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At least 19 recordsLinked to original sources
PubMed1990

Waiting for the family legacy: the experience of being at risk for Machado-Joseph disease.

Every offspring of an individual with Machado-Joseph disease has a 50% chance of inheriting the disease-causing gene, and symptoms usually do not appear until adult life, usually between the ages of 20 and 40. There are no predictive screening tests available for the disease. This paper, drawn from data collected as part of a larger study of the malady among descendants of Azorean-Portuguese in the Azores Islands and in northern California, explores the subjective state of genetic risk. Although individuals at risk vary in their reactions to the threat of Machado-Joseph disease, there are commonalities of concern that cross-cut individual differences. These differences and commonalities are important for what they might tell us about the experience of genetic risk in general, as well as Machado-Joseph disease in particular.

Adult↗
PubMed1991

[A family of Machado-Joseph disease with a patient having frequent apnea in all day].

One male and two female cases in a family of Machado-Joseph disease were reported. Two cases showed typical symptoms that are characterized by bulging eyes, ophthalmoplegia, dystonia, ataxia, spasticity of extremities and amyotrophy, and were consistent with Type II (Rosenberg et al). But another one lacked diversity of the symptoms, showing mainly progressive cerebellar ataxia for over 10 years. We pointed out the existence of a new type of MJD case exhibiting only progressive cerebellar ataxia over a long period. A female patient had dyspnea and insomnia after 20 years in her clinical course, and central sleep apnea was revealed by respiratory monitor. But, the apnea and irregular respiration appeared in both awake and sleep stages. We described the importance of attention to the apnea as a new complication of Machado-Joseph disease.

Adult↗
PubMed1992

Machado-Joseph disease: an autosomal dominant motor system degeneration.

Machado-Joseph disease is an autosomal dominant spinocerebellar degeneration. It expresses itself clinically with variable expression. Type one patients have early onset with a rapid progression of symptoms including spasticity, rigidity and myokymia. Type two patients are the most common phenotype with ataxia and spasticity. Type three patients develop progressive ataxia with variable amyotrophy. All patients have ophthalmoparesis and normal mental status. The neuropathology consists of neuronal loss and gliosis in the substantia nigra, motor cranial nuclei, dentate nucleus of the cerebellum, and variable neuronal loss with gliosis in the cerebellar cortex and neostriatum. The cerebral cortex is normal histologically. The inferior olivary nuclei are normal, thus separating this disease from olivopontocerebellar atrophy (OPCA). The disease has a worldwide distribution including families described in Portugal, the Azores, Spain, Italy, United States, Canada, Brazil, China, Taiwan, and Japan. The gene has not been mapped for this disease but the locus on chromosome 6p mapped for most families with OPCA has been excluded for this disorder.

Chromosome Aberrations↗
PubMed1990

[Auditory brainstem response and somatosensory evoked potential in Machado-Joseph disease in Japanese families].

To clarify physiological aspects of Machado-Joseph disease (MJD), we studied auditory brainstem response (ABR) and somatosensory evoked potential (SEP) in 17 clinically diagnosed patients with MJD aged 32-64 in Japanese families. ABR was recorded in 13 patients. In 8 patients, ABR were abnormal. In 5 patients, the latency of I wave was normal, but other waves could not be evoked. In the other 3 patients, I-III interpeak latency was prolonged. SEP was recorded in 15 patients. In SEP of median nerve, 11 patients had abnormal findings, and SEP of posterior tibial nerve revealed abnormal findings in all 15 patients. In all patients, responses from Erb's point and popliteal fossa were normal in latency, but other peaks were low in amplitude or absent, and the latency and central conduction time (CCT) were prolonged. The result of ABR indicated the involvement of the brainstem auditory pathways in MJD, and the result of SEP suggested that somatosensory pathways, particularly central pathways, would be involved in the disease process. ABR and SEP can be potential diagnostic methods for detection of subclinical abnormality in MJD patients.

Adult↗
PubMed1992

The Machado-Joseph disease locus is different from the spinocerebellar ataxia locus (SCA1).

Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative spinocerebellar ataxia that has been described primarily in families of Azorean or Portuguese descent. MJD and chromosome 6p-linked spinocerebellar ataxia (SCA1) are difficult to differentiate clinically, and it has been suggested that they may be allelic variants of the same disorder. We have tested MJD families for linkage to six DNA sequence polymorphisms located on chromosome 6p, including the highly informative dinucleotide repeat, D6S89. Seventeen centimorgans telomeric to and 41 cM centromeric to D6S89, a region that includes the SCA1 locus reported to be within 3 cM of D6S89, have been excluded. These data provide conclusive evidence that MJD and SCA1 are nonallelic.

Alleles↗
PubMed1992

Machado-Joseph disease in New England: clinical description and distinction from the olivopontocerebellar atrophies.

Experience is described in 25 patients from southern New England with Machado-Joseph Disease, examined serially at annual screening clinics. The disorder is dominantly inherited, with a wide range of phenotypic variation. Core clinical features described include ataxia, nystagmus, dysarthria, facial fasciculations, and lid retraction, producing a characteristic staring expression. In addition, young onset patients have spasticity, extrapyramidal rigidity, and dystonic manifestations. Late onset patients often have distal atrophy and sensory loss. Postural instability is often an early feature. We discuss the distinction of this entity from the olivopontocerebellar atrophies.

Adolescent↗
PubMed1991

[Machado-Joseph disease: description of 5 members of a family].

The authors report the clinical and laboratorial findings of 5 affected members (all males) of a family with Machado-Joseph disease. The mode a inheritance was autosomal dominant. The mean onset age was 38 years (range 30-50 years). The clinical picture was pleomorphic and included cerebellar ataxia, external ophthalmoplegia with bulging eyes, extrapyramidal/pyramidal syndromes, amyotrophy with fasciculations and peripheral neuropathy, in variable degrees of severity. In one patient parkinsonian rigidity was greatly improved with the use of trihexaphenidyl and L-dopa. CT scan examinations disclosed a variable degree of cerebellar atrophy, with mild cerebral atrophy in one patient. Brainstem evoked potentials were normal in two patients. EMG showed denervation in three patients. Muscle biopsy (gastrocnemium) with histochemical studies revealed chronic muscle denervation in four cases. Sural nerve biopsy with conventional pathological study was normal in four cases. This family was living in Florianopolis, Santa Catarina, where there is a great number of Portuguese descendants from the Azores Islands. The worldwide presence of the disease seems to result from the genic diffusion of the disease with the Portuguese emigration during the Great Navigations Era and with some later emigratory settlement.

Adult↗
PubMed1992

[A case of Machado-Joseph disease--cerebral blood flow and cerebral metabolic rate of oxygen].

A 51-year-old woman, with progressive gait disturbance and dysarthria, had been diagnosed as Menzel-type spinocerebellar degeneration. Later, she developed dystonic posture of upper limbs and bulging eyes. She was diagnosed as Machado-Joseph disease from neurological findings, which consisted of cerebellar signs, pyramidal tract signs and extrapyramidal tract signs and peripheral neuropathy. She died suddenly of unknown origin. Her illness lasted about 13 years. Neuropathological findings showed moderate neuronal loss with gliosis in the subthalamic nucleus, globus pallidus, substantia nigra, dentate nucleus, oculomotor and hypoglossal nucleus and anterior horn. Positron emission tomography (PET) using 15O steady state inhalation technique revealed reduction of cerebral blood flow and cerebral metabolic rate of oxygen in not only cerebellum but also cerebral cortex. These findings are different from typical PET findings of spinocerebellar degeneration.

Brain↗
PubMed1992

[Linkage study of Machado-Joseph disease: genetic evidence for the locus different from SCA1].

Spinocerebellar ataxia 1 (SCA1) is the locus symbol of hereditary olivopontocerebellar atrophy, and it is mapped on the short arm of chromosome 6. D6S89 is the polymorphic DNA marker linked tightly to SCA1. In order to examine whether SCA1 and Machado-Joseph disease (MJD) loci are different from each other, we performed linkage study for D6S89 to MJD locus. A total of 20 pedigrees of MJD were analysed. Number of individuals consists of 211 members. Among them, 74 were affected. Consequently, 14 pedigrees showed negative lod score, and 6 showed weak positive lod scores at most of recombination fractions. As a whole, linkage between MJD locus and D6S89 was excluded at recombination fraction of 0.15. Our results further support the concept that MJD is not an allelic disorder but distinct genetic entity from SCA1.

Adult↗
PubMed1990

[A new family of Machado-Joseph disease--an abnormal decrease in signal intensity of the putamen in magnetic resonance imaging].

The propositus (case 1) was a 40 year-old man. He had begun to note unsteady walking at age 26. He was found to have cerebellar ataxia and pyramidal signs in addition to minor features such as progressive external ophthalmoplegia, gaze nystagmus, bulging eyes, intention fasciculation-like movements of facial and lingual muscles, and limb dystonia. These findings were categorized into type II form of the disease. One sister (case 3) aged 37 years, and one brother (case 4) aged 44 years of the propositus had also type II form of the disease. His uncle (case 2) had the same cerebellar and extrapyramidal signs accompanied with peripheral nerve signs such as muscle wasting, weakness, hypo-tonus and decreased deep tendon reflexes, and a diagnosis of type III form of the disease was made. In the T2-weighted magnetic resonance imaging (1.5 T, TR 2000 or 3000 msec, TE 120 msec) of the three patients (case 1, 3 and 4), dorsolateral part of the putamen showed decreased signal intensity. Although hypo-intensity of the putamen is often observed in normal elderly people over 50 years old, it is considered to be abnormal when it exists in relatively young people as in this family members.

Adult↗
PubMed2026

Importin-8 silencing reduces Ataxin-3 aggregation and alleviates Machado-Joseph disease/spinocerebellar ataxia type 3.

Machado-Joseph disease (MJD) is a polyglutamine neurodegenerative disorder characterized by the formation of neuronal intranuclear Ataxin-3 inclusions. The nucleocytoplasmic transport is known to be profoundly dysregulated from early stages of neurodegeneration, further aggravating its progressive nature. To understand the contribution of these proteins in MJD, we screened the effect of 34 transport proteins on Ataxin-3 aggregation. Importin-8 (Ipo8 gene) was selected for further neuropathology and behavior analysis to evaluate its modulatory effect in vitro and in vivo. Our results showed that Ipo8 mRNA expression is increased in MJD and that, upon Ipo8 downregulation, Ataxin-3 aggregation and neuronal dysfunction are reduced in vitro and in vivo. Furthermore, Ipo8 silencing was demonstrated to alleviate ataxic traits in vivo. Collectively, our findings indicate that Importin-8 may exert its protective effect by modulating NF-kb/p65 and Argonaute-2 proteins, also previously linked to MJD, standing as a promising therapeutic target to delay disease progression.

Argonaute-2↗
PubMed1992

[Clinicopathological study of Joseph disease: report of 4 pedigrees and its nosological consideration].

Four pedigrees of Machado-Joseph disease (MJD) were reported. Main clinical features of 21 patients in these pedigrees were cerebellar ataxia, limb spasticity, gaze nystagmus, facio-lingual twitchings, and external ophthalmoparesis. Amyotrophy, hypokinesia, or dystonia were manifested with advance of the illness. In patients with younger onset age, such extrapyramidal signs were dominated. Neuropathological study of one autopsied case disclosed that there were degeneration of spinocerebellar tract, anterior horn cells, pontine nuclei, dentate nucleus, red nucleus, substantia nigra, internal segment of globus pallidus, subthalamic nucleus, and motor nuclei of brain stem; neurons of cerebellar cortex and inferior olivary nucleus were preserved. From these clinical and pathological features, these 4 pedigrees satisfied the criteria of MJD, and were differentiated from hereditary olivopontocerebellar atrophy. Currently, MJD is accepted as a new entity of hereditary spinocerebellar ataxias. However, there are still controversies as to whether Azores-Portuguese MJD and Japanese MJD are identical disorder. Furthermore, the nosological relationship between MJD and a number of similar cases, as reported historically under the diagnosis of Brown type ataxia or Marie's ataxia, has not been clearly established. From reviewing such cases critically, pathological and clinical features of our cases are so similar to those of the latter, indicating that the probably identical genetic disorder has been classified under the different categories.

Adult↗
PubMed1991

[Abnormality of hypothalamic dopaminergic system in neuro-degenerative diseases--evaluation of alpha-melanocyte-stimulating hormone-like immunoreactivity in cerebrospinal fluid].

Dopaminergic neuron controls CNS functions such as meso-limbic, striato-nigral and tubero-infundibular systems. The purpose of the present study is the evaluation of the hypothalamic dopaminergic neuron activity in neuro-degenerative disorders. alpha-melanocyte-stimulating hormone (alpha-MSH) is synthesized in the arcuate nucleus and lateral part of the hypothalamus, and its secretion is under the inhibitory control of the dopaminergic neuron both in the hypothalamus and pituitary. alpha-MSH-like-immunoreactivity (alpha-MSH-LI) in CSF is thought to be representative to the dopaminergic neuron activity in the hypothalamus. We therefore evaluated CSF levels of alpha-MSH-LI in spinocerebellar degenerations and extrapyramidal diseases. The subjects are 11 patients with Parkinson's disease, 16 with Shy-Drager syndrome (SDS), 16 with cerebellar cortical atrophy, 3 with Machado-Joseph disease, 3 with dentato-rubro-pallido-luysian atrophy and 2 with Huntington's disease as well as 24 controls. All patients with Parkinson's disease were administered levodopa and carbidopa. CSF was sampled through lumbar puncture in the morning. After the centrifugation, supernatant of CSF was stored at -40 degrees C until used. alpha-MSH in CSF was extracted by Rainero's method and measured by RIA. alpha-MSH-LI levels in control was 23.9 +/- 2.6 pg/ml (mean +/- SD). The significant elevation was observed in Parkinson's disease (40.3 +/- 7.5, p less than 0.001) and SDS (42.3 +/- 9.4, p less than 0.001). The levels showed not significant correlation with age, duration of illness or severity of autonomic disorder. Most of other diseases demonstrated the levels within normal range.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Hereditary motor and sensory neuropathy with treatable extrapyramidal features.

Seven patients with a sensorimotor peripheral neuropathy followed years later by extrapyramidal manifestations are presented. This appears to be a separate genetic disorder(s) from that described as Machado-Joseph disease. In five subjects, other relatives had similar multisystem involvement. None was of known Portuguese ancestry. The extrapyramidal syndrome was mainly parkinsonian. Pain was prominent in five subjects. In all cases, low or moderate doses of levodopa/carbidopa ameliorated both the pain and the parkinsonian features. In one patient, a randomized placebo-controlled trial of levodopa/carbidopa was found to significantly improve most symptoms and neurologic dysfunction scores related to the extrapyramidal syndrome.

Adult↗
PubMed1992

[Movement-related cortical potential in patients with cerebellar dentate degeneration].

We reported movement-related cortical potentials (MRCPs) in 11 patients with lesion of the dentate nucleus (Machado-Joseph disease (MJD) 7 cases, dentato-rubro-pallido-luysian atrophy (DRPLA)1, myoclonus epilepsy associated with ragged-red fibers (MERRF)1, dyssynergia cerebellaris myoclonica (DCM) 2), and compared with those of 7 cases of multiple system atrophy (MSA) who were postulated to have mild dentate lesions (striato-nigral degeneration 2 cases, Shy-Drager syndrome 2, sporadic olivo-ponto-cerebellar atrophy 3), and 7 control subjects without any neurological findings. Further we classified the diseases into the following two groups based on the lesion of the dentate nucleus. One was MJD group that had normal or slightly abnormal electroencephalogram (EEG), and the other was DN group (DRPLA, MERRF, DCM) that had markedly abnormal EEG. One of the main findings from this study was smaller slope of the Ns' in the MJD and DN group and normal slope of BP. There was no significant difference in the slope of Ns' between MJD patients and DN patients. This result shows EEG abnormalities have no influence on MRCP recordings. These results suggest that Ns' component may reflect the function in the cerebellar dentate nucleus, and that MRCP is a useful diagnostic method in patients with cerebellar ataxia.

Adolescent↗
PubMed2026

Replication analysis of the PRKN V380L (rs1801582) variant in a Japanese cohort of spinocerebellar ataxia type 3.

BACKGROUND: Spinocerebellar ataxia type 3 (SCA3) is caused by CAG repeat expansion in ATXN3, which inversely correlates with age at onset but does not fully account for interindividual variability. A recent study in a mixed European/South and North&#xa0;American cohort suggested that the PRKN V380L variant (rs1801582), particularly in C/C homozygotes, was associated with earlier disease onset. We therefore performed a replication analysis to evaluate the frequency and potential clinical relevance of rs1801582 in a Japanese SCA3 cohort. METHODS: rs1801582 genotypes were determined by Sanger sequencing in 228 genetically confirmed SCA3 patients and 260 SCA6 patients as convenience disease controls. Genotype frequencies were additionally compared with East Asian reference populations from the 1000 Genomes Project Phase 3 dataset. Associations with age at onset were evaluated using multivariable linear regression adjusted for expanded ATXN3 CAG repeat length, normal ATXN3 CAG repeat length, and sex. RESULTS: Genotype frequencies in SCA3 (G/G: 86.0%, G/C: 13.2%, C/C: 0.9%) were similar to those in controls (G/G: 85.8%, G/C: 13.5%, C/C: 0.8%) and closely resembled those reported in East Asian reference populations. Because of the extremely small number of C/C carriers (n&#x2009;=&#x2009;2), subsequent analyses focused on G/G and G/C carriers. In SCA3, median age at onset was comparable between genotypes (42 vs. 41&#xa0;years), and median expanded ATXN3 CAG repeat lengths did not differ between groups (71 vs. 71 repeats). Multivariable regression analysis adjusting for expanded ATXN3 CAG repeat length, normal ATXN3 CAG repeat length, and sex demonstrated that rs1801582 was not independently associated with age at onset (&#x3b2;&#x2009;= -&#x2009;0.42&#xa0;years, p&#x2009;=&#x2009;0.84), whereas expanded CAG repeat length remained a strong predictor (&#x3b2;&#x2009;= -&#x2009;1.68&#xa0;years per repeat, p&#x2009;<&#x2009;0.0001). CONCLUSIONS: The rs1801582 C/C genotype is extremely rare in Japan; therefore, the present cohort had limited statistical power to directly evaluate the previously proposed recessive modifier effect. No detectable association between rs1801582 genotype and age at onset was identified among G/G and G/C carriers in this Japanese cohort. These findings highlight the importance of population-specific validation and adequately powered replication studies when evaluating candidate genetic modifiers in SCA3.

Adult↗