Machado-Joseph disease

Introduction to Machado-Joseph disease Machado-Joseph's disease (MJD) is named after the first two surnames (AntoneJoseph and Machado), and is also known as Azorean disease because of the disease in the Azores Islands. Sexually degenerative nervous system degenerative diseases. Machado-Joseph disease is a type of hereditary spinocerebellar ataxia (type III, SCA3) with cerebellar ataxia, pyramidal tract sign, abnormal muscle tone and tonic and other extrapyramidal syndrome, limbs Muscular atrophy and sensory disturbances, extraocular tendons and nystagmus are characterized by autosomal dominant inheritance. The disease was first reported by Nakano (1972), which was thought to be a hereditary disease of the bloodline of Portugal. It has also been found in black and yellow families in recent years. China first reported in 1988, so it is listed separately here. basic knowledge The proportion of illness: the incidence rate is about 0.006%-0.01% Susceptible people: no special people Mode of infection: non-infectious Complications: ataxia

Cause of Machado-Joseph disease

(1) Causes of the disease

Previous studies have shown that the Machado-Joseph disease gene (MJD1) is located in the chromosome 14q32.1 region, and the third exon of the gene near the 3rd end is an unstable CAG repeat (C: cytosine; A: adenine) ;G:guanine), encoding the MJD1 gene product ataxin-3, the polyglutamine chain, the normal function of ataxin-3 is still unclear, and its extension mutation leads to Machado-Joseph disease, and its CAG copy number is 60~ 84 (normal CAG copy number is 14 to 47), the encoded polyglutamine chain may be the protein basis of the disease, and has a toxic effect on the nervous system.

(two) pathogenesis

Studies have shown that the mutant ataxin-3 can be integrated into cultured cells and damaged areas of MJD patients, resulting in neuronal formation of neuronal intranuclear inclusions (Nlls), and can cause the death of infected cells.

MJD is one of at least 8 neurodegenerative diseases (Huntington's disease, SCA1, etc.) caused by CAG repeats. The number of CAG repeats is positively correlated with the severity of pathological changes. This is an important feature of Machado-Joseph disease, but NII formation and neurons The relationship between denaturation is unclear.

Wang et al. found that ataxin-3 interacts with the homologues RAD23, HHR23A and HR23B of two human yeast DNA repair proteins, and that ataxin-3 interacts with the N-terminal ubiquitin-like region of the HHR23 protein, the latter for nucleosides. Acid excision repair is extremely important. In addition, HHR23A is complemented by ataxin-3 to enter the nuclear inclusion bodies formed by the mutant ataxin-3. The results suggest that this interaction is related to the normal function of ataxin-3, which may exist in MJD. HHR23 dysfunctional protein.

Isica et al. and Yasuhiro compared the CAG repeats of 6 to 12 tissues of Machado-Joseph patients, and found that there are differences in the number of CAG repeats in different tissues, that is, patients with Machado-Joseph disease have somatic mosaicism (SM), but The selectivity of lesions was not found to be related to SM. In 1998, Cancel et al reported that there may be no SM in patients with Machado-Joseph disease. Lima et al considered that highly repetitive CAG haplotypes were associated with early onset age.

Van Alfen et al reported that a Dutch family had 2 generations of 4 people with a CAG repeat number of 53-54, except for the youngest one, which showed restless leg syndrome and sensorimotor axonalism with involuntary contraction of muscle fibers. Polyneuropathy, the authors believe that the number of CAG repeats is related to the pathogenesis, and is related to restless leg syndrome and peripheral nerve damage.

Zhou Yongxing analyzed the CAG (cytosine adenine guanine) repeats at the 3rd end of the gene coding region of 15 patients and 18 healthy people from 4 families. It was found that all 15 patients had CAG repeat extension, and the number of repeats was 72-86. Compared with normal people (14-40), the difference was significant. In addition, the age of onset was significantly negatively correlated with the number of CAG repeats. There was no significant correlation between clinical symptoms and the number of CAG repeats. Further analysis of the number of CAG repeats in each generation of the family It is found that there are intergenerational instability in the number of CAG repeats. This instability is the molecular genetic basis of the phenomenon of clinical genetic premature emergence. Shao Ziqiang et al. studied and compared CAG of more than 30 tissues in 4 Chinese patients with Machado-Joseph disease. The number of repeats suggests that there is no difference in CAG repeat expansion in various tissues of patients with Machado-Joseph disease, but the CAG repeat and its encoded polyglutamine chain play different roles in diseased neurons and other normal tissue cells; The susceptibility of histiocytes to the pathogenic effects of CAG repeats and their expression products polyglutamine chain may play an important role in Machado-Joseph disease.

Pathological changes: pathologically, the central and peripheral nerves are extensively damaged, highly selective invasion of the substantia nigra and the inner side of the globus pallidus, motor neurons of the brainstem and spinal cord, and the dentate nucleus of the cerebellum, manifested as substantia nigra, dentate nucleus, pons, Brain stem cerebral nucleus, Clerke column and anterior horn cells degeneration, mild glial cell proliferation, a small number can affect the cerebral cortex, thalamus, reticular structure, lower olive nucleus and autonomic nerve center.

Another feature of pathology is that the affected parts of the neurons have intranuclear inclusions. Although the cytotoxicity of the inclusion bodies in the nucleus is controversial, the inclusion bodies in the neurons have become the neuropathological features of CAG repeat diseases, involving more nervous systems. In this part, this diffuse nuclear pathology marker can appear in MJD, Huntington's disease, spinal cord and ball muscle atrophy, suggesting that this nuclear pathology may be a characteristic change in many neurons in CAG repeat disease. There is some influence on the nuclear function.

Yamada et al. demonstrated by immunohistochemistry that polyglutamine extended and accumulated a large number of neurons in the nuclear nucleus. These nuclear abnormalities involve many neurons in the central and peripheral nervous system, including previous conventional pathology. In the cerebral cortex, thalamus and autonomic nervous center, these new sites of involvement demonstrated by polyglutamine immunohistochemistry may be associated with recent clinical and neuroradiological cortical dysfunction and autonomic dysfunction.

Fujigasaki and other studies have shown that in two different cases, ataxin-3 is added into the nucleus and participates in the process of inclusion formation in the nucleus. In the normal brain, the primitive ataxin-3 is present in the ubiquitin-positive nuclear inclusion body. In marines co, it is suggested that ataxin-3 is added into the nuclear inclusion bodies, even into the nerve cell nucleus of the polyglutamine chain lacking pathological expansion. In the MJD brain, anti-ataxin-3 antibody, anti-ubiquitin antibody and Immunohistochemical analysis such as monoclonal antibody IC2 identified extended polyglutamine chains. The results showed that the number and diameter of Nlls recognized by different antibodies were different. Immunoblotting with double precision fluorescent immunoassay also confirmed the same inclusion. These results in vivo suggest that the extended ataxin-3 forms a center, while the original ataxin-3 enters the nucleus to surround the central portion and is then activated by the ubiquitin/ATP-dependent pathway. In both cases, ataxin -3 can be added into the nucleus and form intranuclear inclusion bodies, suggesting that ataxin-3 can act under the neurotoxic effects of certain stress factors such as aging and polyglutamine chains acting on nerve cells. Bit into the nucleus.

Coutinho reports the pathological manifestations of a family. In addition to the common lesions, there are sensory centers, medial medial columns and thin bundle nuclei, and degeneration of the wedge bundle nucleus.

Machado-Joseph disease prevention

Genetic counseling, prevention measures include avoidance of close relatives, carrier genetic testing and prenatal diagnosis and selective abortion to prevent the birth of children.

Machado-Joseph disease complications Complications, ataxia

Machado-Joseph disease is a type of hereditary spinocerebellar ataxia (type III, SCA3), with extraclinal syndrome such as cerebellar ataxia, pyramidal tract sign, abnormal muscle tone and tonicity, limbs Muscle atrophy and sensory disturbances, extraocular tendons, and nystagmus are characteristic.

Machado-Joseph disease symptoms common symptoms nystagmus sensory disturbance extrapyramidal damage dysarthria palsy cerebellar ataxia fasciculation sleep disorder ataxia dysplasia myoclonus

1. Main clinical features

Cerebellar ataxia and varying degrees of pyramidal tract signs, extrapyramidal signs or peripheral muscular atrophy are the main clinical features.

2. Clinical classification

The clinical manifestations of patients with different ages of onset were slightly different. Coutinho classified the disease into 3 types according to clinical manifestations: type I accounted for 15%, the age of onset was earlier, 20 to 30 years old, with pyramidal tract sign, extrapyramidal damage sign Progressive extraocular muscle paralysis, may have facial muscles, lingual muscle twitching and mild cerebellar dysfunction and other signs, the fastest progress, mostly died in the age of 45; type II, also known as Joseph disease, accounting for 38%, 30 50 years old, characterized by cerebellar dysfunction and pyramidal tract sign, with or without extraocular tendon, no extrapyramidal signs, mild symptoms, age of death is about 60 years old, type III is also known as Machado disease, accounting for 47%, the age of onset is later, 50-60 years old or 60 years old, with cerebellar dysfunction and motor neuronephropathy (symmetric extremity muscle atrophy), with or without extraocular tendon and cone Body sign, slow progress, good prognosis, not all patients can meet the above 3 types, and some cases are mixed type 3, Jardim et al observed 62 cases of MJD patients, found type I MJD and nuclear eye muscle Paralysis is positively correlated; type III MJD is positively associated with supranuclear ophthalmoplegia The average length CAG elderly and pyramidal signs and related dystonia.

Maruvama et al. proposed a new classification method based on CAG repeat length and clinical research: type A (adolescent type): hyperreflexia and dystonia, no proprioception; type C (adult type): reflex decline and proprioception, no Dystonia; type B (intermediate): mixed type, between the two.

3. Main symptoms and signs

The initial clinical symptoms are mostly ataxia gait. Early manifestations include soft palate, dysarthria, vertical or horizontal nystagmus and difficulty in eyelid opening, difficulty in eyeball vision, convex eyes in the late stage, especially the face. Perioral and lingual muscle fibers tremor and atrophy, eye contracture, some patients have facial or soft diaphragmatic hernia and V, VII, IX ~ XII brain innervation muscle involvement, muscle rigidity, sputum and pathological signs positive pyramidal tract sign There may also be hyperkinesia and dystonia, extrapyramidal signs such as hand and foot, and muscle tremors of the extremities and terminal muscle atrophy. There may also be hypothalamic vibration loss, and about 1/3 of patients have scoliosis. Bow-shaped foot, clubbing and other symptoms of bone deformity.

The eye movement disorder of this disease is quite characteristic. Most cases have extraocular muscle spasm, impulsive eye movement disorder and other abnormal eye movements, horizontal or vertical nystagmus, but also exophthalmos, diplopia, optic atrophy, pigmented retinal degeneration, etc. Eye disease.

Schols et al reported that 45% of patients have restless legs syndrome, and other patients with autosomal dominant cerebellar ataxia are rare. Restless leg syndrome is a common but not the only cause of sleep disorders in MJD patients. Age-related, long-term persistent disease and brain stem involvement.

Shimizu analyzed the abnormalities of eye movement abnormalities in 12 cases of a MJD family in Japan. 12 cases had upper eye palsy, horizontal gaze, converging obstacles, most had rapid swept obstacles, followed eye movement disorders, and opened eyes. Difficulties, a few manifestations of exophthalmos, visual impairment, square wave jerk, etc., pupil shape and photoreaction are normal, the author combined with the clinical manifestations of this family, also reported a case of autopsy, pathological findings: spinal cerebellum Bundle degeneration, Clarke column, anterior horn, dentate nucleus and substantia nigra pars compacta neurons, ocular nerve nucleus neurons were significantly lost, Edinger-Westphal nucleus was relatively preserved, trochlear nucleus was slightly involved, and nucleus was relatively Intact, vestibular nucleus neurons decreased, the midbrain back, including the upper humerus, the anterior and posterior combined neurons, demyelination, gliosis, medial longitudinal beam degeneration, the author believes that the autopsy case oculomotor nucleus Loss, while the Edinger-Westphal nucleus is relatively preserved, which is a characteristic pathological finding.

Machado-Joseph disease check

Polymerase chain reaction (PCR) detection of peripheral blood lymphocytes, amniotic fluid, chorionic villus, etc., can show the number of CAG repeat extensions of the MJD gene.

Brain MRI examination may have brainstem and cerebellar atrophy; T2 weighted images showed that M2D patients had a high signal of 45.2% of cerebral pons, while sporadic cerebral pons cerebellar atrophy patients had high signal, and the control group had no high signal. The MRI features of MJD patients were affected by cerebellar efferent and afferent, and the frontotemporal lobe and globus pallidus were atrophied.

Diagnosis of Machado-Joseph disease

diagnosis

The diagnostic criteria are:

1 autosomal dominant inheritance.

2 The main nervous system manifestations include cerebellar ataxia with pyramidal tract sign (type II), with various degrees of extra-pyramidal signs such as dystonia-stability (type I), or peripheral muscular atrophy and sensory disturbances. (Type III).

3 secondary but more specific signs, such as progressive extraocular muscle paralysis, facial muscles and lingual muscle tremors and exophthalmos, these signs are not required, but help to perform physical examination of the proband family members, Helps early diagnosis of patients.

PCR detection is helpful for diagnosis. Hsieh et al. used PCR to detect the number of CAG repeats extended by MJD gene. It is considered to be a simple, reliable and affordable diagnostic method for patients, pre-symptoms and birth. Pre-diagnosis.

Differential diagnosis

Olive-ponsius-cerebellar atrophy (OPCA) can have eye syndrome similar to MJD. Shimizu compared Shy-Draer syndrome (SDS) eye movement disorder with 27 cases of OPCA and found that convergence is not possible, horizontal nystagmus, verticality Restricted gaze, lack of visual inhibition of warm water response fluoroscopy, the incidence of OPCA is extremely low, the difference is statistically significant, and the eyelid opening is difficult, the exophthalmos and involuntary movement of the eye are unique to MJD, therefore, the sub-components of the eye movement Analysis, the identification of MJD and OPCA is beneficial.

The disease can be typical, and it can also be effective for levodopa, but at the same time, dysfunction including pyramidal and cerebellar signs, peripheral neuropathy and/or anterior horn cells can be identified.

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