Debunking Occam's razor: Diagnosing multiple genetic diseases in families by whole-exome sequencing.

BACKGROUND: Recent clinical whole exome sequencing (WES) cohorts have identified unanticipated multiple genetic diagnoses in single patients. However, the frequency of multiple genetic diagnoses in families is largely unknown. AIMS: We set out to identify the rate of multiple genetic diagnoses in probands and their families referred for analysis in two national research programs in Canada. MATERIALS & METHODS: We retrospectively analyzed WES results for 802 undiagnosed probands referred over the past 5 years in either the FORGE or Care4Rare Canada WES initiatives. RESULTS: Of the 802 probands, 226 (28.2%) were diagnosed based on mutations in known disease genes. Eight (3.5%) had two or more genetic diagnoses explaining their clinical phenotype, a rate in keeping with the large published studies (average 4.3%; 1.4 - 7.2%). Seven of the 8 probands had family members with one or more of the molecularly diagnosed diseases. Consanguinity and multisystem disease appeared to increase the likelihood of multiple genetic diagnoses in a family. CONCLUSION: Our findings highlight the importance of comprehensive clinical phenotyping of family members to ultimately provide accurate genetic counseling.

MELAS: A Multigenerational Impact of the MTTL1 A3243G MELAS Mutation.

BACKGROUND: the maternally inherited MTTL1 A3243G mutation in the mitochondrial genome causes MelaS (Mitochondrial encephalopathy lactic acidosis with Stroke-like episodes), a condition that is multisystemic but affects primarily the nervous system. Significant intra-familial variation in phenotype and severity of disease is well recognized. METHODS: retrospective and ongoing study of an extended family carrying the MTTL1 A3243G mutation with multiple symptomatic individuals. tissue heteroplasmy is reviewed based on the clinical presentations, imaging studies, laboratory findings in affected individuals and pathological material obtained at autopsy in two of the family members. RESULTS: there were seven affected individuals out of thirteen members in this three generation family who each carried the MTTL1 A3243G mutation. the clinical presentations were varied with symptoms ranging from hearing loss, migraines, dementia, seizures, diabetes, visual manifestations, and stroke like episodes. three of the family members are deceased from MelaS or to complications related to MelaS. CONCLUSIONS: the results of the clinical, pathological and radiological findings in this family provide strong support to the current concepts of maternal inheritance, tissue heteroplasmy and molecular pathogenesis in MelaS. neurologists (both adult and paediatric) are the most likely to encounter patients with MelaS in their practice. genetic counselling is complex in view of maternal inheritance and heteroplasmy. newer therapeutic options such as arginine are being used for acute and preventative management of stroke like episodes.

Intravenous immunoglobulin in pediatrics: A review.

There has been a rapid expansion of the use of intravenous immunoglobulin (IVIG) for an ever-growing number of conditions. IVIG is used at a 'replacement dose' (400-600 mg/kg/month) in antibody deficiencies and is used at a high dose (2 g/kg) as an 'immunomodulatory' agent in an increasing number of immune and inflammatory disorders.(1) The limitations for IVIG are the cost of the preparation and the need for intravenous infusions. Due to the cost, shortages and growing use of IVIG there have been attempts to develop evidence-based guidelines for the use of IVIG in a wide variety of immune disorders in children and neonates. This commentary provides the recommendations and recent publication regarding the use of IVIG in various conditions in children.

Recurrent encephalopathy: NAGS (N-acetylglutamate synthase) deficiency in adults.

N-acetyl-glutamate synthase (NAGS) deficiency is a rare autosomal recessive urea cycle disorder (UCD) that uncommonly presents in adulthood. Adult presentations of UCDs include; confusional episodes, neuropsychiatric symptoms and encephalopathy. To date, there have been no detailed neurological descriptions of an adult onset presentation of NAGS deficiency. In this review we examine the clinical presentation and management of UCDs with an emphasis on NAGS deficiency. An illustrative case is provided. Plasma ammonia levels should be measured in all adult patients with unexplained encephalopathy, as treatment can be potentially life-saving. Availability of N-carbamylglutamate (NCG; carglumic acid) has made protein restriction largely unnecessary in treatment regimens currently employed. Genetic counselling remains an essential component of management of NAGS.

Prevalence of childhood epilepsy in Canada.

RATIONALE: Few data exist on the frequency and burden of childhood epilepsy in Canada and on the impact in the general population. We have assessed the point prevalence of childhood epilepsy in Canada. METHODS: We analyzed data from the National Longitudinal Survey of Children and Youth (N=20 025 for Cycle 2, and N= 31 960 for cycle 3). Each cycle was collected over a two year period (2: 1996-1997, 3: 1998-1999). In the survey the following specific question was asked to the person most knowledgeable in the household: "Does the child have any of the following long-term conditions that have been diagnosed by a health professional?" The list of responses included Epilepsy and certain co-morbid conditions. In addition, a subsequent question identified whether the condition was treated by means of a specific anticonvulsant medication. (anticonvulsants or anti-epileptic pills?). Prevalence was based on the national standard population at the time of each survey. RESULTS: In Cycle 2, 80 of 20 025 subjects from 0 to 13 years old were described to have the diagnosis of epilepsy, yielding a weighted point prevalence of 4.03 per 1 000. In Cycle 3 161 of 31 960 children from 0 to 15 were described as having epilepsy, yielding a weighted point prevalence of 5.26 per 1 000. The rate of epilepsy was higher for males and increases with age. CONCLUSION: The overall rates for this age cohort are consistent with those obtained in other developed countries and seem to coincide with rates for youth and adults in Canada.

Status epilepticus in the pediatric ICU: state of the art.

Status epilepticus in the pediatric intensive care setting is a neurological emergency. Its management presents profound challenges for the pediatric intensivist, and neurologist. Understanding the neurobiological factors that are operative in transition of an epileptic seizure to self-sustained status epilepticus is critical to management. Statue epilepticus in children is often heterogeneous in etiology. In this article, I examine the evidence for who is likely to be admitted to the pediatric intensive care unit for management, the risk factors, the relationship of seizure duration and evolution to status epilepticus, and the reasons for seizure refractoriness. The immediate complications and long term consequences leading to morbidity and mortality in this condition are reviewed. The problem of refractory status epilepticus is particularly more frequently encountered in the intensive care setting. Therapeutic options in the initial management and in particular addressing reasons for the development of pharmacoresistance in status epilepticus are presented. Finally, data on outcome in the pediatric ICU setting is discussed providing thus an overview of our current understanding and state of the art in the management of status epilepticus in children.

Children in Conflict Zones.

The nature of war has changed dramatically. Today's conflicts happen where people live and they take a brutal toll on children. Heavy bombardment and destruction in war creates a humanitarian crisis where there is lack of adequate food, clean water and medicine. The consequences of war can have major impact on the health of children for years to come. Traumatic events can have a profound and lasting impact on the emotional, cognitive, behavioral and physiological functioning of an individual. Depending on the circumstances, the psychosocial impacts of disasters can range from mild stress reactions to problems such as anxiety, depression, substance abuse and post traumatic stress disorders (PTSD).

Assessment of systolic and diastolic left ventricular and left atrial function using vector velocity imaging in Takotsubo cardiomyopathy.

Five adult patients with Takotsubo cardiomyopathy (TC) diagnosed by usual criteria were studied with velocity vector imaging (VVI) on admission and at follow-up, when their LV function had improved, as assessed by 2D TTE wall-motion score (WMS) index. Averaged peak segmental longitudinal strain (S) in systole, and velocity (V) and strain rate (SR) in both systole and diastole were measured from apical 4- (A4C) and 2-chamber views (A2C) in all patients. The data obtained by VVI were analyzed separately for involved and uninvolved segments, which were independently assessed by WMS. In the involved segments, systolic S, V, SR, and diastolic SR improved (P-value < 0.05) on follow-up. Diastolic V showed a trend toward improvement but did not reach statistical significance. In the uninvolved segments, none of the parameters improved significantly either during systole or diastole. In three of these five patients, left atrial (LA) walls were also studied by placing region of interest (ROI) points in the middle of each wall. Peak segmental LA systolic and diastolic V and SR as well as systolic S were obtained for both involved and uninvolved LA walls which were assessed independently using WMS similar to LV. In the involved LA walls, none of the atrial systolic and diastolic parameters changed significantly but all parameters with the exception of systolic V showed a tendency toward improvement during follow-up. Among the uninvolved LA walls, none changed significantly but atrial systolic SR and, diastolic V and SR tended to increase during follow-up. Our retrospective study using VVI demonstrates that TC patients also have LV systolic and diastolic longitudinal dysfunction, not just systolic radial dysfunction as assessed by traditional 2D TTE indices. Longitudinal LA dysfunction may also be present.

Live/real time three-dimensional transthoracic echocardiographic assessment of pulmonary regurgitation.

There is no gold standard for the measurement of pulmonary regurgitation (PR) severity. Two-dimensional (2D) transthoracic echocardiography is most commonly used to quantify PR severity using color Doppler criteria for aortic regurgitation. However, this method is limited by visualization of only one or two dimensions of the proximal PR jet or vena contracta (VC) precluding accurate assessment of its shape or size. This limitation would be expected to be obviated by three-dimensional (3D) transthoracic echocardiography, which could provide a more accurate quantitative assessment of PR severity. This study evaluated 82 adult patients with PR using 2D and 3D. PR VC area by 3D was obtained by planimetry by positioning the cropping plane exactly parallel to the VC, which was viewed en face by cropping of the 3D data set. Regurgitant volumes were calculated by 2D (assuming a circular VC) and by 3D as a product of the VC and velocity time integral obtained by color Doppler-guided conventional Doppler interrogation of the PR jet.The 3D VC area correlated with 2D jet width (JW)/right ventricular outflow tract (RVOT) width (r = 0.71) and 2D VC area (r = 0.79). 3D JW/RVOT width correlated with 2D JW/RVOT (r = 0.87). 3D regurgitant volumes also correlated with 2D regurgitant volumes (r = 0.76). The 3D VC values of <0.20, 0.20-0.45, 0.46-1.15, and >1.15 cm(2) and regurgitant volumes of <15 ml, 15-50 ml, 51-115 ml, and >115 ml were effective as cutoffs for grades 1, 2, 3, and 4 PR, respectively. In conclusion, quantification of 3D VC area and regurgitant volumes correlate reasonably well with the current 2D methods for measurement of PR. Since 3D visualizes PR VC in three dimensions, it would be expected to provide a more accurate and more quantitative assessment of PR severity as compared to 2D.

Epilepsy, birth weight and academic school readiness in Canadian children: Data from the national longitudinal study of children and youth.

PURPOSE: Birth weight is an important indicator of prenatal/in-utero environment. Variations in birth weight have been reportedly associated with risks for cognitive problems. The National Longitudinal Survey of Children and Youth (NLSCY) dataset was explored to examine relationships between birth weight, academic school readiness and epilepsy. METHODS: A population based sample of 32,900 children of the NLSCY were analyzed to examine associations between birth weight, and school readiness scores in 4-5-year-old children. Logistic and Linear regression was used to examine associations between having epilepsy and these outcomes. Gestation data was available on 19,867 children, full-term children represented 89.67% (gestation >259days), while 10.33% of children were premature (gestation <258days). There were 20 children with reported epilepsy in the sample. Effects of confounding variables (diabetes in pregnancy, smoking in pregnancy, high blood pressure during pregnancy, and gender of the infant) on birth weight and epilepsy were controlled using a separate structural equation model. RESULTS: Logistic regression analysis identified an association between epilepsy and lower birth weights, as well as an association between lower birth weight, having epilepsy and lower PPVT-R Scores. Model results show the relationship between low birth weight and epilepsy remains statistically significant even when controlling for the influence of afore mentioned confounding variables. CONCLUSION: Low birth weight appears to be associated with both epilepsy and academic school readiness. The data suggest that an abnormal prenatal environment can influence both childhood onset of epilepsy and cognition. Additional studies with larger sample sizes are needed to verify this relationship in detail.

Epilepsy and its Impact on psychosocial outcomes in Canadian children: Data from the National Longitudinal Study of Children and Youth (NLSCY).

PURPOSE: The purpose of this study was to use data from a population-based survey to evaluate the association between childhood epilepsy and social outcomes through tests of mathematics skills, and sense of general self-esteem (GSS). METHODS: Using data from Cycles 1 to 8 of the National Longitudinal Survey of Children and Youth (NLSCY), Hierarchical linear modeling (HLM) was used to compare baseline math scores and changes in math scores and sense of general self esteem (GSS) over time in children with and without epilepsy. Scores of Health Utility Index (HUI) were factored into the analysis. RESULTS: Children with epilepsy do not significantly differ in their scaled math scores in comparison to their peers without epilepsy, at age 12; however, in the two level HLM model the children with epilepsy lagged behind the healthy comparison group in terms of their growth in acquiring knowledge in mathematics. Additionally, when children with epilepsy carry an added health impairment as measured by an imperfect health utility (HUI) score the group shows a slower rate of growth in their math scores over time. Self-esteem measures show variable effects in children with epilepsy alone, and those with added health impairments. The interaction with HUI scores shows a significant negative effect on self-esteem, when epilepsy is associated with added health impairment. CONCLUSION: The findings suggest that the population of Canadian children surveyed with epilepsy are vulnerable to poorer academic outcomes in mathematics in later years, and this problem is compounded further with the presence of other additional health impairments.

Clinical correlations of occipital epileptiform discharges in children.

OBJECTIVES: To determine the frequency of different causes of occipital epileptiform discharges (OEDs) in children and to analyze the EEG features that help predict epilepsy type and prognosis. METHODS: We identified children with OEDs in the absence of other focal discharges using an EEG database at our center; the presence of generalized spike-wave discharges (GSW) or slowing was not an exclusion criterion. Diagnosis, neurologic status, seizure semiology, and seizure remission status were recorded. RESULTS: Of 90 patients with OEDs, 50 (56%) had symptomatic seizures (18 with cerebral palsy, 11 with cerebral dysgenesis, 8 with genetic abnormalities); 31 (34%) had idiopathic seizures, including 6 with benign childhood epilepsy with occipital paroxysms (BCEOP), 8 (9%) had no seizures; and 1 (1%) had febrile seizures. Only two reported ictal visual symptoms. Eighty-seven percent with background slowing had symptomatic seizures, and 87% with normal backgrounds had idiopathic seizures (p < 0.001). Of 72 children with seizures and adequate follow-up, 28 of 45 (62%) with a normal background experienced seizure remission compared with 10 of 27 (37%) with background slowing (p = 0.04). Twenty of 81 patients with epilepsy had GSW. Twelve (60%) of the 20 GSW-positive patients had idiopathic epilepsy compared with 19 of 61 (31%) without GSW (p = 0.02). CONCLUSIONS: Most epilepsy in referred children with OEDs is symptomatic; syndromes such as BCEOP are rare. Visual ictal symptoms are rare. The presence of GSW or a normal background rhythm correlates with idiopathic seizures and a better prognosis.

Argininemia: a treatable genetic cause of progressive spastic diplegia simulating cerebral palsy: case reports and literature review.

Argininemia, a rare autosomal recessive urea cycle disorder, is caused by a deficiency of arginase, with resulting elevated plasma arginine and ammonia levels. Reports to date have focused little on the neurology of this disorder or the efficacy of treatments. A MEDLINE search revealed 25 previously reported cases, to which we have added two brothers who presented with late onset progressive spastic diplegia. Though their degree of enzyme deficiency was comparable, the severity of their phenotypic abnormalities differed substantially. With dietary therapy, both showed improved cognitive and motor function. Late metabolic crises occurred in both, resulting in death of the less severely affected brother. Based on analysis of our clinical database, we report on the full spectrum of neurologic abnormalities seen in argininemia with particular focus on the accompanying progressive spastic diplegia and its response to treatment; progressive decline in head growth; distinctive neuroradiologic findings; and life-threatening later complications. Current and potential future therapies and long-term outcome are summarized.