Identification of novel VMD2 gene mutations in patients with best vitelliform macular dystrophy.

ABSTRACT We report five novel VMD2 mutations in Best's macular dystrophy patients (S16F, I73N, R92H, V235L, and N296S). An SSCP analysis of the VMD2 11 exons revealed electrophoretic mobility shifts exclusively in exons 2, 3, 4, 6 and 8. Direct sequencing indicated that these shifts are caused by mono-allelic transition in exons 2, 4, 6, 8 and transversion in exons 3 and 6. Five novel "silent" polymorphisms are also reported: 213T>C, 323C>A, 1514A>G, 1661C>T, and 1712T>C. Hum Mutat 17:235, 2001.

Outer retinal dysfunction in patients treated with vigabatrin.

OBJECTIVE: To assess early visual impairment related to vigabatrin prospectively in patients with and without visual symptoms. BACKGROUND: Vigabatrin acts as an inhibitor of gamma-aminobutyric acid (GABA) transaminase. GABA-induced ion transport changes in the retinal pigment epithelium have been described. The electro-oculogram (EOG) is a clinical test that reflects photoreceptor and pigment epithelium function. PATIENTS AND METHODS: Of the 22 consecutive patients presenting with a history of partial seizures currently treated with vigabatrin, 20 were included in the study. A complete clinical ophthalmologic and neurologic examination was performed, including static 100-point perimetry, EOG, and electroretinogram (ERG). RESULTS: In 14 of 20 patients, the light/dark ratio (Arden ratio) of the standard EOG was reduced in at least one eye. The a- and b-wave amplitudes and implicit time of the ERG were within the normal range in all patients; however, ERG oscillatory potentials could not be recorded in 10 patients. Twelve patients had visual field constriction; five complained of visual symptoms. The most severe visual impairment was observed in patients treated with both vigabatrin and valproate. CONCLUSIONS: There is some evidence of outer retinal dysfunction in the patients treated with vigabatrin. EOG, a more sensitive diagnostic tool than ERG for screening vigabatrin-treated patients, also appears to be more specific.

Creutzfeldt-Jakob disease: neurophysiologic visual impairments.

OBJECTIVE: The predictive value of electrophysiologic visual testing in Creutzfeldt-Jakob disease (CJD) was investigated, and the retinal pathologic findings in three cases are reported. BACKGROUND: The fatal prognosis of CJD, its transmissibility, and the lack of treatment make early diagnosis essential in averting human-to-human transmission. Electroretinogram and visual evoked potentials have been studied in few cases of CJD. METHODS: A visual electrophysiologic examination was performed in 41 consecutive patients referred with suspected CJD. The disease had been diagnosed in 24 patients (CJD group; 15 were confirmed neuropathologically and 9 by clinicolaboratory methods in accordance with diagnostic criteria). The remaining 17 patients were diagnosed with other neurologic disorders, and served as a control group. RESULTS: Flash electroretinogram revealed a significant decrease in the amplitude of the B1 wave (<60 microV) and the B/A ratio (<2) in the CJD group compared with those in the control group. Flash visual evoked potentials revealed no significant difference in latency, but amplitude was increased (>10 microV) in the CJD group, especially in patients with myoclonus. CONCLUSIONS: The visual electrophysiologic abnormalities provide an interesting noninvasive diagnostic tool in idiopathic CJD. The B1-wave decrease is closely correlated with the outer plexiform layer abnormalities observed on neuropathologic examination.

Visual evoked potentials study in chronic idiopathic inflammatory demyelinating polyneuropathy.

BACKGROUND: The frequency of the association between chronic demyelinating inflammatory polyneuropathy (CIDP) and central nervous system (CNS) demyelinating lesions is probably underestimated. OBJECTIVE: To investigate the occurrence of combined central and peripheral demyelination in CIDP patients and to correlate visual evoked potential (VEP) abnormalities with CNS demyelinating lesions, observed on brain magnetic resonance imaging, and antibodies against glycolipids. METHODS: Nerve conduction studies, brain MRI and antibodies against glycolipids were prospectively studied in 17 patients who fulfilled the diagnostic criteria proposed for CIDP (Cornblath DR, Asbury AK, Albers JW, Feasby TE, Hahn AF, McLeod JG, Mendell JR, Parry GJ, Pollard JD, Thomas PK. Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force. Research criteria for diagnosis of chronic inflammatory demyelinating polyneuropathy. Neurology, 1991;41:617-618). VEPs were performed in each case before and after 6 months treatment with either intravenous immunoglobulins (IVIG) or steroids. RESULTS: Eight patients (47%) had increased latencies in at least one eye or showed increased interocular latency difference. Four patients (23%) presented a significant high signal intensity on T2-weighted brain MRI images. Of these 4 patients, 3 had prolonged VEP latency. Two patients with delayed VEP latency had antibodies against GM1, and SGLPG and anti-sulfatides, respectively. One patient with normal VEPs also had antibodies to GM1. VEP results were not significantly modified after treatment, either with steroids or IVIG. CONCLUSION: This study confirmed the high frequency of abnormal VEPs in CIDP patients, and found that they are poorly correlated with CNS demyelinating lesions and antibodies against glycolipids. The VEP abnormalities of these patients may be explained by the susceptibility to immune-mediated damage of both the peripheral nervous system and the optic nerve.

Autonomic and respiratory dysfunction in Charcot-Marie-Tooth disease due to Thr124Met mutation in the myelin protein zero gene.

OBJECTIVE: To report the clinical and electrophysiological characteristics of a family presenting Charcot-Marie-Tooth disease (CMT) associated with autonomic nervous system disturbances. METHODS: We studied nerve conduction values, postural adaptation, sympathetic skin reflex, the variation in heart rate by the Valsalva ratio and pupillometry in 7 members of a French family in which CMT due to a Thr124Met mutation in the myelin protein zero (MPZ) gene was diagnosed. RESULTS: Clinical and laboratory evidence of autonomic nervous system disturbances were found in the affected individuals. The clinical phenotype was characterized by sensorimotor peripheral neuropathy, defined as axonal type by electrophysiological studies, and was associated with severe pain, bladder dysfunction, sudorimotor disturbances and abolished pupillary reflex to light. Moreover, two patients had severe restrictive respiratory insufficiency requiring noninvasive mechanical ventilation. CONCLUSIONS: Our study demonstrates that autonomic disturbances may be one of the major clinical signs associated with CMT secondary to MPZ gene mutation in codon 124. Testing of pupillary reflex allows the discrimination of affected and unaffected subjects in our family. However, involvement of the autonomic nervous system in this type of neuropathy is unclear and further studies are required to elucidate the role of the MPZ gene in the autonomic nervous system.

Devic's neuromyelitis optica: clinical, laboratory, MRI and outcome profile.

Devic's neuromyelitis optica (NMO) associates optic neuritis and myelitis without any other neurological signs. Many patients with NMO may be diagnosed as having multiple sclerosis (MS), optic neuritis and myelitis being the inaugural symptom in 20% and 5% of MS cases, respectively. The aim of our study was to compare a new NMO cohort with recent studies and to try to determine the place of NMO in the spectrum of MS. We retrospectively studied 13 patients with a complete diagnostic workup for NMO. We compared our data with the most recent studies on NMO and with the criteria proposed by Wingerchuck et al. [Neurology 53 (1999) 1107]. We also determined whether these patients fulfilled the diagnostic criteria for MS. Thirteen patients (10 women and three men, with a mean age of 37.4 years) were included in the study. We found similar results to previously published data, except for an association with vasculitis in 38% of our cases. All but three of the patients fulfilled the clinical criteria for MS and two patients fulfilled both clinical and MRI criteria for MS. However, if we applied more restrictive criteria concerning spinal cord and brain MRI and CSF, none of our NMO patients fulfilled the MS diagnostic criteria. NMO might therefore be differentiated from MS by the application of more stringent criteria. Furthermore, all NMO patients should be investigated for vasculitis, even those with no history of systemic disease.

Pupillary disturbances in multiple sclerosis: correlation with MRI findings.

UNLABELLED: Autonomic nervous system disturbances such as pupillary abnormalities have rarely been evaluated in multiple sclerosis (MS). However, pupillary impairment is not uncommon in MS and its origin is still unclear. The aim of this study was to investigate pupillary disturbances in MS and to try to correlate pupillary defects with spinal cord and brainstem magnetic resonance imaging (MRI) findings. We prospectively studied 45 MS patients and 30 normal subjects. METHODS: The pupillary contraction latency and the amplitude of contraction were recorded by pupillometry. We also determined afferent and efferent pathway defects by comparing the direct and consensual pupillary reflexes. We evaluated brainstem and spinal cord demyelinating lesions and spinal cord cross-sectional area on MRI. At least one pupillometric parameters were significantly impaired in 60% of patients and in none of the controls. We did not find any correlation between pupillary defect and demyelinating lesions on MRI. The most frequent abnormality was efferent pathway shift and this was correlated with spinal cord atrophy (P<0.02). These results confirm that the autonomic nervous system, and especially pupillary function, is frequently impaired in MS. The parasympathetic system is most commonly affected and this is most likely linked to axonal loss (demonstrated by spinal cord atrophy) rather than to demyelinating lesions.

Use of denaturing HPLC and automated sequencing to screen the VMD2 gene for mutations associated with Best's vitelliform macular dystrophy.

We identified three novel VMD2 mutations in patients with Best's macular dystrophy. DHPLC analysis of the 11 VMD2 exons revealed abnormal profiles in exon 8. Direct sequencing showed that these abnormal profiles were due to monoallelic transitions and transversions. We also found three polymorphic sequence changes that have been reported previously and annotated to an online database (http://www.uni-wuerzburg.de/humangenetics/vmd2.html).

Working conditions and health effects of ethylene oxide exposure at hospital sterilization sites.

Ethylene oxide (EtO) is a powerful disinfectant and sterilant for heat-sensitive surgical items and instruments. Its use in hospitals constitutes an important source of occupational exposure that is sometimes underestimated, such as in cases of EtO device malfunction when the safety rules of procedure are not strictly followed or when individual or collective protective equipment is lacking. We carried out a descriptive study of the health care workers who were assigned to EtO sterilization units of the Lille University Hospital Centre in Lille, France (n = 16). Before the modification of the sterilization units in the development of a single, central sterilization site, we studied the workplaces, occupational conditions, and work procedures of the health care workers exposed to EtO. The aim was to assess the risk of EtO overexposure of the workers in order to improve workers' health and security in the future sterilization center. The study was based on a physical examination, a questionnaire covering each subject's personal and occupational history, and a complete ocular examination. For occupational conditions, the studies of each workplace were also performed by the occupational physician. Area and personal breathing air samplings were performed at each exposure site. Fourteen of the 16 operators had posterior and anterior subcapsular lens opacities, three of which seemed to be directly and primarily related to occupational exposure; the other ten seemed to be rather common and compatible with age. High levels of EtO exposure were reported in the oldest site (90 parts per million [ppm] during the changing of the gas bottle), where exposure often exceeded French threshold limits (permissible exposure limit: 1 ppm 8-hour time-weighted average (TWA) in air; short-term excursion limit: 5 ppm 15-minute TWA in air), or the current US recommended and legal exposure limits for EtO advocated by the Occupational Safety and Health Administration and the American Conference of Governmental Industrial Hygienists (permissible exposure limit: 1 ppm 8-hour TWA in air; excursion limit: 5 ppm 15-minute TWA in air), and the National Institute for Occupational Safety and Health standard (recommended exposure limits: 0.1 ppm 8-hour TWA in air; 5 ppm 10-minute TWA in air). The faults in the work processes, such as interruption of the sterilization cycle and disregard for the use of protective devices, were very common.

Altered rep-1 expression due to substitution at position +3 of the IVS13 splice-donor site of the choroideremia (CHM) gene.

PURPOSE: To characterize the effect on mRNA splicing of a yet undescribed mutation located in intron 13 splice-donor sequence (IVS13 + 3A --> C) in the Rab-Escort-protein 1 gene of a patient with choroideremia. METHODS: The base substitution was firstly detected by the Single Strand conformation analysis from genomic DNA. A REP-1 cDNA region encompassing exons 10-14 was then specifically amplified from lymphocytes-derived mRNA. RESULTS: We could demonstrate that this substitution affects REP-1 RNA processing. The patient revealed only one aberrantly spliced mRNA lacking exon 13 and no normal transcript. CONCLUSION: The skipping of exon 13 results in the creation of a stop codon at the misspliced junction. This is the first case of nucleotide substitution at the +3 position of a splice donor site so far described in choroideremia.

[Palpebral and cephalic oculomotor deficits in deep cerebral hematomas]. / Déficits des motricités oculaire palpébrale et céphalique dans les hématomes cérébraux profonds.

Oculomotor functions are analysed by clinical examination and oculography in 21 cases of deep cerebral hematoma. Significant paralysis of verticality and of movements contralateral to the lesions was observed in all cases where the hemorrhage affected the paramedian thalamo-subthalamic region. A slight deficit of elevation and controlateral movements was observed in the external thalamic and capsular hematomas. In the capsulolenticular hematomas the electro-oculographic record revealed discrete disturbances. It is concluded that the oculomotor examination provides important information about the topography of these cerebral hemorrhage and the functional role of the structures concerned. The examination shows the gravity of median lesions which frequently entail serious oculomotor sequelae.

[Fisher's one-and-one half syndrome. Involvement of the 6th cranial nerve nucleus and association with paralytic pontine exotropia]. / Syndrome un et demi de Fisher. Atteinte du noyau du VI associée à une exotropie pontine paralytique.

Total lateral paralysis in a case of "One and half" Fisher's syndrome accompanied by paralytic pontine exotropia is described. Oculographic investigation indicates involvement of the nucleus of the VIth cranial nerve. Paralytic pontine exotropia, may therefore be encountered where the VIth nucleus is involved.

[Refsum's disease. Ophthalmologic symptomatology dominated by tight bilateral miosis]. / Maladie de Refsum. Symptomatologie ophtalmologique dominée par un myosis bilatéral serré.

A case of Refsum's disease in a 62-year-old man, with an ophthalmologic symptomatology dominated by a tight bilateral miosis, is reported. The miosis mechanism in this disease is discussed. The clinical evolution has been stabilized by a diet poor in phytanic acid.

Length variations of the poly(T) tract at the exon 3 splice acceptor site of the choroideremia gene.

By using the single strand conformational analysis to search for point mutations in the choroideremia gene, we have identified an intronic polymorphism within the intron 2 of the CHM gene. We have studied the frequency of this polymorphism in the population from South of France.

[Dysfunction of the magnocellular pathway in Alzheimer's disease]. / Atteinte de la voie magnocellulaire dans la maladie d'Alzheimer.

Visual disturbances are a common feature of Alhzeimer's disease. They are related primarily to visuo-spatial deficits. The pathways mediating visuo-spatial and form identification are at least partially segregated in the brain. The magnocellular pathway has characteristics which make it more suitable for detecting dynamic form, motion and depth. We assessed by means of psychophysical and electrophysiological testings the properties of the parvo and the magnocellular pathways. We found contrast sensitivity deficits for the low and middle spatial frequencies, a significant reduction of the amplitude of the steady-state pattern VEP's at 16, 20 and 24 Hz, abnormal transient pattern VEP's only for the major positivity (P100) and abnormal flash VEP's (delayed P2) as previously observed. The temporal frequency deficits and other abnormalities pointed out in this study, could be related to a dysfunction of the M-pathways in Alzheimer's disease.

[Alternating oblique deviation of the gaze. 3 cases]. / Déviation oblique alternante du regard. Trois cas.

Three cases of alternating skew deviation of gaze are reported. In two patients, it was associated with oculomotor disorders suggestive of a medial mesencephalic lesion. CT scan showed 3rd ventricule abnormalities accounting for the mesencephalic involvement. The third patient had a tuberculous meningo-encephalitis with basal symptoms. The pathophysiological mechanisms of the vertical interocular divergence is discussed. It was probably related to a bilateral disorder of the superior recti and an overaction of the inferior obliques. It suggested a medial supranuclear dysfunction.

[Asymmetry of visual perceptive activity of faces and emotional facial expressions]. / Asymétrie dans l'activité perceptive visuelle des visages et des expressions faciales emotionnelles.

Eye movements were studied in 40 right-handed subjects during perception of symmetrical chimerical faces. These movements were recorded using an original system based on a differential optical method for the detection of corneal reflection and of the pupil made shiny. Under basal conditions, the first fixation was usually located in the left visual hemifield. The subjects spent more time gazing at the right hemiface (P less than 0.04). This visuo-spatial asymmetry in favour of the left hemispace was increased when the subject was requested to determine the emotional expressions of a new series of faces (P less than 0.002). Compared with basal conditions, the increase in the percentage of time spent in the left area was significant (P less than 0.035). An analysis performed on the first 3 seconds confirmed and amplified the differences observed. These results can partly be explained by reading habits and exploratory activity for symmetrical shapes. However, activation of the right hemisphere, specialized in the perception of faces and facial expressions, probably influenced visual exploration by drawing attention to the left area and favouring the left visual hemifield.

[Ocular and head movements in infarctions of the thalamic region]. / La motricité oculaire et céphalique dans les infarctus de la région thalamique.

Oculomotor disorders in 22 infarctions in the thalamic region are recorded. Clinical examination and electro-oculography (17 cases) showed that paramedian thalamo-subthalamic lesions were responsible for clear deficits: upgaze paralysis and in some cases downgaze paralysis, partial paresis of the oculomotor nerve, deficits of lateral eye movements, myosis, paralysis of head flexion combined with downgaze paralysis. Postero-median choroid artery infarction was associated with upgaze paresis, slight deficit of lateral eye movements and myosis. Postero-lateral choroid artery infarction resulted in a partial visual field defect and in some cases, a contralateral hypometria; myosis was slight and inconstant. Infarctions of the internal capsule (anterior choroid artery, deep branches of the middle cerebral artery) were associated with a deficit of contralateral saccades. Ocular pursuit, when possible, was often saccadic, whatever the site of the infarction. This prevailed with gaze towards the lesion side.

[Kjellin syndrome]. / Syndrome de Kjellin.

A previously healthy 30-year-old woman who had cognitive impairment since childhood suddenly developed progressive spastic paraparesis. Visual impairment and characteristic retinal macular spots supported the diagnosis of Kjellin syndrome. This disease, probably transmitted by autosomal recessive inheritance, is seldom observed in clinical practice. We describe the characteristics of Kjellin syndrome and the differential diagnosis, including other macular changes associated with spastic paraparesis.

[Visual evoked potentials and face recognition. Influence of celebrity and emotional expression]. / Potentiels évoqués visuels et reconnaissance des visages: influence de la célébrité et de l'expression émotionnelle.

Visual evoked potentials (VEP) were recorded in the right and left parietal and occipital regions of 40 right-handed controls in a facial recognition task. VEP were studied first according to the renown of the faces, then according to their emotional expression. Asymmetry was noted between the hemispheres: P100 was of greater amplitude and longer latency in the left occipital region. Later components (P400 and P600) were of greater amplitude and longer latency in the right parietal region in all situations. P100 latency on the left side was shorter for renowned faces than for non-renowned faces (P = 0.05). P600 latency was shorter on the right (P < 0.03) and left (P < 0.05) sides for smiling than for non-smiling faces. When the subjects were asked to look for emotional expression of the face (smiling or non-smiling) P400 was very ample and P600 of little amplitude. When the subjects were asked to recognize the face (renowned or not renowned) P600 was very ample and P400 of little amplitude. Thus, there seems to be a differential treatment of information: automatic and rapid to detect emotion (P400), controlled, tardy (P600) and involving memory in the search for renown.