Expansion of the GRIA2 phenotypic representation: a novel de novo loss of function mutation in a case with childhood onset schizophrenia.

Childhood-onset schizophrenia (COS) is a rare form of schizophrenia with an onset before 13 years of age. There is rising evidence that genetic factors play a major role in COS etiology, yet, only a few single gene mutations have been discovered. Here we present a diagnostic whole-exome sequencing (WES) in an Israeli Jewish female with COS and additional neuropsychiatric conditions such as obsessive-compulsive disorder (OCD), anxiety, and aggressive behavior. Variant analysis revealed a de novo novel stop gained variant in GRIA2 gene (NM_000826.4: c.1522 G > T (p.Glu508Ter)). GRIA2 encodes for a subunit of the AMPA sensitive glutamate receptor (GluA2) that functions as ligand-gated ion channel in the central nervous system and plays an important role in excitatory synaptic transmission. GluA2 subunit mutations are known to cause variable neurodevelopmental phenotypes including intellectual disability, autism spectrum disorder, epilepsy, and OCD. Our findings support the potential diagnostic role of WES in COS, identify GRIA2 as possible cause to a broad psychiatric phenotype that includes COS as a major manifestation and expand the previously reported GRIA2 loss of function phenotypes.

[The language of children and young people with 22q11 deletion syndrome]. / Lenguaje de niños y jóvenes con síndrome de deleción 22q11.

INTRODUCTION: The 22q11 deletion syndrome (S22q11) is one of the most prevalent genetic disorders, resulting in multiple systemic and neuropsychological features. AIM: To describe the language profile in a sample of Spanish subjects with S22q11. PATIENTS AND METHODS: A sample of 30 Spanish participants with S22q11 aged between 5 years and 21 years and 11 months (mean: 12.14 ± 4.20 years) was evaluated using standardized tests and a questionnaire administered to parents. RESULTS: Almost half of the subjects obtained better results in expressive language than in comprehensive language and the majority obtained a higher score in language content than in language memory. The results suggest that people with S22q11 present language difficulties that improve with age to a certain level and subsequently stabilize. A specific profile is observed that suggests that pragmatic difficulties are a consequence of this language profile and not only of social difficulties already described in this pathology. CONCLUSIONS: In the sample of the present study, children and young people with S22q11 present specific language and pragmatic disorders. More than half of the study participants did not obtain significant differences between the level of expressive and receptive language. Most presented semantic fluency difficulties. The type and degree of impairment in pragmatic skills suggest that the basic problem may be related to their language difficulties.

TITLE: Lenguaje de niños y jóvenes con síndrome de deleción 22q11.Introducción. El síndrome de deleción 22q11 (S22q11) es uno de los trastornos genéticos más prevalentes, y presenta múltiples alteraciones sistémicas y neuropsicológicas. Objetivo. Describir el perfil de lenguaje y pragmática asociado a este síndrome. Pacientes y métodos. Se evaluó una muestra de 30 participantes españoles con S22q11 de edades comprendidas entre 5 años, y 21 años y 11 meses (media: 12,14 ± 4,2 años) mediante pruebas estandarizadas y un cuestionario administrado a los padres. Resultados. Casi la mitad de la muestra obtuvo mejores resultados en el lenguaje expresivo que en el comprensivo, y la mayoría logró una mayor puntuación en el contenido del lenguaje que en la memoria del lenguaje. Los resultados sugieren que las personas con S22q11 presentan dificultades de lenguaje que mejoran con la edad hasta cierto nivel y, posteriormente, se estabilizan. Se observa un perfil específico que sugiere que las dificultades pragmáticas son consecuencia de este perfil de lenguaje y no sólo de dificultades sociales ya descritas en esta patología. Conclusiones. En la muestra del presente estudio, los niños y jóvenes con S22q11 presentan alteraciones específicas del lenguaje y la pragmática. Más de la mitad de los participantes del estudio no obtuvieron diferencias significativas entre el nivel de lenguaje expresivo y el receptivo. La mayoría presentó dificultades de fluencia semántica. El tipo y el grado de las alteraciones que presentan en las habilidades pragmáticas sugieren que el problema básico podría estar relacionado con sus dificultades lingüísticas.

One novel GRN null mutation, two different aphasia phenotypes.

Progranulin gene (GRN) mutations are among the leading causes of frontotemporal lobar degeneration, a group of neurodegenerative diseases characterized by remarkable clinical heterogeneity. In this article, we report the new GRN 708+4A>T splicing mutation, identified in 2 siblings of a family with several members affected by cognitive, behavioral, and motor disorders. Plasma progranulin dosage and GRN expression analysis, together with in silico prediction studies, supported the pathogenicity of the mutation. Both the patients displayed a clinical syndrome in which language impairment was largely predominant. However, motor speech deficits were the major feature in one case, diagnosed as progressive nonfluent aphasia, whereas marked semantic alterations were present in the other, whose clinical phenotype was in favor of a mixed aphasia. The profile of neuroanatomical alterations from imaging studies was in line with the clinical phenotypes. Therefore, also this novel GRN mutation is associated with haploinsufficiency and phenotypic heterogeneity, which are both typical features of progranulinopathies.

Identification of the PS1 Thr147Ile Variant in a Family with Very Early Onset Dementia and Expressive Aphasia.

BACKGROUND: Early onset dementias have variable clinical presentations and are often difficult to diagnose. We established a family pedigree that demonstrated consistent recurrence of very early onset dementia in successive generations. OBJECTIVE AND METHOD: In order to refine the diagnosis in this family, we sequenced the exomes of two affected family members and relied on discrete filtering to identify disease genes and the corresponding causal variants. RESULTS: Among the 720 nonsynonymous single nucleotide polymorphisms (SNPs) shared by two affected members, we found a C to T transition that gives rise to a Thr147Ile missense substitution in the presenilin 1 (PS1) protein. The presence of this same mutation in a French early-onset Alzheimer's disease family, other affected members of the family, and the predicted high pathogenicity of the substitution strongly suggest that it is the causal variant. In addition to exceptionally young age of onset, we also observed significant limb spasticity and early loss of speech, concurrent with progression of dementia in affected family members. These findings extend the clinical presentation associated with the Thr147Ile variant. Lastly, one member with the Thr147Ile variant was treated with the PKC epsilon activator, bryostatin, in a compassionate use trial after successful FDA review. Initial improvements with this treatment were unexpectedly clear, including return of some speech, increased attentional focus, ability to swallow, and some apparent decrease in limb spasticity. CONCLUSIONS: Our findings confirm the role of the PS1 Thr147Ile substitution in Alzheimer's disease and expand the clinical phenotype to include expressive aphasia and very early onset of dementia.

GRIN2A: an aptly named gene for speech dysfunction.

OBJECTIVE: To delineate the specific speech deficits in individuals with epilepsy-aphasia syndromes associated with mutations in the glutamate receptor subunit gene GRIN2A. METHODS: We analyzed the speech phenotype associated with GRIN2A mutations in 11 individuals, aged 16 to 64 years, from 3 families. Standardized clinical speech assessments and perceptual analyses of conversational samples were conducted. RESULTS: Individuals showed a characteristic phenotype of dysarthria and dyspraxia with lifelong impact on speech intelligibility in some. Speech was typified by imprecise articulation (11/11, 100%), impaired pitch (monopitch 10/11, 91%) and prosody (stress errors 7/11, 64%), and hypernasality (7/11, 64%). Oral motor impairments and poor performance on maximum vowel duration (8/11, 73%) and repetition of monosyllables (10/11, 91%) and trisyllables (7/11, 64%) supported conversational speech findings. The speech phenotype was present in one individual who did not have seizures. CONCLUSIONS: Distinctive features of dysarthria and dyspraxia are found in individuals with GRIN2A mutations, often in the setting of epilepsy-aphasia syndromes; dysarthria has not been previously recognized in these disorders. Of note, the speech phenotype may occur in the absence of a seizure disorder, reinforcing an important role for GRIN2A in motor speech function. Our findings highlight the need for precise clinical speech assessment and intervention in this group. By understanding the mechanisms involved in GRIN2A disorders, targeted therapy may be designed to improve chronic lifelong deficits in intelligibility.

Parietal lobe deficits in frontotemporal lobar degeneration caused by a mutation in the progranulin gene.

OBJECTIVE: To describe the clinical, neuropsychologic, and radiologic features of a family with a C31LfsX35 mutation in the progranulin gene CCDS11483.1). DESIGN: Case series. PATIENTS: A large British kindred (DRC255) with a PGRN mutation was assessed. Affected individuals presented with a mean age of 57.8 years (range, 54-67 years) and a mean disease duration of 6.1 years (range, 2-11 years). RESULTS: All patients exhibited a clinical and radiologic phenotype compatible with frontotemporal lobar degeneration based on current consensus criteria. However, unlike sporadic frontotemporal lobar degeneration, parietal deficits, consisting of dyscalculia, visuoperceptual /visuospatial dysfunction, and/or limb apraxia, were a common feature, and brain imaging showed posterior extension of frontotemporal atrophy to involve the parietal lobes. Other common clinical features included language output impairment with either dynamic aphasia or nonfluent aphasia and a behavioral syndrome dominated by apathy. CONCLUSION: We suggest that parietal deficits may be a prominent feature of PGRN mutations and that these deficits may be caused by disruption of frontoparietal functional pathways.

Progranulin gene mutations associated with frontotemporal dementia and progressive non-fluent aphasia.

Frontotemporal lobar degeneration (FTLD) refers to a focal, non-Alzheimer form of cerebral degeneration that encompasses the distinct clinical syndromes of frontotemporal dementia (FTD), progressive non-fluent aphasia (PNFA) and semantic dementia. Some patients show tau-based pathological changes and in familial cases mutations have been identified in the microtubule-associated protein tau gene (MAPT) on chromosome 17q21. However, many cases are tau-negative, showing instead ubiquitin-immunoreactive (UBQ-ir) neuronal cytoplasmic inclusions and neurites, and in some familial cases UBQ-ir neuronal intranuclear inclusions of a lentiform appearance. Very recently, mutations have been identified in familial cases in the progranulin (PGRN) gene, also on chromosome 17q21. Clinical, pathological and molecular diversity within FTLD highlights the importance of careful examination of clinical-pathological-genetic relationships. This paper reports, for the first time, a clinico-pathological investigation of two FTLD families with PGRN mutations, and compares the clinical characteristics with those of patients studied in the department with MAPT mutations. The clinical profile associated with PGRN mutations constituted, in some patients, a prototypical picture of FTD and in others one of PNFA, both profiles occurring within the same family. Patients with PGRN mutations exhibited phonological deficits, whereas in patients with MAPT mutations language abnormalities, when present in addition to the prominent behavioural disorder, take the form of semantic disturbance. The findings provide compelling evidence for the link between FTD and PNFA, while raising the possibility of identifiable clinical differences between FTLD patients with MAPT and PGRN mutations.

[Evaluation of brain activation by functional magnetic resonance in offspring of epileptic mothers and their parents in pathogenetic aspects of dyslexia]. / Ocena aktywacji mózgu potomstwa matek chorych na padaczke i ich rodziców za pomoca czynnosciowego rezonansu magnetycznego w aspekcie patogenezy dysleksji.

PRINCIPLE: So far, the assessment of cerebral centres activity during fonological awareness test with functional magnetic resonance (fMRI) of families with dyslexia has not been carried out. The up till now published studies concern insignificant number of children or adults with dyslexia, whose results have not been unequivocal. THE AIM: The general aim of the study is the explanation of the pathogenetic mechanisms of dyslexia in offspring of mothers with epilepsy and their family. Detailed aim is the evaluation of the influence of dyslexia occurrence in this particular population on activation of the brain in fMRI during phonological tests. MATERIAL AND METHOD: Before fMRI, all the patients were subjected to classical cerebral MRI to estimate central nervous system structure excluding organic causes of lesions. Finally, the groups subjected to MRI included 7 children with dyslexia, 7 without dyslexia, 7 mothers with dyslexia, 10 women without dyslexia, 4 fathers with dyslexia, 10 fathers without dyslexia and 15 men without dyslexia. The examination was carried out during fonological awareness test. Mean quantities of activated pixels in the areas of interest--prefrontal cortex (1) and Broca's area (2) were compared in the investigated and control groups. RESULTS: fMRI demonstrated significantly lower activity in both areas in frontal lobe in offspring of epileptic mothers with dyslexia as compared to offspring without dyslexia (p = 0.01, p = 0.02). Activity of Broca's area in epileptic mothers with dyslexia was significantly lower than in women with dyslexia from the control group (p = 0.05). Mothers with epilepsy and dyslexia, whose offspring also had dyslexia, had significantly lower Broca's area activity. The activity of frontal areas of fathers was on fMRI similar to the activity in control groups. CONCLUSIONS: Epilepsy in mothers with coexisting dyslexia has a modifying effect on the activity of cerebral areas in frontal lobes during the fonological awareness test. Lower activity of Broca's area is a fonotypic trait transmitted to offspring with dyslexia.

FOXP2 and the mirror system.

An inherited deficit in spoken language has been associated with a mutation in the forkhead box P2 (FOXP2) gene on chromosome 7. A recent functional magnetic resonance imaging study has linked the deficit to underactivity in Broca's area during word generation, which in turn suggests a possible link between FOXP2 and the mirror-neuron system observed in the primate homologue of Broca's area. This link might have implications for the evolution of Broca's area and its role in speech.

Genetic basis of developmental dysphasia. Report of eleven familial cases in six families.

The genetic basis of Developmental Dysphasia is discussed with precise neuropsychological descriptions of 11 cases in six families. In these cases the coexistence in the same family of completely normal and severely impaired siblings suggests a genetic rather than a familial socio-linguistic cause. The possibility of father-son transmission eliminates X-linked inheritance. The results are discussed with a reappraisal of the literature and seem to emphasize the genetic basis, possibly, with autosomal dominant transmission in some cases of Developmental Dysphasia.