Ahm M. Huq

Tourette syndrome is associated with recurrent exonic copy number variants

Background: Multiple rare copy number variants (CNVs) including genomic deletions and duplications play a prominent role in neurodevelopmental disorders such as mental retardation, autism, and schizophrenia, but have not been systematically studied in Tourette syndrome (TS). Methods: We performed a genome-wide screening of single nucleotide polymorphism (SNP) genotyping microarray data to identify recurrent or de novo rare exonic CNVs in a case-control association study of patients with TS. Results: We identified 5 exon-affecting rare CNVs that are either de novo or recurrent in 10 out of 111 patients with TS but were not found in 73 ethnically matched controls or in the entries of the Database of Genomic Variants (containing 21,178 CNVs at 6,558 loci). Three out of the 5 CNVs have been implicated previously by other studies in schizophrenia, autism, and attention-deficit hyperactivity disorder, suggesting that these CNVs produce a continuum of neuropsychiatric disturbances that manifest in different ways depending on other genetic, environmental, or stochastic factors. Conclusions: Rare, recurrent exonic copy number variants are associated in a subset of patients with Tourette syndrome.

No association between the EN2 gene and autistic disorder

A utistic spectrum disorders (MIM 209850), which include autism, Asperger syndrome, and pervasive developmental disorder (PDD) not otherwise specified, are characterised by impairment in communications and social interactions and the presence of stereotyped behaviours. The aetiology of autistic disorder is unknown, but family and twin studies have shown a high monozygotic to dizygotic twin risk ratio and a sib relative risk between 50 and 100, suggesting that inheritance of autism is complex, but the predisposition to develop it is largely genetically determined.1,2 A number of morphological abnormalities including increased brain size and developmental abnormalities of the cerebral cortex, brainstem, and cerebellum have been reported in autism.3,4 Reported brain stem and cerebellar anomalies include hypoplasia of lobules VI and VII, decreased Purkinje cell density, olivary dysplasia, and neuronal heterotopias.3–5 The morphological abnormalities described in the brainstem and cerebellum of autistic subjects suggest that genes involved in cerebellar development are candidate genes in autism. EN2 , a human homologue of Drosophila engrailed gene, is a homeobox gene with an essential role in the development of the midbrain and cerebellum.6 Mice homozygous for a targeted deletion of the EN2 homeobox region were viable but showed abnormal foliation of the cerebellum.7 Petit et al 8 studied two restriction fragment length polymorphisms in the EN2 gene in autism and found an association between autism and a Pvu II polymorphism in the 5′ region of EN2 in 100 autistic children and 100 control children. In this study, we have attempted to replicate the association between the EN2 gene and autism using family based linkage and association studies in 196 multiplex families with autism. The EN2 gene maps to human chromosome 7q36. Information regarding a number of promoter, exon, and intron polymorphisms in the EN2 gene is available in …

Exome sequencing of a pedigree with tourette syndrome or chronic tic disorder

Ten members of a 3‐generation pedigree with 7 showing Tourette syndrome/chronic tic phenotype (TS‐CTD) were evaluated with whole exome sequencing. We identified 3 novel, nonsynonymous single nucleotide variants in the MRPL3, DNAJC13, and OFCC1 genes that segregated with chronic tic phenotype. These variants were not present in 100 control subjects or in dbSNP/1000 Genomes databases. A novel variant in the 5′ untranslated region of the OFCC1 gene was found in 2 TS‐CTD patients from a different pedigree. Further studies will clarify the importance of variants in MRPL3, DNAJC13, and OFCC1 genes in TS. Ann Neurol 2011;69:901–904

Abnormal language pathway in children with Angelman syndrome.

Angelman syndrome is a genetic disorder characterized by pervasive developmental disability with failure to develop speech. We examined the basis for severe language delay in patients with Angelman syndrome by diffusion tensor imaging. Magnetic resonance imaging/diffusion tensor imaging was performed in 7 children with genetically confirmed Angelman syndrome (age 70 ± 26 months, 5 boys) and 4 age-matched control children to investigate the microstructural integrity of arcuate fasciculus and other major association tracts. Six of 7 children with Angelman syndrome had unidentifiable left arcuate fasciculus, while all control children had identifiable arcuate fasciculus. The right arcuate fasciculus was absent in 6 of 7 children with Angelman syndrome and 1 of 4 control children. Diffusion tensor imaging color mapping suggested aberrant morphology of the arcuate fasciculus region. Other association tracts, including uncinate fasciculus, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, and corticospinal tract, were identifiable but manifested decreased fractional anisotropy in children with Angelman syndrome. Increased apparent diffusion coefficient was seen in all tracts except uncinate fasciculus when compared to control children. Patients with Angelman syndrome have global impairment of white matter integrity in association tracts, particularly the arcuate fasciculus, which reveals severe morphologic changes. This finding could be the result of a potential problem with axon guidance during brain development, possibly due to loss of UBE3A gene expression.

Novel FDG-PET Findings in Anti-NMDA Receptor Encephalitis A Case Based Report

The clinical manifestation and nuclear imaging findings in a 15-year-old boy with anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis are described in this case report. The previously healthy patient presented with new onset hallucinations, seizure, and within a week, his mental status rapidly deteriorated to nonverbal with oro-lingual-facial dyskinesias. An extensive laboratory work-up for encephalopathy was negative. Repeated brain magnetic resonance imaging (MRI) studies were normal. On day 26 of admission, nuclear imaging using fluorodeoxyglucose positron emission tomography (FDG-PET) showed global hypometobolism with a prominent focally intense hypermetabolic lesion in the right cerebellar cortex. Diagnosis of anti-NMDAR encephalitis was confirmed with quantitative serology. The patient showed clinical signs of improvement after 2 courses of intravenous immunoglobulin therapy over 4 weeks. On day 46, repeat brain FDG-PET showed overall improvement but in contrast to the previous, the right cerebellar cortex showed focal hypometabolism. This is the first reported case of such findings using FDG-PET in anti-NMDAR encephalitis.

No association between single nucleotide polymorphisms in DLX6 and piccolo genes at 7q21‐q22 and autism

Several independent genome scans have revealed excess allele sharing in an overlapping 40 cM region of 7q21‐34 in autism. DLX6 and Piccolo (PCLO) at 7q21‐q22 are two positional and functional candidate genes in autism. We have investigated a single nucleotide polymorphism (SNP) in exon 4 of the PCLO gene and a SNP in intron 1 of the DLX6 gene for linkage and association in autistic disorder using both qualitative and quantitative analyses. One hundred ninety‐six multiplex autistic disorder families were tested using transmission disequilibrium and two‐point affected sib pair linkage analysis. We found no evidence of association or linkage with the two intragenic markers. In addition, there was also no linkage or association between language and stereotypic behavior quantitative traits in autism and the SNPs. In conclusion, our studies suggest that these two SNPs in DLX6 and PCLO genes are not in linkage disequilibrium with autism.

SCN2A mutation is associated with infantile spasms and bitemporal glucose hypometabolism.

BACKGROUND Genetic mutations play a crucial role in the etiology of cryptogenic infantile spasms, but the cause is still unknown in a significant proportion of patients. Whole exome sequencing technology shows great promise in identifying genetic causes of infantile spasms. METHODS In this study whole exome sequencing was performed with 2-deoxy-2-((18)F)fluoro-d-glucose positron emission tomography scan of an infant boy with infantile spasms. Exome sequencing was also performed in the parents to identify any de novo mutations. RESULTS The positron emission tomography scan showed a pattern of bilateral symmetric temporal lobe glucose hypometabolism. A total of 8171 nonsynonymous variants were identified in the child. Despite the large number of nonsynonymous variants, there was only a single de novo missense mutation in SCN2A in the child (NCBI hg19 assembly, position: Chr2:166234116, K1422E). Subsequent Sanger sequencing confirmed the de novo status of this variant. This mutation has never been reported in 6500 individuals of the exome variant server database. Similarly, this variant is not reported in the Online Mendelian Inheritance in Man Database or the Human Gene Mutation Database. It has previously been shown that SCN2A mutations are associated with hippocampal hyperexcitability. Therefore, this study indicates that infantile spasms and bitemporal hypometabolism in this patient might have been caused by hippocampal hyperexcitability due to SCN2A mutation. CONCLUSIONS The simultaneous presence of an SCN2A mutation and bitemporal hypometabolism in this patient with infantile spasms suggests a plausible hippocampal origin. However, additional mechanistic and clinical studies are required to validate this link.

Infantile Spasms Are Associated With Abnormal Copy Number Variations

The authors tested the hypothesis that de novo copy number variations (CNVs) implicated in known genomic disorders (“pathogenic CNVs”) are significant predisposing factors of infantile spasms. The authors performed a genome-wide analysis of single-nucleotide polymorphism genotyping microarray data to identify the role of de novo/known pathogenic large CNVs in 13 trios of children affected by infantile spasms. A rare, large (4.8 Mb) de novo duplication was detected in the 15q11-13 region of 1 patient. In addition, 3 known pathogenic CNVs (present in the patient as well as 1 of the parents) were detected in total. In 1 patient, a known pathogenic deletion was detected in the region of 2q32.3. Similarly, in 1 other patient, 2 known pathogenic deletions in the regions of 16p11.2 and Xp22.13 (containing CDKL5) were detected. These findings suggest that some specific pathogenic CNVs predispose to infantile spasms and may be associated with different phenotypes.

Exome sequencing and diffusion tensor imaging in developmental disabilities

Background:We had previously shown that arcuate fasciculus is poorly developed in patients with intellectual and developmental disabilities (IDD) using diffusion tensor imaging (DTI). In the present study, we used exome sequencing to identify the candidate variants in IDD patients with and without DTI abnormalities.Methods:Eighteen children with IDD (age: 67 ± 36 mo, 9 females) were included in the present study. The DTI was used to determine the integrity of arcuate fasciculus. The next-generation sequencing was performed on the Solid 4 platform. A novel, analytical strategy was developed to identify a set of candidate genes of interest. We then searched for novel, nonsynonymous variants in the patients within this subset of genes and in known IDD genes.Results:Seven novel, nonsynonymous (all of them were heterozygous, missense) variants belonged to ultraconserved genes that are known to cause abnormal brain morphology in mutant mice. Similarly, three novel, nonsynonymous (all of them were heterozygous, missense) variants belonged to known IDD genes. Two patients with underdeveloped arcuate fasciculus had novel, nonsynonymous variants in genes (MID1 and EN2) regulating axon guidance pathway.Conclusion:Exome sequencing identified several new genetic causes of IDD.

Clinical Benefit of NMDA Receptor Antagonists in a Patient With ATP1A2 Gene Mutation

NMDA receptor antagonists may be effective for behavioral, cognitive, and cerebellar symptoms in patients with ATP1A2 gene mutation. Mutations in the ATP1A2 gene cause familial hemiplegic migraine type 2, alternating hemiplegia of childhood, and cerebellar function deficits, epilepsy, and mental retardation. These symptoms are likely related to glutamatergic hyperexcitability. Our patient is a 12-year-old boy with a history of complex partial seizures, attention-deficit/hyperactivity disorder, and fine motor difficulty. During early childhood, he had episodes of a self-resolving right-sided hemiparesis and focal epilepsy. His seizures did not respond to several antiepileptic medications but stopped after he received valproate. His intermittent episodes of hemiplegia persisted. Additionally, he had pronounced bilateral fine motor impairment and significant executive deficits that gradually worsened. The whole exome sequencing revealed a de novo missense mutation in the ATP1A2 gene and a maternally inherited POLG gene mutation of unknown clinical significance. We hypothesized that glutamatergic excitotoxicity due to the ATP1A2 mutation contributed to the pathogenesis of our patient’s condition. He was started on N-methyl-D-aspartate receptor antagonists (memantine and dextromethorphan), as well as coenzyme Q10. One year later, he showed significant improvement in sustained attention, learning efficiency, general cognitive efficiency, and fine motor dexterity. We postulate that N-methyl-D-aspartate receptor antagonists were effective for behavioral, cognitive, and cerebellar symptoms in our patient with ATP1A2 gene mutation.