Novel variants underlying autosomal recessive intellectual disability in Pakistani consanguineous families.

BACKGROUND: Intellectual disability (ID) is both a clinically diverse and genetically heterogeneous group of disorder, with an onset of cognitive impairment before the age of 18 years. ID is characterized by significant limitations in intellectual functioning and adaptive behaviour. The identification of genetic variants causing ID and neurodevelopmental disorders using whole-exome sequencing (WES) has proven to be successful. So far more than 1222 primary and 1127 candidate genes are associated with ID. METHODS: To determine pathogenic variants causative of ID in three unrelated consanguineous Pakistani families, we used a combination of WES, homozygosity-by-descent mapping, de-deoxy sequencing and bioinformatics analysis. RESULTS: Rare pathogenic single nucleotide variants identified by WES which passed our filtering strategy were confirmed by traditional Sanger sequencing and segregation analysis. Novel and deleterious variants in VPS53, GLB1, and MLC1, genes previously associated with variable neurodevelopmental anomalies, were found to segregate with the disease in the three families. CONCLUSIONS: This study expands our knowledge on the molecular basis of ID as well as the clinical heterogeneity associated to different rare genetic causes of neurodevelopmental disorders. This genetic study could also provide additional knowledge to help genetic assessment as well as clinical and social management of ID in Pakistani families.

Clinical presentations and outcomes of the children with tuberculous meningitis: An experience at a tertiary care hospital.

OBJECTIVE: To determine the clinical presentations and outcomes of the children suffering from tuberculous meningitis. METHODS: This prospective, descriptive study was conducted at the Children's Hospital and the Institute of Child Health, Multan, Pakistan, from February to December 2015. The Pakistan Paediatric Association scoring chart for tuberculosis was used as a tool for the probable diagnosis. The clinical symptoms with their durations were noted. Clinical stages of tuberculous meningitis, cerebrospinal fluid analysis and computerised tomography brain findings were noted for each patient. The outcomes in the form of death or neurological disabilities at the time of hospital discharge were noted. SPSS 19 was used for data analysis. RESULTS: Of the 40 participants, 25(62.5%) were males and 15(37.5%) were females. The mean age of the patients was 4.24±3.32 years. Besides, 26(65%) patients were less than 5 years of age. All the patients (100%) were categorised as stage 3 tuberculous meningitis. The history of prolonged duration of fever 39(97.55%) and altered level of sensorium 40(100%) were the most common clinical presentations. Moreover, 2(5%) patients died during this study. All the 38(95%) survivors had neurological disabilities. There were motor deficits in 37(97.4%) patients, altered level of sensorium in 35(92%), cranial nerve palsies in 9(23.5%), epilepsy in 29(76.3%) and hydrocephalus in 32(84%) patients. CONCLUSIONS: The children were the most vulnerable group for the worst form of tuberculous meningitis and had a grave outcome.

Neurological Wilson disease in children: a three years experience from Multan.

OBJECTIVE: To describe the neurological manifestations, results of investigations and response to treatment in Wilson disease in children from Multan. METHODS: This cross sectional study was conducted at Neurology Department of Children Hospital and Institute of Child Health Multan from June 2005 to May 2008. Fifty children were included in this study. Age at onset of symptoms, sex, duration of symptoms, presenting complaints, consanguinity among parents, family history and response to treatment was noted. Chi square test was used to measure relationship between variables and response to treatment. P value of less than 0.05 was taken as significant. RESULTS: Of the 50 cases studied, 48 were index cases and two were diagnosed on screening. Male female ratio was 2.1:1. Mean age at onset of symptoms was 9.06 +/- 2.65 years. Dystonia, dysarthria and cognitive decline was seen in 92%, drooling in 68%, tremors in 52%, chorea in 24% and seizures in 12% of children. Kayser Fleischer rings and elevated 24 hours urinary copper after penicillamine challenge, 1567 +/- 167.35 microg/day was present in all 50 children. Twenty two (44%) children showed early response, 24 (48%) late response and 4 (8%) children showed no response after one year of treatment. Late, greater than 10 years of age at onset of symptoms, less than 6 months duration of symptoms and urinary copper excretion of less than 1000 microg/day were found statistically significant factors for early response to treatment. CONCLUSION: In the study population, dystonia, dysarthria and cognitive decline were the commonest presentations. Twenty four hour urinary copper was found helpful for diagnosis. Penicillamine was found to be an effective drug for treatment as overall response was noted in 92% of children.

Clinical profile and response to oral prednisolone in infantile spasm.

OBJECTIVE: To evaluate the clinical profile and response to oral prednisolone in infantile spasms. STUDY DESIGN: Case series. PLACE AND DURATION OF STUDY: Neurology Department, The Children Hospital and Institute of Child Health, Multan, from July 2005 to June 2007. METHODOLOGY: Fifty patients of infantile spasms were studied. Age, gender, age at onset of seizures, type of spasms (flexor, extensor or mixed), history of intrapartum asphyxia, developmental history, dysmorphic facial features, any hypopigmented/ hyperpigmented skin lesions, computed tomogram and electroencephalogram findings and response to oral prednisolone was noted. Data was analyzed statistically by SPSS 10. Descriptive statistics was used to find out frequencies and percentages of all above mentioned variables. Chi-square test was applied to determine the association between these variables and response to treatment. P-value of less than 0.05 was taken significant. RESULTS: Male to female ratio was 2.1:1. Mean age of babies was 6.5+/-3.35 months. Mean age at onset of seizures was 5.35+/-3.52 months. Flexor spasms was seen in 32 (64%), extensor spasms in 8 (16%) and mixed spasms in 10 babies (20%). Symptomatic infantile spasms were noted in 48 (96%) babies while two babies (4%) were having cryptogenic infantile spasm. History of intrapartum asphyxia was noted in 54% of symptomatic cases. Favourable response to oral prednisolone was seen in 27 babies (54%). Except male gender, none of the other variable reached the statistical significance for favourable response to treatment. CONCLUSION: Infantile spasms were found more common in males, flexor spasms were the commonest type noted. Symptomatic spasm was noted in 96% of cases and intrapartum asphyxia was the commonest cause of symptomatic group. Response to oral prednisolone was noted in more than half of cases of infantile spasms.

Risk factors, presentations and outcome of the haemorrhagic disease of newborn.

OBJECTIVE: To determine the presentations, associated factors and acute outcome in the haemorrhagic disease of newborn. STUDY DESIGN: Cross-sectional analytical study. PLACE AND DURATION OF STUDY: Paediatric Medicine Unit II, Nishtar Hospital, Multan, from June 2004 to May 2006. METHODOLOGY: Fifty patients with haemorrhagic disease of newborn were studied. Age at onset of symptoms, gender, feeding pattern, place of delivery, site of bleeding and acute outcome of patients were noted. Chi-square test was applied to determine the significance of differences and relationship between variables and outcome. P-value of less than 0.05 was considered significant. RESULTS: The mean age at onset of symptoms was 51.65+/-39.49 days. Male to female ratio was 2.1:1 (p=0.047). Late onset disease (8 days to 6 months of life) was noted in 32 (72%) babies (p=0.094). Exclusive breastfeeding was noted in 45 (90%) babies (p<0.001). Thirty babies (60%) were delivered at homes (p=0.025), 13 (26%) at private clinics and 7 (14%) at government hospitals. Intracranial haemorrhage was noted in 26 (52%) babies, skin bleeding in 09 (18%) babies, gastrointestinal in 08 (16%), bleeding from injection site in 04 (8%), hematuria in 02 (4%) and bleeding from umbilicus in 01 (2%) baby. Forty babies recovered, whereas death occurred in 10 babies. The cause of death was intracranial haemorrhage in all babies (p=0.059) and all were of late onset disease (p=0.088). CONCLUSION: Haemorrhagic disease of newborn was common in male gender, breast-fed infants and spontaneous vaginal deliveries. Intracranial haemorrhage and late onset disease were the causes of mortality in all cases.

Clinical Efficacy and Safety of Injectable Levetiracetam Versus Phenytoin as Second-Line Therapy in the Management of Generalized Convulsive Status Epilepticus in Children: An Open-Label Randomized Controlled Trial.

BACKGROUND AND PURPOSE: There is sparsity of quality evidence for the use of drugs after first-line benzodiazepines in convulsive status epilepticus in children. The aim of the study was to compare the clinical efficacy and safety of intravenous levetiracetam versus intravenous phenytoin as second-line drugs in the management of generalized convulsive status epilepticus in children. METHODS: This open-label randomized controlled trial was conducted in the Emergency Department of The Children's Hospital and The Institute of Child Health, Multan, Pakistan over a period of 4 years and 6 months from January 2014 to June 2018. This study included 600 children with generalized convulsive status epilepticus: 300 in the 40 mg/kg levetiracetam group, and 300 in the 20 mg/kg phenytoin group. Cessation of a clinical seizure (seizure cessation rate) within 30 minutes after the end of drug administration was the primary outcome in this study, and the presence or absence of adverse effects was noted as the secondary outcome. Data were analyzed using SPSS (version 20.0). RESULTS: The children in the levetiracetam and phenytoin were aged 3.5±0.2 and 3.4±0.2 years (mean±SD), respectively, their seizure durations before the start of treatment were 25.1±0.6 and 23.8±0.4 minutes, and their treatment efficacies were 278/300 (92.7%) and 259/300 (83.3%). Levetiracetam was significantly more effective than phenytoin (p=0.012), with no significant difference in safety. Adverse events were observed in eight children in the phenytoin group. CONCLUSIONS: Levetiracetam is significantly more effective than phenytoin for the treatment of convulsive status epilepticus in children who have failed to respond to benzodiazepines.

Hypereosinophilic syndrome causing acute hemiplegia in childhood.

Hypereosinophilic syndrome (HES) is a rare heterogeneous group of disorders, characterized by marked peripheral blood and tissue eosinophilia resulting in end organ damage. This case describes a six-year-old girl child who presented with sudden weakness of right half of body and fever. Computed tomogram of brain showed infarction of left internal capsule and basal ganglia. She had peripheral and bone marrow eosinophilia. No other cause was found for infarction.

Rasmussen encephalitis.

Rasmussen syndrome or Rasmussen encephalitis is a rare, progressive gray matter disease of childhood. A case of 4-year-old boy is reported here, who presented with recurrent episodes of status epilepticus of simple partial fits along with progressive left sided hemiplegia. EEG showed focal discharges from right hemisphere. Serial MRI brain showed progressive atrophy of right cerebral hemisphere with dilatation of ipsilateral ventricle.