DOI: https://doi.org/10.21203/rs.3.rs-2069417/v1
Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is an autosomal dominant genetic disease with substantial heterogeneity in clinical manifestations. It typically starts with ataxia and can be divided into five subtypes. The fourth subtype of SCA3 is characterized by parkinsonian and peripheral neuropathy. However, this phenotype is rare, and it tends to be easily misdiagnosed as Parkinson's disease.
We report a 51-year-old female patient who initially presented with pure parkinsonian symptoms at the age of 30. She responded well to levodopa treatment and had a diagnosis of Parkinson's disease for almost 20 years. Ataxia symptoms, symptom fluctuations and dyskinesia occurred in the late stage of the disease. A literature review was included to summarize the clinical features of the fourth subtype of SCA3 (type IV SCA3) and its relevant pathogenesis.
Type IV SCA3 with 66 CAG repeats was diagnosed by genetic testing. It is initially characterized by a pure parkinsonian phenotype indistinguishable from PD, short CAG repeat expansions, and a good response to levodopa.
Type IV SCA3 should be considered when diagnosing Parkinson's disease, especially in those with a family history. More research is needed to detect the pathogenesis of the parkinsonism phenotype in type IV SCA3.
Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant neurodegenerative disease. The clinical manifestations of SCA3 vary, including ataxia, oculomotor abnormalities, pyramidal syndrome, peripheral neuropathy, and extrapyramidal signs. However, the parkinsonian phenotype presents as the main manifestation in SCA3 is rare. According to clinical manifestations, SCA3 can be divided into five subtypes[1]. Type Ⅰ is characterized by progressive cerebellar ataxia, severe dystonia, pyramidal signs, and progressive external ophthalmoplegia (PEO). Type Ⅱ is the most frequent, characterized by ataxia, pyramidal deficits and PEO. Type Ⅲ is the second most frequent, presenting with cerebellar ataxia and PEO, and peripheral alterations may feature slight pyramidal and extrapyramidal signs. Type Ⅳ presents with parkinsonian and peripheral neuropathy[2]. Type Ⅴ is characterized by marked spastic paraplegia with or without cerebellar ataxia.
Here, we report a case of type IV SCA3 initially with a pure parkinsonian phenotype and a good response to levodopa. Furthermore, we review the relevant literature on type IV SCA3 cases and the relevant pathogenesis.
A 51-year-old female patient was admitted to the Department of Neurology, Taizhou Hospital, Zhejiang Province, in April 2019 because of slow movement, stiff limbs for 20 years and the inability to walk for 3 years. Twenty years before admission, the patient developed bradykinesia, stiffness of the lower limbs, and festinating gait. Fourteen years before admission, the patient developed limb tremors, initially involving the right lower limb and later involving the left upper limb. The patient was treated with medoba, benzhexol hydrochloride tablets, amantadine tablets and piribedil sustained release tablets. The symptoms were well controlled. Three years before admission, the patient's husband died unexpectedly. The patient began to experience sleep disorders, irregular medication use, unstable walking, ambiguous speech, laborious speech, slight choking and coughing when drinking water, general pain, symptom fluctuations and abnormal movements after taking anti-Parkinson’s drugs. Due to the gradual aggravation of the symptoms, she was unable to stand steadily and walk independently. Thus, she came to our hospital for treatment.
The patient's mother, mother's brother and the son of the mother's brother all had a history of walking instability and died at approximately 30 years of age.
The physical examination showed vague speech, low voice, a mask-like facial appearance, and free movement of the bilateral eyeballs in all directions. No exophthalmos or nystagmus was present. The muscle strength of the limbs was grade V, and the muscle tension of the limbs was slightly increased. Bilateral interosseous muscle atrophy was present. Tremor was seen in the left upper limb. Bilateral pathological signs were negative. The patient could not complete the heel-knee-tibia test or finger-nose test. The sensory system was normal.
Routine blood, liver and kidney function, electrolytes, coagulation function, thyroid function and tumour series evaluations were normal.
Brain MRI (Fig. 1) showed atrophy of the cerebellum and brain stem. MRI of the cervical spine (Fig. 2) showed that the spinal cord was thinned. Electromyography showed changes in neurogenic damage and extensive peripheral nerve damage.The results of the genetic analysis (Fig. 3) showed that the CAG copy number in the SCA3 pathogenic gene ATXN3 was 66.
The patient was treated with dobasazide tablets, piribedil sustained-release tablets, vitamin B6 tablets, sertraline hydrochloride tablets, buspirone hydrochloride tablets, coenzyme Q10 and tattireline.
Currently, the patient can only sit in a wheelchair and has ambiguous speech and limb tremors accompanied by symptom fluctuations and dyskinesia.
SCA3 is an autosomal dominant spinocerebellar ataxia with obvious ethnic and geographical differences. The incidence of SCA3 is the highest in some regions of Brazil, Portugal and China[3]. SCA3 usually begins with ataxia. However, some patients may also have extrapyramidal signs in the early stage. Type Ⅳ is relatively rare and mostly occurs in African American patients[4]. Studies have shown that less than 3% of SCA3 patients present with Parkinsonism. In a Brazilian cohort of 167 patients with SCA3, only 4 (2.4%) patients were type Ⅳ[5]. Du YC et al. reported that only one case was type Ⅳ in 667 Chinese SCA3 patients[6]. In another cohort of 452 PD patients in mainland China, Wang et al. found only 4 (1%) cases of type IV SCA3 in 386 sporadic PD and 3 in 66 familial PD[7]. Parkinsonism in SCA3 patients is usually masked by other more prominent features, such as ataxia, dystonia, and spasm[8].
Here, we report a rare case of SCA3 type IV. In our case, the patient initially presented with pure parkinsonism symptoms for a long time and was diagnosed with Parkinson's disease for almost 20 years. As our case showed, type IV SCA3 is difficult to distinguish from Parkinson's disease in the early stage. Therefore, it is critical for clinicians to recognize this type of manifestation and consider this type in diagnosis.
SCA3 is an autosomal dominant neurodegenerative disease caused by abnormal and unstable expansion of the CAG region in the coding region of the ATXN3 gene located on chromosome 14q32.1. The normal CAG expansion number was fewer than 44, and the pathologic expansion number ranged from 52 to 86[2]. The clinical phenotype of SCA3 varies greatly with CAG repeat length[4]. CAG repeat length is negatively correlated with the age of onset and positively correlated with the severity of the disease and the speed of disease progression[9, 10]. The offspring of SCA3 usually become sick earlier and more seriously. Some researchers believe that the CAG amplification range of type IV SCA3 patients is smaller than that of other types, and the age of onset is also later[8, 11]. However, further studies are still needed to understand why CAG in patients with the PD phenotype repeats in lower range expansion[7].
It was found that type Ⅳ SCA3 with 66 CAG repeats had a good levodopa response and developed with motor complications, which was indistinguishable from PD[2]. Interestingly, our case has the same CAG repeats number of 66 and had extremely similar clinical manifestations with that case. It was difficult to distinguish from Parkinson's disease initially and had a good DOPA response and motor complications in the late stage. Regretfully, the patient's mother, her mother’s brother and the son of the mother's brother died relatively early. We were unable to obtain information about their gene mutations and medical history.
We reviewed the relevant literature and summarized the clinical features of type Ⅳ SCA3 cases (Table 1). In these cases, the expansion number of CAG was 58 to 73, and the onset age was 25 to 67 years old. From these cases, we can see that type IV SCA3 is initially characterized by a PD-like phenotype, short CAG repeats expansions, early onset age and a good response to levodopa for a long time.
Study | country | Number of study population/ case report | Number of type IV SCA3 | CAG Expansion number | Onset age(y) | Levodopa response |
---|---|---|---|---|---|---|
Moro et al. (2014)[5] | Brasil | 167 SCA3 patients | 4 | 72.3 ± 4.5 | 36.2 ± 8.2 | No description |
Hardy et al. (2001)[11] | African | Case report | 3 | 73/67/68 | 31/30/57 | +/+/+ |
Wang et al. (2009)[7] | China | 386 sporadic PD | 3 | 58/64/67 | 67/36/38 | +/+/+ |
Wang et al. (2009)[7] | China | 66 familial PD | 4 | 65/69/73/67 | 46/25/40/39 | +/+/±/+ |
Du et al. (2020) [12] | China | 667 SCA3 patients | 1 | 68 | 44 | - |
Lu et al. (2004)[13] | China | 60 patients from 49 families with familial parkinsonism | 3 | 70/70/70 | 38.67 ± 5.13 (33–43) | +/+/+ |
Bettencourt et al. (2011)[4] | Portugal | 70 SCA3 patients | 2 | 72/72 | 30/33 | +/+ |
Zhang et al. (2021)[14] | China | Case report | 1 | 65 | 37 | + |
Song et al. (2006)[15] | China | 5 Parkinson's families | 2 | 66/69 | 25/46 | +/+ |
Kuo et al. (2022)[16] | China | Case report | 1 | 66 | 30 | + |
Buhmann et al.(2003)[17] | Ghana | Case report | 1 | 66 | 36 | + |
At present, the pathogenesis of the SCA3 Parkinson's phenotype is unclear. The reported mechanisms mainly include gene polymorphism, severe subthalamic nuclear damage, and CAG repeat expansions. Studies have suggested that polymorphisms in the DJ-1 and APOE genes may be related to the parkinsonian phenotype of SCA3. The good response to levodopa of type IV SCA3 patients may be related to the greater loss of dopaminergic neurons in the substantia nigra and fewer dopamine receptors in the striatum[8]. However, both SCA3 and Parkinson's disease have severe degeneration of substantia nigra dopaminergic neurons, but only a few SCA3 patients have Parkinson's-like symptoms[4]. Schöls L et al. believed that severe neuronal degeneration in the motor area of the subthalamic nucleus may offset Parkinson's syndrome caused by degeneration of dopaminergic neurons in the substantia nigra[18]. Autopsy data showed that degeneration of subthalamic nuclei may prevent parkinsonism in SCA3[19]. Conventional stereotactic subthalamic excision and high frequency deep brain stimulation of subthalamic nuclei can treat Parkinson's disease. This also suggests that severe subthalamic nucleus damage may be the cause of the parkinsonian phenotype of SCA3. In addition, the recent research of Kuo et al. also suggested that bilateral subthalamic nucleus deep brain stimulation could reverse motor and nonmotor complications in a type IV SCA3 patient[16]. Gwinn-Hardy et al. believed that parkinsonism in SCA3 was associated with smaller CAG repeat expansions[11]. Frequent uninterrupted CAG repeats may prevent SCA3 Parkinson's disease in some way[19]. Moro et al. believed that new symptoms may change the phenotype of the patient during the course of the disease [5]. Charles et al. suggested that the phenotype Parkinsonism can be masked by cerebellar degeneration, which was supported by the clinical observations of cerebellar stroke reducing stiffness in ipsilateral Parkinson's disease patients[20]. This may also be the reason why type IV SCA3 is rare. More research still needs to be conducted to determine the pathogenesis of the SCA3 Parkinson's phenotype.
In conclusion, we report a rare case of SCA3 type Ⅳ. When diagnosing Parkinson's disease, especially with a family history, SCA3 type IV should be considered. The difference between the parkinsonian phenotype of SCA3 and Parkinson’s disease should be investigated, and its identification method should be determined. More studies are needed to explore the pathogenesis of the parkinsonian phenotype in type IV SCA3.
Acknowledgments
We thank the patient in this study.
Conflicts of interest
The authors have no relevant financial or non-financial interests to disclose.
Funding
No funds, grants, or other support was received.
Ethical approval
This study was approved by the Ethics Committee of Taizhou hospital, Zhejiang Province.
Consent to participate and consent to publish
Informed consent was obtained from the patient in the study.
This patient signed informed consent regarding publishing their data and photographs.
Data availability
Data is availability from the authors.
Author contributions
Ting Ling Wang collected the clinical data,performed the literature search and data analysis, and drafted the initial manuscript. Gang Wu and Su Zhi Liu revised the article critically. All authors contributed to the intellectual content of this manuscript and approved the final manuscript as submitted.