Cases Of Machado-Joseph Disease Research Articles

Machado Joseph's Disease in a Togolese Family: A Case Report

Spinocerebellar ataxias (SCAs) are rare neurodegenerative disorders of adults characterized by autosomal dominant inheritance. Machado-Joseph disease (MJD) or ASC type 3 is the most common worldwide. We report the first cases of MJD in a Togolese family. We performed a cross-sectional study based on a case of MMJ disease confirmed by genetic testing. We then conducted a family survey to identify suspected familial cases of the disease. The confirmed case was a 46 year old Togolese woman of Ewe ethnicity (south of Togo), hypertensive, who was seen in consultation for speech and walking disorders that had been progressively worsening for 9 years and had been confined to a wheelchair for 3 years. In the family history, we noted similar cases without a precise diagnosis. On examination, we noted cerebellar dysarthria, difficulties in performing calculations, spastic tetraparesis at 4/5, kinetic and static ataxia. Brain magnetic resonance imaging showed cerebral atrophy more marked in the posterior fossa. Genetic analysis revealed the presence of an expanded allele located in the pathological zone at the ASC3 locus, which confirmed the diagnosis. The family investigation allowed us to identify six suspected cases on clinical grounds. This observation confirms the ubiquitous nature of MJD. The existence of a family history of gait disorders in a patient with cerebellar ataxia should raise the possibility of ASC.

Longitudinal study on MRI intensity changes of Machado–Joseph disease: correlation between MRI findings and neuropathological changes

To disclose the neuropathological progression course of Machado-Joseph disease (MJD), magnetic resonance imaging (MRI) findings of six genetically confirmed MJD cases (four males and two females, including an autopsied female, all unrelated to one another) were further investigated on neurodegeneration. Brain MRI studies were repeated in all cases at different stages of the disease. Ages at the first MRI study ranged from 47 to 65 years (55.2 ± 7.1), with observation periods from 4.5 to 10.6 years (6.95 ± 2.48). We paid particular attention to two types of previously reported MRI findings detectable using T2-weighted images. One is located just outside the internal capsules, and another in the pons. A linear high-intensity change along the internal capsules was detected in all cases, and showed progression during the observation period. A comparison between MRI and autopsy findings suggested that the lesion might reflect degeneration with neuronal loss, astrocytosis, and gliosis in the internal segment of the globus pallidus. A cross-shaped high-intensity change in the pons was well advanced but still incomplete in all cases. In this region, pontine transverse fibers were atrophic, while longitudinal fibers remained intact. Pontine nuclei showed apparent nerve cell loss, and the remaining cells had many 1C2-positive intranuclear inclusions. Since these findings were detected both by lifetime images and by postmortem examination, MRI intensity changes could track the progression of neurodegeneration. Based on a comparison between MRI findings and neuropathology, the degeneration of an internal segment of the globus pallidus (one of the pathological features of MJD) had progressed following the initial symptoms.

Selective occurrence of TDP-43-immunoreactive inclusions in the lower motor neurons in Machado–Joseph disease

Pathological transactivation-responsive DNA-binding protein 43 (TDP-43) has been identified as a component of ubiquitinated inclusions in frontotemporal lobar degeneration with motor neuron disease, as well as in sporadic and some forms of familial amyotrophic lateral sclerosis. To clarify whether pathological TDP-43 is present in other neurodegenerative diseases involving the motor neuron system, we immunohistochemically examined the brain and spinal cord affected by two CAG repeat (polyglutamine) diseases, Machado-Joseph disease (MJD) and spinal and bulbar muscular atrophy (SBMA), using polyclonal antibody against TDP-43. In all the MJD cases, TDP-43-immunoreactive (ir) neuronal cytoplasmic inclusions (NCIs), although few in number, were found only in the lower motor neurons in the brainstem and spinal cord. TDP-43-ir NCIs appeared as linear wisp-like, skein-like, or thick, somewhat rod-like bodies. These inclusions were also visualized with antibodies against phosphoserines 409 and 410 of TDP-43, and ubiquitin, but were not recognized by antibody against expanded polyglutamine stretches or ataxin-3. The ultrastructure of the TDP-43-ir NCIs was similar to that of the inclusions seen in sporadic ALS, consisting of bundles of parallel filaments. None of the SBMA cases showed abnormal TDP-43 immunoreactivity in any of the regions examined. Immunoblot analysis failed to recognize hyperphosphorylated TDP-43 at ~23 kDa in two MJD cases examined. However, the immunohistochemical findings strongly suggested that in MJD, in addition to the polyglutamine-dependent disease process, TDP-43-related pathogenesis is associated with degeneration and death of the lower motor neurons.

Immunohistochemical study of neuronal intranuclear and cytoplasmic inclusions in Machado-Joseph disease.

Machado-Joseph disease (MJD) is a dominantly inherited spinocerebellar disorder, and expansions of trinucleotide (CAG) at chromosome 14 have been shown to be the locus of this disorder. Polyglutamine CAG stretches in the neuronal cytoplasms and nuclei were studied with immunolabeling using 1C2, a monoclonal antibody recognizing polyglutamine stretches, and polyclonal antiubiquitin antibody in six genetically verified cases of MJD. 1C2 clearly labeled two types of neuronal intranuclear inclusions (NII) and neuronal cytoplasmic inclusions (NCI) in the substantia nigra, pontine nucleus, dentate nucleus and spinal anterior horn where NII and NCI were also positive for ubiquitin, as were extracellular dot-like structures and oligodendroglial inclusions. 1C2-positive NII and NCI had a lesion-specific distribution. While the spinal motoneurons contained only 1C2-positive NCI and lacked 1C2-positive NII, the ventral pontine nucleus neurons had many 1C2-positive NII and few 1C2-positive NCI. Semi-quantitative examination of NII and NCI positive for 1C2 or ubiquitin demonstrated that there were more 1C2-positive NII and NCI than ubiquitin-positive ones. It is noteworthy that the nuclei of the spinal motoneurons lacked 1C2-positive immunoreactivity, so that ubiquitination of 1C2-positive structures is presumed to occur late in the course of the disease.

Cerebellar degeneration in hereditary dentatorubral-pallidoluysian atrophy and Machado-Joseph disease.

We examined the mechanism of cerebellar degeneration in brains obtained at autopsy from six cases of hereditary dentatorubral-pallidoluysian atrophy (DRPLA) and six cases of Machado-Joseph disease (MJD), using terminal deoxynucleotidyltransferase-mediated in situ nick end labeling (TUNEL) and immunohistochemistry for apoptosis-related proteins, neurotrophin receptors and glutamate transporters. In three subjects with DRPLA, who developed dementia and cerebellar ataxia at over 50 years of age, the number of Purkinje cells was mildly reduced, TUNEL-positive cells were observed in the molecular layer of the cerebellar cortex, and immunoreactivities for calbindin D28K and excitatory amino acid transporter-1 (EAAT1) were altered in the molecular layer. In addition, all cases of DRPLA showed a reduction of immunoreactivity for EAAT1 in the dentate nucleus. In MJD, augmentation of Bcl-x expression by the Purkinje cells, and increases in Trk B- and GFAP-immunopositive glial cells in the granular layer were observed in half of the cases, whereas immunoreactivity for EAAT-1 was preserved both in the cerebellar cortex and dentate nucleus. One case of MJD showed TUNEL-positive granular cells in the cerebellar cortex. Age-matched control subjects did not show TUNEL-positive cells or immunohistochemical changes in the cerebellum. There were neither TUNEL-positive cells nor alteration of the in situ expression of apoptosis-related proteins in the dentate nucleus in either variant of hereditary spinocerebellar degeneration, although both exhibited grumose degeneration in the dentate nucleus. These findings indicate that latent degeneration in the cerebellar cortex may occur in DRPLA and MJD, in addition to the dentate change, which is the cardinal feature in the neuropathology of these two diseases. The lesion of Purkinje cells and their processes in the molecular layer associated with altered glutamate transport may be important in DRPLA, while the significance of the abnormalities observed in some MJD cases, which might be related to apoptotic mechanism, remains unclear.

Synapses in the hereditary ataxias.

The goal of this investigation was the systematic assessment of synapses in the hereditary ataxias by the immunocytochemical and immunofluorescent visualization of SNAP-25, a protein of the presynaptic membrane. Sections were prepared from the cerebellar cortex, dentate nucleus, basis pontis, inferior olivary nuclei, and the spinal cord in 57 cases of autosomal dominant and recessive ataxia. The neuropathological phenotype included 18 cases of olivopontocerebellar atrophy (OPCA), 14 cases of familial cortical cerebellar atrophy (FCCA), 4 cases of Machado-Joseph disease (MJD), and 21 cases of Friedreich's ataxia (FA). Among the autosomal dominant ataxias, spinocerebellar ataxia type 1 (SCA-1), SCA-2, MJD/SCA-3, and SCA-6 were represented. Expanded guanine-adenine-adenine trinucleotide repeats were confirmed in 7 patients with FA. The abundance of SNAP-25 was estimated by comparing the fluorescence of the regions of interest to that of the frontal cortex, which was considered unaffected by the disease process. Despite severe Purkinje cell loss, abundant SNAP-25 reaction product remained in the molecular layer of FCCA and OPCA. Among the cases of OPCA, those identified as SCA-2 showed the most severe overall synaptic destruction in cerebellum and brain stem. In SCA-1, which caused either OPCA or FCCA, significant synaptic loss was restricted to the inferior olivary nuclei. Sparing of cerebellar cortex and inferior olivary nuclei was the rule for MJD/SCA-3 and FA, though the dentate nucleus showed reduced SNAP-25 immunoreactivity in both ataxias. In FA, preservation of SNAP-25 in the dentate nucleus was characteristic of long survival. Severe cases with short survival revealed synaptic depletion of the dentate nucleus. At the level of the spinal cord, synaptic loss in the dorsal nuclei of Clarke characterized FA and MJD/SCA-3. The inexorable clinical progression of the hereditary ataxias could not be attributed to synaptic loss in a single anatomic structure of cerebellum, brain stem, or spinal cord. Nevertheless, synaptic loss in dentate and inferior olivary nuclei correlated more precisely with the severity of the ataxia than the changes in the cerebellar cortex.

Hypertrophy of the Inferior Olivary Nucleus in Patients with Progressive Supranuclear Palsy

Hypertrophic changes in the inferior olivary nuclei have been occasionally described in patients with progressive supranuclear palsy (PSP). To elucidate the incidence of olivary hypertrophy, we investigated morphologically the olives and their associated pathways in 20 autopsied cases: 11 cases of PSP, 3 cases of Machado-Joseph disease and 6 cases of dentatorubropallidoluysian atrophy (DRPLA) as control diseases that usually exhibited lesions of the cerebellofugal pathway. Olivary hypertrophy was observed in 5 of 11 PSP cases, but not in the other diseases, except for 1 case of DRPLA with an old infarct in the dentate nucleus. In the olivopetal pathway, grumose degeneration of the dentate nucleus and mild neuronal loss in the red nucleus were observed in all patients with PSP and in the control subjects. Atrophy and fibrillary gliosis of the tegmentum of the pons, including that of the bilateral central tegmental tracts, were observed in all patients with PSP, more severe in the cases with hypertrophic neurons in the olives. We speculate that a lesion that involves the central tegmental tracts may play a major role in inducing hypertrophy of the olives in patients with PSP.

Brain regional differences in the expansion of a CAG repeat in the spinocerebellar ataxias: dentatorubral-pallidoluysian atrophy, Machado-Joseph disease, and spinocerebellar ataxia type 1.

Three autosomal dominant spinocerebellar ataxias, dentatorubral-pallidoluysian atrophy (DRPLA), Machado-Joseph disease (MJD), and spinocerebellar ataxia type 1 (SCA1), are associated with the expansion of a CAG repeat in the respective genes. To investigate the association between CAG repeat expansion and neuropathological findings, we analyzed several brain regions from 9 cases of DRPLA, 3 cases of MJD, and 1 case of SCA1. We found that the expanded alleles were smaller in the cerebellar cortex than in other brain regions, such as the frontal cortex, in these three diseases. The discrepancy in the expanded CAG repeat length between cerebellar cortex and other tissues was most prominent in DRPLA, and especially in cases of adult-onset DRPLA. A significant correlation was found between the age at onset of DRPLA and the size of the CAG repeat expansion. Cerebella of DRPLA patients were microscopically dissected into three layers, the molecular and granular layers and the white matter, which were analyzed separately. The lower level of CAG repeat expansion in DRPLA cerebella was representative of CAG repeat expansion in the granule cells. The microdissected samples of the granular layer of the hippocampal formation, which is densely packed with neuronal cells, revealed that the degree of CAG repeat expansion in this layer was similar to that in the cerebellum. These observations suggest that granule cells in the cerebellum and hippocampus have low levels of CAG repeat expansion, and that other types of cells exhibit a higher level of CAG repeat expansion, in spinocerebellar ataxias.

Clinicopathology of spinocerebellar degeneration: its correlation to the unstable CAG repeat of the affected gene.

The recent advances in gene analysis have greatly facilitated the classification of autosomal dominant spinocerebellar ataxia (SCA). Analyses of linkage in large families with SCA have assigned gene foci to at least 8 chromosomes. One gene is located in the short arm of chromosome 6 (6p22-p23) and causes spinocerebellar ataxia type 1 (SCA1). A gene in the long arm of chromosome 14 (14q24.3-q32) underlies Machado-Joseph disease (MJD). A third gene locus is assigned to the short arm of chromosome 12 (12p2-pter) causing dentatorubropallidoluysian atrophy (DRPLA). The gene for spinocerebellar ataxia type 2 (SCA2) is located in the 12q23-24. Subsequently, a sporadic counterpart of hereditary olivopontocerebellar atrophy of the Menzel type is clearly defined, and all the syndromes (non-hereditary olivopontocerebellar atrophy, striatonigral degeneration and Shy-Drager syndrome) are now lumped under the term of multiple system atrophy (MSA). Oligodendroglial cytoplasmic inclusions appear to be specific for and diagnostic of MSA. As the clinical features in SCA are variable and often appear to overlap with one another, which makes accurate classification difficult if not possible, the genotype is required for their unequivocal classification. However, major neuropathological features clearly distinguish SCA1 from SCA3/ MJD cases; the medial segment of the globus pallidus and intermediolateral column lesions in SCA3/MJD, and inferior olive and cerebellar cortical degeneration in SCA1. It has been stated that neurodegeneration in SCA3/MJD is more homogeneous than in SCA1 or SCA2 and that degeneration of the pallidoluysian system is not present in the latter. The pertinent pathology in each of the three types of SCA is illustrated. The background of clinicopathology and genetic analysis of dentatorubropallidoluysian atrophy is also reviewed.

Quantitative study of intermediolateral column cell counts in Machado-Joseph disease

The number of intermediolateral column (ILC) neurons in 6 alternating segments from the 2nd to 12th thoracic segment of the spinal cord were studied in 4 cases with Machado-Joseph disease (MJD), 3 cases with olivopontocerebellar atrophy (OPCA), a case with Shy-Drager syndrome (SDS), and 5 normal controls. We counted the number of ILC neurons with clearly defined nucleoli in 12 sections of each segment, each section 20 μm thick and taken at 100 μm intervals and then divided the 6 alternating segments into 3 groups, upper (Th2, 4), middle (Th6, 8) and lower (Th10, 12). In each of the three groups of normal control cases, the number of ILC neurons had decreased with aging. In all MJD cases, the number of ILC neurons had moderately decreased in comparison with age-matched controls. One of the MJD cases showed a marked decrease in the number of ILC neurons, as did the SDS case. The ILCs of the entire thoracic spinal cord in the MJD cases were moderately involved.

Analysis of CAG trinucleotide expansion associated with Machado-Joseph disease

There are currently some types of autosomal dominant cerebellar ataxias such as Machado-Joseph disease (MJD), spinocerebellar ataxia types 1–5 (SCA1-5), or hereditary dentatorubropallidoluysian atrophy. It is very important for these ataxias to be clinically differentiated, but that is sometimes difficult. In particular, the differential diagnosis between MJD and SCA1 is thought to be the most difficult. Recently, both MJD and SCA1 have been proven to be related to expansions of CAG trinucleotide in their causative genes. In this study, 20 cases of MJD in 13 unrelated Japanese families were genetically and clinically examined in comparison with 20 cases of age at onset- and duration-matched Japanese SCA1. The CAG repeat number of expanded MJD and SCA1 alleles was 72.2 ± 3.1 (mean ± SD, n = 20) and 47.3 ± 4.4 ( n = 20), respectively, and each repeat size was inversely correlated with age at onset in both MJD and SCA1. The repeat number in leukocytes increased from parents to children with acceleration of age at onset (anticipation) in MJD. In MJD, the number of CAG repeats in the expanded allele was lower in sperm than that of leukocytes, but was more in SCA1. However, the number of peaks in the expanded allele was greater in sperm than in leukocytes in both MJD and SCA1 (increased mosaicism level). MJD was clinically characterized by a relatively higher frequency of ocular signs such as eyelid retraction, bulging eyes, ophthalmoparesis, and nystagmus, spasticity in lower limbs, and sensory and urinary disturbances in contrast to the SCA1 patients except for slow eye movement. These results indicate that the expanded CAG repeat and clinical features are correlated in both MJD and SCA1, and MJD can be differentiated from SCA1 by clinical characteristics mentioned above as well as DNA analysis.

Clinicopathological study of the peripheral nervous system in Machado-Joseph disease

Three cases of histologically-proven Machado-Joseph disease (MJD) (clinically, types II and III) are described with special reference to the peripheral nervous system. We systematically and quantitatively analyzed the myelinated fiber densities in various nerves of three MJD patients and compared the results with the patients' clinical features and the pathological findings for the central nervous system (CNS). The results obtained were (1) motor system: The number of intermediate gamma-motoneuron fibers was decreased prominently in all three MJD patients. In the type III MJD cases, the number of large alpha-motoneuron fibers also were decreased. (2) Sensory system: it generally was less involved than the motor system at the root level; but the large fibers of the distal portion were vulnerable. (3) Oculomotor system: the number of large oculomotor fibers was decreased markedly in all three cases, but there was relative preservation of parasympathetic fibers. (4) Autonomic system: the preganglionic sympathetic fibers from the intermediate lateral nucleus generally were preserved. These results suggest that in MJD the vulnerability of the peripheral nerves reflects the degree of loss of their original neuronal cells and varies according to the clinical phenotype. The characteristic peripheral neuropathy of MJD may be the result of axonal degeneration due to perikaryal neuronal damage in the central nervous system.