Analysis of genetic variant in a fetus featuring pontocerebellar hypoplasia type 6 / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a fetus with cerebellar dysplasia and widened lateral ventricles.@*METHODS@#The couple have elected induced abortion after careful counseling. Skin tissue sample from the abortus and peripheral venous blood samples from both parents were collected for the extraction of genomic DNA, which was then subjected to whole exome sequencing. Candidate variant was verified by Sanger sequencing.@*RESULTS@#Prenatal ultrasonography showed increased nuchal translucency (0.4 cm) and widened lateral ventricles. Magnetic resonance imaging revealed infratentorial brain dysplasia. By DNA sequencing, the fetus was found to carry compound heterozygous variants c.1A>G and c.1564G>A of the RARS2 gene, which were inherited from its father and mother, respectively. Among these, c.1A>G was known to be pathogenic, but the pathogenicity of c.1564G>A was unreported previously. Based on the American College of Medical Genetics and Genomics guidelines, the c.1564G>A variant of RARS2 gene was predicted to be likely pathogenic(PM2+PM3+PP3+PP4).@*CONCLUSION@#The compound heterozygous variants c.1A>G and c.1564G>A of RARS2 gene contributed to the fetus suffering from pontocerebellar hypoplasia type 6, which expanded variant spectrum of RARS2 gene.

The ‘Hot Cross Bun’ Sign Is Not Always Multiple System Atrophy: Etiologies of 11 Cases

OBJECTIVE: To clarify the specificity of the ‘hot cross bun’ sign (HCBS) for multiple system atrophy (MSA) in adult cerebellar ataxia or parkinsonism. METHODS: The radiologic information systems at an academic center and affiliated veterans' hospital were queried using the keywords ‘hot cross bun,’ ‘pontocerebellar,’ ‘cruciate,’ ‘cruciform,’ ‘MSA,’ ‘multiple system atrophy,’ and ‘multisystem atrophy.’ Scans were reviewed by a neurologist and neuroradiologist to identify the HCBS. Subjects with the HCBS were reviewed by 2 neurologists to identify the most likely etiology of the patient's neurologic symptoms. RESULTS: Eleven cases were identified. Etiologies included MSA (4 probable, 2 possible), hereditary cerebellar ataxia (3/11), probable dementia with Lewy bodies (1/11), and uncertain despite autopsy (1/11). CONCLUSION: MSA was the most common etiology. However, 5 of the 11 patients did not have MSA. The most common alternate etiology was an undefined hereditary cerebellar ataxia (3/11).

Características clínicas de la atrofia multisistémica: un análisis de 17 casos / Clinical features of multiple system atrophy: an analysis of 17 cases

Introducción: La Atrofia Multisistémica (AMS) es una enfermedad neurodegenerativa caracterizada por parkinsonismo(AMS-P), disfunción cerebelosa (AMS-C) e insuficiencia autonómica en varias combinaciones. El objetivo de este estudio fue describir las características clínicas de esta enfermedad en un centro de neurológico de referencia. Población y métodos: Estudio descriptivo, longitudinal y retrospectivo de pacientes con AMS atendidos desde 1998 al 2008, según la base de datos del Departamento de Enfermedades Neurodegenerativas del Instituto Nacional de Ciencias Neurológicas. Resultados: Diecisiete pacientes cumplieron los criterios diagnósticos. La edad promedio de inicio de enfermedad fue 58.5 años. Encontramos un predominio del sexo masculino (M:F = 2.4:1) y del subtipo AMS-P (76.4%). Los hallazgos iniciales más frecuentes fueron los signos parkinsonianos o cerebelosos. Los estudios de neuroimagen se realizaron en 12 pacientes, de los cuales 10 mostraron alteraciones. La mayoría de los pacientes presentaron síntomas autonómicos (58.8%), pero solo un paciente fue sometido a un test de función autonómica, encontrándose ortostatismo. En 3 pacientes se realizaron EMG de esfínter anal, mostraron denervación del núcleo de Onuf. Conclusiones: Se encontró un predominio del sexo masculino y de la forma AMS-P que concuerdan con la literatura. Nuestra investigación se basó estrictamente en los últimos criterios establecidos; sin embargo, puede no haberse incluido algunos pacientes con síntomas iniciales y sin diagnóstico preciso; en ningún caso se tuvo confirmación neuropatológica. A pesar de estas limitaciones, es la primera vez que se describen las características clínicas de pacientes con AMS en un centro neurológico de referencia en Perú.

Introduction: Multiple System Atrophy (MSA) is a neurodegenerative disease characterized by a combination of parkinsonism (MSA -P), cerebellar dysfunction (MSA-C), and autonomic failure. Our study aimed to describe the clinical features of multiple system atrophy (MSA) in a neurological referral setting. Population and methods: A descriptive, longitudinal and retrospective study was designed, which included every patient diagnosed as AMS since 1998 at 2008 from Neurodegenerative Disease Department database of the Instituto Nacional de Ciencias Neurológicas. Results: Seventeen patients fulfilled the diagnostic criteria. The mean age at onset of the disease was 58.5 years. We found a predominance of males (M:F = 2.4: 1) as well as AMS-P cases (76.4%). The most common initial presenting features were parkinsonism or cerebe11ar signs. Neuroimaging was done in 12patients, 10of which were abnormal. Most of patients documented autonomic symptoms (58.8%); however, autonomic function testing was performed only in one patient in whom orthostatism was recorded. Anal sphincter electromyogram was done in 3 patients, all of them indicated denervation of Onuf' æs nucleus in the sacral cord. Conclusions: A predominance of male as well as MSA-P was found, these fíndings coincide with literature data. As our study strictly adhered to the last consensus criteria. However, missed cases can occur as a result of the early cases misdiagnosed as other types of parkinsonism; also, not all our patients had MRI of the brain performed and no neuropathological confirmation was available. Despite these limitations, this is the first review of the clinical characteristics of MSA patients in a neurological referral setting in Peru.

Multiple system atrophy: clinical-radiological correlation. Report of two cases

Multiple system atrophy (MSA) is a sporadic, neurodegenerative disorder, clinically characterized by parkinsonian, autonomic, cerebellar and pyramidal signs. We describe two patients showing different presentations of the same disease. The patient on case 1 presents features of MSA-C or olivopontocerebellar atrophy with the pontine "cross sign" on brain MRI. The second case reports a patient presenting MSA-P or striatonigral degeneration and the brain MRI shows lenticular nucleus sign alteration. We think that brain MRI might increase the accuracy diagnostic of MSA.

A atrofia de múltiplos sistemas (AMS) é uma doença neurodegenerativa esporádica caracterizada clinicamente por diferentes combinações de sinais parkinsonianos, autonômicos, cerebelares e piramidais. Descrevemos dois pacientes apresentando diferentes formas clínicas da mesma afecção. O caso 1 tem características da AMS-C ou atrofia olivopontocerebelar, apresentando na ressonância magnética (RM) o "sinal da cruz" na ponte. Já o caso 2 tem AMS-P ou degeneração nigro-estriatal, a RM mostra alteração do sinal no núcleo lentiforme entre outras alterações. Acreditamos que a RM cerebral possa contribuir para o melhor diagnóstico da AMS.

Study of brainstem auditory evoked potentials and its correlation with pontine volume in olivopontocerebellar atrophy / 中国应用生理学杂志

<p><b>AIM</b>To investigate the change of latency and interpeak latency of each component of BAEP (brainstem auditory evoked potential, BAEP) and its correlation with PV/PFV (pontine volume/posterior fossa volume, PV/PFV) ratio in OPCA (olivopontocerebellar atrophy, OPCA).</p><p><b>METHODS</b>We used Keypoint EMG/EP to determine waves I PL (peak latency, PL), III PL, V PL and I - III IPL (interpeak latency, IPL), III - V IPL, I - V IPL and used 1.5TMR 3D volume rendering software to determine PV (pontine volume, PV), CV(cerebellar volume, CV) and PFV (posterior fossa volume,PFV). Then calculated PV/PFV ratio, CV/PFV ratio and PV/ CV ratio in OPCA group and control group.</p><p><b>RESULTS</b>Compared with control group, in OPCA group wave IIII PL, I - III IPL were significantly elongated (P < 0.05), III - V IPL was significantly shorten (P < 0.05), PV/PFV ratio was significantly decreased (P < 0.01); there was a positive correlation between III-V IPL and PV/PFV ratio (r = 0.83, P < 0.01).</p><p><b>CONCLUSION</b>In patients with OPCA, III PL, I - III IPL of BAEP were elongated and III - V IPL of BAEP was shorten. III - V IPL became shorter when the volume of pontine decreased.</p>

Clinical and Electro-Oculographic Characteristics of Ocular Flutter

BACKGROUND: Ocular flutter is a rare horizontal eye movement disorder characterized by rapid saccadic oscillations. Excessive discharge of burst neurons, and/or loss of tonic excitation of pause cells cause ocular flutter in several neurologic diseases. Ocular flutter can be easily differentiated from other saccadic oscillations with the aid of electro-oculography (EOG) findings showing an absence of intersaccadic intervals. METHODS: We analyzed EOG findings of ocular flutter in four patients. RESULTS: Ocular flutter, which was shown as rapid, repetitive, horizontal, symmetrical, and sinusoidal movements without intersaccadic intervals on EOG, was confirmed in four patients. The etiology of each patient was olivopontocerebellar atrophy (1 case), meningoencephalitis (2 cases), and lithium intoxication (1 case). CONCLUSIONS: Ocular flutter can be present in numerous neurologic diseases. Characteristic EOG findings are useful in the diagnosis of ocular flutter.

Dejerine-Sottas disease: a case report

CONTEXT: Hereditary peripheral neuropathies (hereditary motor-sensory neuropathies or hereditary demyelinating neuropathies) are abnormalities of Schwann cells and their myelin sheaths, with peripheral nerve dysfunction. They include Charcot-Marie-Tooth disease, Dejerine-Sottas disease, congenital hypomyelinating neuropathy and hereditary neuropathy with liability to pressure palsy. OBJECTIVE: The objective of the present work was to describe a case of Dejerine-Sottas disease. CASE REPORT: A 9-year-old boy presented progressive slight motor deficit in the lower limbs, particularly in the feet, and generalized hyporeflexia. Electromyography disclosed significant reduction in motor and sensory nerve conduction velocities. Sural nerve biopsy showed axons surrounded by a thin myelin sheath and concentrically arranged cytoplasmic processes of Schwann cells forming onion-bulbs. No axon damage was observed

Olivopontocerebellar atrophy presenting with stridor.

The spectrum of degenerative ataxia includes the symptomatic degenerative ataxias and the primary degenerative ataxias. The later may be sporadic and idiopathic or hereditary, being genetically determined. When an individual ataxic patient presents with an adult-onset degenerative ataxia and has a negative family history, the physician is faced with a diagnosis of pure idiopathic sporadic degenerative ataxia or one of the hereditary ataxias. The clinical spectrum of olivopontocerebellar atrophy (OPCA) usually consists of pancerebellar signs with pyramidal and abnormal eye movements. Although Stridor is more commonly found in multisystem atrophy, it is rarely seen in OPCA. We, here report a case of third decade onset of ataxia presenting with stridor.

Spontaneous Intracranial Epidural Hematoma Following Thoracolumbar Schwannoma Removal

We report a case of spontaneous intracranial epidural hematoma following the intraoperative course of a patient who had undergone surgical removal of a thoracolumbar schwannoma in olivo-ponto-cerebellar atrophy. To our knowledge there is no reported case in which the thoracolumbar schwannoma removal was followed by such a complication. Mechanical events leading to this complication are unclear. Abnormal results of a neurological examination in the early postoperative period should suggest this possibility.

Early onset cerebellar ataxia with retained tendon reflexes (EOCA) and olivopontocerebellar atrophy (OPCA): a computed tomographic study.

Computed tomographic (CT) studies in olivopontocerebellar atrophies (OPCA) and 'early onset cerebellar ataxia with retained tendon reflexes (EOCA)' are few and vary widely in methodology and criteria for cerebellar and brainstem atrophy. In this prospective study, CT scan observations on 26 patients (EOCA-11, OPCA-15) were compared with 31 controls using qualitative and quantitative assessment of cisterns, ventricles and atrophy of brain. Vermian and/or cerebellar hemispheric (predominantly anterior) atrophy was present in 80.8% and both were equally common. Cerebral cortical atrophy (26.9%) and leukoariosis (15.4%) were less frequently seen. Statistically significant atrophy of pons, brachium pontis, cerebellum and midbrain was noted in patient group. No significant differences were observed between EOCA and OPCA groups. Evidence of atrophy did not correlate with either the duration of illness or the severity of cerebellar ataxia in both the groups. The severity of brainstem atrophy in 14 patients with and 12 patients without abnormal brainstem auditory evoked response did not differ significantly. This study highlights the methodology of CT evaluation for brainstem and cerebellar atrophy, draws attention to cerebral atrophy and emphasizes the lack of significant differences in CT morphology between OPCA and EOCA patients.

Brain MRI Findings of the Olivopontocerebellar Atrophy

PURPOSE: To demonstrate the MRI findings of olivopontocerebellar atrophy. MATERIALS AND METHODS: We retrospectively reviewed the MRI findings of eight patients who had been diagnosed by clinical manifestation and the peculiar pattern of atrophy and signal change on MRI. RESULTS: Seven patients had an atrophy of the olive, pons and cerebellum and increased signal change of the transverse pontine fiber, median raphe and middle cerebellar peduncle on T2WI. Of these, six patients had severe atrophy of the olive, pons and cerebellum and decreased signal change of the basal ganglia, red nucleus, substantia nigra or dentate nucleus on T2WI. Additionally, four of six patients had a cerebral atrophy. Except one patient who had an urinary incontinence, these 5 patients had not been associated with extrapyramidal or autonomic symptom. The other patient with relatively short duration of the disease had only cerebellar atrophy without signal change on T2WI . CONCLUSION: With progressing of the olivopontocerebellar atrophy, cerebral atrophy and decreased signal change of the basal ganglia, red nucleus, substantia nigra or dentate nucleus on T2WI is combined. Thus, MRI is essential in establishing the diagnosis and evaluating the severity of olivopontocerebellar atrophy.

Avances en la comprensión de las ataxias hereditarias / Advances in the comprehension of hereditary ataxias

Las ataxias hereditarias han constituido siempre un rompecabezas para el neurólogo. Las clasificaciones clínicas y anátomo-patológicas habiéndose mostrado impotentes para aprehenderlas a cabalidad. El desarrollo de la genética inversa y la biología molecular ha permitido por primera vez abordar su estudio de manera satisfactoria. Las ataxias cerebelosas autosómicas dominantes, como la atrofia olivo-ponto-cerebelosa (OPCA), la atrofia cerebelosa cortical familiar, la enfermedad de Machado Joseph, han recibido los apelativos ataxias espino cerebelosas (SCA) 1,2,3,4,5,6,7. La biología y la genética moleculares han demostrado que en una mayoría de ellas la alteración genética consiste en la expansión de un triplete CAG. La enfermedad de Friedreich que es la ataxia recesiva por excelencia ha mostrado por primera vez que puede presentarse bajo fenotipos diferentes. Su mutación ha sido mapeada al cromosoma 9 y se ha demostrado que la anormalidad consiste en la expansión intrónica de un triplete.

Autosomal Dominant Cerebellar Ataxia Type II Associated with Optic Atrophy

Autosomal dominant cerebellar ataxia(ADCA) is an unusual, familial hereditary disorder that ha been called olivopontocerebellar atrophy. ADCA type II is usually accompanied with severely decreased visual acuity and cerebellar ataxia. We experienced a 39 year-old female with ADCA type II who had the severely decreased visual acuity and progressive familial cerebellar ataxia. The diagnosis for ADCA type II was made through several ophthalmic examinations. brain magnetic resonance imaging, and chromosomal study. When ophthalmologists encounter a patient with decreased visual acuity and cerebellar ataxia, this disorder should not be overlooked. We report this unusual case with literature review.

Atrofia olivopontocerebelar: relato de dois casos com ênfase à análise anatomopatológica / Olivo-ponto-cerebellar atrophy: report of 2 cases with emphasis pathological observations

Atrofia olivopontocerebelar (AOPC), uma das representantes das atrofias de múltiplos sistemas, é uma doença neurológica degenerativa crônica pouco comum que afeta o cerebelo, tractos espinocerebelares, olivas e outras estruturas do tronco do éncefalo. Pode manifestar-se clinicamente de diversas maneiras, onde a mais proeminente apresenta sintomas pancerebelares como disartria, nistagmo, ataxia e hipotonia. Rigidez generalizada e parkisonismo também podem ser encontrados em alguns casos. Os autores relatam dois casos clínicos de AOPC em mulheres de 59 e 63 anos, diagnosticados no Hospital de Clínicas da Universidade Federal do Paraná e confirmados por necropsia

Atrofia olivo-ponto-cerebelosa a propósito de un caso / Cerebelosa attophy olive tree ponto with regard to a case

Expone que el término atrofia olivopontocerebelosa fue introducido por primera vez por Dejerine y Thomas en 1990 con el propósito de identificar a un grupo de síndromes heterogeneos cuyo factor común era la pérdida de neuronas en la porción ventral de la protuberancia, los núcleos olivares inferiores y la corteza cerebelosa. Se trata de una mujer de 46 años de edad con marcha titubeante, atáxica, lenguaje disártico, tembloroso de evolución lenta y progresiva en aproximadamente 9 años e incoordinación de extremidades superiores en los últimos meses. El estudio de resonancia magnética nuclear mostró la atrofia olivo-ponto-cerebelosa...

Natural History of MSA-Clinical Evidence for Single Disease entity

BACKGROUND & OBJECT10NS: Multiple system atrophy(MSA) is a heterogenous system disorder affecting extrapyramidal, cerebellar and autonomic nervous system. Clinical spectrum is broad, and depending on the system affected, patients are classified into striato-nigral degeneration (SND), olivo-ponto-cerebellar atrophy (OPCA) and Shy-Draper syndrome (SDS). However, evolution of symptoms during follow-up usually occurs, stirring up a debate between "lumpers" and "splitters". Recent pathological documentation of intracytoplasmic inclusions support "lumpers" that MSA is a specific disease entity with specific pathology. The study was done to analyze the natural course of MSA, and examine whether they are separate or part of the same disease. METHOD: We obtained the clinical data of patients with clinically probable MSA by the criteria of Quinn (1994). In addition to review of medical records, all patients were phone-interviewed or examined personally. RESULTS: Forty four patients were included in the study (male 23, female 21). Mean onset age 52.9 years, and mean follow-up period 19.7 months. Nine patients died during follow-up (mean disease duration 5.2 years). The initial predominant features were parkinsonism in 40% (14/35), cerebellar dysfunction in 25.7% (9/35), autonomic dysfunction in 17.1% (6/35) and others in 17.1%. At the latest follow-up, parkinsonism were noted in 77.1%, cerebellar dysfunction in 88.6% and autonomic dysfunction in 80%. With progression, all the patients showed mixed clinical manifestations, the most common being combination of all 3(60%). CONCLUS10N: The data supports that SND, OPCA and SDS are part of the same disease process.

Monoamine metabolites in normal human cerebrospinal fluid and in degenerative diseases of the central nervous system

Measurement of monoamine metabolites in cerebrospinal fluid (CSF) has been one of the few methods available to study monoamine transmitter function in the human central nervous system (CNS). It has steadily proved to be of much use in clinical research of neurological and psychiatric diseases, in which altered functions of central monoamine neurotransmitters have been identified. In this work 3-methoxy-4-hydroxyphenylethylglycol (MHPG), 3-4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) were quantified in normal CSF and in patients with untreated Parkinson's disease (PD) and olovopontocerebellar atrophy (OPCA). Normal CSF was ovtained from 162 patients at the time of spinal anesthesia for surgery. Reference values for monoamine metabolites were established for normal adult lumbar CSF. Up to the age of 70 years no relation of monoamine metabolite concentration with age or sex were encountered. In individuals above 70 years of age higher levels of MHPG, HVA, and 5-HIAA weew present in women, while in men only higher levels of MHPG could be detected. A strong correlation between 5-HIAA and HVA concentrations were observed in all groups. PD patients exhibited normal CSF metabolite levels, but and altered 5-HIAA/HVA, favoring 5-HIAA. Dominant and recessive OPCA differed essentially in HVA concentration-diminished in the first group and elevated in the last. Comparing the results obtained in PD and dominant OPCA, we suggest that the decrease of CSF HVA in the latter group might not reflect nigrostriatal degeneration as we previously thought. Possibly another factor influencing dopamine function in the CNS is involved

Tc-99m HMPAO SPECT in Olivopontocerebellar Atrophy

We studied local cerebral blood flow with Tc-99m HMPAO SPECT in 15 patients with olivopontocerebellar atrophy(OPCA) and 15 age-matched control subjects without neurological desease. The diagnosis of OPCA was based upon the history and physical findings and upon the exclusion of other cerebellar ataxia by means of laboratory investigations. Computed tomographic scan and MRI revealed some degree of atrophy of the cerebellum in most patient with OPCA, and many also had atrophy of the brain stem. SPECT studies in these patients revealed decreased cerebral blood flow in the cerebellum in comparison with the normal control subjects(p<0.001). Two patients with minimal atrophy or no structural changes in the cerebellum also showed decreased perfusion. Tc-99m HMPAO SPECT may be useful as a diagnostic test in patients with OPCA. Some instances suggest that Tc-99m HMPAO SPECT may show abnormal finding earlier than other neuroimaging methods.

A Clinical Study of 38 Cases of Olivopontocerebellar Atrophy

Olivopontocerebellar atrophy (OPCA) is a form of degenerative disease associated with neuronal degeneration in the cerebellar cortex, pons, and inferior olives. The authors have reviewed 38 cases, clinically diagnosed as OPCA, admitted in department of neurology, Seoul National University Hospital From January, 1985 to August, 1989. Seven cases of familial and 31 cases of sporadic forms have been gathered. Gait ataxia and dizziness are the most frequent initial manifestations and the cerebellar ataxia and pyramidal tract signs are frequent neurologic findings in both familial and sporadic forms. Age of onset is earlier in the familial form (mean 31.4y) than in the sporadic form (mean 47.5y). The duration of the disease is longer in the former(6.8y) than in the latter (2.9y). Abnormal ocular movement and nystagmus are more frequent in the familial form, while autonomic changes and parkinsonian features in the sporadic form.