Prenatal diagnosis of spinocerebellar ataxia type 3/Machado-Joseph disease in China's Mainland A case report

Spinocerebellar ataxia type 3/Machado-Joseph disease （SCA3/MJD） is a progressive, currently untreatable and ultimately fatal ataxic disorder that belongs to the group of neurological disorders known as CAG-repeat or polyglutamine diseases. Here, we present the first prenatal diagnosis of SCA3/MJD in China's Mainland in a woman who was known to carry an expanded CAG-trinucleotide repeat in the MJD1 gene. After evaluating motivation and psychological tolerance of the couple, amniocentesis was performed after 14 weeks of gestation. Polymerase chain reactions followed by T-vector cloning and direct sequencing were employed to evaluate the CAG-repeat number of the fetal MJD1 gene. We identified a truncated CAG expansion of 78 repeats in the MJD1 gene of the fetus compared with 81 repeats in his mother.

Spinocerebellar ataxia type 3 with dopamine-responsive dystonia:A case report

BACKGROUND Spinocerebellar ataxia type 3(SCA3)is a rare neurodegenerative disease with high genetic heterogeneity.SCA3 mainly manifests as progressive cerebellar ataxia accompanied by paralysis of extraocular muscles,dysphagia,lingual fibrillation,pyramidal tract sign,and extrapyramidal system sign.However,it rarely has clinical manifestations similar to Parkinson-like symptoms,and is even rarer in patients sensitive to dopamine.We report a patient initially diagnosed with dopamine-responsive dystonia who was ultimately diagnosed with SCA3 by genetic testing,which was completely different from the initial diagnosis.CASE SUMMARY A 40-year-old Chinese woman was admitted to hospital due to severe inflexibility.At the beginning of the disease,she presented with anxiety and sleep disorder.At the later stage,she presented with gait disorder,which was similar to Parkinson's disease.Her medical history was unremarkable,but her mother,grandmother,and uncle all had similar illnesses and died due to inability to take care of themselves and related complications.Laboratory and imaging examinations showed no abnormalities,but electromyography and electroencephalography revealed delayed somatosensory evoked potentials and slow background rhythm,respectively.Her symptoms fluctuated during the daytime,and we initially diagnosed her with dopamine-responsive dystonia.After treatment with lowdose levodopa,the patient’s symptoms were significantly improved,but the final genetic diagnosis was SCA3.CONCLUSION SCA3 has various clinical phenotypes and needs to be differentiated from Parkinson's syndrome and dopamine-responsive dystonia.

Emerging Concepts of Pathogenesis and Comprehensive Therapeutic Strategies for Spinocerebellar Ataxia Type 3

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph Disease (MJD), is an autosomal dominant neurodegenerative disorder that predominantly involves the cerebellar, pyramidal, extrapyramidal, motor neuron and oculomotor systems. SCA3 presents strong phenotypic heterogeneity and its causative mutation of SCA3 consists of an expansion of a CAG tract in exon 10 of the ATXN3 gene, situated at 14q32.1. The ATXN3 gene is ubiquitously expressed in neuronal and non-neuronal tissues, and also participates in cellular protein quality control pathways. Mutated ATXN3 alleles present about 45 to 87CAG repeats, which result in an expanded polyglutamine tract in ataxin-3. After mutation, the polyQ tract reaches the pathological threshold (about 50 glutamine residues);the protein is considered that it might gain a neurotoxic function through some unclear mechanisms. We reviewed the literature on the pathogenesis and therapeutic strategies of spinocerebellar ataxia type 3 patients. Conversion of the expanded protein is possible by enhancing protein refolding and degradation or preventing proteolytic cleavage and prevents the protein to reach the site of toxicity by altering its ability to translocate between the nucleus and cytoplasm. Proteasomal degradation and enhancing autophagic aggregate clearance are currently proposed remarkable therapy. In spite of extensive research, the molecular mechanisms of cellular toxicity resulting from mutant ataxin-3 remain no preventive treatment is currently available. These therapeutic strategies might be able to improve sign symptoms of SCA3 as well as slow the disease progression.

Nerve Growth Factor for the Treatment of Spinocerebellar Ataxia Type 3： An Open-label Study

Background： Spinocerebellar ataxia type 3 （SCA3） is the most common subtype of SCA worldwide, and runs a slowly progressive and unremitting disease course. There is currently no curable treatment available. Growing evidence has suggested that nerve growth factor （NGF） may have therapeutic effects in neurodegenerative diseases, and possibly also in SCA3. The objective of this study was to test the efficacy of NGF in SCA3 patients. Methods： We performed an open-label prospective study in genetically confirmed adult （〉18 years old） SCA3 patients. NGF was administered by intramuscular injection （18 μg once daily） fbr 28 days consecutively. All the patients were evaluated at baseline and 2 and 4 weeks after treatment using the Chinese version of the scale for assessment and rating of ataxia （SARA）. Results： Twenty-one SCA3 patients （ 10 men and 11 women, mean age 39.14 ± 7.81 years, mean disease duration 4.14 ± 1.90 years, mean CAG repeats number 77,57 ± 2.27） were enrolled. After 28 days of NGF treatment, the mean total SARA score decreased significantly from a baseline of 8.48± 2.40 to 6.30 ± 1.87 （P 〈 0.001 ）. Subsections SARA scores also showed significant improvements in stance （P = 0.003）, speech （P = 0.023）, finger chase （P = 0.015）, fast alternating hand movements （P = 0.009）, and heel-shin slide （P = 0.001）. Conclusions： Our preliminary data suggest that NGF may be effective in treating patients with SCA3.

Automated Behavioral Phenotyping Reveals Presymptomatic Alterations in a SCA3 Genetrap Mouse Model

Characterization of disease models of neurodegenerative disorders requires a systematic and comprehensive phenotyping in a highly standardized manner. Therefore, automated high-resolution behavior test systems such as the homecage based LabMaster system are of particular interest. We demonstrate the power of the automated LabMaster system by discovering previously unrecognized features of a recently characterized atxn3 mutant mouse model. This model provided neurological symptoms including gait ataxia, tremor, weight loss and premature death at the age of 12 months usually detectable just 2 weeks before the mice died. Moreover, using the LabMaster system we were able to detect hypoactivity in presymptomatic mutant mice in the dark as well as light phase. Additionally, we analyzed inflammation, immunological and hematological parameters, which indicated a reduced immune defense in phenotypic mice. Here we demonstrate that a detailed characterization even of organ systems that are usually not affected in SCA3 is important for further studies of pathogenesis and required for the preclinical therapeutic studies.