Tipu Sultan

Mutations in MBOAT7, Encoding Lysophosphatidylinositol Acyltransferase I, Lead to Intellectual Disability Accompanied by Epilepsy and Autistic Features.

The risk of epilepsy among individuals with intellectual disability (ID) is approximately ten times that of the general population. From a cohort of >5,000 families affected by neurodevelopmental disorders, we identified six consanguineous families harboring homozygous inactivating variants in MBOAT7, encoding lysophosphatidylinositol acyltransferase (LPIAT1). Subjects presented with ID frequently accompanied by epilepsy and autistic features. LPIAT1 is a membrane-bound phospholipid-remodeling enzyme that transfers arachidonic acid (AA) to lysophosphatidylinositol to produce AA-containing phosphatidylinositol. This study suggests a role for AA-containing phosphatidylinositols in the development of ID accompanied by epilepsy and autistic features.

Expanding the genetic heterogeneity of intellectual disability

Intellectual disability (ID) is a common morbid condition with a wide range of etiologies. The list of monogenic forms of ID has increased rapidly in recent years thanks to the implementation of genomic sequencing techniques. In this study, we describe the phenotypic and genetic findings of 68 families (105 patients) all with novel ID-related variants. In addition to established ID genes, including ones for which we describe unusual mutational mechanism, some of these variants represent the first confirmatory disease–gene links following previous reports (TRAK1, GTF3C3, SPTBN4 and NKX6-2), some of which were based on single families. Furthermore, we describe novel variants in 14 genes that we propose as novel candidates (ANKHD1, ASTN2, ATP13A1, FMO4, MADD, MFSD11, NCKAP1, NFASC, PCDHGA10, PPP1R21, SLC12A2, SLK, STK32C and ZFAT). We highlight MADD and PCDHGA10 as particularly compelling candidates in which we identified biallelic likely deleterious variants in two independent ID families each. We also highlight NCKAP1 as another compelling candidate in a large family with autosomal dominant mild intellectual disability that fully segregates with a heterozygous truncating variant. The candidacy of NCKAP1 is further supported by its biological function, and our demonstration of relevant expression in human brain. Our study expands the locus and allelic heterogeneity of ID and demonstrates the power of positional mapping to reveal unusual mutational mechanisms.

PYCR2 Mutations cause a lethal syndrome of microcephaly and failure to thrive.

A study was undertaken to characterize the clinical features of the newly described hypomyelinating leukodystrophy type 10 with microcephaly. This is an autosomal recessive disorder mapped to chromosome 1q42.12 due to mutations in the PYCR2 gene, encoding an enzyme involved in proline synthesis in mitochondria.

Dyke-Davidoff-Masson Syndrome: An unusual cause of status epilepticus

The Dyke-Davidoff-Masson Syndrome (DDMS) results from an insult to the growing brain in utero or early infancy, which lead to loss of neurons compromising the growth of the brain. Clinical presentation includes seizures, hemiparesis, facial asymmetry, and learning disability. Radiological findings include cerebral atrophy on one side. Here, we present a case with status epilepticus who had underlying DDMS. It is a rare syndrome and uncommon cause for status epilepticus. Infections of CNS, hypoxic ischemic encephalopathy, intracranial bleed, trauma, congenital vascular malformations are the common causes of this syndrome. Diagnosis is established after clinical history, examination, and MRI. Intractable seizures can be controlled with appropriate anticonvulsants. Subsequently, these children may require physiotherapy, speech therapy, and occupational therapy in addition to the anticonvulsant medication. Outcome is better if the seizures are controlled.

Clinical Spectrum And Outcome Of Cerebral Venous Sinus Thrombosis In Children

OBJECTIVE To determine clinical spectrum, neuroimaging finding and outcome of cerebral venous sinus thrombosis (CVST) in children. STUDY DESIGN Descriptive and cross-sectional study. PLACE AND DURATION OF STUDY Department of Paediatric Neurology, Childrens Hospital and Institute of Child Health, Lahore, from 2015 to 2016. METHODOLOGY Data was collected in a predesigned proforma by non-probability purposive sampling technique from all enrolled 32 patients fulfilling the inclusion criteria. We analysed descriptively the clinical presentation, neuroimaging findings, associated risk factors and outcome. Chi-square test was used to check the association between demographic variables and findings at five percent level of significance. RESULTS Out of 32 patients enrolled, 75% (24) patients were male; median age was 2.5 years. Fever was found the most common presentation followed by headache and lethargy. Neuroimaging showed superior sagital sinus thrombosis in all (100%), while 25% (8) have additional thrombosis of internal cerebral veins. Ischemic infarction was found in 11 (35%), while hemorrhagic infarction was found in 9 (29%) patients. Death occurred in 6.25% of children. CONCLUSION Infections were the common cause of CVST in children followed by anemia and dehydration. Mortality trend was low with earlier diagnosis and aggressive treatment. Anticoagulant treatment along with adequate hydration, antibiotics and correction of anemia can lead to a better outcome. A large local and regional prospective multicenter studies for pediatric cerebral venous sinus thrombosis is suggested to evaluate the risk factors and plan guidelines for managing this condition in children.

Mutations in LNPK, Encoding the Endoplasmic Reticulum Junction Stabilizer Lunapark, Cause a Recessive Neurodevelopmental Syndrome

The dynamic shape of the endoplasmic reticulum (ER) is a reflection of its wide variety of critical cell biological functions. Consequently, perturbation of ER-shaping proteins can cause a range of human phenotypes. Here, we describe three affected children (from two consanguineous families) who carry homozygous loss-of-function mutations in LNPK (previously known as KIAA1715); this gene encodes lunapark, which is proposed to serve as a curvature-stabilizing protein within tubular three-way junctions of the ER. All individuals presented with severe psychomotor delay, intellectual disability, hypotonia, epilepsy, and corpus callosum hypoplasia, and two of three showed mild cerebellar hypoplasia and atrophy. Consistent with a proposed role in neurodevelopmental disease, LNPK was expressed during brain development in humans and mice and was present in neurite-like processes in differentiating human neural progenitor cells. Affected cells showed the absence of full-length lunapark, aberrant ER structures, and increased luminal mass density. Together, our results implicate the ER junction stabilizer lunapark in establishing the corpus callosum.

Correction to: Expanding the genetic heterogeneity of intellectual disability

Variant nomenclature discrepancy was identified in the article.

1515 Infantile Spasm in Children: Clinical Features and Outcome

Objective Clinical features and outcome of children with infantile spasms. Study Design Interventional and observational study. Place and Duration of Study The Department of Neurology, Children’s Hospital, Lahore, Pakistan, from January 2010 to December 2011. Methodology Children aged <2 years presented with history of infantile spasms were assessed. Clinical presentation, EEG findings and response of anti-epileptic drugs was analyzed. Results A total of 51,370 children visited Neurology outpatient department of Children Hospital, Lahore. Out of them, 450 infants had infantile spasms at their first presentation. Mean age at presentation was 6.6 + 2.5 months. Out of 450 children, 76% children presented at age < 6 month, 72% presented due to infantile spasms and 18% because of global developmental delay. Spasm types were mixed (38%), flexors (44%), extensor (16%) and asymmetric (2%). Symptomatic seizures were seen in 72% and cryptogenic in 28%. Hypsarrhythmia (67%) was the predominant EEG finding followed by modified hypsarrhythmia (24%) and other forms of epileptic discharges in 9% children. Majority of children were receiving oral Phenobarbitone, Carbamzaepine or Valproate sodium. We initiate the management with oral Prednisolone followed by Clonazepam or valproate acid. ACTH therapy was administered in only 5 children. Conclusion Infantile spasms are one of the refractory epilepsy in children. Abnormal EEG findings predominantly the hypsarrhythmia or modified hypsarrhythmia are the hallmark. Majority of children received conventional AED with poor response. Oral prednisolone is proved to be the most effective AED. These children should be referred to the tertiary care paediatric neurology centers.