Natural History and Progression of Dentatorubral–Pallidoluysian Atrophy (DRPLA): A Retrospective Study of 22 Patients

Abstract

Background

Dentatorubral–pallidoluysian atrophy (DRPLA) is a rare neurodegenerative disorder and exhibits diverse clinical phenotypes depending on the age at disease onset. Motor and swallowing functions gradually deteriorate as the disease progresses.

Objective

This study aimed to evaluate natural history and progression of DRPLA.

Methods

We retrospectively analyzed patients with DRPLA (n = 22; juvenile‐onset: 9, adult‐onset: 13), investigating their age at disease onset and the associated clinical features. We determined the age at the beginning of gait disturbance, wheelchair requirement, and bedridden state as motor milestones, in addition to the age at the initiation of enteral nutrition.

Results

The mean ages at disease onset were 12.4 and 36.7 years in juvenile‐ and adult‐onset groups, respectively. Overall, epilepsy and myoclonus were observed more frequently in the juvenile‐onset than in the adult‐onset group, whereas choreoathetosis and psychiatric symptoms exhibited the opposite trend. Ataxia and cognitive impairment were observed in all patients. Additionally, median intervals from the onset of gait disturbance to wheelchair requirement and to bedridden state were 3.0 and 9.0 years in juvenile‐onset group compared to 7.0 and 12.0 years in the adult‐onset group. Enteral nutrition was administered to 17 patients (77.3%) and the age of initiation almost coincided with the age at which patients became bedridden.

Conclusions

Our analysis showed that the duration from wheelchair requirement to becoming bedridden was approximately 5 years in these two groups despite their different phenotypes, with several factors likely contributing to this outcome. Our findings help predict disease progression for patients and their families.

Dentatorubral–pallidoluysian atrophy (DRPLA) is a rare autosomal dominant neurodegenerative disorder caused by CAG trinucleotide expansion in the ATN1 gene. Patients affected by DRPLA have the CAG repeats ≥48, whereas unaffected people generally have the CAG repeats ranging from 6 to 35. ¹ The prevalence of DRPLA is higher in Japan than in other countries. ¹ , ² DRPLA is a subtype of spinocerebellar ataxia (SCA), and neuropathological or radiologic evaluation reveal marked atrophy of the cerebellum and brainstem. ³ , ⁴ , ⁵ DRPLA is clinically characterized by various combinations of symptoms that typically include ataxia, choreoathetosis, myoclonus, epilepsy, cognitive impairment, and psychiatric symptoms. Clinical presentations depend primarily on the age at disease onset, and the clinical severity is generally higher in younger patients. Age is inversely correlated with expanded size of CAG repeat length. ⁶ , ⁷ To clearly distinguish the various clinical phenotypes, they are routinely classified according to age at disease onset as follows. First, DRPLA phenotypes are categorized into two major groups according to age at onset: (I) juvenile‐onset (<20 years) and (II) adult‐onset (≥20 years). Second, adult‐onset DRPLA may be further subcategorized into two types depending on the age at onset: (II‐1) early adult type (20–39 years) and (II‐2) late adult type (≥40 years). ⁶ , ⁷

Juvenile‐onset patients often initially present with myoclonic epilepsy, followed by ataxia and cognitive impairment. In contrast, late adult‐onset patients often initially present with ataxia, subsequently develop choreoathetosis, cognitive and behavioral impairments, and frequently lack epilepsy. Early adult‐onset patients exhibit an intermediate phenotype between juvenile‐ and late adult‐onset phenotypes. In other words, early adult‐onset patients exhibit myoclonic epilepsy and ataxia, in addition to choreoathetosis. ¹ , ² , ⁸ Even within a single pedigree with DRPLA, affected family members have different clinical phenotypes by generation owing to genetic anticipation, which is more prominent in paternal transmission than in maternal transmission. ⁹

In terms of disease progression, symptoms lead to progressive motor and swallowing functional disorders, resulting in decreased activities of daily living (ADL) and difficulties with oral ingestion. It is postulated that juvenile‐onset patients typically experience more rapid progression than adult‐onset patients. ¹ , ⁷

However, information regarding the longitudinal progression of DRPLA is extremely limited in the literature. ¹ Therefore, we investigated the occurrence of milestone events to determine natural history and progression of DRPLA, and simultaneously assessed the clinical presentations of this disease.

Methods

Patients

We conducted a retrospective study of patients with DRPLA (n = 22), using data retrieved from our institution's medical records for the period January 2011 to July 2024. Nineteen patients were diagnosed based on the expanded CAG repeat length in the DRPLA gene and were tested after informed consent was obtained. Of the 19 patients, 16 had the number of CAG repeat length identified. Although three patients did not undergo genetic analyses for DRPLA, they exhibited clinical symptoms characteristic of DRPLA, and their families were diagnosed by genetic analyses. Consequently, the patients were clinically diagnosed with DRPLA. Among the enrolled patients, four family pedigree patients (A–D) were included. Patients #1‐A and #2‐A, patients #6‐B and #10‐B, and patients #8‐C, #14‐C, #15‐C, and #17‐C were siblings. Patients #9‐D and #12‐D were siblings and #22‐D was their paternal aunt (Fig. 1). It should be noted that several patients were not enrolled because of insufficient information regarding their clinical features or disease progression.

Figure 1.

Pedigree charts of the four families (A–D) with DRPLA. Squares (male) or circles (female) filled with black represent DRPLA‐affected family members. Slash marks indicate deceased individuals. A double bar denotes consanguineous marriage. Arrows identify the subjects in this study.

We examined the medical records of 22 patients with DRPLA in terms of the age at disease onset, initial manifestations, common and distinctive clinical features, and CAG repeat length. Specifically, the common features of this disease were regarded as ataxia, choreoathetosis, myoclonus, epilepsy, cognitive impairment, and psychiatric symptoms. Disease onset was defined as the first symptom considered to be affected by DRPLA, including intellectual disability, seizures, ataxia, and spasticity. Intellectual disability was defined as a significant deficit in both cognitive functioning and the adaptive skills necessary for daily living before the age of 18 years. Poor academic grades alone were not regarded as indicative of disease onset. Clinical signs were considered absent if not documented in the medical records.

The enrolled patients were divided into juvenile‐onset (n = 9) and adult‐onset (n = 13) groups. We statistically analyzed early‐ and late adult‐onset types combined as the adult‐onset group because of the limited number of patients with the late adult type in this study.

We also reviewed the ages at the onset of gait disturbance, wheelchair requirement, bedridden state, age at initiation of enteral feeding, and performance of tracheostomy. We considered the onset of gait disturbance, wheelchair requirement, and bedridden state as motor milestones during the period of ADL decline. If tracheostomy was performed, the purpose of the surgery was assessed. Additionally, if a patient died, the age at death and the cause of death were evaluated. Enteral feeding indicated that nutrition was administered through a nasal feeding tube or gastrostomy tube due to severe dysphagia. We excluded cases in which enteral feeding was temporarily required because of pneumonia or other complications.

Genetic Analysis

Genomic DNA was extracted from peripheral blood leukocytes of the aforementioned 19 patients by standard methods. The expanded CAG repeat length in the DRPLA gene was detected by PCR amplification.

Statistical Analysis

EZR version 1.52 (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R version 4.1.0 (The R Foundation for Statistical Computing, Vienna, Austria) was used to perform statistical analysis. ¹⁰ Student's t‐test was used to compare the age at disease onset and the number of CAG repeat length between the juvenile‐ and adult‐onset groups. Kaplan–Meier analysis was utilized to estimate the rate of ADL decline assessed by the motor milestones. Log‐rank test was applied to compare the rate between these two groups. The correlations between CAG repeat length and the ages at motor milestones were also analyzed using the log‐rank test, and the cutoff value of the CAG repeat length was estimated to be 65. ¹¹ A P value of <0.05 was considered statistically significant.

Results

Clinical Features

Based on data of the 22 patients with DRPLA, the clinical characteristics of individual juvenile‐ and adult‐onset patients are summarized in Tables 1 and 2, respectively. In juvenile‐onset patients (n = 9), the mean age at disease onset was 12.4 ± 4.3 years (mean ± SD) and the initial manifestations were seizure (n = 7) and intellectual disability (n = 2). In contrast, in adult‐onset patients (n = 13), the mean age at disease onset was 36.7 ± 11.8 years (mean ± SD) and initial manifestations were predominantly body balance disorders, specifically, ataxic gait (n = 4) as well as difficulty in riding a bicycle (n = 3) and abnormal running (n = 1) before the manifestation of ataxic gait. Only patient #16 initially presented with spastic gait 9 years before the manifestation of ataxia. In addition, four patients with adult‐onset disease initially presented with seizures at the ages of 20s or 30s.

TABLE 1.

Clinical characteristics of juvenile‐onset patients

Patient	Sex	CAG repeat length	Initial manifestation	Distinctive features
#1‐A	M	68	Intellectual disability	Irritability, Violent behavior
#2‐A	M	68	Seizure	Occasional mind‐wandering
#3	F	67	Intellectual disability	Post VNS due to refractory epilepsy
#4	M	65	Seizure	Mind‐wandering, Irritability, Postural tremor
#5	F	64	Seizure	Restlessness, Visual hallucination, Head titubation
#6‐B	M	68	Seizure	Agitation
#7	M	Expanded	Seizure	Irritability, Shouting
#8‐C	F	63	Seizure	Extrapyramidal symptoms, Axial and cervical dystonia
#9‐D	F	66	Seizure	Nocturnal abnormal behavior, Restlessness, Head titubation

Patient	Age (years)
	At disease onset	At onset of gait disturbance	At becoming wheelchair‐bound	At becoming bedridden	At starting enteral feeding	At performing tracheostomy	Current (At death)
#1‐A	6	19	20	‐	‐	‐	23
#2‐A	9	18	19	‐	‐	‐	21
#3	9	25	27	30	30	‐	35
#4	10	15	23	28	24	29	33
#5	11	26	27	35	29	33	(37)
#6‐B	16	27	30	31	31	31	44
#7	17	21	33	35	35	‐	(36)
#8‐C	17	21	28	29	29	31	(41)
#9‐D	17	23	30	33	31	38	(44)

Note: The clinical characteristics of the individual juvenile‐onset patients are described.

Abbreviations: M, Male; F, female; VNS, vagus nerve stimulation.

TABLE 2.

Clinical characteristics of adult‐onset patients

Patient	Sex	CAG repeat length	Initial manifestation	Distinctive features
#10‐B	F	64	Seizure	Cervical dystonia, Shouting
#11	F	68	Seizure	Agitation, Shouting
#12‐D	M	61	Seizure	Agitation, Restlessness
#13	F	65	Difficulty in riding a bicycle	Somatic hallucination, Cervical dystonia
#14‐C	F	62	Ataxic gait	Paroxysmal apraxia
#15‐C	F	Expanded	Ataxic gait	Delusion, Utterance of violent words
#16	M	Expanded	Spastic gait with a limp	Ataxia after spasticity, Shouting
#17‐C	M	N/A	Seizure	Irritability, Restlessness, Shouting
#18	F	N/A	Ataxic gait	Postictal psychosis
#19	M	63	Abnormal running	Irritability, Restlessness, Resting tremor
#20	F	57	Difficulty in riding a bicycle	Agitation, Head titubation
#21	M	58	Difficulty in riding a bicycle	Impatience, Irritability, Postural tremor
#22‐D	F	N/A	Ataxic gait	Delusion, Postural tremor

Patient	Age (years)
	At disease onset	At onset of gait disturbance	At becoming wheelchair‐bound	At becoming bedridden	At starting enteral feeding	At performing tracheostomy	Current (At death)
#10‐B	23	29	32	36	36	‐	42
#11	23	27	37	39	41	47	(57)
#12‐D	23	38	42	43	46	‐	54
#13	28	34	37	51	‐	‐	52
#14‐C	34	34	46	48	46	‐	(50)
#15‐C	35	35	45	48	49	‐	49
#16	35	35	52	53	52	‐	(53)
#17‐C	36	36	42	48	‐	‐	(50)
#18	37	37	48	51	51	51	(58)
#19	38	41	50	51	51	‐	53
#20	53	59	62	65	65	‐	65
#21	55	64	70	71	69	‐	(71)
#22‐D	57	57	64	68	‐	‐	(69)

Note: The clinical characteristics of the individual adult‐onset patients are described.

Abbreviations: M, male; F, female; N/A, not available.

With regard to common features with frequencies during the clinical course, ataxia and cognitive impairment were present in all juvenile‐ and adult‐onset patients. While juvenile‐ and early adult‐onset patients had epilepsy, except for Patient #16, none of the three late adult‐onset patients had epilepsy. Choreoathetosis and psychiatric symptoms were observed in adult‐onset patients rather than in juvenile‐onset patients, whereas myoclonus was observed in juvenile‐onset patients rather than in adult‐onset patients (Table 3).

TABLE 3.

Common features with frequencies during the clinical course in juvenile‐ and adult‐onset groups

Common features	Juvenile‐onset group (n = 9)	Adult‐onset group (n = 13)
Ataxia	100% (n = 9)	100% (n = 13)
Choreoathetosis	55.6% (n = 5)	100% (n = 13)
Myoclonus	88.9% (n = 8)	46.2% (n = 6)
Epilepsy	100% (n = 9)	69.2% (n = 9)
Cognitive impairment	100% (n = 9)	100% (n = 13)
Psychiatric symptom	77.8% (n = 7)	92.3% (n = 12)

Note: Choreoathetosis was absent in Patients #1‐A, #2‐A, #4, and #7. Myoclonus was absent in Patients #7, #10‐B, #12‐D, #14‐C, #15‐C, #20, #21, #22‐D. Epilepsy was absent in Patients #16, #20, #21, #22‐D. Psychiatric symptom was absent in Patients #2‐A, #3, #14‐C.

As a side note, cognitive and psychiatric characteristics were similar between juvenile‐ and adult‐onset patients. In cases of cognitive impairment, not only memory disturbances but also difficulties in understanding complex statements and composing long sentences were prominent. Reduced word fluency was noted in some patients, while constructional apraxia was present in others. Moreover, in cases of psychiatric symptoms, restlessness and irritability were sometimes observed. Several patients exhibited emotional incontinence, characterized by episodes of crying, shouting, or sudden anger. Their demeanor tended to become immature. A few patients developed hallucinations or delusions.

Clinical Progression and Prognosis

Median intervals (median ± SE) between the beginning of gait disturbance and that of wheelchair dependence were 3.0 ± 1.3 years in juvenile‐onset patients, and 7.0 ± 1.2 years in adult‐onset patients (P = 0.154). Likewise, median intervals between the beginning of gait disturbance and that of bedridden state were 9.0 ± 1.4 years in juvenile‐onset patients, and 12.0 ± 1.1 years in adult‐onset patients (P = 0.251). In terms of these median intervals, there appeared to be a trend toward slightly shorter duration from the onset of gait disturbance to wheelchair dependence in the juvenile‐onset group than in the adult‐onset group, although the difference was not statistically significant. On the other hand, the adult‐onset group showed reduced ADL status almost as rapidly as the juvenile‐onset group throughout the period from wheelchair dependence to becoming bedridden (Fig. 2).

Figure 2.

Kaplan–Meier curves, showing differences in time from the onset of gait disturbance to becoming wheelchair‐bound (A) and bedridden (B) between juvenile‐ and adult‐onset groups.

As shown in Tables 1 and 2, enteral feeding was administered to 17 patients (77.3%) and the age at initiation almost coincided with the age at which they became bedridden. In contrast, tracheostomy was performed in seven patients (31.8%), and the main purpose of the surgery was the management of aspiration pneumonia or sputum retention. Eleven patients died before the time of registry enrollment, and the main causes of death were aspiration pneumonia or other infections, and a large volume of pleural effusion. In addition to these causes of death, patient #16 died due to an apnea attack and patient #14‐C died after coronavirus disease 2019 (COVID‐19).

Correlation between Age at Disease Onset and CAG Repeat Length

Of the patients (n = 16) with available data, the number of CAG repeat length ranged from 63 to 68 (66.1 ± 2.0, mean ± SD) in juvenile‐onset patients and from 57 to 68 (62.3 ± 3.6, mean ± SD) in adult‐onset patients (P = 0.02) (Tables 1 and 2).

Correlation between CAG Repeat Length (Cut‐off Value: 65) and Age at Motor Milestones

We categorized the 16 patients into two groups based on CAG repeat length ≥65 or <65. The median age at onset of gait disturbance was significantly younger in patients with repeats ≥65 than in those with repeats <65 (24 years vs. 36 years, P < 0.01). Similarly, the median age at becoming wheelchair‐bound was significantly younger in patients with repeats ≥65 than in those with repeats <65 (28.5 years vs. 44 years, P = 0.01). The median age at becoming bedridden was also considerably younger in patients with repeats ≥65 than in those with repeats <65 (36.5 years vs. 51.5 years, P = 0.05).

Discussion

In this retrospective study involving 22 patients with DRPLA, we examined the clinical features and ages at which important disease milestones were reached. Our results revealed that seizures occurred as an initial manifestation in juvenile‐onset patients, as well as in early adult‐onset patients. Moreover, all juvenile‐onset and early adult‐onset patients, except one (patient #16), experienced epilepsy during the disease course, whereas none of the late adult‐onset patients experienced epilepsy. These findings suggest that the prevalence of epilepsy decreases with advancing age at disease onset, which is consistent with previous reports. ¹ , ²

Our investigation demonstrated that ataxic gait was the initial manifestation in adult‐onset patients. Interestingly, the symptom of difficulty riding a bicycle or abnormal running can be an early sign of disease onset before the overt manifestation of ataxic gait. Notably, spastic gait occasionally occurs before the manifestation of ataxia, as in patient #16.

Overall, our research indicated that the frequent clinical features in juvenile‐onset patients were epilepsy, cognitive impairment, ataxia, and myoclonus, followed by psychiatric symptoms and choreoathetosis. On the other hand, the frequent clinical features of adult‐onset patients include choreoathetosis, cognitive impairment, ataxia, and psychiatric symptoms, followed by epilepsy and myoclonus. This result is similar to those of previous reports. ¹ , ² , ⁸

Concerning disease progression using the data of milestone events, our analysis revealed that it took approximately 3 years for the juvenile‐onset group and 7 years for the adult‐onset group to become wheelchair‐bound from the onset of gait disturbance. Similarly, it took approximately 9 years for the juvenile‐onset group and 12 years for the adult‐onset group to become bedridden from the onset of gait disturbance. Although there was no statistically significant difference between these two groups regarding the durations from the onset of gait disturbance to becoming wheelchair‐bound, the durations tended to be slightly shorter in the juvenile‐onset group than in the adult‐onset group. This may be attributable to the fact that atrophic changes in the cerebellum and brainstem, which reflect the degree of ataxia, were slightly greater throughout this period in the juvenile‐onset group than in the adult‐onset group. Notably, it took approximately half a decade to become bedridden from the onset of wheelchair use in these two groups, despite the different phenotypes. Several factors likely contribute to the worsening clinical symptoms of DRPLA as well as various complications that can occur during the latter stages of ADL decline. In our cases, progressive limbic and truncal ataxia, severe involuntary movements, infections, joint contracture arising from disuse, or chronic subdural hematoma due to head trauma deteriorated ADL, which could occur in both the juvenile‐ and adult‐onset groups. Aging may also influence the final stages of ADL decline to some extent in late adult‐onset patients.

Our analysis further suggested that severe dysphagia developed relatively concurrently with a substantial decline in ADL, approaching the bedridden stage, as evidenced by the age at which enteral feeding was initiated. Importantly, the poor prognosis of DRPLA can be partially attributed to severe dysphagia leading to aspiration pneumonia or sputum retention, which may result in death.

Furthermore, we confirmed that the mean number of CAG repeat length was significantly larger in the eight juvenile‐onset patients than in the eight adult‐onset patients, indicating a strong inverse correlation between age at disease onset and CAG repeat length, as reported in previous studies. ⁶ , ⁷ Recently, Hasegawa et al ¹¹ demonstrated that patients with ≥65 CAG repeats became wheelchair‐bound and died earlier than those with <65 CAG repeats. Similarly, our study showed that patients with ≥65 CAG repeats manifested gait disturbance and became wheelchair‐bound and bedridden at an earlier age than patients with <65 CAG repeats.

Our study had several limitations. First, it was conducted at a single institution, and the cohort of enrolled patients with DRPLA was small, particularly among late adult‐onset patients. Second, we retrospectively reviewed the patients’ medical records, and we could not evaluate more detailed motor or cognitive functions using scales such as Scale for the Assessment and Rating of Ataxia (SARA) or Mini‐Mental State Examination (MMSE). Additionally, the determination of motor milestones, including the onset of gait disturbance or wheelchair dependence, may have been influenced by subjective elements, as specific criteria for defining these milestones were not applied for individual patients. Third, we did not evaluate progressive atrophy of the cerebellum and brainstem because of insufficient data from long‐term neuroimaging scans. Fourth, data regarding the number of CAG repeats were not available for some patients.

In conclusion, our study highlighted the natural history and progression of DRPLA through the comparison between juvenile‐ and adult‐onset groups. Interestingly, the duration from wheelchair dependence to becoming bedridden was approximately half a decade in both groups despite their different phenotypes, and was likely influenced by various factors. Our findings will be beneficial for patients with DRPLA, their families, and clinicians in predicting disease progression, based on the patients' clinical phenotypes. We expect that further research with larger sample sizes will elucidate more detailed clinical characteristics, disease progression, prognosis, and the relationship between phenotypic variation and expanded counts of CAG repeat length.

Author Roles

(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique.

H.A.: 1A, 1C, 2A, 3A.

K.N.: 2A, 2B, 2C, 3B.

N.F.: 3B.

Disclosures

Ethical Compliance Statement: This study was approved by the Ethics Committee of our hospital (approval number: 24–03; date: June 17, 2024). Informed consent was obtained from all study participants through the institution's website using the opt‐out method. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Sources and Conflicts of Interest: This work was supported by Grants‐in‐Aid from the Research Committee of Ataxia, Health Labour Sciences Research Grant, the Ministry of Health, Labour and Welfare, Japan (JPMH20FC1041). The authors declare that there are no conflicts of interest relevant to this work.

Financial Disclosures for the previous 12 months: The authors declare that there are no additional disclosures to report.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.