RESUMEN
Genomic technologies such as next-generation sequencing (NGS) are revolutionizing molecular diagnostics and clinical medicine. However, these approaches have proven inefficient at identifying pathogenic repeat expansions. Here, we apply a collection of bioinformatics tools that can be utilized to identify either known or novel expanded repeat sequences in NGS data. We performed genetic studies of a cohort of 35 individuals from 22 families with a clinical diagnosis of cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS). Analysis of whole-genome sequence (WGS) data with five independent algorithms identified a recessively inherited intronic repeat expansion [(AAGGG)exp] in the gene encoding Replication Factor C1 (RFC1). This motif, not reported in the reference sequence, localized to an Alu element and replaced the reference (AAAAG)11 short tandem repeat. Genetic analyses confirmed the pathogenic expansion in 18 of 22 CANVAS-affected families and identified a core ancestral haplotype, estimated to have arisen in Europe more than twenty-five thousand years ago. WGS of the four RFC1-negative CANVAS-affected families identified plausible variants in three, with genomic re-diagnosis of SCA3, spastic ataxia of the Charlevoix-Saguenay type, and SCA45. This study identified the genetic basis of CANVAS and demonstrated that these improved bioinformatics tools increase the diagnostic utility of WGS to determine the genetic basis of a heterogeneous group of clinically overlapping neurogenetic disorders.
Asunto(s)
Ataxia Cerebelosa/etiología , Biología Computacional/métodos , Intrones , Repeticiones de Microsatélite , Polineuropatías/etiología , Proteína de Replicación C/genética , Trastornos de la Sensación/etiología , Enfermedades Vestibulares/etiología , Algoritmos , Ataxia Cerebelosa/patología , Estudios de Cohortes , Familia , Femenino , Genómica , Humanos , Masculino , Persona de Mediana Edad , Polineuropatías/patología , Trastornos de la Sensación/patología , Síndrome , Enfermedades Vestibulares/patología , Secuenciación Completa del GenomaRESUMEN
Cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS) is a recently recognized neurodegenerative disease with onset in mid- to late adulthood. The genetic basis for a large proportion of Caucasian patients was recently shown to be the biallelic expansion of a pentanucleotide (AAGGG)n repeat in RFC1. Here, we describe the first instance of CANVAS genetic testing in New Zealand Maori and Cook Island Maori individuals. We show a novel, possibly population-specific CANVAS configuration (AAAGG)10-25(AAGGG)exp, which was the cause of CANVAS in all patients. There were no apparent phenotypic differences compared with European CANVAS patients. Presence of a common disease haplotype among this cohort suggests this novel repeat expansion configuration is a founder effect in this population, which may indicate that CANVAS will be especially prevalent in this group. Haplotype dating estimated the most recent common ancestor at â¼1430 ce. We also show the same core haplotype as previously described, supporting a single origin of the CANVAS mutation.
Asunto(s)
Alelos , Vestibulopatía Bilateral/genética , Ataxia Cerebelosa/genética , Efecto Fundador , Nativos de Hawái y Otras Islas del Pacífico/genética , Proteína de Replicación C/genética , Adulto , Anciano , Vestibulopatía Bilateral/diagnóstico , Vestibulopatía Bilateral/etnología , Ataxia Cerebelosa/diagnóstico , Ataxia Cerebelosa/etnología , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nativos de Hawái y Otras Islas del Pacífico/etnología , LinajeRESUMEN
Ataxia, causing imbalance, dizziness and falls, is a leading cause of neurological disability. We have recently identified a biallelic intronic AAGGG repeat expansion in replication factor complex subunit 1 (RFC1) as the cause of cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) and a major cause of late onset ataxia. Here we describe the full spectrum of the disease phenotype in our first 100 genetically confirmed carriers of biallelic repeat expansions in RFC1 and identify the sensory neuropathy as a common feature in all cases to date. All patients were Caucasian and half were sporadic. Patients typically reported progressive unsteadiness starting in the sixth decade. A dry spasmodic cough was also frequently associated and often preceded by decades the onset of walking difficulty. Sensory symptoms, oscillopsia, dysautonomia and dysarthria were also variably associated. The disease seems to follow a pattern of spatial progression from the early involvement of sensory neurons, to the later appearance of vestibular and cerebellar dysfunction. Half of the patients needed walking aids after 10 years of disease duration and a quarter were wheelchair dependent after 15 years. Overall, two-thirds of cases had full CANVAS. Sensory neuropathy was the only manifestation in 15 patients. Sixteen patients additionally showed cerebellar involvement, and six showed vestibular involvement. The disease is very likely to be underdiagnosed. Repeat expansion in RFC1 should be considered in all cases of sensory ataxic neuropathy, particularly, but not only, if cerebellar dysfunction, vestibular involvement and cough coexist.
Asunto(s)
Ataxia/fisiopatología , Ataxia Cerebelosa/fisiopatología , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Neuronitis Vestibular/fisiopatología , Anciano , Anciano de 80 o más Años , Ataxia/complicaciones , Cerebelo/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Examen Neurológico/efectos adversos , Enfermedades del Sistema Nervioso Periférico/complicaciones , Reflejo Anormal/fisiología , Trastornos de la Sensación/etiología , Trastornos de la Sensación/fisiopatología , Síndrome , Neuronitis Vestibular/complicacionesRESUMEN
Variants in RORB have been reported in eight individuals with epilepsy, with phenotypes ranging from eyelid myoclonia with absence epilepsy to developmental and epileptic encephalopathies. We identified novel RORB variants in 11 affected individuals from four families. One was from whole genome sequencing and three were from RORB screening of three epilepsy cohorts: developmental and epileptic encephalopathies (n = 1021), overlap of generalized and occipital epilepsy (n = 84), and photosensitivity (n = 123). Following interviews and review of medical records, individuals' seizure and epilepsy syndromes were classified. Three novel missense variants and one exon 3 deletion were predicted to be pathogenic by in silico tools, not found in population databases, and located in key evolutionary conserved domains. Median age at seizure onset was 3.5 years (0.5-10 years). Generalized, predominantly absence and myoclonic, and occipital seizures were seen in all families, often within the same individual (6/11). All individuals with epilepsy were photosensitive, and seven of 11 had cognitive abnormalities. Electroencephalograms showed generalized spike and wave and/or polyspike and wave. Here we show a striking RORB phenotype of overlap of photosensitive generalized and occipital epilepsy in both individuals and families. This is the first report of a gene associated with this overlap of epilepsy syndromes.
Asunto(s)
Epilepsias Parciales/genética , Epilepsia Generalizada/genética , Epilepsia Refleja/genética , Predisposición Genética a la Enfermedad/genética , Miembro 2 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Mutación , LinajeRESUMEN
Benign paroxysmal positional vertigo (BPPV) is the most common peripheral vestibular disorder that is diagnosed based solely on clinical findings. Rarely, central lesions can present with positional vertigo and nystagmus, mimicking BPPV. Recognised red flags that may help distinguish central mimics from BPPV include the presence of additional neurological symptoms and signs, atypical nystagmus patterns, and the absence of a sustained response to repositioning manoeuvres. We present seven cases that illustrate how heuristic bias may affect the detection of these features in practice. Furthermore, our cases suggest that isolated downbeat positional nystagmus (simulating anterior canal BPPV) and apogeotropic horizontal nystagmus on the supine roll test (simulating horizontal canal BPPV) should be considered additional red flags.
Asunto(s)
Vértigo Posicional Paroxístico Benigno/diagnóstico , Enfermedades Cerebelosas/diagnóstico , Nistagmo Patológico/diagnóstico , Nistagmo Fisiológico , Adulto , Anciano , Enfermedades Cerebelosas/complicaciones , Enfermedades Cerebelosas/patología , Toma de Decisiones Clínicas , Diagnóstico Diferencial , Resultado Fatal , Femenino , Heurística , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Nistagmo Patológico/etiología , Nistagmo Fisiológico/fisiologíaRESUMEN
INTRODUCTION: Sensory impairment in Friedreich ataxia (FRDA) is generally accepted as being due to a ganglionopathy. The degree of contribution from axonal pathology remains a matter of debate. Nerve ultrasound may be able to differentiate these processes. METHODS: The ultrasound cross-sectional area of median, ulnar, tibial, and sural nerves of 8 patients with FRDA was compared with 8 age- and gender-matched healthy controls and with reference values in our population. RESULTS: The nerves of the patients with FRDA were significantly larger than those of healthy controls at all upper limb sites (P < 0.05) but not significantly different in the lower limbs. DISCUSSION: Our findings add additional weight to the theory that dorsal root ganglionopathy is not the sole cause of peripheral sensory loss in FRDA. Peripheral neuropathic processes are also likely to play a role. Muscle Nerve 57: 852-856, 2018.
Asunto(s)
Ataxia de Friedreich/diagnóstico por imagen , Nervios Periféricos/diagnóstico por imagen , Ultrasonografía Doppler/métodos , Adulto , Anciano , Estudios de Casos y Controles , Evaluación de la Discapacidad , Femenino , Ataxia de Friedreich/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Conducción Nerviosa/fisiología , Nueva Zelanda , Estadísticas no ParamétricasRESUMEN
The acute vestibular syndrome is common and usually has a benign cause. Sometimes, however, even experienced neurologists can find it difficult to determine the cause clinically. Furthermore, neuroimaging is known to be insensitive.We describe two cases of acute vestibular syndrome where conflicting clinical findings contributed to a delay in making the correct diagnosis. The first patient with symptomatic vertigo had signs consistent with horizontal benign paroxysmal positional vertigo but also had an abnormal horizontal head impulse test, superficially suggesting acute vestibular neuritis but later accounted for by the finding of a vestibular schwannoma (acoustic neuroma). The second patient also had an abnormal horizontal head impulse test, with skew deviation suggesting stroke as the cause. However, later assessment identified that a long-standing fourth nerve palsy was the true cause for her apparent skew. We discuss potential errors that can arise when assessing such patients and highlight ways to avoid them.
Asunto(s)
Vértigo/etiología , Neuronitis Vestibular/complicaciones , Neuronitis Vestibular/diagnóstico , Anciano , Diagnóstico Diferencial , Femenino , Prueba de Impulso Cefálico , Humanos , Accidente Cerebrovascular/diagnósticoRESUMEN
INTRODUCTION: We report preliminary findings of nerve ultrasound in patients with cerebellar ataxia neuropathy vestibular areflexia syndrome (CANVAS) who have sensory impairment due to dorsal root ganglionopathy. METHODS: The ultrasound cross-sectional area (CSA) of median and ulnar nerves of 7 CANVAS patients was compared with 7 age- and gender-matched controls and with the mean CSA of our reference population. RESULTS: The nerve CSA of CANVAS patients was significantly smaller than that of controls at all sites (P < 0.01). All but 1 individual measurement of CSA at the mid-forearm level in the CANVAS patients fell outside the normal control range and was >2 standard deviations below the reference mean. CONCLUSIONS: The small nerves in CANVAS probably reflect nerve thinning from axonal loss secondary to ganglion cell loss. Our data show a role for ultrasound in the diagnosis of CANVAS ganglionopathy. This may also be applicable to ganglionopathy from other causes. Muscle Nerve 56: 160-162, 2017.
Asunto(s)
Ataxia Cerebelosa/diagnóstico por imagen , Nervios Periféricos/diagnóstico por imagen , Ultrasonografía/métodos , Enfermedades Vestibulares/diagnóstico por imagen , Adulto , Anciano , Estudios de Casos y Controles , Ataxia Cerebelosa/complicaciones , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Vestibulares/complicacionesRESUMEN
Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is a recently recognized neurodegenerative ganglionopathy. Prompted by the presence of symptomatic postural hypotension in two patients with CANVAS, we hypothesized that autonomic dysfunction may be an associated feature of the syndrome. We assessed symptoms of autonomic dysfunction and performed autonomic nervous system testing among 26 patients from New Zealand. After excluding three patients with diabetes mellitus, 83% had evidence of autonomic dysfunction; all patients had at least one autonomic symptom and 91% had more than two symptoms. We also found a higher rate of downbeat nystagmus (65%) than previously described in CANVAS. We confirmed that sensory findings on nerve conduction tests were consistent with a sensory ganglionopathy and describe two patients with loss of trigeminal sensation consistent with previous pathological descriptions of trigeminal sensory ganglionopathy. Our results suggest that autonomic dysfunction is a major feature of CANVAS. This has implications for the management of patients with CANVAS as the autonomic symptoms may be amenable to treatment. The findings also provide an important differential diagnosis from multiple system atrophy for patients who present with ataxia and autonomic failure.
Asunto(s)
Enfermedades del Sistema Nervioso Autónomo/fisiopatología , Ataxia Cerebelosa/fisiopatología , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Enfermedades Vestibulares/fisiopatología , Adolescente , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Enfermedades del Sistema Nervioso Autónomo/complicaciones , Ataxia Cerebelosa/complicaciones , Mareo/fisiopatología , Femenino , Fuerza de la Mano/fisiología , Frecuencia Cardíaca/fisiología , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Examen Neurológico , Nueva Zelanda , Nistagmo Patológico/etiología , Nistagmo Patológico/fisiopatología , Enfermedades del Sistema Nervioso Periférico/complicaciones , Reflejo Vestibuloocular/fisiología , Síndrome , Maniobra de Valsalva , Enfermedades Vestibulares/etiología , Pruebas de Función Vestibular , Vitamina E/sangre , Adulto JovenRESUMEN
INTRODUCTION: Bilateral vestibular failure (BVF) is an uncommon condition with numerous etiologies. It causes chronic oscillopsia and imbalance and is usually irreversible. We report 2 cases of BVF due to unusual causes, both of which improved with treatment of the underlying condition. CASE REPORTS: The first patient was a 39-year-old female who developed profound BVF due to neurosarcoidosis. She was started on steroids and azathioprine and her vestibular function gradually improved, with essentially normal function 4.5 years after starting treatment. The second patient was a 54-year-old female who developed BVF in the context of glucagonoma. After treatment with octreotide, her vestibular function improved to almost normal, and she thus met the criteria for a probable paraneoplastic syndrome. CONCLUSIONS: While BVF is usually permanent, this report demonstrates that some cases are likely to be reversible with treatment of the underlying cause. It is therefore imperative for clinicians to ensure that patients with BVF are thoroughly investigated.
Asunto(s)
Enfermedades Vestibulares , Adulto , Femenino , Humanos , Persona de Mediana Edad , Enfermedades Vestibulares/complicacionesRESUMEN
Objectives: To determine the incidence of gentamicin vestibulotoxicity with current dosing regimens, and to evaluate the feasibility of routine video-oculography on all patients given gentamicin. Materials and methods: In this prospective incidence study serial horizontal vestibulo-ocular reflex (HVOR) gain measurements were recorded using video-oculography on adult inpatients receiving intravenous gentamicin. The primary outcome was the proportion of patients developing impairment of their HVOR gain. Results: After exclusions, 42 patients were included in the analysis. Three patients (7.1%) developed asymptomatic vestibulotoxicity, exact 95% confidence interval 1.5-19.5%. In two of these patients the deficit resolved within several hours. No patients developed symptomatic vestibulotoxicity. There was no evidence for a generalised reduction in group HVOR gain with time. HVOR gain was not associated with total gentamicin dose, dynamic visual acuity or subjective imbalance. Conclusions and significance: Gentamicin may cause reversible, asymptomatic vestibulotoxicity. Video-oculography may be useful to monitor for vestibulotoxicity in patients treated with gentamcin; however, testing all patients routinely may be challenging.
Asunto(s)
Gentamicinas/efectos adversos , Ototoxicidad/etiología , Reflejo Vestibuloocular/efectos de los fármacos , Vestíbulo del Laberinto/efectos de los fármacos , Grabación en Video , Adulto , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Gentamicinas/uso terapéutico , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Nueva Zelanda , Ototoxicidad/diagnóstico , Estudios Prospectivos , Medición de Riesgo , Centros de Atención Terciaria , Enfermedades Vestibulares/inducido químicamenteRESUMEN
Episodic ataxia is a heterogenous group of uncommon neurological disorders characterised by recurrent episodes of vertigo, dysarthria, and ataxia for which a variety of different genetic variations have been implicated. Episodic ataxia type two (EA2) is the most common and also has the largest number of identified causative genetic variants. Treatment with acetazolamide is effective in improving symptoms, so accurate diagnosis is essential. However, a large proportion of patients with EA2 have negative genetic testing. We present a patient with a typical history of EA2 who had a novel variant in the CACNA1A gene not previously described. Report of such variations is important in learning more about the disease and improving diagnostic yield for the patient.
RESUMEN
The aim of this prospective register-based study was to compare video Head Impulse Tests (vHIT) with caloric tests on 173 patients assessed by a tertiary Neurology referral centre who had been referred for investigation of dizziness or vertigo and whose symptom duration was one month or longer. Abnormal vHIT was defined as angular velocity gain (peak eye velocity/peak head velocity) less than 0.79 at 80â¯ms and 0.75 at 60â¯ms, which was two standard deviations below our institutions' lower limit of normal; together with refixation saccades. Abnormal bi-thermal caloric testing defined unilateral hypofunction as a 25% difference using Jongkee's formula and bilateral hypofunction was defined by the sum of the peak slow phase velocities over the four irrigations being <20°/s. Sixty patients had abnormal results on one or both tests, of whom 51 had unilateral and nine bilateral hypofunction. With caloric testing considered as the gold standard, the sensitivity (95% CI) of the vHIT was 18/52, 34.6% (22.0-49.1), and the specificity (95% CI) was 113/121, 93.4% (87.4-97.1). However vHIT was more sensitive in the nine patients with bilateral hypofunction with 100% abnormal vHIT results while only 4/9, 44% had abnormal caloric results. In conclusion these results support the continued use of both vHIT and caloric tests in patients with sub-acute and chronic vestibular symptoms, especially if the vHIT is normal.
Asunto(s)
Pruebas Calóricas/métodos , Prueba de Impulso Cefálico/métodos , Enfermedades Vestibulares/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Sensibilidad y Especificidad , Centros de Atención Terciaria , Adulto JovenRESUMEN
Uveitis-glaucoma-hyphema syndrome is a rare late complication of anterior segment surgery. We present 2 unusual cases of this syndrome that were mistakenly diagnosed as amaurosis fugax, leading to contraindicated treatment. These cases illustrate the need for ophthalmologic examination during an episode of symptoms.
Asunto(s)
Amaurosis Fugax/diagnóstico , Hipema/diagnóstico , Hipema/etiología , Lentes Intraoculares/efectos adversos , Anciano , Cámara Anterior/patología , Vasos Sanguíneos/lesiones , Diagnóstico Diferencial , Femenino , Glaucoma/etiología , Humanos , Iris/irrigación sanguínea , Masculino , Persona de Mediana Edad , Recurrencia , Síndrome , Uveítis Anterior/etiologíaRESUMEN
BACKGROUND: The head impulse test (HIT) is a recognised clinical sign of the high frequency vestibulo-ocular reflex (VOR), which can be quantified with video-oculography. This measures the VOR gain as the ratio of angular eye velocity to angular head velocity. Although normative data is available for VOR gain with video-oculography, most normal studies in general include small numbers of subjects and do not include analysis of variation of VOR gain with age. The purpose of our study was to establish normative data across 60 control subjects aged 20 to 80 years to represent a population distribution. METHODS: Sixty control subjects without any current or previous form of brain disorder or vertigo participated in this study and form the basis for future comparison to patients with vestibular lesions. The relationship between the horizontal vestibulo-ocular reflex (HVOR) velocity gain and age was analysed using a mixed regression model with a random effect for subjects. Differences in testing technique were assessed to ensure reliability in results. RESULTS: The mean HVOR velocity gain of 60 normal subjects was 0.97 (SD = 0.09) at 80 ms and 0.94 (SD = 0.10) at 60 ms. The 2 SD lower limit of normal HVOR velocity gain was 0.79 at 80 ms and 0.75 at 60 ms. No HVOR velocity gain fell below 0.76 and 0.65 at 80 ms and 60 ms respectively. The HVOR velocity gain declined by 0.012 and 0.017 per decade as age increased at 80 ms and 60 ms respectively. A non-physiologically high horizontal HVOR velocity gain was found to occur in tests where passive HITs were predictable in direction and time and where target distance was below 0.70 m. CONCLUSIONS: Normative data with respect to HVOR velocity gain decreases slightly with age, but with careful attention to methodology the 2 SD lower limit of normal is relatively robust across a wide age range and into the eighth decade, without requirement for adjustment with age.
Asunto(s)
Electrooculografía , Reflejo Vestibuloocular/fisiología , Grabación en Video , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Prueba de Impulso Cefálico , Humanos , Masculino , Persona de Mediana Edad , Valores de Referencia , Enfermedades Vestibulares/diagnóstico , Enfermedades Vestibulares/fisiopatología , Adulto JovenRESUMEN
OBJECTIVE: To elucidate the neuropathology in cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS), a novel cerebellar ataxia comprised of the triad of cerebellar impairment, bilateral vestibular hypofunction, and a peripheral sensory deficit. METHOD: Brain and spinal neuropathology in 2 patients with CANVAS, together with brain and otopathology in another patient with CANVAS, were examined postmortem. RESULTS: Spinal cord pathology demonstrated a marked dorsal root ganglionopathy with secondary tract degeneration. Cerebellar pathology showed loss of Purkinje cells, predominantly in the vermis. CONCLUSION: The likely underlying sensory pathology in CANVAS is loss of neurons from the dorsal root and V, VII, and VIII cranial nerve ganglia-in other words, it is a "neuronopathy" rather than a "neuropathy." Clinically, CANVAS is a differential diagnosis for both spinocerebellar ataxia type 3 (or Machado-Joseph disease) and Friedreich ataxia. In addition, there are 6 sets of sibling pairs, implying that CANVAS is likely to be a late-onset recessive or autosomal dominant with reduced penetrance disorder, and identification of the culprit gene is currently a target of investigation.
Asunto(s)
Ataxia Cerebelosa/patología , Ataxia Cerebelosa/fisiopatología , Cerebelo/patología , Cerebelo/fisiopatología , Ganglios Espinales/patología , Ganglios Espinales/fisiopatología , Nervios Periféricos/patología , Nervios Periféricos/fisiopatología , Reflejo Anormal/fisiología , Reflejo Vestibuloocular/fisiología , Trastornos de la Sensación/patología , Trastornos de la Sensación/fisiopatología , Médula Espinal/patología , Médula Espinal/fisiopatología , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Degeneración Nerviosa/patología , Degeneración Nerviosa/fisiopatología , Examen Neurológico , Neuronas/patología , Neuronas/fisiología , Nistagmo Patológico/fisiopatología , Nistagmo Patológico/psicología , Movimientos Sacádicos/fisiología , Síndrome , Ganglio del Trigémino/patología , Ganglio del Trigémino/fisiopatología , Nervio Vestibular/patología , Nervio Vestibular/fisiopatologíaRESUMEN
The c.1529C >T change in the SPG7 gene, encoding the mutant p.Ala510Val paraplegin protein, was first described as a polymorphism in 1998. This was based on its frequency of 3 % and 4 % in two separate surveys of controls in the United Kingdom (UK) population. Subsequently, it has been found to co-segregate with disease in a number of different populations. Yeast expression studies support its having a deleterious effect. In this paper a consanguineous sibship is described in which four members who are homozygous for the p.Ala510Val variant present with a spectrum of disease. This spectrum encompasses moderately severe hereditary spastic paraparesis (HSP) with more minor ataxia in two siblings, moderately severe ataxia without spasticity in the third, and a very mild gait ataxia in the fourth. Two of the siblings also manifest vestibular failure. The remaining eight unaffected siblings are either heterozygous for the p.Ala510Val variant, or do not carry it at all. Homozygosity mapping using a high-density SNP array across the whole genome found just 11 genes (on two regions of chromosome 3) outside the SPG7 region on chromosome 16, which were homozygously shared by the affected siblings, but not shared by the unaffected siblings; none of them are likely to be causative. The weight of evidence is strongly in favour of the p.Ala510Val variant being a disease-causing mutation. We present additional data from the Auckland City Hospital neurogenetics clinic to show that the p.Ala510Val mutation is prevalent amongst HSP patients of UK extraction belying any suggestion that European p.Ala510Val haplotypes harbour a disease-causing mutation which the UK p.Ala510Val haplotypes do not. Taken together with previous findings of a carrier frequency of 3-4 % in the UK population (giving a homozygosity rate of 20-40/100,000), the data imply that the p.Ala510Val is the most common mutation causing neurogenetic disease in adults of UK ancestry, albeit the penetrance may be low or the disease caused may be mild.
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Alanina/genética , Predisposición Genética a la Enfermedad/genética , Metaloendopeptidasas/genética , Mutación/genética , Paraplejía Espástica Hereditaria/genética , Valina/genética , ATPasas Asociadas con Actividades Celulares Diversas , Adulto , Edad de Inicio , Femenino , Pruebas Genéticas , Genotipo , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Linaje , Paraplejía Espástica Hereditaria/fisiopatología , Reino Unido , Enfermedades Vestibulares/genética , Población Blanca/genéticaRESUMEN
This study examines diurnal variation in the result of the Dix-Hallpike manoeuvre when testing for benign paroxysmal positional vertigo in a randomised crossover study of the order of diagnostic testing in a community out-reach clinic for a tertiary neurological centre in Wellington, New Zealand. Study participants were adults referred for physiotherapy treatment. Dix-Hallpike manoeuvres were performed to both ears, and groups were randomly allocated to have a morning, then afternoon, sequence of testing or vice versa. The results of the Dix-Hallpike manoeuvres were digitally recorded and reviewed by a second blinded assessor. A total of 27 of 50 participants (54%) tested positive on at least one of the days, six of 27 (22%) had discordant results. The difference in marginal proportions was 0% (95% confidence interval: -9.6 to 9.6), p=1.0. The time of day is not a factor in false negative Dix-Hallpike manoeuvres, although 22% of those with positive results tested negative on one of the two measurements.
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Ritmo Circadiano/fisiología , Examen Neurológico/métodos , Vértigo/diagnóstico , Anciano , Vértigo Posicional Paroxístico Benigno , Estudios Cruzados , Interpretación Estadística de Datos , Mareo/diagnóstico , Método Doble Ciego , Reacciones Falso Positivas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Resultado del TratamientoRESUMEN
The association of bilateral vestibulopathy with cerebellar ataxia was first reported in 1991 and delineated as a distinct syndrome with a characteristic and measurable clinical sign--an absent visually enhanced vestibulo-ocular reflex--in 2004. We reviewed 27 patients with this syndrome and show that a non-length-dependent sensory deficit with absent sensory nerve action potentials is an integral component of this syndrome, which we now call "cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome" (CANVAS). All patients had brain MRI and 22/27 had evidence of cerebellar atrophy involving anterior and dorsal vermis, as well as the hemispheric crus I. Brain and temporal bone pathology in one patient showed marked loss of Purkinje cells and of vestibular, trigeminal, and facial ganglion cells, but not of spiral ganglion cells. There are two sets of sibling pairs, suggesting CANVAS is a late-onset recessive disorder. The characteristic clinical sign-the visual vestibulo-ocular reflex deficit-can be demonstrated and measured clinically using video-oculography.
Asunto(s)
Ataxia Cerebelosa/diagnóstico , Enfermedades del Nervio Oculomotor/diagnóstico , Enfermedades Vestibulares/diagnóstico , Adulto , Anciano , Ataxia Cerebelosa/patología , Ataxia Cerebelosa/fisiopatología , Diagnóstico Diferencial , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedades del Nervio Oculomotor/patología , Enfermedades del Nervio Oculomotor/fisiopatología , Pronóstico , Reflejo Anormal/fisiología , Reflejo Vestibuloocular/fisiología , Estudios Retrospectivos , Síndrome , Hueso Temporal/patología , Enfermedades Vestibulares/patología , Enfermedades Vestibulares/fisiopatología , Pruebas de Función VestibularRESUMEN
AIMS: The aim of this project was to employ interdepartmental and cross district health board collaboration to reach a regional consensus on the management of patients who may benefit from carotid endarterectomy. METHODS: All regional stroke physicians, neurologists, and vascular surgeons met to review relevant literature and local audits and to discuss best management strategies suited to the region. RESULTS: A consensus statement was agreed upon and is presented here along with a summary of the supporting scientific evidence. DISCUSSION: Regional interdisciplinary collaboration proved an effective way to reach a carotid endarterectomy management consensus across a wider geographical area that is served by a single vascular surgery department. This approach could serve as a model for other regional initiatives.