PurposeThis study aimed to delineate the genetic basis of congenital ocular motor apraxia (COMA) in patients not otherwise classifiable. MethodsWe compiled clinical and neuroimaging data of individuals from six unrelated families with distinct clinical features of COMA who do not share common diagnostic characteristics of Joubert syndrome or other known genetic conditions associated with COMA. We used exome sequencing to identify pathogenic variants and functional studies in patient-derived fibroblasts. ResultsIn 15 individuals, we detected familial as well as de novo heterozygous truncating causative variants in the Suppressor of Fused (SUFU) gene, a negative regulator of the Hedgehog (HH) signaling pathway. Functional studies showed no differences in cilia occurrence, morphology, or localization of ciliary proteins, such as smoothened. However, analysis of expression of HH signaling target genes detected a significant increase in the general signaling activity in COMA patient–derived fibroblasts compared with control cells. We observed higher basal HH signaling activity resulting in increased basal expression levels of GLI1, GLI2, GLI3, and Patched1. Neuroimaging revealed subtle cerebellar changes, but no full-blown molar tooth sign. ConclusionTaken together, our data imply that the clinical phenotype associated with heterozygous truncating germline variants in SUFU is a forme fruste of Joubert syndrome.

6q21q22.2 Deletion Syndrome with Ataxia and Congenital Ocular Motor Apraxia (Cogan´s Syndrome)

Congenital oculomotor apraxia, also known as Cogan´s syndrome [Cogan-type congenital ocular motor apraxia (COMA, OMIM 257550)], is a rare hereditary disease that affects the eye insofar as it cannot make horizontal movements voluntary. Of unknown etiology, it was described by Cogan in 1952 and, classically considered as a sporadic disease with autosomal dominant inheritance in some cases, and as an indicator of partial metabolic alterations or defects of neurological development in others. We present a newborn with 6q21q22.1 microdeletion, result of gestation after in vitro fertilization, which clinically manifests movement disorders including ataxia and characteristic clinical picture of Cogan´s syndrome (oculomotor apraxia); highlighting microcephaly and peculiar phenotype characterized by small eyes, sparse hair, broad nasal root with epicanthus and hypoplasia of nasal wings. Cerebral ultrasound showed Cysts of the Subependymal. Germinal Matrix. The 6q deletions are infrequent, with around 100 cases described, associated with variable phenotypes, including dysmorphic features, growth retardation, upper limb malformations, and Prader-Willi (PW)-like features; and few of them studied with high resolution cytogenetic techniques. Recently, in the study of three patients (one with ataxia and two with movement disorders), the 6q22.1 region has been proposed as critical (including the MARCKS, HDAC2, and HS3ST5 genes), a region that is also affected in our patient, and correlated with the ataxia phenotype, as the most outstanding data. So, from these results, the genetic heterogeneity of Cogan syndrome is inferred. In this article we also review the bibliography related to oculomotor apraxia associated with other movement disorders such as ataxia.

Could Congenital Ocular Motor Apraxia be Caused by a Celebeller Vermis Dysfunction?

Could Congenital Ocular Motor Apraxia be Caused by a Celebeller Vermis Dysfunction?

Nosological delineation of congenital ocular motor apraxia type Cogan: an observational study.

BackgroundThe nosological assignment of congenital ocular motor apraxia type Cogan (COMA) is still controversial. While regarded as a distinct entity by some authorities including the Online Mendelian Inheritance in Man catalog of genetic disorders, others consider COMA merely a clinical symptom.MethodsWe performed a retrospective multicenter data collection study with re-evaluation of clinical and neuroimaging data of 21 previously unreported patients (8 female, 13 male, ages ranging from 2 to 24 years) diagnosed as having COMA.ResultsOcular motor apraxia (OMA) was recognized during the first year of life and confined to horizontal pursuit in all patients. OMA attenuated over the years in most cases, regressed completely in two siblings, and persisted unimproved in one individual. Accompanying clinical features included early onset ataxia in most patients and cognitive impairment with learning disability (n = 6) or intellectual disability (n = 4). Re-evaluation of MRI data sets revealed a hitherto unrecognized molar tooth sign diagnostic for Joubert syndrome in 11 patients, neuroimaging features of Poretti-Boltshauser syndrome in one case and cerebral malformation suspicious of a tubulinopathy in another subject. In the remainder, MRI showed vermian hypo-/dysplasia in 4 and no abnormalities in another 4 patients. There was a strong trend to more severe cognitive impairment in patients with Joubert syndrome compared to those with inconclusive MRI, but otherwise no significant difference in clinical phenotypes between these two groups.ConclusionsSystematical renewed analysis of neuroimaging data resulted in a diagnostic reappraisal in the majority of patients with early-onset OMA in the cohort reported here. This finding poses a further challenge to the notion of COMA constituting a separate entity and underlines the need for an expert assessment of neuroimaging in children with COMA, especially if they show cognitive impairment.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-016-0486-z) contains supplementary material, which is available to authorized users.

Infantile-onset saccade initiation delay (congenital ocular motor apraxia).

Infantile-onset saccade initiation delay, also known as congenital ocular motor apraxia, typically presents in early infancy with horizontal head thrusts once head control is achieved. Defective initiation of horizontal saccades and saccade hypometria with normal saccadic velocity are characteristic findings. Isolated impairment of vertical saccades is rare. Impaired smooth ocular pursuit may be seen. Other relatively common features include developmental delay, hypotonia, ataxia, or clumsiness. Brain MRI may be normal or show a diverse range of abnormalities, most commonly involving the cerebellum. Defective slow phases of the optokinetic response are commonly associated with brain MRI abnormalities. Isolated defect of vertical saccade initiation may indicate supratentorial brain abnormalities on MRI. Joubert syndrome, a developmental midbrain-hindbrain malformation, and ataxia telangiectasia are both commonly associated with defective volitional and reflexive saccade initiation, saccade hypometria, and head thrusts. Both horizontal and vertical saccades are impaired in these two disorders.

Do the Clinical Features in Infantile-Onset Saccade Initiation Delay (Congenital Ocular Motor Apraxia) Correlate With Brain Magnetic Resonance Imaging Findings?

Infantile-onset saccade initiation delay (ISID) is a defect in saccade initiation. Other features may include impaired smooth ocular pursuit, developmental delay, hypotonia, and ataxia. Brain magnetic resonance imaging (MRI) can be normal or show supratentorial or infratentorial abnormalities. Our aim was to correlate the clinical features of ISID with brain MRI findings. Detailed review of the English medical literature between 1952 and 2012 revealed 67 studies with possible ISID. Patients without a brain MRI or with inadequate information, Joubert syndrome, neurodegenerative disorders, and acquired saccade initiation delay were excluded. Ninety-one patients (age range, 3 months to 45 years) met the inclusion criteria and were divided into 3 groups based on their brain MRI findings: normal (n = 55), supratentorial abnormalities (n = 17), and infratentorial abnormalities (n = 19). The patients' clinical features including the direction of head thrusts, smooth pursuit, optokinetic response (OKR), tone, development, and coordination were compared and analyzed among the MRI groups using χ test. Horizontal head thrusts were significantly more common in patients with infratentorial abnormalities or normal brain MRI, whereas vertical head thrusts were more common among patients with supratentorial abnormalities (P < 0.0001). The slow phases of the OKR were significantly more likely to be impaired in patients with supratentorial or infratentorial abnormalities than in those with a normal MRI (P = 0.011). Other neuro-ophthalmological, neurological, and developmental features were similar among patients in the 3 neuroimaging groups. The direction of head thrust and the integrity of the slow phases of the OKR are useful clinical indicators of possible sites of abnormality on brain MRI in patients with ISID.

Congenital ocular motor apraxia with wheel-rolling ocular torsion—a neurodiagnostic phenotype of Joubert syndrome

Joubert syndrome is a multisystem disorder that is associated with a constellation of cyclic ocular motor disturbances. We describe 2 children with congenital ocular motor apraxia who displayed wheel-rolling torsional eye movements and tonic alternating cyclodeviations of the eyes on retinal examination as a neurodiagnostic phenotype of Joubert syndrome.

Congenital ocular motor apraxia, the NPHP1 gene, and surveillance for nephronophthisis

We present an 11-month-old girl with congenital ocular motor apraxia (COMA) and Joubert syndrome found to have a compound heterozygous mutation in the NPHP1 gene that is responsible for juvenile nephronophthisis type 1. The association of congenital ocular motor apraxia and juvenile nephronophthisis is reviewed. The patient does not currently manifest signs of renal failure, although her mutation indicates that she is at risk for the development of juvenile nephronophthisis type 1.

The Syndrome of Infantile-Onset Saccade Initiation Delay

Infantile-onset saccade initiation delay (ISID), also known as congenital ocular motor apraxia, is characterized by the inability to initiate volitional horizontal saccades. Other abnormalities including developmental delay and ataxia have been reported. The frequency of these abnormalities is unknown. We performed a detailed review of the medical literature to quantify features of ISID. We searched the English medical literature for articles related to ISID from 1952 to 2010. Whenever possible, patients were excluded if they had acquired SID, Joubert syndrome or neurodegenerative conditions. The minimum prevalence was calculated for each abnormality. Sixty-six articles with information on 288 patients were included in the analysis. Head thrusts were reported in 84.7%. Blinks without head thrusts were used to initiate saccades in 41%. The fast phases of the optokinetic response and vestibulo-ocular reflex were impaired in 69.8% and 34.4% respectively. Smooth ocular pursuit was abnormal in 33%. Global developmental delay occurred in 41.3%, speech or language delay in 36.5%, cognitive delay in 17%, hypotonia in 35.8%, motor delay in 48.6%, and ataxia/clumsiness in 49.3% of patients. Neuroimaging was performed on 197 patients and was normal in 39.1%. Abnormalities involved the cerebellum (24.9%), cerebrum (15.7%), other infratentorial structures (11.7%), and corpus callosum (6.1%). Infantile-onset saccade initiation delay is frequently associated with deficits in reflexive saccades and less frequently with impaired smooth ocular pursuit. Developmental delay, hypotonia, and ataxia occur frequently in ISID, suggesting more global brain impairment and not just a saccadic disorder.

Disconnections in Infantile-Onset Saccade Initiation Delay: A Hypothesis

Infantile-onset saccade initiation delay (ISID), commonly known as congenital ocular motor apraxia, is characterized by difficulty in triggering horizontal volitional saccades. It typically presents with head thrusts in infancy and is often associated with developmental delay. Patients with ISID are reported to have abnormalities in various brain regions including the corpus callosum, brainstem, and cerebellum. We propose that ISID is caused by the disruption or disconnection of axons linking analogous brain regions involved in processing saccades across the two sides of the brain or bilateral damage to these regions.

An unusual cause of head drops

The presence of vertical ocular motor apraxia should prompt a careful assessment to detect an underlying neurometabolic condition. But congenital vertical ocular motor apraxia is a rare entity that may be attributed to perinatal stroke, hypoxia or kernicterus. We report a case of a 5-year old girl with congenital vertical ocular motor apraxia. Her magnetic resonance imaging (MRI) brain showed symmetrical high signal in the inferomedial thalamic nuclei in the distribution of the vessel of Percheron, a rare posterior cerebral artery variant. Awareness of this rare cause of childhood stroke may obviate unnecessary investigation.

MRI with fibre tracking in Cogan congenital oculomotor apraxia

Congenital ocular motor apraxia (COMA) occasionally shares with Joubert syndrome (JS) and related disorders (JSRDs) a peculiar malformation, the 'molar tooth sign' (MTS). In JSRDs, the absence of superior cerebellar peduncles (SCP) decussation is reported. To investigate whether COMA demonstrates similar abnormal axonal pathways. Eight healthy age-matched controls, three children with clinical COMA and one child with clinical JSRD underwent examination with a 1.5-T MRI scanner. Diffusion-weighted imaging (DWI), colour-coded fractional anisotropy maps and three-dimensional diffusion tensor imaging (DTI) tractography of the cerebellorubral network were analyzed. On DTI cartography, the 'red dot' originally supposed to represent the SCP decussation in the midbrain was present in controls as well in those with COMA but absent in the single case with JS. In none of the subjects including controls was 3-D FT able to depict the SCP decussation. When seeded, the red dot resulted in the ventral tegmental decussation (VTD). It was normal in controls and in patients with COMA but was absent in our single patient with JSRD. MTS was identified in alla patients with COMA and in the patient with JSRD. MTS can be present in both COMA and JSRD but the underlying anatomy depicted by fibre tracking is distinct. The main difference is the integrity of the VTD in COMA.

Congenital Ocular Motor Apraxia

Congenital ocular motor apraxia is a rare disease characterized by defective or absent voluntary and optically induced horizontal saccadic movements. Jerky head movements or thrusts on attempted lateral gaze are a compensatory sign. Most affected children have delayed motor and speech development. Cases associated with systemic diseases, neurologic maldevelopment, metabolic deficits, and chromosomal abnormalities have been described. Case report and review of the scientific literature. The authors describe the ophthalmologic, pediatric, and neurologic evaluations and follow up of a child with impaired horizontal saccades, jerky head movements, and delayed motor and speech development. Congenital ocular motor apraxia is an uncommon disorder of ocular motility. Even so, ophthalmologists should be aware of the developmental delay and the other associated conditions, in order to grant the patients the multidisciplinary assistance they often require.

Congenital Ocular Motor Apraxia

The clinical and neuroradiological findings, and long-term intellectual prognosis in 10 patients (4 boys and 6 girls) with congenital ocular motor apraxia (COMA) are reviewed by researchers at Tottori University, Yonago, Japan.

Congenital ocular motor apraxia: Clinical and neuroradiological findings, and long-term intellectual prognosis

The severity of intellectual sequelae and prognosis varies in patients with congenital ocular motor apraxia (COMA). Here, we explored this phenomenon with regard to the accompanying oculomotor signs and gross motor development, as well as the subtentorial structure defects. Ten patients diagnosed with COMA (M:F = 4:6, 4–37 years old) were reviewed. Four individuals who gained the ability to walk at 2 years or earlier showed normal intellect and social skills. Those who walked later often showed accompanying intellectual (5/6) and speech (6/6) disabilities. In this latter group, atypical oculomotor signs for COMA (presence of nystagmus, mild limitation of vertical gaze, slower head thrust, and marked improvement of lateral saccade during early childhood) were often noted (4/6). Minor anomalies of fingers and toes were also common in this group. Neuroimaging was conduced in nine patients (pneumoencepharography 1; computed tomography: 8, magnetic resonance imaging: 2). Dilatation of the fourth ventricle, mainly at the level of the midbrain or upper pons ( n = 7), and hypoplastic cerebellar vermis ( n = 6) were commonly observed in both the early- and late-walking groups. ‘Molar tooth’ signs ( n = 3) were exclusively noted in the late-walking group, and often accompanied by atypical oculomotor signs (3/3) and intellectual disabilities (2/3). Vermian hypoplasia and dilatation of the fourth ventricle at the upper brainstem level in COMA patients, with or without intellectual disabilities, suggested that the cardinal lesion for OMA may exist in these areas. The presence of a subset of ‘atypical’ COMA patients may suggest that COMA with subtle infratentorial abnormality represents a heterogeneous disease category, showing similar oculomotor disturbance. This review indicated that clinical and neuroradiological inspection might be valuable for prediction of long-term intellectual prognosis in COMA patients.

Neurodevelopmental implications of ocular motor apraxia

Ocular motor apraxia (OMA), a disorder of saccadic initiation, may be congenital or acquired. While the acquired form is frequently associated with significant neuropathology, the congenital form is often regarded as relatively benign. Many children with congenital OMA who were observed clinically have shown neurodevelopmental disturbance over time. A retrospective review was taken of 34 consecutive patients (22 males and 12 females), seen over a 20–year period, to evaluate the frequency and type of associated neurodevelopmental problems. Age at presentation ranged from 8 weeks to 14 years, with a mean age of 10 years. Of 29 children with congenital OMA, 15 had imaging evidence of structural central nervous system abnormalities (with cerebellar hypoplasia the most frequent abnormality detected). Eleven of the 14 patients with no structural abnormality showed abnormal neurodevelopment. This study suggests that congenital OMA is not a benign diagnosis, even in the absence of overt neurological disturbance at the time of presentation.

Neurodevelopmental implications of ocular motor apraxia

Ocular motor apraxia (OMA), a disorder of saccadic initiation, may be congenital or acquired. While the acquired form is frequently associated with significant neuropathology, the congenital form is often regarded as relatively benign. Many children with congenital OMA who were observed clinically have shown neurodevelopmental disturbance over time. A retrospective review was taken of 34 consecutive patients (22 males and 12 females), seen over a 20-year period, to evaluate the frequency and type of associated neurodevelopmental problems. Age at presentation ranged from 8 weeks to 14 years, with a mean age of 10 years. Of 29 children with congenital OMA, 15 had imaging evidence of structural central nervous system abnormalities (with cerebellar hypoplasia the most frequent abnormality detected). Eleven of the 14 patients with no structural abnormality showed abnormal neurodevelopment. This study suggests that congenital OMA is not a benign diagnosis, even in the absence of overt neurological disturbance at the time of presentation.