Background
Machado–Joseph Disease (MJD) otherwise known as Spinocerebellar Ataxia3 (SCA3) is an autosomal dominant neurological disorder characterized by Progressive cerebellar ataxia and incoordination of gait. Sometimes it appears as a dystonic-rigid syndrome associated with Parkinsonism features. This condition was mainly due to the abnormal Cytosine, adenine, guanine (CAG) trinucleotide repeat expansion in a Ataxin-3 gene (ATXN3) [1]. There exist usually three phenotypes of MJD as type 1 with pyramidal and extra-pyramidal signs, type 2 characterized by cerebellar and Pyramidal signs, type 3 associated with cerebellar signs and anterior horn cell degenerative symptoms, and finally fourth variant as Parkinsonism with cerebellar dysfunction [2]. Hereby we report a case of rare type 4 phenotype of patient with MJD associated Parkinsonism.
Case Presentation
A 20-year-old male patient was presented to Government General Hospital, Kadapa with the chief complaints of abnormal posturing of toes of both lower limbs, choreiform movement of both lower limbs, tightness of upper limbs and lower limbs, and tremulousness of right hand. He remains asymptomatic till 3 years back and symptoms started from past 1 year. Later on admission, he developed nystagmus, incoordination of gait, and nasal regurgitation of foods. His past medical history reveals no other health related illness. As his symptoms were getting worse, his blood sample was collected and sent for Genomic DNA analysis which revealed MJD with Parkinsonism. Magnetic resonance imaging (MRI) brain with screening of spine revealed cerebral atrophy (Figure 1).
On general examination, the patient was conscious and oriented, PR—70/mt, blood pressure —120/80 mm of Hg, respiratory rate —20/mt, Planta—Right and Left withdrawal sensory, cardiovascular system —S1S2 normal, and Lungs—Clear.
His laboratory investigations were normal except for RBC—2.8 millions/Cu mm, packed cell volume (PCV)—33%, others includes Sr. Creatinine—0.99 mg/dl, Sr. Sodium—139 mmol/l, Sr. Urea—20 mg/dl, serum glutamic oxaloacetic transaminase —24 IU/l, serum glutamate-pyruvate transaminase —17 IU/l, Sr. Alkaline phosphatase—69 IU/l, Albumin—4.3 gm/ dl, Total protein—7.1 g/dl, total bilirubin—0.8 mg/dl, Conjugated bilirubin—0.1 mg/dl, Sr. creatinine kinase —80 IU/l, hemoglobin —15 gm%, Total count—8,400 cells/cu mm, erythrocyte sedimentation rate —8 mm/ hours, Platelets count—2.70 lakhs/Cu mm, RBC—2.8 millions/Cu mm, PCV—33%, mean corpuscular hemoglobin—33 pg, random blood sugar —80 mg/dl, tri-iodothyronine —136.50 ng/dl, thyroxine —8.45 ng/dl, thyroid stimulating hormone —1.80 μIU/ml, human immune deficiency virus —Negative, hepatitis C virus —Negative, hepatitis B virus surface antigen — Negative, antistreptolysin O —195.57 IU/ml.
Following drug chart was used to treat the condition.
| DRUG | DOSE | ROUTE OF ADMINISTRATION | FREQUENCY | NO OF DAYS USED |
|---|---|---|---|---|
| Tetrabenazines | 25 mg | Oral | Once in day (OD) | Seven |
| Clonazepam | 0.25 mg | Oral | OD | Seven |
| Trihexyphenidyl Hydrochloride | 2 mg | Oral | OD | Seven |
| Levodopa and Carbidopa | 100 mg | Oral | OD | Seven |
| Sodium valproate | 500 mg | Oral | OD | Seven |
| Amantadine Hydrochloride | 100 mg | Oral | OD | Seven |
Discussion
Parkinsonism with cerebellar dysfunction is a rare type 4 phenotype of MJD. It was first genetically confirmed SCA subtype in a patient with the levodopa-responsive Parkinson disease [3]. This condition was often caused by repeated expansions of CAG encoding the polyglutamine (poly Q) and had the pathological evidence of involvement of both basal ganglia and the substantia nigra with dopamine depletion associated with marked cell loss and gliosis in SCA2 and SCA3 [4]. In MJD genes that are affected were present on the chromosome no 14 with normal repeat size of about 12–40 but in this condition, there was expansion size of about 55–86 [5]. In our case the upper repeat size of CAG is 79 which is abnormal, heterozygous status for SCA1 and homozygous status for SCA2 (Table 2). Also, patient had a tremor which becomes slow as get progress and was observed in the distal and proximal regions hence termed as Orthostatic as described in the literature [6]. The condition was onset for the patient at an age of 20 years which was early, and his parents were acting as asymptomatic carriers in this case with autosomal recessive genes. The pathogenesis of Parkinsonism in MJD is mainly associated with the gene called Beta-glucocerebrosidase (GBA). Other protein that is related to ataxin-3 in the pathogenesis of Parkinsonism is Parkin. Additive effect or mutations of both the genes ataxin-3 and GBA were independently associated with the manifestations of Parkinsonism in this patient as evident from the literature [7]. Finally, in all neurodegenerative disease’s protein aggregation with expanded glutamine domain was the basis of disease. However, all the neurodegenerative diseases should not be misdiagnosed because protein aggregation was the basis but the repeated expansions of CAG or polyglutamine tract was observed only in the selective diseases like MJD [8].
Conclusion
It is very important to manage this condition with symptomatic therapy because there were more chances of death to patient due to further complications, such as aspirational pneumonia with dysphagia (Respiratory diseases), Ataxia, and Infectious diseases, like sepsis.
Hence, the patient was provided with the symptomatic relief and physiotherapy options to relieve the Parkinsonism features to prevent the further worsening of the condition. After the follow-up for a period of 1 week, he was found to be stable as Parkinsonism features were resolved and got discharged.