Chitra Prasad

The floppy infant: contribution of genetic and metabolic disorders

The floppy infant syndrome is a well-recognized entity for pediatricians and neonatologists. The condition refers to an infant with generalized hypotonia presenting at birth or in early life. The diagnostic work up in many instances is often complex, and requires multidisciplinary assessment. Advances in genetics and neurosciences have lead to recognition of newer diagnostic entities (several congenital myopathies), and rapid molecular diagnosis is now possible for several conditions such as spinal muscular atrophy (SMA), congenital muscular dystrophies (CMD), several forms of congenital myopathies and congenital myotonic dystrophy. The focus of the present review is to describe the advances in our understanding in the genetic, metabolic basis of neurological disorders, as well as the investigative work up of the floppy infant. An algorithm for the systematic evaluation of infants with hypotonia is suggested for the practicing pediatrician/neonatologist.

Cryptic chromosome rearrangements detected by subtelomere assay in patients with mental retardation and dysmorphic features

The regions near telomeres of human chromosomes are gene rich. Chromosome subtelomere rearrangements occur with a frequency of 7–10% in children with mild‐to‐moderate mental retardation (MR) and approximately 50% of cases are familial. Clinical investigation of subtelomere rearrangements is now prompted by fluorescence in situ hybridization (FISH) analysis using specific DNA probes from all relevant chromosome ends. In our study, 40 children were selected for subtelomere assay using either the Chromophore Multiprobe‐T Cytocell device or the VYSIS TelVision probes. Inclusion criteria were: developmental delay or MR; a normal 550 G‐band karyotype; FRAXA negative; and at least one other clinical criterion. Exclusion criteria included an identified genetic or environmental diagnosis. Of the 40 patients analysed, four (10%) were found to have subtelomere rearrangements. Three of 40 (7.5%) were found to have an unbalanced subtelomere rearrangement and one of 40 (2.5%) was found to have an apparently normal variant subtelomere deletion. The first of the three with an unbalanced karyotype was the result of a familial translocation, the second was a de novo finding, and the origin of the third could not be determined. The subtelomere FISH assay detected almost twice the frequency of unbalanced karyotypes as those detected by 550 G‐banding in our cytogenetics laboratory (4.7%). In addition, subtelomere screening was eight times more likely than fragile X screening in our DNA laboratory (1%) to detect genetic abnormalities in mentally handicapped individuals. Our findings support the view that screening for subtelomere rearrangements has a greater positive yield than other commonly used genetic investigations and, if cost and resources permit, should be the next diagnostic test of choice in a child with unexplained MR/dysmorphisms and a normal 550 G‐band karyotype.

Rib defects in patterns of multiple malformations: A retrospective review and phenotypic analysis of 47 cases

Rib anomalies may occur in isolation, as well as in association with abnormalities of vertebral segmentation and multi‐system malformations. Specific entities include the VACTERL and MURCS associations, spondylocostal dysostosis, and spondylothoracic dysostosis. The relative significance of rib anomalies in other lesser known syndromes and associations remains unclear. To document the diagnoses and related defects in patients with rib anomalies as part of broader pattern of anomalies, we retrospectively identified 47 cases from a hospital population, and evaluated specific costal findings and associated birth defects. In our study, fusion was the most common pattern of rib anomaly (72%), followed by bifid (28%) and hypoplastic ribs (26%). Unrecognized patterns of multiple congenital anomalies (MCA) and VACTERL association were the commonest specific diagnoses with a frequency of 30 and 28%, respectively. An associated vertebral defect was found in 72% of the patients. Of those with no vertebral anomaly, the combinations of “rib and cardiac defects alone” and “rib and renal defects alone” were seen in one‐third of the patients (4/13). Both the occurrence and type of rib anomaly were helpful in defining certain syndromes and enhanced the likelihood of identifying related malformations.

The Floppy Infant: Retrospective Analysis of Clinical Experience (1990—2000) in a Tertiary Care Facility

We describe the results of a retrospective study of floppy infants evaluated at the Childrens Hospital of Winnipeg, a tertiary care childrens facility. Cases were ascertained by a systematic search of clinical databases, hospital and electromyographic records for “floppy” infants age < 1 year, referred over a period of 11 years (1990—2000). Eighty-nine infants, 42 female (47.2%) and 47 male (52.8%), were included in the study. A definitive diagnosis was established in 60 (67.4%) cases, in 24 cases (40%) on purely clinical grounds, whereas in 36 (60%) cases, additional investigations were necessary. Karyotype, molecular diagnostics, cranial imaging, and muscle and skin biopsy provided diagnostic information. Genetic disorders in 18 of 60 (20.2%), congenital or acquired disorders of the central nervous system in 22 of 60 (24.7%), and disorders of the lower motor unit in 9 of 60 (10.1%) contributed to the majority of diagnoses. Eight of 89 (8.9%) infants died in the first year, and 2 of 89 (2.6%) were on home ventilation. Of the 61 infants surviving beyond 12 months, 38 of 61 (62.3%) were found to be globally delayed, and only 30 of 61 (49.2%) achieved independent ambulation at their last clinical evaluation. Systematic evaluation of a floppy infant followed by careful selection of investigations (karyotype, DNA-based diagnostic tests, and cranial imaging) can maximize diagnostic yield. (J Child Neurol 2005;20:803—808).

Congenital Indifference to Pain and Deletion of Chromosome 10q—: New Association

We describe a case of a de novo terminal deletion of the long arm of chromosome 10 with the novel feature of congenital indifference to pain in a 2-year 10-month-old boy. Relative indifference to pain defined by a lack of emotional response to pain has not been described previously in association with the terminal deletion of the long arm of chromosome 10. (J Child Neurol 2006;21:174—177; DOI 10.2310/7010.2006.00045).

Genetic Aspects of Human Epilepsy

Advances in genetics and molecular genetics are shaping new insights in our understanding of inheritance patterns and phenotypic variability in human epilepsy. It is now generally accepted that traditional monogenic Mendelian inheritance patterns leading to human epilepsy syndromes are relatively rare in comparison to more common (idiopathic) epilepsies with complex genetics. Inheritance patterns in the latter can be explained by a polygenic heterogeneity model, involving a dosage effect resulting from the combined effect of both common and rare variants of susceptibility genes. The evidence thus far suggests that ion channel dysfunction constitutes a key mechanistic pathway among many in determining seizure susceptibility. Several monogenic epilepsy syndromes are now proven to be channelopathies with mutations in genes coding of voltage-gated and ligand-gated channel subunits resulting in altered excitability patterns in neuronal networks and epileptogenesis. There are other genetic mechanisms that lead to seizure susceptibility involving gene deletions/duplications, copy number variations, chromosomal aberrations and biochemical perturbations from inborn errors of metabolism. In this chapter, we will discuss selected genetic epilepsy syndromes, inheritance patterns, the clinical aspects, molecular basis, and current understanding of pathology and mechanisms leading to epileptogenesis in genetic epilepsy. We further discuss a bedside approach to identify the genetic basis of epilepsy syndromes, the role of molecular genetic testing relevance, and clinical utility in the diagnosis and management of epilepsy.