Autosomal dominant mitochondrial membrane protein-associated neurodegeneration (MPAN).

BACKGROUND: Mitochondrial membrane protein-associated neurodegeneration (MPAN) is caused by pathogenic sequence variants in C19orf12. Autosomal recessive inheritance has been demonstrated. We present evidence of autosomal dominant MPAN and propose a mechanism to explain these cases. METHODS: Two large families with apparently dominant MPAN were investigated; additional singleton cases of MPAN were identified. Gene sequencing and multiplex ligation-dependent probe amplification were used to characterize the causative sequence variants in C19orf12. Post-mortem brain from affected subjects was examined. RESULTS: In two multi-generation non-consanguineous families, we identified different nonsense sequence variations in C19orf12 that segregate with the MPAN phenotype. Brain pathology was similar to that of autosomal recessive MPAN. We additionally identified a preponderance of cases with single heterozygous pathogenic sequence variants, including two with de novo changes. CONCLUSIONS: We present three lines of clinical evidence to demonstrate that MPAN can manifest as a result of only one pathogenic C19orf12 sequence variant. We propose that truncated C19orf12 proteins, resulting from nonsense variants in the final exon in our autosomal dominant cohort, impair function of the normal protein produced from the non-mutated allele via a dominant negative mechanism and cause loss of function. These findings impact the clinical diagnostic evaluation and counseling.

The effect of stimulus context on pitch representations in the human auditory cortex.

Neuroimaging studies of pitch coding seek to identify pitch-related responses separate from responses to other properties of the stimulus, such as its energy onset, and other general aspects of the listening context. The current study reports the first attempt to evaluate these modulatory influences using functional magnetic resonance imaging (fMRI) measures of cortical pitch representations. Stimulus context was manipulated using a 'classical stimulation paradigm' (whereby successive pitch stimuli were separated by gaps of silence) and a 'continuous stimulation paradigm' (whereby successive pitch stimuli were interspersed with noise to maintain a stable envelope). Pitch responses were measured for two types of pitch-evoking stimuli; a harmonic-complex tone and a complex Huggins pitch. Results for a group of 15 normally hearing listeners revealed that context effects were mostly observed in primary auditory regions, while the most significant pitch responses were localized to posterior nonprimary auditory cortex, specifically planum temporale. Sensitivity to pitch was greater for the continuous stimulation conditions perhaps because they better controlled for concurrent responses to the noise energy onset and reduced the potential problem of a non-linear fMRI response becoming saturated. These results provide support for hierarchical processing within human auditory cortex, with some parts of primary auditory cortex engaged by general auditory energy, some parts of planum temporale specifically responsible for representing pitch information and adjacent regions that are responsible for complex higher-level auditory processing such as representing pitch information as a function of listening context.