Five to ten per cent of school-age children fail to learn to read in spite of normal intelligence, adequate environment and educational opportunities. Thus defined, developmental dyslexia (hereafter referred to as dyslexia) is usually considered of constitutional origin, but its actual mechanisms are still mysterious and currently remain the subject of intense research endeavour in various neuroscientific areas and along several theoretical frameworks. This article reviews evidence accumulated to date that favours a dysfunction of neural systems known to participate in the normal acquisition and achievement of reading and other related cognitive functions. Historically, the first arguments for a neurological basis of dyslexia came from neuropathological studies of brains from dyslexic individuals. These early studies, although open to criticism, for the first time drew attention towards a possible abnormality in specific stages of prenatal maturation of the cerebral cortex and suggested a role of atypical development of brain asymmetries. This has prompted a large amount of subsequent work using in vivo imaging methods in the same vein. These latter studies, however, have yielded less clear-cut results than expected, but have globally confirmed some subtle differences in brain anatomy whose exact significance is still under investigation. Neuropsychological studies have provided considerable evidence that the main mechanism leading to these children's learning difficulties is phonological in nature, namely a basic defect in segmenting and manipulating the phoneme constituents of speech. A case has also been made for impairment in brain visual mechanisms of reading as a possible contributing factor. This approach has led to an important conceptual advance with the suggestion of a specific involvement of one subsystem of vision pathways (the so-called magnosystem hypothesis). Both phonological and visual hypotheses have received valuable contribution from modern functional imaging techniques. Results of recent PET and functional MRI studies are reported here in some detail. Finally, one attractive interpretation of available evidence points to dyslexia as a multi-system deficit possibly based on a fundamental incapacity of the brain in performing tasks requiring processing of brief stimuli in rapid temporal succession. It is proposed that this so-called 'temporal processing impairment' theory of dyslexia could also account for at least some of the perceptual, motor and cognitive symptoms very often associated with the learning disorder, a coincidence that has remained unexplained so far.

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The neurological basis of developmental dyslexia: an overview and working hypothesis.

The small circle of mitochondrial DNA (mtDNA) present in all human cells has proven to be a veritable Pandora's box of pathogenic mutations and rearrangements. In this review, we summarize the distinctive rules of mitochondrial genetics (maternal inheritance, mitotic segregation, heteroplasmy and threshold effect), stress the relatively high prevalence of mtDNA‐related diseases, and consider recent additions to the already long list of pathogenic mutations (especially mutations affecting protein‐coding genes). We then discuss more controversial issues, including the functional or pathological role of mtDNA haplotypes, the pathogenicity of homoplasmic mutations and the still largely obscure pathophysiology of mtDNA mutations.

Mitochondrial DNA and disease

Approximately 3-10% of people have specific difficulties in reading, despite adequate intelligence, education, and social environment. We report here the characterization of a gene, DYX1C1 near the DYX1 locus in chromosome 15q21, that is disrupted by a translocation t(2;15)(q11;q21) segregating coincidentally with dyslexia. Two sequence changes in DYX1C1, one involving the translation initiation sequence and an Elk-1 transcription factor binding site (-3G --> A) and a codon (1249G --> T), introducing a premature stop codon and truncating the predicted protein by 4 aa, associate alone and in combination with dyslexia. DYX1C1 encodes a 420-aa protein with three tetratricopeptide repeat (TPR) domains, thought to be protein interaction modules, but otherwise with no homology to known proteins. The mouse Dyx1c1 protein is 78% identical to the human protein, and the nonhuman primates differ at 0.5-1.4% of residues. DYX1C1 is expressed in several tissues, including the brain, and the protein resides in the nucleus. In human brain, DYX1C1 protein localizes to a fraction of cortical neurons and white matter glial cells. We conclude that DYX1C1 should be regarded as a candidate gene for developmental dyslexia. Detailed study of its function may open a path to understanding a complex process of development and maturation of the human brain.

https://www.pnas.org/content/pnas/100/20/11553.full.pdf

A candidate gene for developmental dyslexia encodes a nuclear tetratricopeptide repeat domain protein dynamically regulated in brain

The epidemiology of mitochondrial disorders—past, present and future

In this study, we examined the neuroanatomy of dyslexic (14 males, four females) and control (19 males, 13 females) children in grades 4-6 from a family genetics study. The dyslexics had specific deficits in word reading relative to the population mean and verbal IQ, but did not have primary language or motor deficits. Measurements of the posterior temporal lobe, inferior frontal gyrus, cerebellum and whole brain were collected from MRI scans. The dyslexics exhibited significantly smaller right anterior lobes of the cerebellum, pars triangularis bilaterally, and brain volume. Measures of the right cerebellar anterior lobe and the left and right pars triangularis correctly classified 72% of the dyslexic subjects (94% of whom had a rapid automatic naming deficit) and 88% of the controls. The cerebellar anterior lobe and pars triangularis made significant contributions to the classification of subjects after controlling for brain volume. Correlational analyses showed that these neuroanatomical measurements were also significantly correlated with reading, spelling and language measures related to dyslexia. Age was not related to any anatomical variable. Results for the dyslexic children from the family genetics study are discussed with reference to dyslexic adults from a prior study, who were ascertained on the basis of a discrepancy between phonological coding and reading comprehension. The volume of the right anterior lobe of the cerebellum distinguished dyslexic from control participants in both studies. The cerebellum is one of the most consistent locations for structural differences between dyslexic and control participants in imaging studies. This study may be the first to show that anomalies in a cerebellar-frontal circuit are associated with rapid automatic naming and the double-deficit subtype of dyslexia.

Anatomical correlates of dyslexia: frontal and cerebellar findings.

Summary Hearing loss involves both genetic and environmental factors. A mutation (A1555G) in the mtDNA has been associated with aminoglycoside-induced and nonsyndromic sensorineural deafness. The pathological significance of this mutation in Caucasoid families has not been established, and its relationship with antibiotic treatment is not well understood. We studied 70 Spanish families with sensorineural deafness (36 congenital and 34 late onset) for the mtDNA A1555G mutation. The A1555G mutation was found in 19 families with maternally transmitted deafness but not in the other 51 families or in 200 control subjects. In 12 families all the patients with the A1555G mutation who received aminoglycosides became deaf, representing 30.3% of the deaf patients in these families. None of the deaf patients from seven other families received aminoglycosides. Overall, only 17.7% of the patients with deafness and the A1555G mutation had been treated with aminoglycosides. The age at onset of deafness was lower (median age 5 years, range 1–52 years) in those treated with aminoglycosides than in those who did not receive antibiotics (median age 20 years, range 1–65 years) ( P

https://www.cell.com/ajhg/pdf/S0002-9297(07)60119-0.pdf

Enrique Romero

Papers

Familial Progressive Sensorineural Deafness Is Mainly Due to the mtDNA A1555G Mutation and Is Enhanced by Treatment with Aminoglycosides