Search for missing schizophrenia genes will require a new developmental neurogenomic perspective.

Even the most powerful experimental designs in search of genetic causes of schizophrenia have not met the desired goal. It is imperative to review the reasons for such an outcome and to formulate novel strategies for the future direction of this research in the new era of individual genomes. Here, we will review aspects of neurodevelopmental hypothesis of schizophrenia in the light of novel genomic and epigenomic insights. Specifically, we will argue for the involvement of de novo mutations and epigenetic modifications during neurodevelopment that may result in schizophrenia. Our conclusion is that the successful elucidation of hereditary mechanisms in neuropsychiatric disorders must begin with attention to discrete endophenotypes; consideration of ontogeny, forethought of genome structure including temporal and spatial patterns of (epi) mutations and the use of judicious techniques that go beyond association studies.

Duchenne muscular dystrophy: a clinical, histopathological and genetic study at a neurology tertiary care center in Southern India.

BACKGROUND: Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy that affects young boys and the dystrophin gene on the X chromosome has been found to be associated with the disorder. MATERIALS AND METHODS: In this prospective study, 112 clinically diagnosed DMD patients had muscle biopsy and were tested for exon deletions. Genotyping was also carried out at STR44, STR45, STR49 and STR 50 markers in 15 families. RESULTS: Of the 112 clinically suspected DMD patients, the diagnosis of DMD was confirmed by histopathology and/or genetics in 101 patients. The mean age of onset was 3.1+/-1.44 years (1-6 years) and the mean age at presentation was 8.0+/-3.1 years (1.1-18.0 years). Delayed motor milestones were present in 63 (62.3%) patients. The mean creatine kinase value was 11822.64+/-8206.90 U/L (1240-57,700). Eighty-four patients had muscle biopsy and immunohistochemistry was done in 60 muscle samples, all of which demonstrated absence of dystrophin staining. Of the 60 dystrophin-negative cases, 73% showed deletion of at least one exon. Single exon deletion was found in 20.4%. Distal hotspot Exons 45, 47, 49 and 50 were the commonly deleted xenons and the deletion rates were 36%, 35%, 33.7% and 38.5% respectively. CONCLUSIONS: In this study population in south India the deletion rate was 73% and were more frequent in the distal end exon. With the availability of genetic analysis, the first investigation of choice in DMD should be genetic studies and muscle biopsy should be considered only if the genetic tests are negative or not available.

SCA 1, SCA 2 & SCA 3/MJD mutations in ataxia syndromes in southern India.

BACKGROUND & OBJECTIVE: Spinocerebellar ataxias (SCAs) are often caused by expansions of CTG/ CAG trinucleotide repeat in the genome. Expansions at the SCA1, 2 and 3 loci are the most frequent, but differences in their relative proportion in regions occur across the world. We carried out this study to assess the occurrence of SCA1, 2 and 3, at a tertiary neuro-psychiatric center in Bangalore, Karnataka. METHODS: Probands (N=318) who were diagnosed to have an ataxia syndrome (progressive degenerative ataxia of unknown cause) attending the clinical services of the National Institute of Mental Health and Neuro Sciences (NIMHANS), Bangalore, were evaluated over a period of three years. Standard protocols were used for both clinical and molecular diagnosis. RESULTS: Genotyping established that SCA1, 2 and 3 accounted for more than one third of the ataxia cases seen in the clinic. In the cases with established family history and autosomal dominant inheritance SCA1 was most prevalent followed by SCA2 and SCA3. INTERPRETATION & CONCLUSION: Our findings suggested SCA1 rather than SCA2 to be the more common mutation in southern India. Large numbers of SCA3 probands were also identified. Differences in prevalence of these syndromes within India need to be explored further for founder effects, correlations with phenotype, and patterns of outcome. Family history was not apparent in almost a fifth of those tested positive, highlighting the value of testing even in the absence of family history. Molecular testing should be extended to cover the other forms of ataxia, of which a large number are now known. Combined efforts to confirm the presence of these less common forms, as well as family studies to detect novel mutations, are necessary in this context in India.