Brain stem and cerebellum volumetric analysis of Machado Joseph disease patients / Análise volumétrica de cerebelo e tronco cerebral de pacientes com doença de Machado Joseph

Machado-Joseph disease, or spinocerebellar ataxia type 3(MJD/SCA3), is the most frequent late onset spinocerebellar ataxia and results from a CAG repeat expansion in the ataxin-3 gene. Previous studies have found correlation between atrophy of cerebellum and brainstem with age and CAG repeats, although no such correlation has been found with disease duration and clinical manifestations. In this study we test the hypothesis that atrophy of cerebellum and brainstem in MJD/SCA3 is related to clinical severity, disease duration and CAG repeat length as well as to other variables such as age and ICARS (International Cooperative Ataxia Rating Scale). Whole brain high resolution MRI and volumetric measurement with cranial volume normalization were obtained from 15 MJD/SCA3 patients and 15 normal, age and sex-matchedcontrols. We applied ICARS and compared the score with volumes and CAG number, disease duration and age. We found significant correlation of both brain stem and cerebellar atrophy with CAG repeat length, age, disease duration and degree of disability. The Spearman rank correlation was stronger with volumetric reduction of the cerebellum than with brain stem. Our data allow us to conclude that volumetric analysis might reveal progressive degeneration after disease onset, which in turn is linked to both age and number of CAG repeat expansions in SCA 3.

Doença de Machado-Joseph, ou ataxia espinocerebelar tipo 3 (MJD/SCA3) é ataxia espinocerebelar de início tardio mais frequente e resulta de uma expansão da repetição CAG no gene da ataxina-3. Estudos precedentes encontraram correlação entre a atrofia do cerebelo e do tronco cerebral com a idade e número de expansões CAG. Tais correlações não foram encontradas em relação ao tempo de doença ou manifestações clínicas. Neste estudo testamos a hipótese de que a atrofia do cerebelo e do tronco encefálico em MJD/SCA3 está relacionada à gravidade clínica, duração da doença e número de repetições CAG, bem como com outras variáveis como a idade e a ICARS (escala cooperativa internacional de avaliação de ataxias). Foram realizados estudos de imagem pela ressonância magnética de alta resolução e volumetria com normalização de volume craniano de 15 pacientes portadores de MJD/SCA3 e 15 controles pareados por idade e sexo. Nós aplicamos a ICARS e correlacionamos com o escore de volumes e número de CAG, duração da doença e idade. Encontramos correlação significativa entre atrofia de tronco cerebral e cerebelo com duração da doença, repetição CAG, idade e grau de acometimento da doença. O índice de correlação de Spearman foi maior em relação à atrofia de cerebelo do que à atrofia de tronco. Nossos dados permitem concluir que a análise volumétrica pode revelar degeneração progressiva após o início da doença que, por sua vez, está ligada à idade e número de expansões CAG em SCA 3.

Hereditary motor and autonomic neuronopathy 1 maps to chromosome 20q13.2-13.3

The spinal muscular atrophies (SMA) or hereditary motor neuronopathies result from the continuous degeneration and death of spinal cord lower motor neurons, leading to progressive muscular weakness and atrophy. We describe a large Brazilian family exhibiting an extremely rare, late-onset, dominant, proximal, and progressive SMA accompanied by very unusual manifestations, such as an abnormal sweating pattern, and gastrointestinal and sexual dysfunctions, suggesting concomitant involvement of the autonomic nervous system. We propose a new disease category for this disorder, `hereditary motor and autonomic neuronopathy', and attribute the term, `survival of motor and autonomic neurons 1' (SMAN1) to the respective locus that was mapped to a 14.5 cM region on chromosome 20q13.2-13.3 by genetic linkage analysis and haplotype studies using microsatellite polymorphic markers. This locus lies between markers D20S120 and D20S173 showing a maximum LOD score of 4.6 at D20S171, defining a region with 33 known genes, including several potential candidates. Identifying the SMAN1 gene should not only improve our understanding of the molecular mechanisms underlying lower motor neuron diseases but also help to clarify the relationship between motor and autonomic neurons.

Thr(118)Met amino acid substitution in the peripheral myelin protein 22 does not influence the clinical phenotype of Charcot-Marie-Tooth disease type 1A due to the 17p11.2-p12 duplication

The Thr(118)Met substitution in the peripheral myelin protein 22 (PMP22) gene has been detected in a number of families with demyelinating Charcot-Marie-Tooth (CMT1) neuropathy or with the hereditary neuropathy with liability to pressure palsy, but in none of them has it consistently segregated with the peripheral neuropathy. We describe here a CMT1 family (a 63-year-old man, his brother and his niece) in which two mutations on different chromosomes were found in the PMP22 gene, the 17p duplication, detected by fluorescent semiquantitative polymerase chain reaction (PCR) of microsatellite markers localized within the duplicated region on chromosome 17p11.2-p12, and the Thr(118)Met substitution, detected by direct sequencing the four coding exons of the PMP22 gene. A genotype/phenotype correlation study showed that the neuropathy segregates with the duplication and that the amino acid substitution does not seem to modify the clinical characteristics or the severity of the peripheral neuropathy. We did not find any evidence to characterize this substitution as a polymorphism in the population studied and we propose that the high frequency reported for this point mutation in the literature suggests that the Thr(118)Met substitution may be a hotspot for mutations in the PMP22 gene

Normal median near nerve potential

In routine studies of sensory nerve conduction, only fibers 37 mum in diameter are analyzed. The late components which originate from thinner fibers are not detected. This explains why a normal sensory action potential (SAP) may be recorded in patients with peripheral neuropathies and sensory loss. In the present study we investigated the late component of the median SAP with a near nerve needle electrode technique in 14 normal volunteers (7 men and 7 women), aged 34.5 + 14.8 years. The stimulus consisted of rectangular pluses of 0.2-ms duration at a frequency of 1 Hz with an intensity at least 6 times greater than the threshold value for the main component. Five hundred to 2000 sweep averagings were performed. The duration of analysis was 40 or 50 ms and the wave analysis frequency was 200 (-6 dB/oct) to 3000 Hz (-12 dB/oct). We used an apparatus with a two-channel amplifier system, 200 MW or more of entry impedance and a noise level of 0.7 muVrms or less. The main component mean amplitude, conduction velocity and lactency and the late component mean amplitude, conduction velocity and latency were respectively (mean + SD): 26.5 + 5.42 muV, 56.8 + 5.42 m/s, 3.01 + 0.31 ms, 0.12 + 0.04 muV, 16.4 + 2.95 m/s and 10.6 + 2.48 ms. More sophisticated equipment has an internal noise of 0.6 muVrms. These data demonstrate that the technique can now be employed study thin fiber neuropathies, like in leprosy, using commercial electromyographs, even in non-academic practices.

[Peripheral neuropathies in the State of São Paulo from 1939 to 1985]. / Estudo das neuropatias periféricas no Estado de São Paulo de 1939 a 1985.

Studies on peripheral neuropathies by investigators residing in the State of São Paulo, Brazil, and published since the 1930 and 1940 decades until 1985 were revised in the present survey. Investigations in the area were greatly encouraged by the appearance of the journal Arquivos de Neuro-Psiquiatria(São Paulo). Oswaldo Freitas Julião may be considered the author who began these studies in the State and his most important contributions were related to leprosy and to Andrade disease, although he also published papers on other types of peripheral neuropathies. Horacio Martins Canelas also made a very important contribution to the study of different neuropathies, especially those due to vitamin B12 deficiency. A series of papers on neuropathies published by neurologists residing in the State is summarized. We also present a catalogue of the major university centers where groups of neurologists preferentially devote their time to the study of neuromuscular disease in São Paulo and a selected bibliography about neuropathies by investigators from this State.

Normal median near nerve potential.

In routine studies of sensory nerve conduction, only fibers > or = 7 microns in diameter are analyzed. The late components which originate from thinner fibers are not detected. This explains why a normal sensory action potential (SAP) may be recorded in patients with peripheral neuropathies and sensory loss. In the present study we investigated the late component of the median SAP with a near nerve needle electrode technique in 14 normal volunteers (7 men and 7 women), aged 34.5 +/- 14.8 years. The stimulus consisted of rectangular pulses of 0.2-ms duration at a frequency of 1 Hz with an intensity at least 6 times greater than the threshold value for the main component. Five hundred to 2000 sweep averagings were performed. The duration of analysis was 40 or 50 ms and the wave analysis frequency was 200 (-6 dB/oct) to 3000 Hz (-12 dB/oct). We used an apparatus with a two-channel amplifier system, 200 M omega or more of entry impedance and a noise level of 0.7 microVrms or less. The main component mean amplitude, conduction velocity and latency and the late component mean amplitude, conduction velocity and latency were respectively (mean +/- SD): 26.5 +/- 5.42 microV, 56.8 +/- 5.42 m/s, 3.01 +/- 0.31 ms, 0.12 +/- 0.04 microV, 16.4 +/- 2.95 m/s and 10.6 +/- 2.48 ms. More sophisticated equipment has an internal noise of 0.6 microVrms. These data demonstrate that the technique can now be employed to study thin fiber neuropathies, like in leprosy, using commercial electromyographs, even in non-academic practices.

[Diagnosis of peripheral neuropathies: general characteristics of the population study]. / Diagnóstico das neuropatias periféricas: aspectos gerais da população em estudo.

The objective of the present investigation was to study the general characteristics of a population of 209 patients with peripheral neuropathies seen at the University Hospital of Ribeirão Preto from March 1985 to February 1987. Few studies have been devoted to the evaluation of patients in order to investigate the factors that may or may not contribute to the diagnosis of these conditions. The types of neuropathy detected were (in decreasing order of frequency): polyneuropathies, mononeuropathies and multineuropathies. Acquired forms were particularly outstanding in the first group and brachial plexus injuries in the second. Mean patient age was 36.4 years (range: 18 days to 81 years). Polyneuropathies prevailed among males and mononeuropathies among females, whereas multineuropathies equally affected males and females. Patient follow-up was less than 6 months for 52.6% of cases and less than one year for 7.3%. The significance and importance of these findings are discussed.

[Diagnosis of peripheral neuropathies: various factors of relevance for diagnosis]. / Diagnóstico das neuropatias periféricas: alguns fatores relevantes para a realização do diagnóstico.

The present study was undertaken to evaluate the influence of clinical examination and complementary tests on the diagnosis of peripheral neuropathies. Most of the patients (81.8%) were submitted to laboratory tests, 47.4% were submitted to electromyography, and 22.5% to biopsy. A syndromic diagnosis was made in 99.0% of the patients, topographic diagnosis in 98.6%, and etiological diagnosis in 73.2%. An average of 4.8 tests per patient were requested and 36 of the 93 different tests always gave normal results. The importance of the findings is discussed.

[Diagnosis of peripheral neuropathies: syndromic, topographic, and etiological diagnoses]. / Diagnóstico das neuropatias periféricas: diagnósticos sindrômicos, topográficos e etiológicos.

A retrospective study was conducted to identify the syndromic, topographic and etiological diagnoses made for a group of 209 patients with peripheral neuropathies. Anamnesis and clinical-neurological examination were of fundamental importance for the syndromic and topographic diagnoses. Electromyography played an important role, especially with respect to the topographic diagnoses. The etiological diagnoses depended on additional complementary tests such as: blood glucose levels and blood glucose tolerance test; nutritional evaluation; family evaluation; nerve, skin, pharynx and maxillary sinus biopsies; qualitative tests for the presence of porphyrins in urine; urinary levels of delta-aminolevulinic acid and porphobilinogen; and radiological examinations. The most frequently encountered polyneuropathies were those consequent to alcoholism or to diabetes, and those of the acute demyelinating inflammatory or hereditary type. Among the cases of mononeuropathy, the most frequently diagnosed conditions were carpal tunnel syndromes, traumatic injury to the VII cranial nerve, and trigeminal neuralgias. Leprosy, brachial plexus injury and thoracic outlet compression syndrome predominated among the multineuropathies.

[Diagnosis of peripheral neuropathies: age, sex, and occupation in relation to etiology]. / Diagnóstico das neuropatias periféricas. Idade, sexo e ocupação em relação as etiologias.

The etiology of 209 cases of peripheral neuropathies was studied taking into account the most affected age ranges, as well as the sex and occupation of the patients. The age ranges of our patients for the polyneuropathies consequent to alcoholism, for diabetic polyneuropathy, for Guillain-Barré syndrome and for hereditary sensorimotor neuropathies were 20 to 50 years, 10 to 70 years and 0 to 30 years. The age range of patients with leprosy and nerve injury was 20 to 50 years, and more frequently up to 30 years. Alcoholic and diabetic polyneuropathies predominantly affected males, whereas injury to the median polyneuropathies affected laborers. Inactivity was reported by 1/3 of the patients with diabetic polyneuropathies, by 25% of the patients with polyneuropathies consequent to alcoholism and by 24% of the patients with undefined polyneuropathies.

[Diagnosis of peripheral neuropathies: profile of patients without established etiological diagnosis]. / Diagnóstico das neuropatias periféricas. Perfil dos pacientes sem diagnóstico etiológico estabelecido.

No etiological diagnosis was obtained for 35 of 209 patients studied. Mean patient age was 37.7 years and the preferentially affected age range was 20 to 50 years. Laboratory investigation was more extensive among these patients than among patients with a defined diagnosis. An 11:1 ratio was obtained between normal and abnormal laboratory tests. The major topographic diagnoses were: axonal polyneuropathies, 5 cases; multineuropathies and radiculopathies, 3 cases each. The present findings are discussed and compared with the literature concerning neuropathies of undefined diagnosis.