Haplogroup heterogeneity of LHON patients carrying the m.14484T>C mutation in India

Purpose: To investigate the clinical and mitochondrial DNA (mtDNA) haplogroup background of Indian Leber Hereditary Optic Neuropathy (LHON) patients carrying the m.14484T>C mutation. Methods: Detailed clinical investigation and complete mtDNA sequencing analysis was carried out for eight Indian LHON families with the m.14484T>C mutation. Haplogroup was constructed based on the evolutionarily important mtDNA variants. Results: In the present study, we characterized eight unrelated probands selected from 187 LHON cases. The overall penetrance of the disease was estimated to be 19.75% (16/81) in eight pedigrees with the m.14484T>C mutation and showed substantially higher sex bias (male:female = 13:3). The mtDNA haplogrouping revealed that they belong to diverse haplogroups; i.e. F1c1, M31a, U2a, M*, I1, M6, M3a1 and R30a. Interestingly, we did not find an association of the m.14484T>C mutation with any specific haplogroup within the Indian population. We also did not find any secondary mutation(s) in these pedigrees, which might affect the clinical expression of LHON. Conclusions: Contrary to earlier reports showing preferential association of the m.14484T>C mutation with western Eurasian haplogroup J and increased clinical penetrance when present in J1 subhaplogroup background, the present study shows that m.14484T>C arose independently in a different mtDNA haplogroup and ethnic background in India, which may influence the clinical expression of the disease

Novel SPG11 mutations in Asian kindreds and disruption of spatacsin function in the zebrafish

Autosomal recessive hereditary spastic paraplegia with thin corpus callosum (HSP-TCC) maps to the SPG11 locus in the majority of cases. Mutations in the KIAA1840 gene, encoding spatacsin, have been shown to underlie SPG11-linked HSP-TCC. The aim of this study was to perform candidate gene analysis in HSP-TCC subjects from Asian families and to characterize disruption of spatacsin function during zebrafish development. Homozygosity mapping and direct sequencing were used to assess the ACCPN, SPG11, and SPG21 loci in four inbred kindreds originating from the Indian subcontinent. Four novel homozygous SPG11 mutations (c.442+1G>A, c.2146C>T, c.3602_3603delAT, and c.4846C>T) were identified, predicting a loss of spatacsin function in each case. To investigate the role of spatacsin during development, we additionally ascertained the complete zebrafish spg11 ortholog by reverse transcriptase PCR and 5′ RACE. Analysis of transcript expression through whole-mount in situ hybridization demonstrated ubiquitous distribution, with highest levels detected in the brain. Morpholino antisense oligonucleotide injection was used to knock down spatacsin function in zebrafish embryos. Examination of spg11 morphant embryos revealed a range of developmental defects and CNS abnormalities, and analysis of axon pathway formation demonstrated an overall perturbation of neuronal differentiation. These data confirm loss of spatacsin as the cause of SPG11-linked HSP-TCC in Asian kindreds, expanding the mutation spectrum recognized in this disorder. This study represents the first investigation in zebrafish addressing the function of a causative gene in autosomal recessive HSP and identifies a critical role for spatacsin during early neural development in vivo

Characterization of greater middle eastern genetic variation for enhanced disease gene discovery

The Greater Middle East (GME) has been a central hub of human migration and population admixture. The tradition of consanguinity, variably practiced in the Persian Gulf region, North Africa, and Central Asia1-3, has resulted in an elevated burden of recessive disease4. Here we generated a whole-exome GME variome from 1,111 unrelated subjects. We detected substantial diversity and admixture in continental and subregional populations, corresponding to several ancient founder populations with little evidence of bottlenecks. Measured consanguinity rates were an order of magnitude above those in other sampled populations, and the GME population exhibited an increased burden of runs of homozygosity (ROHs) but showed no evidence for reduced burden of deleterious variation due to classically theorized ‘genetic purging’. Applying this database to unsolved recessive conditions in the GME population reduced the number of potential disease-causing variants by four- to sevenfold. These results show variegated genetic architecture in GME populations and support future human genetic discoveries in Mendelian and population genetics

Pattern recognition on brain magnetic resonance imaging in alpha dystroglycanopathies

Alpha dystroglycanopathies are heterogeneous group of disorders both phenotypically and genetically. A subgroup of these patients has characteristic brain imaging findings. Four patients with typical imaging findings of alpha dystroglycanopathy are reported. Phenotypic features included: global developmental delay, contractures, hypotonia and oculomotor abnormalities in all. Other manifestations were consanguinity (3), seizures (3), macrocephaly (1), microcephaly (3), retinal changes (2) and hypogenitalism (2). Magnetic resonance imaging (MRI) of the brain revealed polymicrogyria, white matter changes, pontine hypoplasia, and subcortical cerebellar cysts in all the patients, ventriculomegaly, callosal abnormalities, and absent septum pellucidum in two and Dandy -Walker variant malformation in three. Magnetic resonace imaging of the first cousin of one the patient had the same characteristic imaging features. Brain imaging findings were almost identical despite heterogeneity in clinical presentation and histopathological features. Pattern recognition of MR imaging features may serve as a clue to the diagnosis of alpha dystroglycanopathy

Ictal Generalized EEG Attenuation (IGEA) and hypopnea in a child with occipital type 1 cortical dysplasia - Is it a biomarker for SUDEP?

An interesting association of ictal hypopnea and ictal generalized EEG attenuation (IGEA) as possible marker of sudden unexpected death in epilepsy (SUDEP) is reported. We describe a 5-years-old girl with left focal seizures with secondary generalization due to right occipital cortical dysplasia presenting with ictal hypopnea and IGEA. She had repeated episodes of the ictal apnoea in the past requiring ventilator support and intensive care unit (ICU) admission during episodes of status epilepticus. The IGEA lasted for 0.26-4.68 seconds coinciding with the ictal hypopnea during which both clinical seizure and electrical epileptic activity stopped. Review of literature showed correlation between post-ictal apnoea and post ictal generalized EEG suppression and increased risk for SUDEP. The report adds to the growing body of literature on peri-ictal apnea, about its association with IGEA might be considered as a marker for SUDEP. She is seizure free for 4 months following surgery

Genetic analysis of ATP7B in 102 south Indian families with Wilson disease

Wilson disease (WD) is an autosomal recessive disorder, characterized by excessive deposition of copper in various parts of the body, mainly in the liver and brain. It is caused by mutations in ATP7B. We report here the genetic analysis of 102 WD families from a south Indian population. Thirty-six different ATP7B mutations, including 13 novel ones p.Ala58fs*19, p.Lys74fs*9, p.GIn281*, p.Pro350fs*12, p.Ser481*, p.Leu735Arg, p.Va1752Gly, p.Asn812fs*2, p.Va1845Ala, p.His889Pro, p.11e1184fs*1, p.Va11307Glu and p.Ala1339Pro], were identified in 76/102 families. Interestingly, the mutation analysis of affected individuals in two families identified two different homozygous mutations in each family, and thus each affected individual from these families harbored two mutations in each ATP7B allele. Of 36 mutations, 28 were missense, thus making them the most prevalent mutations identified in the present study. Nonsense, insertion and deletion represented 3/36, 2/36 and 3/36 mutations, respectively. The haplotype analysis suggested founder effects for all the 14 recurrent mutations. Our study thus expands the mutational landscape of ATP7B with a total number of 758 mutations. The mutations identified during the present study will facilitate carrier and pre-symptomatic detection, and prenatal genetic diagnosis in affected families