SCN1A-related epilepsy with recessive inheritance: Two further families.

BACKGROUND: Variants in SCN1A gene, encoding the voltage-gated sodium channel Nav1.1, are associated with distinct epilepsy syndromes ranging from the relatively benign genetic epilepsy with febrile seizures plus (GEFS+) to Dravet syndrome, a severe developmental and epileptic encephalopathy (DEE). Most SCN1A pathogenic variants are heterozygous changes inherited in a dominant or de novo inheritance and many cause a loss-of-function of one allele. To date, recessive inheritance has been suggested in only two families with affected children harboring homozygous SCN1A missense variants while their heterozygous parents were asymptomatic. The aim of this report is to describe two additional families in which affected individuals have biallelic SCN1A variants possibly explaining their phenotype. METHODS AND RESULTS: We report two novel homozygous SCN1A missense variants in two patients from related parents. Both patients had fever-sensitive epilepsy beginning in the first months of life, followed by afebrile seizures, without severe cognitive impairment. Parents were asymptomatic. Next generation sequencing excluded a pathogenic variant in other genes involved in DEE. Estimation of pathogenicity scores by in-silico tools suggests that the impact of these SCN1A variants is less damaging than that of dominant pathogenic variants. CONCLUSION: This study provides additional evidence that homozygous variants in SCN1A can cause GEFS+. This recessive inheritance would imply that hypomorphic variants may not necessarily cause epilepsy at the heterozygous state but may decrease the seizure threshold when combined.

Impairments in musical abilities reflected in the auditory brainstem: evidence from congenital amusia.

Congenital amusia is a neurogenetic condition, characterized by a deficit in music perception and production, not explained by hearing loss, brain damage or lack of exposure to music. Despite inferior musical performance, amusics exhibit normal auditory cortical responses, with abnormal neural correlates suggested to lie beyond auditory cortices. Here we show, using auditory brainstem responses to complex sounds in humans, that fine-grained automatic processing of sounds is impoverished in amusia. Compared with matched non-musician controls, spectral amplitude was decreased in amusics for higher harmonic components of the auditory brainstem response. We also found a delayed response to the early transient aspects of the auditory stimulus in amusics. Neural measures of spectral amplitude and response timing correlated with participants' behavioral assessments of music processing. We demonstrate, for the first time, that amusia affects how complex acoustic signals are processed in the auditory brainstem. This neural signature of amusia mirrors what is observed in musicians, such that the aspects of the auditory brainstem responses that are enhanced in musicians are degraded in amusics. By showing that gradients of music abilities are reflected in the auditory brainstem, our findings have implications not only for current models of amusia but also for auditory functioning in general.

Successful measurement of the mismatch negativity despite a concurrent movie soundtrack: reduced amplitude but normal component morphology.

OBJECTIVE: To examine the mechanisms responsible for the reduction of the mismatch negativity (MMN) ERP component observed in response to pitch changes when the soundtrack of a movie is presented while recording the MMN. METHODS: In three experiments we measured the MMN to tones that differed in pitch from a repeated standard tone presented with a silent subtitled movie, with the soundtrack played forward or backward, or with soundtracks set at different intensity levels. RESULTS: MMN amplitude was reduced when the soundtrack was presented either forward or backward compared to the silent subtitled movie. With the soundtrack, MMN amplitude increased proportionally to the increments in the sound-to-noise intensity ratio. CONCLUSION: MMN was reduced in amplitude but had normal morphology with a concurrent soundtrack, most likely because of basic acoustical interference from the soundtrack with MMN-critical tones rather than from attentional effects. SIGNIFICANCE: A normal MMN can be recorded with a concurrent movie soundtrack, but signal amplitudes need to be set with caution to ensure a sufficiently high sound-to-noise ratio between MMN stimuli and the soundtrack.

Pitch discrimination without awareness in congenital amusia: evidence from event-related potentials.

Congenital amusia is a lifelong disorder characterized by a difficulty in perceiving and producing music despite normal intelligence and hearing. Behavioral data have indicated that it originates from a deficit in fine-grained pitch discrimination, and is expressed by the absence of a P3b event-related brain response for pitch differences smaller than a semitone and a bigger N2b-P3b brain response for large pitch differences as compared to controls. However, it is still unclear why the amusic brain overreacts to large pitch changes. Furthermore, another electrophysiological study indicates that the amusic brain can respond to changes in melodies as small as a quarter-tone, without awareness, by exhibiting a normal mismatch negativity (MMN) brain response. Here, we re-examine the event-related N2b-P3b components with the aim to clarify the cause of the larger amplitude observed by Peretz, Brattico, and Tervaniemi (2005), by experimentally matching the number of deviants presented to the controls according to the number of deviants detected by amusics. We also re-examine the MMN component as well as the N1 in an acoustical context to investigate further the pitch discrimination deficit underlying congenital amusia. In two separate conditions, namely ignore and attend, we measured the MMN, the N1, the N2b and the P3b to tones that deviated by an eight of a tone (25 cents) or whole tone (200 cents) from a repeated standard tone. The results show a normal MMN, a seemingly normal N1, a normal P3b for the 200 cents pitch deviance, and no P3b for the small 25 cents pitch differences in amusics. These results indicate that the amusic brain responds to small pitch differences at a pre-attentive level of perception, but is unable to detect consciously those same pitch deviances at a later attentive level. The results are consistent with previous MRI and fMRI studies indicating that the auditory cortex of amusic individuals is functioning normally.

Congenital amusia persists in the developing brain after daily music listening.

Congenital amusia is a neurodevelopmental disorder that affects about 3% of the adult population. Adults experiencing this musical disorder in the absence of macroscopically visible brain injury are described as cases of congenital amusia under the assumption that the musical deficits have been present from birth. Here, we show that this disorder can be expressed in the developing brain. We found that (10-13 year-old) children exhibit a marked deficit in the detection of fine-grained pitch differences in both musical and acoustical context in comparison to their normally developing peers comparable in age and general intelligence. This behavioral deficit could be traced down to their abnormal P300 brain responses to the detection of subtle pitch changes. The altered pattern of electrical activity does not seem to arise from an anomalous functioning of the auditory cortex, because all early components of the brain potentials, the N100, the MMN, and the P200 appear normal. Rather, the brain and behavioral measures point to disrupted information propagation from the auditory cortex to other cortical regions. Furthermore, the behavioral and neural manifestations of the disorder remained unchanged after 4 weeks of daily musical listening. These results show that congenital amusia can be detected in childhood despite regular musical exposure and normal intellectual functioning.

Congenital amusia in childhood: a case study.

Here we describe the first documented case of congenital amusia in childhood. AS is a 10-year-old girl who was referred to us by her choir director for persisting difficulties in singing. We tested her with the child version of the Montreal Battery for the Evaluation of Amusia (MBEA) which confirmed AS's severe problems with melodic and rhythmic discrimination and memory for melodies. The disorder appears to be limited to music since her audiometry as well as her intellectual and language skills are normal. Furthermore, the musical disorder is associated to a severe deficit in detecting small pitch changes. The electrical brain responses point to an anomaly in the early stages of auditory processing, such as reflected by an abnormal mismatch negativity (MMN) response to small pitch changes. In singing, AS makes more pitch than time errors. Thus, despite frequent and regular musical practice, AS's profile is similar to the adult form of congenital amusia.

Early integration of vowel and pitch processing: a mismatch negativity study.

OBJECTIVE: Several studies have explored the processing specificity of music and speech, but only a few have addressed the processing autonomy of their fundamental components: pitch and phonemes. Here, we examined the additivity of the mismatch negativity (MMN) indexing the early interactions between vowels and pitch when sung. METHODS: Event-related potentials (ERPs) were recorded while participants heard frequent sung vowels and rare stimuli deviating in pitch only, in vowel only, or in both pitch and vowel. The task was to watch a silent movie while ignoring the sounds. RESULTS: All three types of deviants elicited both an MMN and a P3a ERP component. The observed MMNs were of similar amplitude for the three types of deviants and the P3a was larger for double deviants. The MMNs to deviance in vowel and deviance in pitch were not additive. CONCLUSIONS: The underadditivity of the MMN responses suggests that vowel and pitch differences are processed by interacting neural networks. SIGNIFICANCE: The results indicate that vowel and pitch are processed as integrated units, even at a pre-attentive level. Music-processing specificity thus rests on more complex dimensions of music and speech.

Automatic brain responses to pitch changes in congenital amusia.

Congenital amusia is a lifelong disorder affecting the processing of pitch. This pitch deficit can be traced down to abnormal brain responses elicited by pitch changes smaller than a semitone in conditions requiring attention. Here, we use the mismatch negativity (MMN) to investigate pre-attentive pitch change detection in 10 amusics and eight matched controls. Results indicate similar MMN in amusics and controls, even for an eighth of a tone change, revealing that the amusic brain can process small pitch changes at a pre-attentive level. Thus, the pitch deficit in congenital amusia may be related to a problem of perceptual awareness.

Integrated preattentive processing of vowel and pitch: a mismatch negativity study.

This study examines the additivity of the Mismatch Negativity (MMN) as an index of the early interactions between vowels and pitch when sung. Event-related potentials (ERPs) were recorded while participants were presented with sung vowels. Sixteen percent of stimuli deviated in pitch only, in vowel only, or in both pitch and vowel. All three kinds of deviants elicited an MMN of similar amplitude. The MMNs to vowel and pitch deviants did not show significant additivity. This suggests that vowel and pitch are processed by shared neural substrates at the preattentive level.