Genetically confirmed Huntington's disease masquerading as motor neuron disease

We describe a patient with Huntington's disease (HD) who showed asymmetrical upper limb amyotrophy as a main manifestation. Chorea and psychiatric symptoms were not prominent. Electromyography revealed generalized active and chronic denervation and fasciculations. A genetic test showed 46 CAG repeats in the huntingtin gene. Asymmetrical amyotrophy restricted to the upper limb has been reported in some patients with progressive chorea and amyotrophy without acanthocytosis, but genetically proven cases of HD have rarely been reported. It is not known why only a few HD patients show the motor neuronal loss; however, certain as‐yet‐unidentified genetic factors combined with some environment factors and the underlying cellular dysfunctions by polyglutamine aggregation could be responsible for the motor neuronal loss similar to that in amyotrophic lateral sclerosis. © 2008 Movement Disorder Society     

Huntington's disease like-2 neuropathology.

Huntington's disease like-2 (HDL-2) neurodegeneration is a recently described autosomal dominant disorder with features similar to Huntington's disease (HD). Only one case report has described neuropathology from an affected patient. We describe the clinical presentation and illustrate the pathology in two additional molecularly confirmed patients, compare these with the previously published case, and contrast them with HD. We examined two patients with HDL-2. Their charts were reviewed, their brains were examined using standard neuropathology techniques, including immunoperoxidase stains, and their diagnoses were confirmed with a PCR-based assay for repeat length. The first patient presented with obsessive suspiciousness, while the second had depression and decreased visual acuity. Both patients developed increased tone and cogwheel rigidity, but neither developed choreoathetosis. Extensive degeneration affected the caudate nucleus and putamen, especially dorsally and laterally. In addition, the first patient showed lateral temporal, lateral frontal, and orbitofrontal cortical atrophy, while the second patient displayed marked degeneration in the occipital and parietal cortices. Neither patient showed significant changes in the cerebellum or brainstem. Both cases had ubiquitin-immunoreactive neuronal intranuclear inclusions (NII). The patients with of HDL-2 reviewed here were remarkable for significant frontal inhibition with parkinsonism, a lack of choreiform movements, and African ancestry. Pathologically, HDL-2 is similar to HD in its effect on the neostriatum but may differ, at least in some cases, in its degree of focal cortical involvement, including the occipital lobe.     

Markedly asymmetrical parkinsonism as a leading feature of adult-onset Huntington's disease.

We report on a 28-year-old man who presented with right hand tremor, bradykinesia, and rigidity of his right side extremities. Our case report emphasizes that markedly asymmetrical parkinsonism can be an initial presentation of adult-onset Huntington's disease (HD), and different clinical presentations can be observed in members of an individual HD family with the same CAG repeat length.     

Seizures in juvenile Huntington's disease: Frequency and characterization in a multicenter cohort

Little is known about the epilepsy that often occurs in the juvenile form of Huntington's disease (HD), but is absent from the adult‐onset form. The primary aim of this study was to characterize the seizures in juvenile HD (JHD) subjects with regard to frequency, semiology, defining EEG characteristics, and response to antiepileptic agents. A multicenter, retrospective cohort was identified by database query and/or chart review. Data on age of HD onset, primary HD manifestations, number of CAG repeats, the presence or absence of seizures, seizure type(s), antiepileptic drugs used, subjects' response to antiepileptic drugs (AEDs), and EEG results were assembled, where available. Ninety subjects with genetically confirmed JHD were included. Seizures were present in 38% of subjects and were more likely to occur with younger ages of HD onset. Generalized tonic‐clonic seizures were the most common seizure type, followed by tonic, myoclonic, and staring spells. Multiple seizure types commonly occurred within the same individual. Data on EEG findings and AED usage are presented. Seizure risk in JHD increases with younger age of HD onset. Our ability to draw firm conclusions about defining EEG characteristics and response to AEDs was limited by the retrospective nature of the study. Future prospective studies are required. © 2012 Movement Disorder Society     

MR‐spectroscopic findings in juvenile‐onset Huntington's disease

Seven HD gene positive individuals under the age of 21 years are described with clinical examination and proton‐MR‐spectroscopy (¹H‐MRS) profiles of the putamen. Despite clinical variability, the predominate ¹H‐MRS abnormality is elevated glutamate, expressed well beyond the confines of the basal ganglia, and low striatal creatine. © 2008 Movement Disorder Society     

Neurochemical correlates of caudate atrophy in Huntington's disease

The precise pathogenic mechanisms of Huntington's disease (HD) are unknown but can be tested in vivo using proton magnetic resonance spectroscopy (¹H MRS) to measure neurochemical changes. The objective of this study was to evaluate neurochemical differences in HD gene mutation carriers (HGMCs) versus controls and to investigate relationships among function, brain structure, and neurochemistry in HD. Because previous ¹H MRS studies have yielded varied conclusions about HD neurochemical changes, an additional goal was to compare two ¹H MRS data analysis approaches. HGMCs with premanifest to early HD and controls underwent evaluation of motor function, magnetic resonance imaging, and localized ¹H MRS in the caudate and the frontal lobe. Analytical approaches that were tested included absolute quantitation (unsuppressed water signal as an internal reference) and relative quantification (calculating ratios of all neurochemical signals within a voxel). We identified a suite of neurochemicals that were reduced in concentration proportionally to loss of caudate volume in HGMCs. Caudate concentrations of N‐acetylaspartate (NAA), creatine, choline, and caudate and frontal lobe concentrations of glutamate plus glutamine (Glx) and glutamate were correlated with caudate volume in HGMCs. The relative, but not the absolute, quantitation approach revealed disease‐related differences; the Glx signal was decreased relative to other neurochemicals in the caudate of HGMCs versus controls. This is the first study to demonstrate a correlation among structure, function, and chemical measures in HD brain. Additionally, we demonstrate that a relative quantitation approach may enable the magnification of subtle differences between groups. Observation of decreased Glx suggests that glutamate signaling may be disrupted relatively early in HD, which has important implications for therapeutic approaches. © 2014 International Parkinson and Movement Disorder Society     

Diffusion tensor imaging in presymptomatic and early Huntington's disease: Selective white matter pathology and its relationship to clinical measures.

Atrophy of cortical and subcortical gray matter is apparent in Huntington's disease (HD) before symptoms manifest. We hypothesized that the white matter (WM) connecting cortical and subcortical regions must also be affected early and that select clinical symptoms were related to systems degeneration. We used diffusion tensor magnetic resonance imaging (DTI) to examine the regional nature of WM abnormalities in early HD, including the preclinical period, and to determine whether regional changes correlated with clinical features. We studied individuals in early stages (HD), presymptomatic individuals known to carry the genetic mutation that causes HD (Pre-HD), and matched healthy controls. DTI indices of tissue integrity were obtained from several regions of interest, including the corpus callosum (CC), internal capsule (IC), and basal ganglia, were compared across groups by t tests, and were correlated to cognitive and clinical measures. WM alterations were found throughout the CC, in the anterior and posterior limbs of the IC, and in frontal subcortical WM in HD subjects, supporting the selective involvement of the pyramidal tracts in HD; a similar distribution of changes was seen in Pre-HD subjects, supporting presymptomatic alterations. There was a significant relationship between select DTI measures and cognitive performance. Alterations in diffusion indices were also seen in the striatum that were independent of atrophy. Our findings support that WM alterations occur very early in HD. The distribution of the changes suggests that these changes contribute to the disruption of pyramidal and extrapyramidal circuits and also support a role of compromised cortical circuitry in early cognitive and subtle motor impairment during the preclinical stages of HD.     

Late-onset Huntington's disease: Diagnostic and prognostic considerations

ObjectiveTo address diagnostic and prognostic issues in patients with late-onset Huntington's disease (HD).MethodsWe analyzed a cohort of 41 late-onset (≥60 years) HD patients and compared them to 39 late-onset patients referred for HD testing that were negative for the HD-expansion and to 290 usual-onset (20–59 years) HD patients. Disease severity was assessed by the Total Functional Capacity Scale.ResultsLate-onset HD comprised 11.5% of our HD cohort. In total, 70.7% of late-onset HD patients had positive family history compared to 15.4% of late-onset expansion-negative patients (p < 0.001). Clinical features at onset or presentation could not usefully distinguish between late-onset expansion-positive and negative patients, excepting hemichorea, which was absent from the HD group (p = 0.024). Chorea was the first clinical feature in 53.7% and a presenting feature in 90.2% of late-onset HD. The mutation hit rate for late-onset patients was 51.3%, lower than in usual-onset patients (p = 0.04). Frequencies of chorea, cognitive impairment and psychiatric manifestations at onset or presentation were not significantly different between late-onset and usual-onset HD patients. Gait unsteadiness however was more common at presentation in late-onset HD (p = 0.007). Late-onset HD patients reached a severe stage of illness on average 2.8 years earlier than usual-onset HD patients (p = 0.046).ConclusionsA positive family history suggestive of HD, although absent in a third of patients, remains a helpful clue in diagnosing late-onset HD. Prognosis of late-onset HD in terms of Total Functional Capacity appears no better and shows a trend of being somewhat less favorable compared to usual-onset HD.     

Reduced Purkinje cell density in Huntington's disease

We studied, in a "blind" and quantitative fashion, the density of cerebellar Purkinje cells in 17 adult cases of Huntington's disease (HD), 17 patients with other movement disorders, 17 with schizophrenia, and 23 normal controls. There was a highly significant reduction in Purkinje cell density in HD compared with any of the other three groups. A much smaller difference in neuronal density between patients with other movement disorders and normal controls was barely significant. Eight of the 17 HD patients and only 1 of the other 57 subjects had Purkinje cell density less than 50% of the mean for the normal controls. The low density of Purkinje cells in HD could not be attributed to aging, seizures, or cause of death, nor was it merely a part of a generalized brain atrophy. The loss of large Purkinje cells suggests that the neuronal loss in HD may not be restricted to small and medium-size neurons.     

Psychopathology in Huntington's disease patients

A retrospective study of 30 Huntington's disease families (110 patients: 75 alive and 35 dead) known to a regional genetic centre, using multiple sources of information, showed the minimum lifetime prevalence of depression to be 39% in the prodrome and the diagnosed disease phase of the illness. The frequency of symptomatic schizophrenia was found to be about 9% and significant personality changes were found in 72% of the sample, some of them leading to gross behavioural anomalies. The findings reinforce the point that depression and schizophrenia, unaccompanied or preceded by organic personality changes and/or very early neural symptoms, are unlikely to lead to the eventual manifestation of the disease.     

Prevalence of Huntington's disease in Southern Sardinia,Italy

BackgroundThe frequency of Huntington's disease (HD) may vary considerably, with higher estimates in non Asian populations. In Italy, two recent studies performed in Ferrara county and Molise provided different prevalence estimates, varying from 4.2 × 10⁵ to 10.8 × 10⁵. Here we present a study performed in the Southern part of Sardinia, a large Italian mediterranean island that is considered a genetic isolate.MethodsThe study area included the two neighbouring counties of South Sardinia and Cagliari with 353,830 and 431,955 inhabitants respectively on December 31st, 2017 (prevalence date). Case-patients were ascertained through multiple sources in Sardinia and Italy.ResultsWe identified 54 individuals with HD, of whom 47 were alive on prevalence date. The resulting prevalence rate was 5.98 × 10⁵ in the overall study area, however with marked variations between South Sardinia and Cagliari (9.6 × 10⁵ vs. 3.0 × 10⁵, p = 0.02). In the two study areas, we found similar CAG repeat length in normal alleles (17.5 ± 2.1 vs. 17.7 ± 2.2, p = 0.5).ConclusionsThe overall prevalence of HD in Sardinia is close to the correspondent estimates in Europeans. Our findings also highlighted the possibility of local microgeographic variations in the epidemiology of HD.     

Huntington's disease as caused by 34 CAG repeats

Huntington's disease (HD) is an autosomal dominantly inherited neurodegenerative disorder caused by an abnormal expansion of a polymorphic stretch of CAG repeats in the coding 5′ part of the HD gene on chromosome 4p. Expansions of CAG blocks beyond 35 repeats are associated with the clinical presentation of HD. There is an intermediate range of rare alleles between 27 and 35 CAG repeats with a higher risk for further expansion in subsequent generations. Here, we report a 75‐year‐old male with clinical features of HD and 34 CAG repeat units. © 2008 Movement Disorder Society     

Hyperhomocysteinaemia in treated patients with Huntington's disease homocysteine in HD.

Significantly increased plasma total homocysteine levels (t-Hcys) appeared in treated Huntington disease (HD) patients compared to controls and untreated HD subjects. Because the protein Huntingtin interacts with the homocysteine metabolism modulating enzyme cystathionine beta-synthase, we hypothesize that homocysteine promotes neurodegeneration in HD.     

Short-term effects of tetrabenazine on chorea associated with Huntington's disease.

We sought to assess the short-term clinical effects of tetrabenazine (TBZ) on choreic movements in Huntington's disease patients. A total of 10 patients on stable doses of TBZ were enrolled in this observational study. Patients took their evening dose of TBZ and presented the next day to the Baylor College of Medicine Movement Disorders Clinic without taking the usual morning dose. They were assessed using the Unified Huntington's Disease Rating Scale (UHDRS) motor assessment and Beck Depression Inventory. The usual morning dose of TBZ was then administered and patients were followed with serial UHDRS motor examinations approximately every 2 hours until choreic movements subsided and then returned. TBZ decreased the UHDRS chorea score on average 42.4% +/- 17.8%. The duration of effect varied from a minimum of 3.2 hours to a maximum of 8.1 hours (mean = 5.4 +/- 1.3). No patient experienced an adverse event related to TBZ or its withdrawal. During short-term follow-up after a single dose, TBZ improves chorea for approximately 5 hours.     

The current clinical management of Huntington's disease

Huntington's disease is a neurodegenerative condition, characterized by movement disorders, cognitive decline, and psychiatric disturbance. We review the pharmacological management of the various movement disorders associated with the disease, the cognitive decline and the commonly encountered behavioral disturbances. We discuss the nonclassical features of the disease, important in the management of these patients. Nonpharmacological support including genetic counseling and therapy and the importance of palliative care are also addressed. Finally, experimental approaches that may soon impact upon clinical practice are discussed. © 2008 Movement Disorder Society     

Minocycline in Huntington's disease: a pilot study.

Minocycline is a caspase inhibitor, decreases inducible nitric oxide synthase (iNOS), and has been shown to delay disease progression in the mouse model R6/2 of Huntington's disease (HD). This safety and tolerability study included 30 patients with HD who were given minocycline over a 6-month period and underwent assessments every 2 months with laboratory studies, the Abnormal Involuntary Movements Scale, the Unified Huntington's Disease Rating Scale, and the Mini-Mental State Examination. Minocycline was well tolerated during this study period and no serious adverse events were noted.     

Association of obsessive-compulsive disorder and pathological gambling with Huntington's disease in an Italian pedigree: possible association with Huntington's disease mutation

This paper describes a pedigree with Huntington's disease (HD), in which three cases of obsessive-compulsive disorder (OCD) and two cases of pathological gambling (PG) were identified. The mutation analysis of the HD gene was carried out in the examined individuals who were at risk for HD. In fact, OCD and PG only occurred in carriers of the HD expansion. The possible implications of this finding are discussed.