Do variants in the coding regions of FOXP2, a gene implicated in speech disorder, confer a risk for congenital amusia?

Congenital amusia is a lifelong disorder that compromises the normal development of musical abilities in 1.5-4% of the general population. There is a substantial genetic contribution to congenital amusia, and it bears similarities to neurodevelopmental disorders of language. Here, we examine the extent to which variants in the forkhead box P2 gene (FOXP2)-the first gene to be identified as causal in developmental speech deficits-are associated with the amusic trait. Using a cohort of 49 individuals with amusia, of which 27 were unrelated, the role of FOXP2 variants in amusia was evaluated. Fourteen variants were examined in the cohort. None segregated with the amusic trait among participants for whom family information was available; nor were they predicted to be deleterious to protein function. Thus, variants in FOXP2 are not likely to cause amusia. Implications for ongoing debates about the distinction between musicality and language are discussed.

Congenital amusia-pathology of musical disorder.

Amusia also known as tone deafness affects roughly 1.5% population. Congenital amusia appears from birth and lasts over life span. Usually, it is not associated with other diseases. Its link to hearing impairment has been definitively excluded. Neurobiological studies point to asymmetrical processing of musical signals in auditory cortex of left and right brain hemispheres. The finding was supported by discovering microlesions in the right-side gray matter. Because of its connection with asymmetry, amusia has been classified to disconnection syndromes. Alternatively to the neurobiological explanation of amusia background, an attention was turned to the significance of genetic factors. The studies done on relatives and twins indicated familial aggregation of amusia. Molecular genetic investigations linked amusia with deletion of 22q11.2 chromosome region. Until now no specific genes responsible for development of amusia were found.

Resistance to noise-induced gap detection impairment in FVB mice is correlated with reduced neuroinflammatory response and parvalbumin-positive neuron loss.

Exposure to loud noises results in neuroinflammatory responses in the central auditory pathway. Noise-induced neuroinflammation is implicated in auditory processing deficits such as impairment in gap detection. In this study, we examined whether strain differences between the FVB and C57BL/6 mice in noise-induced impairment in gap detection are correlated with strain differences in neuroinflammatory responses. We found that noise induced more robust TNF-α expression in C57BL/6 than in FVB mice. Noise-induced microglial deramification was observed in C57BL/6 mice, but not in FVB mice. Furthermore, noise exposure resulted in a reduction in parvalbumin-positive (PV+) neuron density in the C57BL/6 mice, but not in FVB mice. These results suggest that neuroinflammatory responses and loss of PV+ neurons may contribute to strain differences in noise-induced impairment in gap detection.

Multi-level evidence of an allelic hierarchy of USH2A variants in hearing, auditory processing and speech/language outcomes.

Language development builds upon a complex network of interacting subservient systems. It therefore follows that variations in, and subclinical disruptions of, these systems may have secondary effects on emergent language. In this paper, we consider the relationship between genetic variants, hearing, auditory processing and language development. We employ whole genome sequencing in a discovery family to target association and gene x environment interaction analyses in two large population cohorts; the Avon Longitudinal Study of Parents and Children (ALSPAC) and UK10K. These investigations indicate that USH2A variants are associated with altered low-frequency sound perception which, in turn, increases the risk of developmental language disorder. We further show that Ush2a heterozygote mice have low-level hearing impairments, persistent higher-order acoustic processing deficits and altered vocalizations. These findings provide new insights into the complexity of genetic mechanisms serving language development and disorders and the relationships between developmental auditory and neural systems.

Emotional prosody in congenital amusia: Impaired and spared processes.

Congenital amusia is a lifelong deficit of music processing, in particular of pitch processing. Most research investigating this neurodevelopmental disorder has focused on music perception, but pitch also has a critical role for intentional and emotional prosody in speech. Two previous studies investigating amusics' emotional prosody recognition have shown either some deficit or no deficit (compared to controls). However, these previous studies have used only long sentence stimuli, which allow for limited control over acoustic content. Here, we tested amusic individuals for emotional prosody perception in sentences and vowels. For each type of material, participants performed an emotion categorization task, followed by intensity ratings of the recognized emotion. Compared to controls, amusic individuals had similar recognition of emotion in sentences, but poorer performance in vowels, especially when distinguishing sad and neutral stimuli. These lower performances in amusics were linked with difficulties in processing pitch and spectro-temporal parameters of the vowel stimuli. For emotion intensity, neither sentence nor vowel ratings differed between participant groups, suggesting preserved implicit processing of emotional prosody in amusia. These findings can be integrated into previous data showing preserved implicit processing of pitch and emotion in amusia alongside deficits in explicit recognition tasks. They are thus further supporting the hypothesis of impaired conscious analysis of pitch and timbre in this neurodevelopmental disorder.

SCN1A mutations in focal epilepsy with auditory features: widening the spectrum of GEFS plus.

Epilepsy with auditory features (EAF) is a focal epilepsy syndrome characterized by prominent auditory ictal manifestations. Two main genes, LGI1 and RELN, have been implicated in EAF, but the genetic aetiology remains unknown in half of families and most sporadic cases. We previously described a pathogenic SCN1A missense variant (p.Thr956Met) segregating in a large family in which the proband and her affected daughter had EAF, thus satisfying the minimum requirement for diagnosis of autosomal dominant EAF (ADEAF). However, the remaining eight affected family members had clinical manifestations typically found in families with genetic epilepsy with febrile seizures plus (GEFS+). We aimed to investigate the role/impact of SCN1A mutations in EAF. We detailed the phenotype of this family and report on SCN1A screening in a cohort of 29 familial and 52 sporadic LGI1 variant-negative EAF patients. We identified two possibly pathogenic missense variants (p.Tyr790Phe and p.Thr140Ile) in sporadic patients (3.8%) showing typical EAF and no antecedent febrile seizures. Both p.Thr956Met and p.Tyr790Phe were previously described in unrelated patients with epilepsies within the GEFS+ spectrum. SCN1A mutations may be involved in EAF within the GEFS+ spectrum, however, the role of SCN1A in EAF without features that lead to a suspicion of underlying GEFS+ remains unclear and should be elucidated in future studies.

Musical auditory processing, cognition, and psychopathology in 22q11.2 deletion syndrome.

Chromosome 22q11.2 deletion syndrome (22q11DS) is associated with impairment in multiple domains of cognition and risk for several psychiatric disorders. Musical auditory processing is highly heritable, and is impaired in individuals with schizophrenia and other neurodevelopmental disorders, but has never been studied in 22q11DS, notwithstanding anecdotal evidence of its sparing. We aimed to characterize musical auditory processing in 22q11DS and explore potential relationships with other cognitive domains, musical engagement, and psychiatric disorders. The Distorted Tunes Task and Global Musical Sophistication Index were used to assess pitch discrimination and general musical engagement in 58 individuals with 22q11DS aged 8-29 years. Psychopathology was assessed with sections from the modified Schedule for Affective Disorders and Schizophrenia for School-Age Children and the Structured Interview for Prodromal Syndromes. The Penn computerized neurocognitive battery (CNB) examined four domains of cognition (executive functioning, episodic memory, complex cognition, and social cognition). Significant musical auditory processing impairment and reduced musical engagement were found in individuals with 22q11DS. However, deficits in musical auditory processing were not associated with reduced musical engagement. After covarying for age and sex, episodic memory and overall CNB performance accuracy were significantly related to performance in musical auditory processing. There were no relationships between musical auditory processing and presence of any psychiatric diagnoses. Individuals with 22q11DS experience significant deficits in musical auditory processing and reduced musical engagement. Pitch discrimination is associated with overall cognitive ability, but appears to be largely independent of psychiatric illness.

Congenital amusics use a secondary pitch mechanism to identify lexical tones.

Amusia is a pitch perception disorder associated with deficits in processing and production of both musical and lexical tones, which previous reports have suggested may be constrained to fine-grained pitch judgements. In the present study speakers of tone-languages, in which lexical tones are used to convey meaning, identified words present in chimera stimuli containing conflicting pitch-cues in the temporal fine-structure and temporal envelope, and which therefore conveyed two distinct utterances. Amusics were found to be more likely than controls to judge the word according to the envelope pitch-cues. This demonstrates that amusia is not associated with fine-grained pitch judgements alone, and is consistent with there being two distinct pitch mechanisms and with amusics having an atypical reliance on a secondary mechanism based upon envelope cues.

Prevalence of congenital amusia.

Congenital amusia (commonly known as tone deafness) is a lifelong musical disorder that affects 4% of the population according to a single estimate based on a single test from 1980. Here we present the first large-based measure of prevalence with a sample of 20 000 participants, which does not rely on self-referral. On the basis of three objective tests and a questionnaire, we show that (a) the prevalence of congenital amusia is only 1.5%, with slightly more females than males, unlike other developmental disorders where males often predominate; (b) self-disclosure is a reliable index of congenital amusia, which suggests that congenital amusia is hereditary, with 46% first-degree relatives similarly affected; (c) the deficit is not attenuated by musical training and (d) it emerges in relative isolation from other cognitive disorder, except for spatial orientation problems. Hence, we suggest that congenital amusia is likely to result from genetic variations that affect musical abilities specifically.

15q13.3 homozygous knockout mouse model display epilepsy-, autism- and schizophrenia-related phenotypes.

The 15q13.3 microdeletion syndrome is caused by a 1.5-MB hemizygous microdeletion located on 15q13.3 affecting seven genes: FAN1; MTMR10; TRPM1; miR-211; KLF13; OTUD7A; and CHRNA7. The 15q13.3 microdeletion increases the risk of intellectual disability, epilepsy, autism spectrum disorder and schizophrenia, though the clinical profile varies considerably. Two mouse models of this syndrome, with hemizygous deletion of the orthologous region in the murine genome, have recently been shown to recapitulate a number of the behavioral and physiological deficits that characterize the human condition. Still, little is known of the underlying biological mechanisms. Eleven human cases with homozygous deletion of the 15q13.3 region have been reported, all with severe functional and physiological impairments. We therefore hypothesized that a 15q13.3 homozygous knockout would confer more pronounced behavioral and physiological deficits in mice than the 15q13.3 hemizygous deletion. Here we report the characterization of a 15q13.3 knockout mouse. We observed marked deficits including altered seizure susceptibility, autistic behavior-related phenotypes, and auditory sensory processing. Several of these deficits, albeit less pronounced, were also found in the 15q13.3 hemizygous littermates indicating a gene-dosage dependency. Our findings strongly indicate that studies of the hemi- and homozygous 15q13.3 mouse strains will facilitate understanding of the biological mechanisms of severe mental disorders.

Heritability of non-speech auditory processing skills.

Recent insight into the genetic bases for autism spectrum disorder, dyslexia, stuttering, and language disorders suggest that neurogenetic approaches may also reveal at least one etiology of auditory processing disorder (APD). A person with an APD typically has difficulty understanding speech in background noise despite having normal pure-tone hearing sensitivity. The estimated prevalence of APD may be as high as 10% in the pediatric population, yet the causes are unknown and have not been explored by molecular or genetic approaches. The aim of our study was to determine the heritability of frequency and temporal resolution for auditory signals and speech recognition in noise in 96 identical or fraternal twin pairs, aged 6-11 years. Measures of auditory processing (AP) of non-speech sounds included backward masking (temporal resolution), notched noise masking (spectral resolution), pure-tone frequency discrimination (temporal fine structure sensitivity), and nonsense syllable recognition in noise. We provide evidence of significant heritability, ranging from 0.32 to 0.74, for individual measures of these non-speech-based AP skills that are crucial for understanding spoken language. Identification of specific heritable AP traits such as these serve as a basis to pursue the genetic underpinnings of APD by identifying genetic variants associated with common AP disorders in children and adults.

Identifying musical difficulties as they relate to congenital amusia in the pediatric population.

INTRODUCTIONS/OBJECTIVES: Approximately 4% of the population fails to develop basic music skills and can be identified as "amusic". Congenital amusia (CA), or "tone deafness", is thought to be a hereditary disordera predominantly affecting the perception and production of music. The gold standard for diagnosis is the Montreal Battery for Evaluation of Amusia (MBEA). This study aims to pinpoint factors in the history that may help identify amusic children and to determine if amusic pediatric patients can be identified using a widely available, shorter test validated in adults. METHODS: Subjects ages 7-17 years were recruited to take an online test, validated against the MBEA, for CA. The sections tested recognition of "off-beat" (OB), "mistuned" (MT), and "out-of-key" (OOK) conditions. Parents filled out a questionnaire regarding the subject's past medical, educational, musical exposure, and family history. RESULTS: Of 114 subjects recruited, complete data was available on 105 with a mean age of 12.5 years. According to adult criteria, 63/105 (60%) of subjects scored in the "amusic" range. Children >10 years of age scored significantly higher on the off-beat section (p=0.001) and total scores (p=0.025). Subjects who were born prematurely scored significantly lower (p=0.045). Children whose father had difficulties with music scored significantly lower on the off-beat section (p=0.003) and total scores (p=0.008). CONCLUSIONS: CA is a disorder that has implications for quality of life. Earlier identification may help elucidate the pathogenesis of the condition and, in the future, the institution of prompt treatment. Further studies are needed to identify the most appropriate and convenient tests, as well as the optimal timing of testing, for reliably diagnosing CA in children.

Decreased temporal precision of neuronal signaling as a candidate mechanism of auditory processing disorder.

The sense of hearing is the fastest of our senses and provides the first all-or-none action potential in the auditory nerve in less than four milliseconds. Short stimulus evoked latencies and their minimal variability are hallmarks of auditory processing from spiral ganglia to cortex. Here, we review how even small changes in first spike latencies (FSL) and their variability (jitter) impact auditory temporal processing. We discuss a number of mouse models with degraded FSL/jitter whose mutations occur exclusively in the central auditory system and therefore might serve as candidates to investigate the cellular mechanisms underlying auditory processing disorders (APD).

Importance of a multidisciplinary approach and monitoring in fetal warfarin syndrome.

Warfarin is a synthetic oral anticoagulant that crosses the placenta and can lead to a number of congenital abnormalities known as fetal warfarin syndrome. Our aim is to report on the follow-up from birth to age 8 years of a patient with fetal warfarin syndrome. He presented significant respiratory dysfunction, as well as dental and speech and language complications. The patient was the second child of a mother who took warfarin during pregnancy due to a metallic heart valve. The patient had respiratory dysfunction at birth. On physical examination, he had a hypoplastic nose, pectus excavatum, and clubbing of the fingers. Nasal fibrobronchoscopy showed upper airway obstruction due to narrowing of the nasal cavities. He underwent surgical correction with Max Pereira graft, zetaplasty, and osteotomies for the piriform aperture. At dental evaluation, he had caries and delayed eruption of the upper incisors. Speech and language assessment revealed high palate, mouth breathing, little nasal patency, and shortened upper lip. Auditory long latency and cognitive-related potential to auditory stimuli demonstrated functional changes in the cortical auditory pathways. We believe that the frequency of certain findings observed in our patient may be higher in fetal warfarin syndrome than is appreciated, since a significant number result in abortions, stillbirths, or children evaluated in the first year of life without a follow-up. Thus, a multidisciplinary approach and long-term monitoring of these patients may be necessary.

Defining the biological bases of individual differences in musicality.

Advances in molecular technologies make it possible to pinpoint genomic factors associated with complex human traits. For cognition and behaviour, identification of underlying genes provides new entry points for deciphering the key neurobiological pathways. In the past decade, the search for genetic correlates of musicality has gained traction. Reports have documented familial clustering for different extremes of ability, including amusia and absolute pitch (AP), with twin studies demonstrating high heritability for some music-related skills, such as pitch perception. Certain chromosomal regions have been linked to AP and musical aptitude, while individual candidate genes have been investigated in relation to aptitude and creativity. Most recently, researchers in this field started performing genome-wide association scans. Thus far, studies have been hampered by relatively small sample sizes and limitations in defining components of musicality, including an emphasis on skills that can only be assessed in trained musicians. With opportunities to administer standardized aptitude tests online, systematic large-scale assessment of musical abilities is now feasible, an important step towards high-powered genome-wide screens. Here, we offer a synthesis of existing literatures and outline concrete suggestions for the development of comprehensive operational tools for the analysis of musical phenotypes.

Mutation of Dcdc2 in mice leads to impairments in auditory processing and memory ability.

Dyslexia is a complex neurodevelopmental disorder characterized by impaired reading ability despite normal intellect, and is associated with specific difficulties in phonological and rapid auditory processing (RAP), visual attention and working memory. Genetic variants in Doublecortin domain-containing protein 2 (DCDC2) have been associated with dyslexia, impairments in phonological processing and in short-term/working memory. The purpose of this study was to determine whether sensory and behavioral impairments can result directly from mutation of the Dcdc2 gene in mice. Several behavioral tasks, including a modified pre-pulse inhibition paradigm (to examine auditory processing), a 4/8 radial arm maze (to assess/dissociate working vs. reference memory) and rotarod (to examine sensorimotor ability and motor learning), were used to assess the effects of Dcdc2 mutation. Behavioral results revealed deficits in RAP, working memory and reference memory in Dcdc2(del2/del2) mice when compared with matched wild types. Current findings parallel clinical research linking genetic variants of DCDC2 with specific impairments of phonological processing and memory ability.

α2δ3 is essential for normal structure and function of auditory nerve synapses and is a novel candidate for auditory processing disorders.

The auxiliary subunit α2δ3 modulates the expression and function of voltage-gated calcium channels. Here we show that α2δ3 mRNA is expressed in spiral ganglion neurons and auditory brainstem nuclei and that the protein is required for normal acoustic responses. Genetic deletion of α2δ3 led to impaired auditory processing, with reduced acoustic startle and distorted auditory brainstem responses. α2δ3(-/-) mice learned to discriminate pure tones, but they failed to discriminate temporally structured amplitude-modulated tones. Light and electron microscopy analyses revealed reduced levels of presynaptic Ca(2+) channels and smaller auditory nerve fiber terminals contacting cochlear nucleus bushy cells. Juxtacellular in vivo recordings of sound-evoked activity in α2δ3(-/-) mice demonstrated impaired transmission at these synapses. Together, our results identify a novel role for the α2δ3 auxiliary subunit in the structure and function of specific synapses in the mammalian auditory pathway and in auditory processing disorders.

Smooth pursuit eye movement, prepulse inhibition, and auditory paired stimuli processing endophenotypes across the schizophrenia-bipolar disorder psychosis dimension.

BACKGROUND: This study examined smooth pursuit eye movement (SPEM), prepulse inhibition (PPI), and auditory event-related potentials (ERP) to paired stimuli as putative endophenotypes of psychosis across the schizophrenia-bipolar disorder dimension. METHODS: Sixty-four schizophrenia probands (SZP), 40 psychotic bipolar I disorder probands (BDP), 31 relatives of SZP (SZR), 26 relatives of BDP (BDR), and 53 healthy controls (HC) were tested. Standard clinical characterization, SPEM, PPI, and ERP measures were administered. RESULTS: There were no differences between either SZP and BDP or SZR and BDR on any of the SPEM, PPI, or ERP measure. Compared with HC, SZP and BDP had lower SPEM maintenance and predictive pursuit gain and ERP theta/alpha and beta magnitudes to the initial stimulus. PPI did not differ between the psychosis probands and HC. Compared with HC, SZR and BDR had lower predictive pursuit gain and ERP theta/alpha and beta magnitudes to the first stimulus with differences ranging from a significant to a trend level. Neither active symptoms severity nor concomitant medications were associated with neurophysiological outcomes. SPEM, PPI, and ERP scores had low intercorrelations. CONCLUSION: These findings support SPEM predictive pursuit and lower frequency auditory ERP activity in a paired stimuli paradigm as putative endophenotypes of psychosis common to SZ and BD probands and relatives. PPI did not differ between the psychosis probands and HC. Future studies in larger scale psychosis family samples targeting putative psychosis endophenotypes and underlying molecular and genetic mediators may aid in the development of biology-based diagnostic definitions.