What Is Machado-Joseph Disease?

Bibliographic records began in 1972. The original reported families were of Portuguese descent, but in recent years they have been confirmed to be a global disease. Analysis of the linkage of different families has mapped its disease gene to 14q32.1, and found that some SCA similar to the clinical manifestations of MJD are also related to 14q32.1 and named SCA-3. At present, most scholars believe that SCA-3 and MJD are caused by mutations in the MJDl gene and are called SCA-3 / MJD genotypes. In recent years, researches on autosomal dominant SCA families have found that SCA-3 / MJD is the main genotype.

Machado-Joseph disease

Machado-Joseph disease (MJD) is cerebellar ataxia, cone and extrapyramidal symptoms, progressive extraocular muscle paralysis, distal muscle atrophy, facial muscle twitching, exophthalmos, etc. It is characterized by autosomal dominant inherited spinal cerebellar degeneration (SCA-3 / MJD). Classified as ADCAI (OMIM: 109150).

Overview of Machado-Joseph disease

Machado-Joseph disease epidemiology

Nakano et al. (1972) first discovered an autosomal dominant ataxia family in Portuguese descendants living in New England. Members of this family were founded by the island of San Miguel in the Azores archipelago in the late 19th and early 20th centuries. Moved to Massachusetts, USA. Most patients begin to show ataxia gait around the age of 40, as well as various other symptoms associated with the nervous system. The possible sites of involvement are in the cerebellum and brain stem. They are named Machado disease after their common ancestor William Maehado. In the same year, Woods and Schaumburg reported a dominant genetic ataxia Thomas family, also descended from the Azores, with clinical manifestations of substantia nigra-spinal-dentate degeneration with nuclear ophthalmoplegia. Rosenberg (1976) found that Joseph's family was relocated from the Flores Islands of the Azores to California, and the patient developed symptoms of striatum-substantia nigra degeneration, called Joseph disease. Rosenberg et al. (1997) also found a dominant genetic ataxia family that moved from the Azores to Massachusetts, and speculated that these four dominant genetic ataxias with common ethnic origin are the same disease. The pathological difference may be a phenotypic variation known as Azorean disease. Since then, researchers have renamed it Machado-Joseph disease due to the discovery of many similar cases of non-Azores origin.

Since then, many MJD families of Portuguese origin have been found in the Azores, Portugal, Brazil, the United States, Canada, Japan and other places. The prevalence of MJD in Portugal is 0.6 / 100,000, of which the Azores is 40.8 / 100,000 and Flores Island is as high as 9/1000. Initial research suggested that MJD was limited to Portugal and Portuguese descendants. As more families were discovered worldwide, it has been confirmed that MJD is distributed on five continents, and many families do not have any Portuguese blood relationship. Among SCA patients of Portuguese origin, the positive rate of SCA-3 / MJD is as high as 41% to 74%, which is the highest incidence of autosomal dominant ataxia. Domestic and foreign studies have found that SCA-3 / MJD positive rates are as high as 17% to 55% even in non-Portuguese populations, which are also the most common genotypes of SCA; and SCA-1, SCA-2, SCA-6, The positive rates of DR PLA were 3% to 27%, 5% to 13%, 6% to 27%, and 1% to 20% of SCA, respectively. The differences in these results were related to racial differences and genetic background. At present, it is more consistent that SCA-3 / MJD is the most common SCA subtype, while DRPLA is mainly found in the Japanese population, and SCA-7 is mainly found in the United States and France.

Molecular Genetics and Pathogenesis of Machado-Joseph Disease

Takiyama (1993) used linkage analysis to locate the MJD gene on the long arm of chromosome 14. Kawaguchi (1994) used chromosomal in situ hybridization technology to find the related gene MJD1 located at 14q32.1 as the best candidate gene for MJD. Using CAG repeats in this gene to further analyze clinically and pathologically confirmed MJD family members and normal people It was found that the (CAG) n structure had undergone heterozygous amplification in MJD patients, and the cDNA sequence of the entire MJD-1 gene was cloned, thereby confirming that MJD was located in the coding region of the disease gene MJD-1 protein. Neural system degeneration caused by CAG trinucleotide repeat amplification mutation. Later, in the study of another 14q32.1 neurological degenerative disease, SCA-3, it was also found to be related to the mutation of the MJDl gene, and was called the SCA-3 / MJD genotype.

The MJD-1 gene is composed of 1776 bases (bp), which contains a long open coding structure. The CAG repeat is located at the C-terminus of the open coding region and encodes a polyglutamine sequence. There are three places within the CAG repeat that can be interrupted by two variable sequences (CAA or AAG). Northern blot showed that 1776bp mRNA was expressed in all tissues, but strong 2kb mRNA was expressed in testis; and reverse transcription PCR (RT-PCR) showed that two different CAG mRNAs were expressed in the human brain; These results suggest that both alleles are expressed in the human brain and that the CAG repeat number of each allele is polymorphic. However, there was no significant difference in MJDl mRNA levels in different brain tissue levels of MJD patients, indicating that there are other regulatory factors in selective neuronal degeneration of brain tissue.

The protein encoded by MJDl gene, ataxin-3 protein, is a cytosolic protein containing polyglutamine (polyGln), and its normal function is unclear. When ataxin-3 protein contains abnormally extended polyGln peptide chains, it may acquire new functions, causing the formation of neuronal intranuclear inclusions (NIIs) and degeneration of neurons in specific regions of the nervous system. Similar to other neurodegenerative diseases caused by repeated dynamic mutations of CAG trinucleotides, such as SCAl, Huntington's disease (HD), and DRPLA, similar disease genes containing abnormal amplification (CAG) n produce abnormally amplified polyGln peptide chains After being hydrolyzed in the cytoplasm by caspase, etc., fragments of abnormally amplified polyGln residues with different molecular weights are formed. Such fragments enter the nucleus and continue to aggregate to form nuclear inclusions. Causes cell death. The study found that only truncated ataxin-3 cDNA fragments containing abnormally amplified polyGln residues can enter the nucleus, aggregate to form nuclear inclusions and cause cell death; while full-length ataxin containing normal polyGln or containing abnormally amplified polyGln -3 cDNA has no such changes. This result has been confirmed in studies of transfected cells and transgenic animals.

At present, it is speculated that this selective nervous system damage may be related to the protein-protein interaction of a mutant protein containing abnormally amplified polyGln with a specific protein in the cytoplasm, and eventually lead to the formation of NIIs and degeneration of selective neurons. . This interaction may be related to the domain sequences on both sides of the polyGln.

MJDl MJDl gene and clinical relevance in Machado-Joseph disease

The structure of normal human MJDl gene (CAG) n is polymorphic, n is between 12 and 41, of which n is 14 with the highest frequency, and the proportion of n and 14 in the Chinese population is 44% and 20%, respectively. Heterozygous amplification of (CAG) n of the MJD1 gene in SCA-3 / MJD patients usually occurs between 62 and 84. There are obvious differences (CAG) n between normal people and patients without overlap, which can be used as the basis for SCA-3 / MJD genetic diagnosis and pre-symptom diagnosis. The number of CAG amplification of the MJDl gene is closely related to the clinical manifestations of patients. At present, studies on SCA-3 / MJD families in different regions and races have found that: The number of CAG repeats abnormally amplified is related to the age of the patient and the severity of the disease. Negative correlation, that is, the greater the number of (CAG) n repeated amplifications, the earlier the age of onset, and the more severe the clinical symptoms. The CAG repeat number has intergenerational instability, and the increase is more than the decrease. This provides a reasonable explanation for the clinical premature genetic phenomenon in patients with SCA-3 / MJD, that the early onset and exacerbation of the offspring are due to the increase in the number of trinucleotide repeat copies during passage. At the same time, most studies have found that SCA-3 / MJD has a paternal inheritance tendency, that is, the number of CAG repetitive amplification increases greatly during paternal inheritance, but this instability is far less obvious than HD, SCA-1 and DRPLA. When further studying the number of extended CAG repeats in sperm of SCA-3 / MJD male patients, it was found that 92% of CAG repeats in peripheral blood autologous cells of the same patient were different, of which 32% appeared to increase and 60% to shorten. Intergenerational instability may also be related to imbalanced allele segregation amplified in meiosis in male patients. The number of CAG repeats is related to the appearance of certain clinical symptoms and signs. For example, in the Takiyama study, the number of CAG amplification repeats was positively correlated with exophthalmos and pyramidal tract signs, while Durr found that abnormal tendon reflexes, disappearance of vibration sense, and axonal neuropathy had a certain correlation with CAG amplification repeats. But it is not enough to explain the difference in symptoms between individuals. Because the study of the correlation between the main clinical symptoms and signs and the number of CAG repeats is not consistent in different families, and the CAG repeat number can only be a genetic marker of the disease, there are other modification factors that affect the phenotype of the disease, so it cannot be completely analyzed. The CAG repeat number was used as a predictor of the clinical manifestations of SCA-3 / MJD.

Machado-Joseph disease pathology

Spinal cerebellar tract, dentate nucleus, pontine, vestibular nucleus, hypothalamus and extrapyramidal structures are usually characterized by degeneration of the substantia nigra, red nucleus, pale globules, and lewy bodies, and also include the neuromotor nucleus, anterior horn of spinal cord Nerve cells including cells, Clarke column, and medial lateral column were lost, while cerebellar cortex, cerebral cortex, and lower olive nucleus were normal. The pathological changes better explain some of the clinical characteristics of the patient, such as the cerebral cortex and thalamus are rarely involved. The cognitive function is relatively retained in most SCA-3 / MJD cases. The loss of nerve cells in the medial lateral column of the spinal cord is clinically related to some patients. The appearance of autonomic symptoms is consistent.

Compared with SCA-1, basal ganglia damage was more severe in patients with SCA-3 / MJD, especially the degeneration of the medial paleosphere and hypothalamus nucleus was more pronounced, while the degeneration of SCA-1 paleosphere was mainly lateral. In contrast, olive and cerebellar cortical lesions are mainly seen in SCA-1, manifested by Purkinje cell loss and cerebellar degeneration. In addition, although both have spinal cord damage, the locations are different: posterior column involvement is more common in SCA-1, Clarke column involvement is more common in SCA-3 / MJD, and medial lateral column degeneration exists only in SCA-3 / MJD . Compared with DRPLA, the latter usually does not have loss of ocular motor neuron cells, and paleoglobular degeneration is limited to the lateral side.

It is worth noting that although the pathological changes of SCA-3 / MJD have certain characteristics, the degree of involvement in different parts of different cases may be different, and sometimes there is heterogeneity. For example, in the pathological changes of two Chinese SCA-3 / MJD patients, pale globules, Lewy bodies, and dentate nuclei were less affected, substantia nigra, red nuclei, neurokinesis, Clarke column, spinal cerebellar tract, and anterior horn cells Severely affected. In addition, in cases where the pathological changes reported by Cancer corresponded to DRPLA, the genetic diagnosis was SCA-3 / MJD.

Clinical manifestations of Machado-Joseph disease

SCA 3 / MJD are mostly middle-aged. The average reported age abroad is 37.4 ± 14.1 years, but it can be from 1 to 73 years. The average survival time is 20 years. Most of the deaths are due to repeated pulmonary infection or bulbar function. Central respiratory failure caused by disorders. The average age of onset of SCA-3 / MJD patients in domestic genetic diagnosis is 33.9 ± 9.5 years.

The main clinical manifestations of patients with SCA-3 / MJD are cerebellar ataxia, dysarthria, dysphagia, convulsions, pyramidal tract signs, etc., which may be accompanied by exophthalmos, facial tongue tremor, exophthalmos, gaze Paralysis, slow eye activity, muscular atrophy, dystonia, extrapyramidal signs, autonomic symptoms, etc.

Coutinho (1978) classified SCA-3 / MJD into three types: type I is mainly composed of dystonia-tonic extrapyramidal symptoms, pyramidal tract signs and progressive extraocular muscle paralysis, and type is composed of cerebellar signs and cones. The physical signs are mainly, and the type III is mainly distal symmetrical muscle atrophy and cerebellar signs. The signs of peripheral neuropathy are obvious, including muscle weakness, muscle atrophy, and dull feeling. Secondary symptoms such as progressive extraocular muscle paralysis, facial tongue muscle tremor, and exophthalmos, although not common, are characteristic manifestations of SCA-3 / MJD. The age at onset of each type of patients was: type I averaged 24.3 years, type averaged 40.5 years, and type averaged 46.8 years; CAG extension repeats were: type I 79.4 ± 1.0, type 74.6 ± 0.5, Type 72.6 ± 1.1; CAG repeat number was significantly negatively correlated with age at onset. Rosenberg supplemented type IV with age-related symptoms, obvious Parkinson's signs with ataxia, distal muscle atrophy, and loss of sensation. Some patients with type IV began to be diagnosed with Parkinson's disease. In addition, SCA-3 / MJD can also appear in the phenotype of spastic paraplegia. Some patients with clinical manifestations of typical spastic paraplegia have been genetically diagnosed as SCA-3 / MJD. Of course, many cases do not exist independently in one subtype, but show obvious overlap and transition between types, that is, clinical symptoms of different subtypes at different stages of the disease course.

Machado-Joseph disease diagnosis

Dr. Sakai's diagnostic criteria: the genealogical lineage pattern of autosomal dominant genetic disease; clinical symptoms can be divided into the above three symptoms; those with the following 6 clinical characteristics are more likely to SCA-3 / MJD : Facial muscle, lingual muscle tremor, obvious horizontal nystagmus, normal intelligence, progressive extraocular muscle paralysis, exophthalmos, dystonia. The clinical manifestations of SCA-3 / MJD and SCA-1 are similar. Both cases show extraocular muscle paralysis, muscle atrophy, and spasticity, but the former is more common, and extrapyramidal symptoms and dystonia are rarely seen in SCA- 1; SCA-2 is characterized by weakened tendon reflexes, dementia, and slow eye activity. However, due to genetic heterogeneity and phenotypic heterogeneity of SCA, the clinical manifestations of various subtypes often overlap.

At the 3rd International MJD Conference, Nicholson reported an Australian family with clinical manifestations of MJD but with SCA-1 gene mutation; Larrini found a French family lined on chromosome 14q32.1, with MJD and SCA appearing in three generations. -1 and the clinical symptoms of spinal pontine ataxia; Cancel also found a mutation in the MJDl gene in a family with a phenotype of DRPLA in France. Among genetically diagnosed Chinese SCA-3 / MJD patients, a small number of patients with mental retardation and weakened tendon reflexes are difficult to distinguish clinically from SCA-2 and some SCA-1 patients. Therefore, although SCA-3 / MJD has certain clinical characteristics, due to its obvious clinical heterogeneity, it is difficult to make a correct diagnosis based on clinical manifestations only, and it can only be confirmed by genetic diagnosis.

Machado-Joseph disease test

Head MRI showed atrophy of the cerebellum and brain stem. Characteristic changes include atrophy of the cerebellum afferent and efferent fibers, as well as atrophy of the frontal lobe, temporal lobe, and pale bulb. Leaf atrophy, half of patients with T2 weighted images and proton weighted images may have high signal changes in lateral pontine fibers, and some patients with T2 weighted images can see low signals on the dorsal outer side of the putamen. The degree of atrophy of the cerebellar vermis and brainstem on the patient's head MRI was not only related to the age of onset, but also positively correlated with the number of CAG amplifications. Except for cerebellum and brainstem atrophy, patients with SCA-3 / MJD may have significant dilatation of the four ventricles; while patients with SCA-1 and SCA-2 mainly exhibit pontine and cerebellar atrophy, and SCA-6 is pure cerebellar atrophy.

SPECT showed a significant decrease in local cerebral blood flow (rCBF), but the degree of rCBF reduction was not consistent with the degree of cerebellar atrophy shown by MRI. In addition to PET, in addition to the cerebellar hemisphere, cerebellar vermiform, and brainstem, the occipital cortex also has obvious localized low metabolism.

Somatosensory evoked potentials and auditory evoked potentials are abnormal in most SCA-3 / MJD patients. Transcranial magnetic stimulation studies found that the amplitude of motor evoked potentials was significantly abnormal in patients with SCA-3 / MJD, the central motor conduction time was prolonged and the threshold of motor evoked potentials was increased in patients with SCA-1, while patients with SCA-2 were rarely abnormal. It is suggested that electrophysiological examination has certain significance in the clinical identification of SCA.

In addition, SCA-1, SCA-2, and SCA-3 / MJD can also be initially clinically identified through eye movement detection (rapid saccade eye movement amplitude, rapid saccade eye movement rate, or presence or absence of gaze-induced nystagmus): Gaze-induced nystagmus was present in SCA-3 / MJD patients, and the saccade amplitude was significantly increased in SCA-1 patients, while the saccade rate was significantly reduced in SCA-2 patients.

Machado-Joseph disease genetic diagnosis

Because the repeat number of the MJDl gene (CAG) n is significantly different between normal people and patients and there is no overlap, using appropriate primers for polymerase chain reaction (PCR) amplification can make accurate genetic diagnosis. A PCR amplified fragment containing the MJDl gene (CAG) n structure is obtained by PCR amplification technology. If one or at least one of the PCR product fragments exceeds the normal range, it can be diagnosed as an SCA-3 / MJD patient or symptom. Former patients. According to the results reported in the literature, the CAG repeat number of two alleles of the normal human MJDl gene is between 12 and 41 times, while the CAG repeat number of patients with at least one allele is more than 56 times, and most of them are 62 to 84. Between times. However, the exact CAG repeat number must be known by sequencing analysis.