Anelyssa D'Abreu

Caring for Machado-Joseph disease: current understanding and how to help patients.

Machado-Joseph disease or spinocerebellar ataxia 3 (MJD/SCA3) is a clinically heterogeneous, neurodegenerative disorder characterized by varying degrees of ataxia, ophthalmoplegia, peripheral neuropathy, pyramidal dysfunction and movement disorder. MJD/SCA3 is caused by a CAG repeat expansion mutation in the protein coding region of the ATXN3 gene located at chromosome 14q32.1. Current hypotheses regarding pathogenesis favor the view that mutated ataxin-3, with its polyglutamine expansion, is prone to adopt an abnormal conformation, engage in altered protein-protein interactions and aggregate. Expanded CAG repeat length correlates with the range and severity of the clinical manifestations and inversely correlates with age of disease onset. Though MJD/SCA3 is classically described as affecting the cerebellum, brainstem and basal ganglia, recent neuropathology and neuroimaging series demonstrate involvement of other areas such as the thalamus and cerebral cortex. Clinically, much emphasis has been placed in the description and recognition of the non-motor symptoms observed in these patients, such as pain, cramps, fatigue and depression. Currently, no disease modifying treatment exists for MJD/SCA3. Standard of care includes genetic counseling, exercise/physical therapy programs, and speech and swallow evaluation. Symptomatic treatment for clinical findings such as depression, sleep disorders, parkinsonism, dystonia, cramps, and pain is important to improve the quality of life for those with MJD/SCA3.

Nonmotor and extracerebellar features in Machado-Joseph disease: a review.

Spinocerebellar ataxia type 3 or Machado‐Joseph disease is the most common spinocerebellar ataxia worldwide, and the high frequency of nonmotor manifestations in Machado‐Joseph disease demonstrates how variable is the clinical expression of this single genetic entity. Anatomical, physiological, clinical, and functional neuroimaging data reinforce the idea of a degenerative process involving extracerebellar regions of the nervous system in Machado‐Joseph disease. Brain imaging and neuropathologic studies have revealed atrophy of the pons, basal ganglia, midbrain, medulla oblongata, multiple cranial nerve nuclei, and thalamus and of the frontal, parietal, temporal, occipital, and limbic lobes. This review provides relevant information about nonmotor manifestations and extracerebellar symptoms in Machado‐Joseph disease. The main nonmotor manifestations of Machado‐Joseph disease described in previous data and discussed in this article are: sleep disorders, cognitive and affective disturbances, psychiatric symptoms, olfactory dysfunction, peripheral neuropathy, pain, cramps, fatigue, nutritional problems, and dysautonomia. In addition, we conducted a brief discussion of noncerebellar motor manifestations, highlighting movement disorders.

Prospective neuroimaging study in hereditary spastic paraplegia with thin corpus callosum.

Our objective was to estimate the frequency as well as to establish the clinical and neuroimaging profile of hereditary spastic paraplegia with thin corpus callosum (HSP‐TCC). HSP‐TCC was recognized as a specific clinical subtype of HSP and mapped to chromosome (ch) 15q13‐15 in Japanese families. It has been considered rare in western countries. We assessed 45 patients with autosomal recessive HSP from 20 different families in search of clinical and imaging criteria for the diagnosis of HSP‐TCC. In addition, HSP‐TCC patients underwent further neurological, imaging and genetic evaluation. MRI scans were performed in a 2T scanner and sagittal T1 weighted images used for semiautomated volumetric measurements of corpus callosum, cerebellum, and brain. In seven patients, a 2‐year follow‐up MRI scan was performed. We genotyped seven microsatellite markers flanking the 15q13‐15 candidate region and calculated two‐point and multipoint LOD scores (Z). We identified 13 patients from seven unrelated families with HSP‐TCC. MRI showed significant corpus callosum, cerebral and cerebellar volumetric reductions (P < 0.001, P = 0.03, and P = 0.01, respectively). In the prospective analysis, we found progressive corpus callosum atrophy (P = 0.04). Two‐point and multipoint LOD scores were significantly negative for markers genotyped on ch 15q. However, independent pedigree analysis did not yield significant results. HSP‐TCC was found in 35% of families with autosomal recessive HSP. MRI volumetry showed cerebral and cerebellar atrophy in association with progressive corpus callosum thinning. Genetic studies did not show evidence for linkage to ch 15q.

Dentate nuclei T2 relaxometry is a reliable neuroimaging marker in Friedreich's ataxia

In Friedreichs ataxia (FRDA), frataxin deficiency results in iron redistribution in the dentate nuclei (DNC). Clusters of iron cause inhomogeneities in a magnetic field and result in a reduction in T2 relaxation time (T2).

Cerebral cortex involvement in Machado−Joseph disease

Machado−Joseph disease (MJD/SCA3) is the most frequent spinocerebellar ataxia, characterized by brainstem, basal ganglia and cerebellar damage. Few magnetic resonance imaging based studies have investigated damage in the cerebral cortex. The objective was to determine whether patients with MJD/SCA3 have cerebral cortex atrophy, to identify regions more susceptible to damage and to look for the clinical and neuropsychological correlates of such lesions.

Progression of ataxia in patients with Machado-Joseph disease†

Although ataxia is the most distressing manifestation of Machado‐Joseph disease (MJD), little is known about its natural history. Therefore, we prospectively followed a cohort of patients with MJD for 13 months to characterize the progression of ataxia and identify its contributory factors. The international cooperative ataxia rating scale (ICARS) was used to estimate severity of ataxia at baseline and at follow‐up. Thirty‐four patients were enrolled in the study, 22 of whom were men. Mean age at onset of the disease was 34.7 years and length of expanded CAG repeat was 66. Mean ICARS scores at baseline was 37.6 and at follow‐up was 42.7 (P < 0.001). Multivariate analysis did not find significant association of progression of disease and age at disease onset, length of expanded (CAG), or duration of disease.

Longitudinal magnetic resonance imaging study shows progressive pyramidal and callosal damage in Friedreich's ataxia

Spinal cord and peripheral nerves are classically known to be damaged in Friedreichs ataxia, but the extent of cerebral involvement in the disease and its progression over time are not yet characterized. The aim of this study was to evaluate longitudinally cerebral damage in Friedreichs ataxia

MRI shows dorsal lesions and spinal cord atrophy in chronic sensory neuronopathies

Sensory neuronopathies (SN) represent a specific subgroup of peripheral nervous system diseases, characterized by degeneration of dorsal root ganglia (DRG) and its projections. We tried to estimate the frequency and extent of spinal cord MRI abnormalities in a group of patients with SN and correlate these with clinical and neurophysiological features.

Clinical features and management of hereditary spastic paraplegia

Hereditary spastic paraplegia (HSP) is a group of genetically-determined disorders characterized by progressive spasticity and weakness of lower limbs. An apparently sporadic case of adult-onset spastic paraplegia is a frequent clinical problem and a significant proportion of cases are likely to be of genetic origin. HSP is clinically divided into pure and complicated forms. The later present with a wide range of additional neurological and systemic features. To date, there are up to 60 genetic subtypes described. All modes of monogenic inheritance have been described: autosomal dominant, autosomal recessive, X-linked and mitochondrial traits. Recent advances point to abnormal axonal transport as a key mechanism leading to the degeneration of the long motor neuron axons in the central nervous system in HSP. In this review we aim to address recent advances in the field, placing emphasis on key diagnostic features that will help practicing neurologists to identify and manage these conditions.

Prospective study of peripheral neuropathy in Machado–Joseph disease

Peripheral neuropathy (PN) has long been recognized in Machado–Joseph disease (MJD), but its natural history is an unsettled issue. Therefore, we prospectively assessed 40 with MJD for 13 months with nerve conduction (NC) studies and the revised total neuropathy score (TNSr) to study the progression of PN. There was no significant change in the TNSr score over the follow‐up period. In contrast, the average sural sensory nerve action potential (SNAP) amplitude decreased significantly over the same interval from a mean of 13.2 μV to 9.8 μV (P < 0.001). There was an inverse correlation between the change in the sural SNAP amplitude and the length of the CAG triplet repeat expansion (r = 0.574, P < 0.001). The reduction in the mean sural SNAP amplitude also correlated with progression of ataxia. This indicates that PN progresses faster in individuals with larger (CAG)n expansions, and nerve conduction studies may be useful to study disease progression in MJD. Muscle Nerve, 2009