Human genetics of face recognition: discovery of MCTP2 mutations in humans with face blindness (congenital prosopagnosia).

Face recognition is important for both visual and social cognition. While prosopagnosia or face blindness has been known for seven decades and face-specific neurons for half a century, the molecular genetic mechanism is not clear. Here we report results after 17 years of research with classic genetics and modern genomics. From a large family with 18 congenital prosopagnosia (CP) members with obvious difficulties in face recognition in daily life, we uncovered a fully cosegregating private mutation in the MCTP2 gene which encodes a calcium binding transmembrane protein expressed in the brain. After screening through cohorts of 6589, we found more CPs and their families, allowing detection of more CP associated mutations in MCTP2. Face recognition differences were detected between 14 carriers with the frameshift mutation S80fs in MCTP2 and 19 noncarrying volunteers. Six families including one with 10 members showed the S80fs-CP correlation. Functional magnetic resonance imaging found association of impaired recognition of individual faces by MCTP2 mutant CPs with reduced repetition suppression to repeated facial identities in the right fusiform face area. Our results have revealed genetic predisposition of MCTP2 mutations in CP, 76 years after the initial report of prosopagnosia and 47 years after the report of the first CP. This is the first time a gene required for a higher form of visual social cognition was found in humans.

A novel PSEN1 (S230N) mutation causing early-onset Alzheimer's Disease associated with prosopagnosia, hoarding, and Parkinsonism.

We describe clinical and biomarker findings in an index patient with the onset of Alzheimer's disease (AD) symptoms at age 57 and a family history consistent with an autosomal dominant pattern of inheritance. She had the atypical early features of visual agnosia and prosopagnosia followed by hoarding behavior and Parkinsonism. Structural MRI revealed global atrophy that was most severe in the lateral temporal lobes and insular cortex bilaterally. CSF biomarker assessment showed Aß42, p-tau181, and total tau levels consistent with AD. Genetic assessment revealed a novel mutation in the PSEN1 gene (S230N) in the index patient and her affected brother which was absent in her two clinically unaffected and AD-biomarker negative sisters. The serine residue at codon 230 in PSEN1 is highly conserved across species and in PSEN2, providing strong evidence for its pathogenicity in this family.

Incidental memory for faces in children with different genetic subtypes of Prader-Willi syndrome.

The present study examined the effects of genetic subtype on social memory in children (7-16 years) with Prader-Willi syndrome (PWS). Visual event-related potentials (ERPs) during a passive viewing task were used to compare incidental memory traces for repeated vs single presentations of previously unfamiliar social (faces) and nonsocial (houses) images in 15 children with the deletion subtype and 13 children with maternal uniparental disomy (mUPD). While all participants perceived faces as different from houses (N170 responses), repeated faces elicited more positive ERP amplitudes ('old/new' effect, 250-500ms) only in children with the deletion subtype. Conversely, the mUPD group demonstrated reduced amplitudes suggestive of habituation to the repeated faces. ERP responses to repeated vs single house images did not differ in either group. The results suggest that faces hold different motivational value for individuals with the deletion vs mUPD subtype of PWS and could contribute to the explanation of subtype differences in the psychiatric symptoms, including autism symptomatology.

Congenital prosopagnosia is associated with a genetic variation in the oxytocin receptor (OXTR) gene: An exploratory study.

Face-recognition deficits, referred to with the term prosopagnosia (i.e., face blindness), may manifest during development in the absence of any brain injury (from here the term congenital prosopagnosia, CP). It has been estimated that approximately 2.5% of the population is affected by face-processing deficits not depending on brain lesions, and varying a lot in severity. The genetic bases of this disorder are not known. In this study we tested for genetic association between single-nucleotide polymorphisms (SNPs) in the oxytocin receptor gene (OXTR) and CP in a restricted cohort of Italian participants. We found evidence of an association between the common genetic variants rs53576 and rs2254298 OXTR SNPs and prosopagnosia. This association was also found when including an additional group of German individuals classified as prosopagnosic in the analysis. Our preliminary data provide initial support for the involvement of genetic variants of OXTR in a relevant cognitive impairment, whose genetic bases are still largely unexplored.

Developmental prosopagnosia.

A Quick guide to developmental prosopagnosia, a condition definied by problems in recognising faces that, in contrast with acquired prosopagnosia, develop in the absence of manifest brain injury.

Curiouser and curiouser: genetic disorders of cortical specialization.

The processes by which cortical areas become specialized for high-level cognitive functions may be revealed by the study of familial developmental disorders such as dyslexia, dyscalculia, prosopagnosia, color agnosia and amusia. These disorders are characterised by the inability to integrate information across multiple areas and the consequent failure to develop representations of the knowledge of some category based on its associated attributes. In contrast, synesthesia may be seen as a hyper-associative condition, possibly due to a failure to properly segregate areas into distinct networks. Here, I consider recent advances in our understanding of the genetic and neurobiological bases of these conditions and the developmental mechanisms underlying the specialization of cortical areas and networks.

Semantic dementia associated with mutation V363I in the tau gene.

A 46-year-old woman who presented with prosopagnosia was clinically evaluated. Results of neuropsychological measures showed severe impairment in oral naming with anomia and a marked deficit in naming and recognition of famous faces. The clinical diagnosis was semantic dementia (SD). Genetic testing revealed a missense mutation V363I in exon 12 of the microtubule-associated protein tau (MAPT) gene. This is the description of an association between a mutation in the MAPT gene and a case of SD. The same mutation was recently described in a case of progressive non-fluent aphasia, but the prominent presenting feature in tau gene mutation cases is the behavioral variant of frontotemporal dementia, with typical symmetrical frontotemporal atrophy.

Comment on prevalence of hereditary prosopagnosia (HPA) in Hong Kong Chinese population.

Kennerknecht et al. [Kennerknecht et al. (2008); Am J Med Genet Part A 146A] estimate that 1.9% of the Chinese population are hereditary prosopagnosics. I discuss concerns about their assumption that the great majority of prosopagnosia resulting from developmental problems are heritable and present data from my laboratory that suggests that a considerable proportion of developmental prosopagnosics do not have relatives who share their face recognition deficits.

Prevalence of hereditary prosopagnosia (HPA) in Hong Kong Chinese population.

Prosopagnosia (PA), or the inability to recognize a familiar person by the face alone, had been considered to be a rare dysfunction mainly acquired by trauma to the brain. Recently we have shown that the congenital form of PA, which was considered to be even rarer, is common in Caucasians, with a prevalence of 2.5%. As these cases were familial we coined the term Hereditary Prosopagnosia (HPA). The present study is the first systematic screening for HPA in a defined population of ethnic Chinese. In 2004-2005, 533 out of around 750 medical students of The University of Hong Kong took part in a questionnaire-based screening. The responses of 133 students indicated that they were likely to be candidates for PA. One hundred twenty agreed for diagnostic interview. Finally we made the clinical diagnosis of PA in 10 subjects. A prevalence of 1.88% (95% CI, 1.05-2.71) is established which is in the same range as in Caucasians. We took a detailed family history of four index prosopagnosic persons and were able to further investigate the families of four probands. Each had other first-degree relatives with the same visual cognitive dysfunction. Thus, as in the Caucasians, regular autosomal dominant inheritance might best explain the segregation pattern.

Congenital prosopagnosia--a common hereditary cognitive dysfunction in humans.

The apparent selectivity of agnosia for faces is termed prosopagnosia or face blindness. This cognitive dysfunction can be seen after traumatic events--involving at least the right occipital temporal region--or very frequently congenital in the absence of any detectable lesions. The familiarity of congenital prosopagnosia was studied in two independently ascertained collections of subjects with prosopagnosia. One was an unselected group of pupils and students who underwent a questionnaire based screening. The others were self reported subjects after having heard for the first time about the phenomenon of prosopagnosia from mass media citing our studies and/or from our homepage (www.prosopagnosia.de). Those who agreed with consecutive studies of their family members had mostly one or more prosopagnosic first degree relatives. The segregation patterns derived from 39 families are compatible with autosomal dominant inheritance. Hence, mutation(s) in one gene are sufficient for manifestation of the phenotype. Still fitting the concept of autosomal dominant inheritance, we have evidence for a slightly reduced penetrance (4 normal transmitters from distinct families) and one or two de novo mutations.

Neural and genetic foundations of face recognition and prosopagnosia.

Faces are of essential importance for human social life. They provide valuable information about the identity, expression, gaze, health, and age of a person. Recent face-processing models assume highly interconnected neural structures between different temporal, occipital, and frontal brain areas with several feedback loops. A selective deficit in the visual learning and recognition of faces is known as prosopagnosia, which can be found both in acquired and congenital form. Recently, a hereditary sub-type of congenital prosopagnosia with a very high prevalence rate of 2.5% has been identified. Recent research results show that hereditary prosopagnosia is a clearly circumscribed face-processing deficit with a characteristic set of clinical symptoms. Comparing face processing of people of prosopagnosia with that of controls can help to develop a more conclusive and integrated model of face processing. Here, we provide a summary of the current state of face processing research. We also describe the different types of prosopagnosia and present the set of typical symptoms found in the hereditary type. Finally, we will discuss the implications for future face recognition research.

Cognitive heterogeneity in genetically based prosopagnosia: a family study.

Congenital prosopagnosia (CP) is a selective difficulty in recognizing familiar faces that is present from birth. There is mounting evidence for a familial factor in CP, possibly due to a simple autosomal inheritance pattern. However, potential candidate genes remain to be established, and the question whether genetically based CP is a single trait, or a cluster of related subtypes differing in the pattern of impairments to specific components of the face-processing system, remains unanswered. In addition, since the great majority of so far described cases with CP were adult at the time of investigation, it remains unknown which specific aspects of face processing are impaired in small children with CP. Here we present the first study that specifically addresses these questions by elucidating the specific mechanisms underlying face-recognition impairments in seven individuals with CP (aged 4-87 years) belonging to four generations of the same family. Our results indicate that genetically based CP is not a single trait but a cluster of related subtypes, since the pattern of impairments to specific components of the face-processing system varies in individuals belonging to the same family. In addition, we show that the heterogeneity of the cognitive profile in CP with respect to specific aspects of face processing is apparent from early childhood.

Hereditary prosopagnosia: the first case series.

Prosopagnosia is defined as a specific type of visual agnosia characterised by a discernible impairment in the capacity to recognise familiar people by their faces. We present seven family pedigrees with 38 cases in two to four generations of suspected hereditary prosopagnosia, detected using a screening questionnaire. Men and women are impaired and the anomaly is regularly transmitted from generation to generation in all pedigrees studied. Segregation is best explained by a simple autosomal dominant mode of inheritance, suggesting that loss of human face recognition can occur by the mutation of a single gene. Eight of the 38 affected persons were tested on the Warrington Recognition Memory Test for Faces (RMF; Warrington, 1984), famous and family faces tests, learning tests for internal and external facial features and a measure of mental imagery for face and non-face images. As a group, the eight participants scored significantly below an age- and education-matched comparison group on the most relevant test of face recognition; and all were impaired on at least one of the tests. The results provide compelling evidence for significant genetic contribution to face recognition skills and contribute to the promise offered by the emerging field of cognitive neurogenetics.

Family resemblance: ten family members with prosopagnosia and within-class object agnosia.

We report on neuropsychological testing done with a family in which many members reported severe face recognition impairments. These 10 individuals were high functioning in everyday life and performed normally on tests of low-level vision and high-level cognition. In contrast, they showed clear deficits with tests requiring face memory and judgements of facial similarity. They did not show deficits with all aspects of higher level visual processing as all tested performed normally on a challenging facial emotion recognition task and on a global-local letter identification task. On object memory tasks requiring recognition of particular cars and guns, they showed significant deficits so their recognition impairments were not restricted to facial identity. These results strongly suggest the existence of a genetic condition leading to a selective deficit of visual recognition.

Gaze behaviour in hereditary prosopagnosia.

Prosopagnosia is the inability to recognize someone by the face alone in the absence of sensory or intellectual impairment. In contrast to the acquired form of prosopagnosia we studied the congenital form. Since we could recently show that this form is inherited as a simple monogenic trait we called it hereditary form. To determine whether not only face recognition and neuronal processing but also the perceptual acquisition of facial information is specific to prosopagnosia, we studied the gaze behaviour of four hereditary prosopagnosics in comparison to matched control subjects. This rarely studied form of prosopagnosia ensures that deficits are limited to face recognition. Whereas the control participants focused their gaze on the central facial features, the hereditary prosopagnosics showed a significantly different gaze behaviour. They had a more dispersed gaze and also fixated external facial features. Thus, the face recognition impairment of the hereditary prosopagnosics is reflected in their gaze behaviour.

Can generic expertise explain special processing for faces?

Does face recognition involve face-specific cognitive and neural processes ('domain specificity') or do faces only seem special because people have had more experience of individuating them than they have of individuating members of other homogeneous object categories ('the expertise hypothesis')? Here, we summarize new data that test these hypotheses by assessing whether classic face-selective effects - holistic processing, recognition impairments in prosopagnosia and fusiform face area activation - remain face selective in comparison with objects of expertise. We argue that evidence strongly supports domain specificity rather than the expertise hypothesis. We conclude that the crucial social function of face recognition does not reflect merely a general practice phenomenon and that it might be supported by evolved mechanisms (visual or nonvisual) and/or a sensitive period in infancy.

First report of prevalence of non-syndromic hereditary prosopagnosia (HPA).

Acquired prosopagnosia (PA) is a rare condition after, for example, a stroke or brain injury. The congenital form of PA is generally considered to be even less common. Beside a few single case reports and anecdotal mentioning of familial cases no data on the epidemiology exists. Following a questionnaire-based screening in local secondary schools and at our medical faculty, candidates suspicious for PA underwent a semi-structured interview followed by examinations of first degree relatives. Among 689 local pupils and medical students of our university we found 17 with congenital PA. This corresponds to a prevalence rate of 2.47% (95% CI 1.31-3.63). The frequency is among the highest known for a monogenic disorder. All those index subjects (n = 14) of the target group who agreed to further examinations of their family members had other first degree relatives with the same cognitive disorder. This study provides epidemiological evidence that congenital PA is a very common cognitive disorder which almost always runs in families. The segregation pattern of this hereditary prosopagnosia (HPA) is fully compatible with autosomal dominant inheritance.