Abstract
Background
Juvenile‐onset Huntington's Disease (JoHD) or Huntington's disease (HD) with age of onset ≤20 years, is a rare clinical entity that often differs phenotypically from adult HD and represents only 1–15% of total HD cases.
Objective
To characterize the genetic and clinical characteristics of 32 JoHD patients seen in a Peruvian Neurogenetics clinic from 2000–2018.
Methods
This study is a retrospective clinical and genetic review. The clinical database in Lima, Peru was searched for HD patients seen in clinic between 2000 and 2018. Inclusion criteria were: (1) genetically confirmed disease; and (2) HD age of onset ≤20 years, according to the documented medical history.
Results
Among 475 patients with genetically confirmed HD in the database, 32 patients (6.7%) had symptom onset at ≤20 years. Among JoHD patients with a known transmitting parent (30 of 32), paternal transmission accounted for 77% of cases. Anticipation was higher with paternal transmission compared to maternal transmission (27.5 ± 11.5 vs. 11.3 ± 7.1 years). Overall expanded CAG repeat length ranged from 44 to 110, with a mean length of 65.6 ± 15.4, and 14 (44%) cases had repeat length under 60. Of the 32 patients included in the study, 25 had detailed clinical symptomatology available, and many patients had unique clinical features such as prominent sleep disturbance (60% of patients), or parkinsonism (73%).
Conclusions
This large case series of JoHD patients characterizes the Peruvian JoHD population, reports on unique familial relationships in JoHD, and highlights the varied symptomatic presentation of this rare disease.
Keywords: juvenile Huntington's disease, chorea, juvenile‐onset Huntington's disease, ataxia, Peru
Huntington's Disease (HD) is a progressive, autosomal dominant neurodegenerative disease caused by an unstable trinucleotide (CAG) repeat expansion in the HTT gene (Chr 4p16.3). 1 In Latin America, HD prevalence is estimated at 0.5–4 per 100,000 inhabitants, although among certain subpopulations, particularly those in Venezuela around Lake Maracaibo or in Peru around the Cañete valley, disease rates are over 10 times higher. 2 , 3 A cohort of 392 individuals representing four unrelated families in Oman had particularly high rates of HD with an early onset. 4 The typical age of onset for HD is between ages 30 and 50, though age of onset can vary widely, with documentation in the literature of initial onset ranging from early pediatric to old ages. 5 Presentation before age 21, historically referred to as Juvenile Huntington Disease (JHD), or more recently, Juvenile‐onset Huntington's Disease (JoHD), accounts for approximately 6% of all global HD cases. 6 , 7
JoHD patients have varied clinical presentations, which usually differ from the classical clinical triad of a movement disorder, cognitive decline, and psychiatric disturbances observed among the adult‐onset HD population. JoHD patients may present with primary symptoms of rigidity, bradykinesia, ataxia, seizures or learning disabilities in addition to the more classic chorea phenotype. 5 , 8 , 9
The significant symptomatic variability in the presentation of JoHD and the small number of case series with substantial numbers of patients (Table 1) leads to challenges in classification and management. An age‐driven sub‐classification scheme dividing JoHD cases into infantile or childhood‐onset (age ≤ 10 years) and adolescent‐onset (11–20 years) has been used in prior case series, although this approach has limited clinical utility. In addition, a more recent editorial calls for creating a distinction between JoHD, which encompasses both adults and children with HD symptoms that began in their youth (prior to age 21), and pediatric HD, which would only include young people affected by HD who are currently <18 years of age. 10 The current study presents a large case series of 32 JoHD patients seen in a Peruvian Neurogenetics clinic.
TABLE 1.
Juvenile HD literature review, select case series with >10 subjects included
| Study | Population | Subjects | Male/female | % Paternal inheritance | Median CAG repeat (range) | Age of onset, mean ± SD (range) |
|---|---|---|---|---|---|---|
| Telenius et al. 11 | Canada | 42 | 19/23 | 64% (28) | 56 (44–121) | 14.5 ± 5.5 (4–20) |
| Siesling et al. 12 | Netherlands | 53 | 36/17 | 79% (42) | 55 a | 12.6 ± 5.0 (3–19) |
| Cannella et al. 13 | Italy | 48 | ‐ | 71% (35) | 59 (43–120) a | 17.5 ± 4.5 (3–20) |
| Gonzalez‐Alegre and Afifi 14 | USA | 12 | 7/5 | 67% (9) | 73 (66–130) a | 7.9 ± 3.9 (4–14) |
| Ribai et al. 15 | France | 29 | 8/21 | 72% (21/28) b | 61 (45–89) | 14.2 ± 5.1 (5–20) |
| Cloud et al. 8 | USA | 90 | 45/45 | ‐ | 68 c (43–169) | 13.0 ± 5.3 (3–21) |
| Koutsis et al. 16 | Greece | 24 | 12/12 | 71% (18) | 61 (47–94) | 14.0 ± 5.4 (3–19) |
| Gatto et al. 17 | Argentina | 14 | 6/8 | 71% (11) | 53 (40–80) | 12.6 ± 5.2 (5–21) |
| Fusilli et al. 18 | Argentina, Italy | 36 | 19/17 | 83% (31) | 60 (50–68) | 16 (8–19) |
| Achenbach et al. 16 | Germany | 32 | 19/13 | 70% (17) | 62 (48–85) a | 14 ± 5.9 (1–20) |
CAG repeats reported for subset of cases.
One patient was adopted, so 28 patients were considered.
Mean rather than median CAG repeat size is reported.
Methods
Setting
The Neurogenetics Research Center (NRC) of the Instituto Nacional de Ciencias Neurologicas (INCN) in Lima, Peru, is a specialized center within the public neurologic institute that offers genetic testing and clinical care for patients with various neurogenetic disorders, with a particular focus on the large Peruvian HD population. 19 Outreach clinics are conducted by the NRC in the Cañete valley, a known focus of HD located approximately 3 hours south of Lima. 20 Patient data from outreach clinics in Cañete as well as outpatient visits at the NRC in Lima are aggregated in the NRC HD clinical database.
Design
This study is a retrospective clinical and genetic review using the database which captures all clinical visits to the NRC. The database was initially searched for all HD patients evaluated in a clinical context between the years of 2000–2018. Study inclusion criteria were (1) genetically confirmed HD, and (2) age of onset ≤20 years according to the documented clinical history. The number of CAG repeats was determined using standard PCR in accordance with previously established protocols. 21 Symptoms, age of onset, clinical signs at onset, family history, and disease origin were determined through retrospective chart review. The standardized clinical intake forms allowed the evaluating clinician to document the first HD‐related symptom, but this was not restricted in terms of whether this was a motor, cognitive, or psychiatric symptom. Age of onset was thus defined based on the age of onset of this first documented HD‐related symptom, which was often based on medical documentation outside of the Neurogenetics clinic, or on parental report. Origin was defined as place of origin of oldest recorded HD‐affected ancestor and is categorized into Lima, Cañete province, or other provinces. Seven of 32 patients were included in the presentation of genetic results but were excluded from review of clinical symptomatology due to incomplete medical records. Parental diagnosis of HD and parental age of onset were based on review of parental clinical records when available, or by report of family history when they were not; parental diagnosis did not require genetic confirmation, as this was not available before 2000 and did not become routine until several years later. The study was approved by the local Ethics Committee at INCN. All patients provided written informed consent for use of their genetic and clinical data for anonymized research studies at the time of their genetic testing.
Statistical Analysis
We used descriptive statistics to describe our overall cohort, including means and standard deviations (SD) for normally‐distributed numeric variables, medians and interquartile range (IQR) for non‐normally distributed numeric variables, and percentages for categorical variables.
Results
Among 475 patients with genetically confirmed HD in the NRC database, 32 patients (6.7%) had symptom onset at ≤20 years (Table 2). The mean ± SD documented age of onset in the JoHD subset was 13.9 ± 5.4 years, and diagnostic delay was 5.5 ± 4.9 years. Among JoHD patients with a known transmitting parent (30 of 32), paternal transmission accounted for 77% of cases. Age of onset for JoHD patients was similar with maternal disease transmission and paternal transmission (14.0 ± 6.2 vs. 13.6 ± 5.2 years), although expanded CAG repeat length was slightly higher in patients with paternal transmission (66.1 ± 14.4) compared to maternal transmission (63.3 ± 18.8) and anticipation, or the difference between parental age of onset and child age of onset, was dramatically higher with paternal transmission compared to maternal transmission (27.5 ± 11.5 vs. 11.3 ± 7.1 years). Overall expanded CAG repeat length ranged from 44 to 110, with a mean length of 65.6 ± 15.4, and 14 (44%) cases had repeat length under 60. Transmitting parent CAG repeat length was available for only 1 parent in our case series due to the lack of available genetic testing prior to 2002. With regard to patient demographics, 38% of JoHD patients were born in the city of Lima, 28% in Cañete province, and 34% in the rest of Peru.
TABLE 2.
Patient age of onset and genetic characteristics
| Patient ID | Age of onset | Sex | Patient | Affected parent | ||||
|---|---|---|---|---|---|---|---|---|
| Origin | Diagnostic delay | Anticipation | Expanded allele size | Sex | Age of onset/current age or age of death | |||
| CN‐01a | 3 | M | Cañete | 1 | 35 | 110 | M | 38/D40 from meningitis |
| CN‐02 | 3 | M | Lima | 8 | 14 | 82 | F | 17/D27 |
| CN‐03 | 3 | F | Other | 3 | 35 | 85 | M | 38/A43 |
| CN‐04 | 5 | M | Lima | 15 | 25 | 72 | M | 30/D50 |
| CN‐05 | 6 | F | Cañete | 0 | 24 | 97 | F | 30/D32 |
| CN‐06 | 6 | F | Other | 3 | 23 | 74 | M | 29/− |
| CN‐07 | 10 | M | Lima | 5 | ‐ | 77 | M | ‐ |
| CN‐08 | 10 | M | Cañete | 2 | ‐ | 72 | M | ‐ |
| CN‐09 | 12 | F | Other | 0 | 16 | 64 | M | 28/D42 |
| CN‐10 | 12 | M | Lima | 16 | 43 | 44 | M | 55/− |
| CN‐11 | 12 | M | Lima | 3 | 47 | 77 | M | 59/A63 |
| CN‐12 | 14 | M | Lima | 2 | ‐ | 88 | ‐ | ‐ |
| CN‐13 | 14 | F | Lima | 5 | ‐ | 75 | M | −/A46 affected |
| CN‐14 | 14 | M | Other | 6 | 19 | 65 | M | 33/− |
| CN‐15 | 15 | F | Other | 6 | ‐ | 50 | M | D30 unaffected |
| CN‐16b | 15 | M | Lima | 1 | 21 | 65 | M | 36/D40 |
| CN‐17 | 15 | F | Other | 7 | 19 | 70 | M | 34/D41 |
| CN‐18b | 16 | M | Lima | 4 | 20 | 69 | M | 36/D40 |
| CN‐19 | 16 | M | Cañete | 11 | 2 | 50 | F | 18/D28 |
| CN‐20 | 16 | M | Lima | 8 | 2 | 58 | F | 18/A33 |
| CN‐21 | 17 | M | Other | 14 | 49 | 57 | M | 66/D68 |
| CN‐22 | 18 | M | Cañete | 2 | 14 | 45 | M | 32/D42 |
| CN‐23 | 18 | F | Other | 8 | 12 | 54 | F | 30/D50 |
| CN‐24c | 19 | F | Other | 2 | ‐ | 67 | M | ‐ |
| CN‐25a | 19 | M | Cañete | 1 | 19 | 56 | M | 38/D40 |
| CN‐26 | 19 | M | Other | 20 | ‐ | 51 | M | ‐ |
| CN‐27 | 19 | M | Lima | 1 | 11 | 46 | F | 30/D54 |
| CN‐28 | 19 | M | Cañete | 4 | ‐ | 58 | M | ‐ |
| CN‐29c | 20 | F | Other | 3 | ‐ | 56 | M | ‐ |
| CN‐30 | 20 | M | Cañete | 7 | ‐ | 63 | M | ‐ |
| CN‐31 | 20 | M | Cañete | 3 | ‐ | 46 | ‐ | ‐ |
| CN‐32 | 20 | F | Lima | 4 | 14 | 56 | F | 34/− |
Note: The superscripts a, b, and c denote individual sibling pairs.
The most common symptoms within the entire JoHD cohort for which detailed symptomatology was available (25 patients) were cognitive decline (93%), psychiatric disturbance (72%), dysarthria (72%), and parkinsonism (73%) (see Table 3). Additional notable symptoms in our cohort included sleep disorders (present in 60% of patients, with severe manifestations in CN‐16, CN‐01, and CN‐03), autonomic dysfunction (CN‐13), and a cranio‐cervical dystonia with risus sardonicus (CN‐15, CN‐17, CN‐18). The observed JoHD cohort included 3 sets of siblings and 3 JoHD patients who were offspring of mothers who themselves had JoHD. For the 25 patients included in the symptom and follow up review (Table 3), the median number of clinic visits was 3 (IQR 2–8), and the median duration of follow up was 2 (IQR 1.5–4.5).
TABLE 3.
Disease onset, progression, and follow up in JoHD
| Patient ID | Number of visits | Years of follow up | Narrative summary of disease onset, progression, and follow up | Regression/delay | Chorea | Parkinsonism | Dystonia | Cerebellar signs | Seizures | Dysphagia | Dysarthria | Psychiatric disorder | Sleep disorder |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| CN‐01a | 3 | 1 | Language and motor regression at age 3. Feeding difficulties, malnutrition, aggression, hyperkinetic movements, seizures throughout the day (treated with valproic acid) and mutism began at age 4. Died due to respiratory infection at age 4. | + | − | − | − | + | + | + | + | − | + |
| CN‐02 | 3 | 5 | Global developmental delay and regression at age 3, with later severe intellectual disability, hyperactivity, parkinsonism, stereotypic movements of the upper extremities, and persistent bruxism. | + | + | + | − | + | − | − | − | − | − |
| CN‐03 | 9 | 3 | Onset with learning disabilities, frequent falls, and parkinsonism. Clinical course with severe seizures (treated with valproic acid, then lamotrigine, then levetiracetam), rigidity and bradykinesia (treated with pramipexole), abnormal behavior with panic attacks, dysphagia, malnutrition, sleep disorder, and anarthria by age 11. | + | − | + | + | + | + | + | + | − | − |
| CN‐04 | 2 | 1 | Febrile seizure at age 2, but onset age 5 with learning difficulties and difficulty walking. Presentation to clinic at age 20, with significant bradykinesia, hypomimia, rigidity, frequent falls, dysarthria, abnormal behaviors and severe daytime sleepiness. | + | + | + | − | + | − | + | + | + | + |
| CN‐05 | 1 | 1 | Onset with choreiform movements and dysarthria at age 6, with presentation to clinic at age 7. Course complicated by seizures (treated with valproic acid), increased rigidity, ataxic gait, frequent falls, and cognitive decline. | + | + | + | + | + | + | + | + | + | − |
| CN‐06 | 7 | 6 | Onset with language regression, behavioral changes with anti‐social behavior and sleep disorders (nocturnal irritability) at age 6. Course complicated by dystonic postures, and cognitive decline. | + | − | − | + | + | − | − | − | − | − |
| CN‐07 | 1 | 1 | Onset with chorea and dysarthria/stuttering. | + | − | + | − | + | − | − | |||
| CN‐08 | 5 | 2 | Onset with cervical dystonia, behavioral changes, and cognitive impairment. Clinical course complicated by incontinence and self‐mutilating behaviors. Died after 4 years of follow up. | − | − | + | − | + | − | + | + | − | − |
| CN‐09 | 20 | 9 | Onset with behavior changes (depression, irritability, self‐isolation, self‐injurious behaviors), and visual hallucinations. Course complicated by chorea, rigidity, bradykinesia, sleep disturbance, cognitive decline, gait instability and dysphagia. | − | + | + | − | − | − | − | − | + | + |
| CN‐11 | 2 | 2 | Onset with behavior changes (aggression), depression, and walking difficulties. Course complicated by rigidity, bradykinesia, dystonic postures, dysphagia, and progressive dysarthria culminating in anarthria. Bedbound from age 18, died at age 21 (recurrent respiratory infections). | − | − | + | + | − | − | + | + | + | − |
| CN‐13 | 24 | 4 | Onset with behavior and walking difficulties. Then, worsened psychiatric manifestations (suicidality, visual disturbance), rigidity, bradykinesia, dystonic postures, frequent falls, dysautonomia, and frequent infections. Died age 23 (respiratory infection). | − | − | + | + | − | − | + | + | + | + |
| CN‐14 | 2 | 2 | Onset with behavior changes (alcohol/tobacco abuse, delusions, aggression). Course complicated by severe rigidity/bradykinesia. Hospitalized at a psychiatric hospital. | − | − | − | + | − | − | − | + | + | + |
| CN‐15 | 9 | 10 | Onset with irritability, rigidity, and bradykinesia. Course complicated by psychiatric disturbances (aggression, psychosis), anarthria, and chorea. | − | − | + | − | − | − | + | − | + | + |
| CN‐16b | 3 | 2 | Onset with aggression, and bradykinesia. Clinical course with sleep–wake cycle inversion, gait disturbance, parkinsonism, and anarthria. | − | + | + | + | − | − | + | + | + | + |
| CN‐17 | 4 | 2 | Onset with mild choreiform movements of the face and upper limbs and walking difficulties. Course complicated by severe parkinsonism (treated with pramipexole with limited response), postural instability, irritability, dysphagia and episodic falls. | + | + | + | + | + | − | + | + | +. | + |
| CN‐18b | 11 | 4 | Onset with behavioral disturbances and learning difficulties. Course complicated by chorea, bradykinesia, frequent falls, dystonia, dysarthria, and dysphagia. Died age 24 (respiratory infections). | − | − | + | + | − | − | + | + | + | − |
| CN‐20 | 6 | 5 | Onset with behavioral changes, depression, hyperkinetic movements and parkinsonism. Course complicated by psychosis, sleep–wake cycle inversion, and worsening parkinsonism. | − | + | + | + | − | − | + | + | + | + |
| CN‐21 | 2 | 1 | Onset with behavior changes (irritability, aggression), and psychiatric disturbances (hallucinations), and rigidity. Diagnosed with schizophrenia, then developed chorea, rigidity, mutism, and dysphagia. Fully dependent by age 27. | − | + | − | + | − | − | + | + | + | + |
| CN‐22 | 2 | 3 | Onset with gait disturbances, generalized chorea, dysarthria and behavioral problems. | − | + | + | + | + | − | + | + | + | + |
| CN‐23 | 2 | 1 | Onset with chorea, ataxia and irritability. | − | + | − | − | + | − | − | + | + | + |
| CN‐25a | 1 | 1 | Onset with mild chorea, and depressed mood. | − | + | − | − | − | − | − | − | + | − |
| CN‐26 | 1 | 1 | Onset with choreiform movements. | − | + | + | − | − | − | − | + | + | − |
| CN‐27 | 3 | 2 | Onset with abnormal behavior, sleep disturbances leading to hospitalization in a psychiatric hospital (treated with risperidone and valproic acid). Course complicated by difficulty walking, rigidity, postural tremor, weight loss, and cognitive decline. | − | − | + | − | − | − | − | − | + | + |
| CN‐28 | 4 | 2 | Onset with hyperkinetic movements, behavioral changes. Course complicated by dystonia, sleep–wake inversion, irritability. | − | + | + | + | + | − | + | + | − | − |
| CN‐32 | 10 | 7 | Onset with chorea, depression and irritability. Clinical course complicated by sleep–wake cycle inversion, suicidality, bruxism, ataxia, and dysphagia. | − | + | − | + | − | − | − | − | + | − |
Note: The superscripts a and b denote individual sibling pairs. The dark grey indicates present symptoms.
Discussion
JoHD patients accounted for 6.7% of all HD patients in the NRC database, consistent with the overall global prevalence of JoHD initially reported by Hayden (5.7%), 22 and roughly substantiated in a more recent meta‐analysis (4.92% [4.07–5.84]). 6 Although as in our study, the JoHD prevalence among HD cohorts is commonly reported to be 6% in reference texts, 7 higher rates have also been reported in isolated cohorts, such as the Omani HD population. 4 There is no other clinic offering genetic testing or comprehensive care for HD in Peru, so referral bias affecting our result should be limited. However, not all patients, particularly those from regions far away from Lima or the Cañete valley, would have the resources or ability to access medical care in Lima, and there could be increased motivation to access care for children as compared to older adults. Our findings were also aligned with classic findings regarding maternal and paternal anticipation. Whereas a recent case series found no difference in anticipation between paternally and maternally inherited cases of JoHD, 15 we identified increased anticipation in paternally inherited cases (27.5 ± 11.5 vs. 11.3 ± 7.1 years) within our series. This finding was also influenced by the low age of onset of the mothers compared to the fathers (25.3 ± 6.7 vs. 39.4 ± 11.4).
Additionally, although JoHD is traditionally associated with greater than 60 CAG repeats, 1 , 23 43% of our patients had fewer than 60 CAG repeats and 4 of our cases (13%) had fewer than 50 CAG repeats. Consistent with our findings, multiple recent studies of large JoHD populations have found many patients with CAG repeats under 60 (46% under 60 in Ribai et al., median repeat size of 56 in Telenius et al). It has been postulated that various genetic modifiers beyond CAG repeat number affect age of onset as well as clinical presentation. 24
Though our sample includes three JoHD sibling pairs, clinical presentation and age of onset seemed more correlated to CAG repeat number variance rather than familial relations. For example, CN‐25 with 56 CAG repeats had a choreic phenotype, whereas his younger brother, CN‐1, with 110 CAG repeats, had onset at age 3 with ataxia, developmental regression, and seizures. In the second sibling set, CN‐16 (65 CAG repeats) and CN‐18 (69 CAG repeats) had similar ages of onset (15 and 16) and repeat sizes, and both presented with parkinsonism.
Our sample was also notable for three JoHD patients born of mothers with JoHD. JoHD mother‐to‐child transmission has rarely been reported, 25 and the high number of familial correlations in this JoHD series is consistent with previous studies that have shown aggregation of age of onset within families. 11 , 26
In addition to the familial correlations noted above, several infrequently characterized symptoms were identified in our JoHD series. Sleep disturbances were a troubling symptom for over 50% of JoHD patients in our series. Patient CN‐16 had a severely inverted sleep cycle and suffered from intractable insomnia with yelling and increased aggression throughout the night, while patients CN‐01 and CN‐03 also suffered from nightmares and frequent movements causing nighttime wakefulness. Sleep disturbance has been widely described in adult onset HD, 15 , 27 but few previous studies have characterized sleep disturbance in JoHD.
Autonomic dysfunction and thermal dysregulation coinciding with the onset of HD was also observed in one case in our series (CN‐13). The patient felt inappropriately warm and had minute‐long episodes of severe sweats up to five times per day. Both hyperthermia and hypothermia have been clinically observed in HD; 28 hyperthermia has been largely attributed to psychotropic drug use in a therapeutic context, while profound hypothermia has been observed in murine models of HD. 29 Additionally, clinical symptoms suggestive of autonomic dysfunction such as tachycardia and excessive perspiration correlated with sympathetic nervous system hyperfunction observed in autonomic testing in early‐stage HD. 30
Our series also included several cases that had predominantly cerebellar symptoms in patients with very high CAG counts (CN‐01 with 104 repeats and CN‐06 with 97 repeats). Multiple case reports exist that highlight the prominence of a distinct cerebellar, or ataxic phenotype among those with JoHD, with differential features on pathology and imaging. 31 , 32 , 33 , 34 Imaging studies comparing the MRI Brain for an 18 month‐old Algerian patient presenting with global developmental delay and ataxia with his imaging of his choreic HD father showed reduced cerebellar volume in the infant, and only caudate atrophy in father. 32 Neuropathological studies comparing a choreic father and son with ataxia similarly highlight cerebellar volume loss solely in the child. 31 Overall, the reported ataxic HD cases are typically extremely early‐onset, with very large CAG repeat number and they are usually associated with severe developmental delay or regression as well as seizures, though the precise pathological reason for cerebellar atrophy in these cases is unknown. 13 , 25 , 33 , 34 Our series included several of these extremely rare cerebellar‐predominant cases, although pathologic and radiologic correlation was not available.
Our study is limited by the lack of standardized and prolonged follow up periods, reliance on retrospective analyses of clinician assessments rather than prospective data collection, and the fact that our study draws from a single medical center. In addition, our series reports on the presence or absence of certain symptoms during the documented visits, although a different set of symptoms may have emerged over time if our follow up period had been more complete.
Given the clinical heterogeneity, persistent diagnostic delay, and complexity of management, it is necessary to continue studying and reporting the phenotypic variability of JoHD. This case series characterizes the Peruvian JoHD population, reports on unique familial relationships in JoHD, and provides new insight into the varied symptomatic presentation of the disease.
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.
A.V.: 1A, 1B, 1C, 2A, 2B, 3A.
M.C‐O.: 1A, 1B, 1C, 2C, 3A, 3B.
E.S‐C.: 1C, 3B.
M.I‐M.: 1B, 1C, 2B, 2C, 3B.
D.R.: 3A, 3B.
K.M‐N.: 1C, 3B.
P.M.: 3B.
T.B.: 3B.
Disclosures
Ethical Compliance Statement: The study was approved by the Ethics Committee at INCN, called the “Comite Institucional de Etica en Investigacion del Instituto Nacional de Ciencias Neurologicas,” IRB number 561‐2019‐CIEI‐INCN. All patients provided written informed consent for use of their genetic and clinical data for anonymized research studies at the time of their genetic testing. 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 research did not receive any specific grant from funding agencies in the public, commercial, or not‐for‐profit sectors. However, this research work was partially supported by the Peruvian Institution PROCIENCIA‐CONCYTEC within the framework of the convention of Research Projects in Health EU‐LAC (Contract No. 098‐2017‐FONDECYT). Research training for AV during the execution of this project was supported by NIH Research Training Grant #R25 TW009345 funded by the Fogarty International Center, the NIH Office of the Director, Office of AIDS Research, the NIH Office of the Director Office of Research on Women's Health, the National Heart, Lung, and Blood Institute, the National Institute of Mental Health and the National Institute of General Medical Sciences. We have no conflicts of interest to report.
Financial Disclosures for the Previous 12 Months: Anastasia Vishnevetsky: The Contributor has received financial and material support for this research and work regardless of date from the following sources: Research training support provided by NIH Research Training Grant #R25 TW009345 funded by the Fogarty International Center, the NIH Office of the Director, Office of AIDS Research, the NIH Office of the Director Office of Research on Women's Health, the National Heart, Lung, and Blood Institute, the National Institute of Mental Health and the National Institute of General Medical Sciences. In the past year from the date of submission, the Contributor has also received the following support unrelated to this research: Employment at the Brigham Mass General Neuro‐immunology Fellowship. Mario Cornejo‐Olivas: In the past year from the date of submission, the Contributor has also received the following support unrelated to this research: Research grant from FONDECYT‐CONCYTEC. Elison Sarapura‐Castro: In the past year from the date of submission, the Contributor has also received the following support unrelated to this research: Research grant from FONDECYT‐CONCYTEC. Miguel Inca‐Martinez: In the past year from the date of submission, the Contributor has also received the following support unrelated to this research: Fellow at the Latin American Training Program (LATP) 2018, Society for Neuroscience‐IBRO. Danielle Rabinowitz: In the past year from the date of submission, the Contributor has also received the following support unrelated to this research: Employment at the Boston Children's Hospital residency program. Karina Milla‐Neyra: In the past year from the date of submission, the Contributor has also received the following support unrelated to this research: Research grant from FONDECYT‐CONCYTEC. Pilar Mazzetti: In the past year from the date of submission, the Contributor has also received the following support unrelated to this research: Research grant from FONDECYT‐CONCYTEC. Honoraria from Grünenthal Peruana S.A. Thomas Bird: In the past year from the date of submission, the Contributor has also received the following support unrelated to this research: Licensing fees from Athena Diagnostic Inc.
Acknowledgments
We thank Victoria Marca, Olimpio Ortega, Renato Velit, and Herbert Capuñay, for their help with genetic analysis and the organization of the NRC clinical database. We thank Joseph Zunt for his continued support of the Neurogenetics Research Center, and our clinical and research projects.
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