Coronal T2-weighted brain magnetic resonance imaging of patient PAD-036-001. Diffuse cortical, subcortical, and bilateral caudate nucleus atrophy with enlargement of the frontal horns of the lateral ventricles. Hypointensity of the putamen and lenticular nuclei.
Ribaï P, Nguyen K, Hahn-Barma V, Gourfinkel-An I, Vidailhet M, Legout A, Dodé C, Brice A, Dürr A. Psychiatric and Cognitive Difficulties as Indicators of Juvenile Huntington Disease Onset in 29 Patients. Arch Neurol. 2007;64(6):813-819. doi:10.1001/archneur.64.6.813
Copyright 2007 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.2007
Juvenile Huntington disease (JHD) is a rare clinical entity characterized by an age at onset younger than 20 years. Patients usually have an expansion of more than 60 CAG repeats in the Huntington disease (HD) gene, and the disease is usually inherited from the father. In general, precise age at onset is difficult to assess in HD because of insidious onset and anosognosia. Onset of motor difficulty signs is usually used to define age at onset.
To evaluate diagnosis delay in patients with JHD and to analyze the clinical and genetic features of JHD.
Retrospective clinical and genetic review.
Referral center for HD at Salpêtrière Hospital, Paris, France.
Twenty-nine patients with HD with onset before or at age 20 years who carried an abnormal CAG repeat expansion in the HD gene.
The mean ± SD delay before diagnosis was 9 ± 6 years (range, 0-21 years). The most remarkable signs at onset were severe psychiatric and cognitive disturbances (19 of 29 [65.5%]); rigidity was absent. Unusual signs at onset included myoclonic head tremor in 3 patients, severe isolated drug or alcohol addiction in 2, psychotic disorder in 1, and difficulty writing in 1. One patient had progressive cerebellar signs associated with cerebellar atrophy on cerebral magnetic resonance imaging before signs suggestive of HD appeared. During the course of the disease, psychiatric disturbances were severe, with at least 1 suicide attempt in 7 of 29 patients. Transmission was maternal in 25% of patients. Forty-six percent of patients with JHD had fewer than 60 CAG repeats; 6 of these patients inherited the disease from their father. Anticipation (mean ± SD, 18 ± 9 vs 25 ± 11 years; P = .27) and age at onset (mean ± SD, 17.14 ± 2.2 vs 13.29 ± 5.5 years; P = .09) was similar in patients with maternal compared with paternal transmission, respectively.
Patients with JHD started showing disease symptoms through nonspecific features, mostly psychiatric and cognitive difficulties. This led to misdiagnosis or diagnosis delay, especially in cases without a familial history of HD. Maternal transmissions and expansions of fewer than 60 CAG repeats were unexpectedly frequent in this series and should not be considered exceptional.
Huntington disease (HD) is a predominantly inherited neurodegenerative disease with onset in midlife that is caused, in the vast majority of cases, by an abnormal CAG repeat expansion in the HD gene. The number of CAG repeats is inversely correlated with age at onset of the disease.1 Juvenile HD (JHD) is defined by onset before the age of 20 years and accounts for less than 10% of all patients with HD.1 Whereas patients with adult-onset HD carry 40 to 50 CAG repeats on the mutant allele, patients with JHD usually have more than 60 CAG repeats. The longest reported expansion had 250 repeat units.2 Transmission of JHD is paternal in 80% to 90% of cases.3,4 Clinical features of adult-onset HD classically include chorea, psychiatric disturbances, and cognitive decline. Classically, patients with onset before age 20 years have less chorea and their clinical manifestations are dominated by rigidity.5,6 In our referral center for HD at the Salpêtrière Hospital, we were puzzled by the delay for diagnosis in adults and especially in patients with JHD. We report a series of 29 patients with JHD and describe the reasons for diagnosis delay, and the patients' clinical and genetic features.
Among 1452 patients referred for diagnosis purposes to our HD clinic between 1990 and 2005, 29 had disease onset before age 20 years and molecularly confirmed HD. The number of CAG repeats in the HD gene was determined by standard procedures.7 All patients were examined by a neurologist. Through interviews with patients and relatives, age at onset was determined; it was defined as the age when the first important change was noticed, either in motor, cognitive, or behavioral capacities, which led to social, professional, academic, or affective withdrawal. The family history, the patient's medical history, and results of the neurological examination were recorded, which included the age at onset and sex of the disease-transmitting parent, and the number of CAG repeats in the patients and, if possible, the transmitting parent. If follow-up was interrupted, family members were interviewed about their affected relatives.
Four patients underwent neuropsychological testing for subcortical dementia.8,9 The Montgomery-Aasberg Depression Rating and Covi Anxiety scales were used to evaluate depression and anxiety, respectively. The Mini-Mental State Examination and the Mattis Dementia Rating Scale were used to evaluate global cognitive efficiency. Attention and working memory were assessed by the digit span subtest of the Wechsler Adult Intelligence Scale–Revised. Executive functions were evaluated with the Trail-Making Test (for mental shifting) and the Stroop Test (for inhibitory control). Memory tests suited to the patient's capacities, such as the Wechsler Memory Scale, the California Verbal Learning Test, or the Grober and Buschke test, were used. For the other 25 patients, cognitive decline was determined from their medical history. Means and SDs were compared using analysis of variance, and frequencies were compared using the χ2 or Fisher test, as appropriate.
The mean ± SD age at onset was 14 ± 5 years (range, 5-20 years), and the mean ± SD age at examination was 25.5 ± 8 years (range, 9-40 years). The mean ± SD delay before diagnosis was 9 ± 6 years (range, 0-21 years). Motor difficulty was the trait that was first noticed in 10 patients; cognitive difficulty was first noticed in 10 patients; and in 9 patients, psychiatric difficulty was first noticed (Table 1). Motor difficulty signs included myoclonic tremor (n = 3), chorea (n = 3), falls (n = 2), writing difficulty (n = 1), and shoulder twitching (n = 1). The mean age ± SD at onset of motor difficulty signs was 20 ± 9 years (range, 5-39 years); signs occurred a mean of 6 years after cognitive or psychiatric changes. Psychiatric difficulty signs included severe depression (n = 3), isolated alcohol and drug addiction (n = 3), and behavioral changes (n = 3), such as psychotic disorders, compulsive behavior, fugues, or violence. Patient SAL-020-008 showed aggressive and violent behavior at age 7 years and was diagnosed with psychosis. By age 14 years, she had attempted suicide 4 times and had had several psychiatric hospitalizations. At age 14 years, she lived in a psychiatric institution; chorea appeared at age 15 years. Patient SAL-2021-001 had drug and alcohol addictions since age 13 years and was observed by a neurologist for complications due to multiple drug abuses (peripheral neuropathy). Chorea was first clearly diagnosed at age 34 years. At that time, the patient's 69-year-old father was not affected.
Among the 10 patients whose disease onset began with cognitive decline, 6 experienced rapid deterioration in school performance (observed in elementary school classes), including loss of comprehension and memory difficulties. All of these patients had been withdrawn from school. A single patient with school performance deterioration (SAL-2181-016) had a progressive cerebellar syndrome associated with cerebellar atrophy on cerebral magnetic resonance imaging before chorea appeared. Brain magnetic resonance imaging at 27 and 30 years showed nonprogressive cerebellar and cortical atrophy with normal caudate nuclei.
The longest delay before diagnosis was 21 years in 2 patients: SAL-2021-001, who started the disease with alcohol and drug addiction, and SAL-2110-006, who started with severe depression. In both patients, psychiatric features persisted and worsened before motor difficulty signs occurred much later.
Three patients did not have a family history of HD. When patient SAL-2021-001 was diagnosed with HD, his asymptomatic transmitting father had a normal examination at age 69 years. The father of SAL-2148-008 was diagnosed with schizophrenia but not with HD. Patient PAD-036-001 was adopted and her family history was unknown.
The mean ± SD number of CAG repeats was 62 ± 11 (range, 45-89 repeats). Almost half of the patients (13 of 28 [46%]) had fewer than 60 CAG repeats (range, 45-58 repeats); 6 of them had inherited the disease from their fathers. Transmission was maternal in 25% of patients (7 of 28 patients). The mean ± SD age at onset was similar in patients who had inherited the disease from their mother and patients who had inherited the disease from their father (17.14 ± 2.2 vs 13.29 ± 5.5 years, respectively; P = .09); mean ± SD was also similar in disease-transmitting mothers and fathers (33 ± 8 vs 38 ± 11 years; P = .55). In addition, anticipation (ie, the difference in age at onset between patient and transmitting parent) was similar in father-child and mother-child pairs (25 ± 11 [n = 16] vs 18 ± 9 [n = 3] years, respectively; P = .27). Nevertheless, the mean ± SD number of CAG repeats was larger in the paternal inheritance group (65 ± 11 vs 51 ± 5 repeats; P = .002), and the mean ± SD instability (ie, increase in CAG repeats during transmission) was greater in father-child pairs (n = 14, 17 ± 11 CAG repeats increase) than in the 1 mother- child pair (3 CAG repeats increase). The mean ± SD instability for the whole group was 16 ± 11 CAG repeats increase (range, 2-41 repeats). All cases with onset before age 10 years were paternally inherited, with a mean ± SD number of CAG repeats of 74.5 ± 9 (range, 64-89 repeats).
After a mean ± SD disease duration of 11 ± 6 years (range, 3-21 years), the overall clinical phenotype was a combination of neurological, psychiatric, and cognitive dysfunction (Table 2). All 27 patients had cognitive decline; most had behavioral disturbances (23 of 29 [79%]), such as carelessness, irritability, aggression, anorexia, drug addiction, and social withdrawal. Seven patients attempted suicide at least once. Cognitive decline ranged from slight attention difficulties to subcortical dementia. The 4 patients who underwent neuropsychological examination had attention deficit and altered executive functions, such as slowness, difficulties with mental shifting, and problems with working memory (Table 3). Three of these patients showed initial signs of dementia; the other (patient SAL-2449-008) had a low IQ score (IQ = 81) but no dementia. The severity of executive dysfunction was not correlated with the CAG repeat length or disease duration. The disease began in patient SAL-2449-008 with deterioration of school performance, but after 14 years of disease duration, she was less impaired than the 3 other patients when assessed on neuropsychological tests.
Motor difficulty signs at examination included dystonia (21 of 29 patients), chorea (18 of 29 patients), parkinsonism (18 of 29 patients), cerebellar signs (7 of 29 patients), and seizures (6 of 29 patients). Among the 6 patients who had tonic-clonic seizures, 1 (SAL-034-015) had an isolated, unprovoked generalized seizure. The 5 others had intractable epilepsy that required an antiepileptic polytherapy.
Cerebral magnetic resonance imaging showed cortical and caudate atrophy in all patients (n = 7). Four of them also had abnormal signals in the basal ganglia, especially the putamen (Figure).
Eleven patients died at a mean ± SD age of 28 ± 9 years (range, 13-41 years) after a mean ± SD disease duration of 15.6 ± 6.2 years. There was significant inverse correlation between CAG expansion length and age at death (r = −0.7; P = .02). Causes of death were bronchopneumonia secondary to swallowing difficulties (n = 4), cardiac arrest in bedridden patients (n = 3), neurovegetative crises (sweating, hyperthermia, and hypertonic posture in opisthotonos; n = 2), bronchopneumonia with progressive myoclonic epilepsy (n = 1), and ionic disturbances secondary to dehydration (n = 1). The 2 patients with neurovegetative crises had been treated with neuroleptic drugs; however, malignant neuroleptic syndrome could be ruled out, as these treatments had been withdrawn months before.
Juvenile Huntington disease is rare and was found in 2% of our patients with HD (29 of 1452). Motor difficulty onset was recorded in 34.5% of patients (10 of 29), but chorea was the initial sign in only 3. Nevertheless, 62% developed this sign later. Most of the motor difficulty signs at onset were atypical, including myoclonic head or limb tremor, shoulder twitching, and writing difficulties. Rigidity is classically the most prominent feature in patients with JHD and distinguishes patients with JHD from patients with adult-onset HD.10 Interestingly, none of our patients started the disease with rigidity. During the course of the disease, parkinsonism (rigidity and hypokinesia) was present in 62% of patients (18 of 29), but dystonia was the most frequent movement disorder (72%).
Psychiatric and behavioral difficulties were severe enough to be reported as the first sign by patients and relatives in 65.5% of patients (19 of 29). We considered these psychiatric and cognitive signs to be related to the disease and could be a sign of disease onset. Other authors reported a 3-year-old girl with psychomotor regression and seizures as presenting signs of HD. They found an expansion of 214 CAG repeats and concluded that HD may be considered in children with progressive neurodegenerative disease.11 In our patients, even if the psychiatric disturbances were as common as depression or aggression in adolescence, they were severe enough to lead to suicide attempts, psychosis, severe drug addiction, or other troubles that changed the patient's life. In addition, there was no relapse between the onset of psychiatric and/or cognitive features and the motor difficulty signs. Patients with reported cognitive or psychiatric onset always showed a combination of signs, which worsened until signs suggestive of HD appeared. Although these signs remained atypical, they were not considered to be the first signs of HD, which possibly explains the long diagnosis delay, even in patients with an HD-positive family history.
Another cause for diagnosis delay was the absence of HD family history, which was due to anticipation, adoption, or misdiagnosis in the transmitting parent. The observation of a carrier father who was still asymptomatic at age 69 years confirms that rare cases with expansions of 40 CAG repeats may be associated with reduced penetrance.12
Although JHD is classically associated with expansions of more than 60 repeats,3 JHD with expansions in the range of 45 to 58 CAG repeats was common in our group; 46% of our patients with JHD had fewer than 60 repeats. A high proportion of patients with JHD (25%) inherited the disease from their mothers. Even if we only consider those with motor difficulty onset (n = 10), 2 were maternally transmitted (20%), which is an unusually high proportion among patients with JHD. Higher frequencies of maternal transmissions or maternal transmissions with unusually large expansions have been described.2,13,14
Patients with maternal inheritance had fewer CAG repeat expansions but did not experience disease onset significantly later than those with paternal inheritance. However, similar to the greater instability of paternally inherited CAG expansions,5,13 patients with paternal inheritance had more CAG repeat expansions; all cases with onset before age 10 years were inherited paternally. In addition, anticipation was not greater in father-child pairs than in mother-child pairs, as in previous reports.13,15 The mean disease duration in our patients with JHD was comparable to previous descriptions,16,17 and has been found to be similar in patients with juvenile-onset and adult-onset HD. Foroud et al17 found a shorter disease duration in patients with juvenile- and late-onset (age at on set, >50 years) HD compared with patients with midlife-onset HD (age at onset, 20-49 years), but no difference was noted between juvenile patients and patients with an older age at onset. Foroud et al17 agreed that disease duration is shorter in male patients who inherited the disease from their father.
As described by others,18,19 some patients with JHD (4 of 7) had an abnormal T2-weighted magnetic resonance imaging signal in the basal ganglia, suggesting gliosis with caudate and cortical atrophy. The 4 patients who had a detailed neuropsychological examination showed characteristic patterns of HD,8,9,20,21 which included preserved reasoning but difficulties with mental shifting, working memory, and attention.
We conclude that diagnosis delay was, at least partly, the result of psychiatric or cognitive difficulties not having been taken into account as signs of disease onset. In our view, it is important to consider these difficulties as being related to HD, because they were multiple, severe, and progressive. Frequently, age at onset in HD is based on the age of motor difficulty onset. This underestimates juvenile-onset cases and delays treatment of behavioral and psychiatric difficulties. In addition, the high proportion of maternal transmission, CAG repeats of fewer than 60, and similar anticipation in father-child and mother-child pairs are part of JHD. We suggest that HD be considered as a diagnostic hypothesis in a child or young adult with atypical movement disorder and severe, progressive psychiatric or cognitive disturbances, even in the absence of an HD-positive family history. It is important to recognize these unusual features to provide appropriate family counseling and treatment without delay.
Correspondence: Alexandra Dürr, MD, PhD, Hôpital de la Salpêtrière, INSERM U679, Bâtiment pharmacie 4è étage, Boulevard de l’Hôpital 47, 75013 Paris, France (email@example.com).
Accepted for Publication: January 3, 2006.
Author Contributions: Study concept and design: Nguyen and Dürr. Acquisition of data: Ribaï, Nguyen, Hahn-Barma, Gourfinkel-An, Vidailhet, Legout, Dodé, and Dürr. Analysis and interpretation of data: Ribaï, Nguyen, Hahn-Barma, Gourfinkel-An, Brice, and Dürr. Drafting of the manuscript: Ribaï, Nguyen, Gourfinkel-An, Legout, Dodé, and Dürr. Critical revision of the manuscript for important intellectual content: Ribaï, Hahn-Barma, Gourfinkel-An, Vidailhet, Brice, and Dürr. Statistical analysis: Ribaï and Dürr. Obtained funding: Ribaï. Administrative, technical, and material support: Ribaï, Hahn-Barma, and Dodé. Study supervision: Nguyen, Vidailhet, Legout, Brice, and Dürr.
Financial Disclosure: None reported.
Funding/Support: Dr Ribaï has received a fellowship from the European Neurological Society and the Collège de Médicine des Hôpitaux de Paris.
Acknowledgment: The authors are grateful to Merle Ruberg, PhD, and the Réseau Huntington de Langue Française for their help.