DCTN1 mutations in Perry syndrome.

Perry syndrome consists of early-onset parkinsonism, depression, severe weight loss and hypoventilation, with brain pathology characterized by TDP-43 immunostaining. We carried out genome-wide linkage analysis and identified five disease-segregating mutations affecting the CAP-Gly domain of dynactin (encoded by DCTN1) in eight families with Perry syndrome; these mutations diminish microtubule binding and lead to intracytoplasmic inclusions. Our findings show that DCTN1 mutations, previously associated with motor neuron disease, can underlie the selective vulnerability of other neuronal populations in distinct neurodegenerative disorders.

Pallidonigral TDP-43 pathology in Perry syndrome.

OBJECTIVE: Autosomal dominant parkinsonism, hypoventilation, depression and severe weight loss (Perry syndrome) is an early-onset rapidly progressive disease. At autopsy, previous studies have found severe neuronal loss in the substantia nigra without Lewy bodies. Transactive response DNA-binding protein of 43 kDa (TDP-43) has recently been identified as a major ubiquitinated constituent of neuronal and glial inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions and in amyotrophic lateral sclerosis. This study reports clinical, genetic and neuropathologic investigations of Perry syndrome. METHODS: Clinical data and autopsy brain tissue samples were collected from eight patients from four genealogically unrelated kindreds with Perry syndrome. Brain tissue was studied with immunohistochemistry and biochemistry for TDP-43. Patients were screened for mutations in the progranulin (GRN) and TDP-43 (TARDBP) genes. RESULTS: The mean age at onset was 47 years (range 40-56), and the mean age at death was 52 years (range 44-64). In all patients, we identified TDP-43-positive neuronal inclusions, dystrophic neurites and axonal spheroids in a predominantly pallidonigral distribution, and we demonstrated changes in solubility and electrophoretic mobility of TDP-43 in brain tissue. The inclusions were highly pleomorphic and predominated in the extrapyramidal system, sparing the cortex, hippocampus and motor neurons. There were no mutations in GRN or TARDBP. INTERPRETATION: Perry syndrome displays unique TDP-43 pathology that is selective for the extrapyramidal system and spares the neocortex and motor neurons.

[Pure amusia reavealing an ischaemic lesion of right temporal planum. Participation of the right temporal lobe in perception of music]. / Amusie isolée révélatrice d'une lésion ischémique du planum temporal droit. Rôle du lobe temporal dans l'appréhension de la musique.

Amusia is the impaired perception and performance of music due to brain lesions that do not affect motor or sensory skills. Amusia is usually associated with other neuropsychological disorders. We report an exceptional case of pure amusia of sudden onset in a professional choir conductor, following right-sided temporal planum infarction revealing internal carotid occlusion. We describe this patient's symptoms in relation to published observations and to the conclusions of PET scanning. This clinical case confirms that singing disorders and impaired timbre and melodic perception are particularly linked to the right temporal lobe, whereas rhythm perception involves the left temporal lobe.

[Perry and Purdy's syndrome (familial and fatal parkinsonism with hypoventilation and athymhormia)]. / Le syndrome de Perry et Purdy (parkinsonisme familial et fatal avec hypoventilation et athymhormie).

The authors describe three new cases of this familial form of Parkinson's disease, together with its clinical and histological particularities and pathophysiological basis.