Family History Of Developmental Delay Research Articles

A-318 Pseudo-hypertriglyceridemia in a 2-year-old Male with Global Developmental Delay, Myopathy and Adrenal Hypoplasia

Abstract Background Pseudo-hypertriglyceridemia is an overestimation of serum triglyceride levels due to laboratory assays that measure free glycerol concentrations instead of triglycerides directly. Consequently, conditions presenting with elevated levels of endogenous or exogenous free glycerol, such as glycerol kinase deficiency, result in an overestimation of serum triglycerides. Glycerol kinase deficiency (GKD) is caused by pathogenic variants of the GK gene on chromosome Xp21. Three forms of GKD are recognized, characterized as infantile, juvenile, and adult forms. While the juvenile and adult forms are recognized as isolated GKD, the infantile form manifests itself as part of the Xp21.3 contiguous gene deletion syndrome, also known as complex GKD. This syndrome is composed of genes associated with Duchenne muscular dystrophy (DMD), X-linked congenital adrenal hypoplasia (NR0B1), and intellectual disability (IL1RAPL1). GKD is characterized biochemically by hyperglycerolaemia and glyceroluria. Case Description A 2-year-old male presented to the genetics clinic with a history of global developmental delay (gross motor and speech), axial hypotonia, poor head control and inability to sit unassisted or walk. Significant findings on examination included a startled appearance, absent eyebrows and temporal thinning, high forehead, frontal bossing, axial hypotonia and peripheral hypertonia. Laboratory findings included elevated creatine kinase (CK) of 14809 units/L (normal 27–160 units/L), aspartate aminotransferase (AST) of 307 (normal 20–60 units/L), alanine aminotransferase (ALT) 265 (normal 15–45 units/L), Adrenocorticotropic Hormone (ACTH) 156 (normal 6–48 pg/mL), and elevated triglycerides at 683 (normal 44–157 mg/dL). There was also a family history of developmental delay and intellectual disability in patient's mother and younger sister. Method Triglycerides are commonly measured indirectly with different enzyme reagents. The Triglycerides in this boy were measured by an automated chemistry analyzer based on a colorimetric serial enzymatic reaction including lipase, glycerol kinase and L-α-glycerol-phosphate oxidase1. Urinary organic acids profile including glycerol was extracted from acidified urine (pH 1-2) using diethyl ether. Organic extracts are then evaporated to dryness under nitrogen and trimethysilyl derivatized by the addition of N, O-bis (trimethylsilyl) trifluoroacetamide with 1% trimethylchorosilane (BSTFA/TMCS) and analyzed by gas chromatography-mass spectrometry (GC-MS). Results A comprehensive work-up including qualitative urinary organic acid analysis and chromosomal microarray was carried out. Urinary organic acids analysis revealed very abnormal accumulation of glycerol. Chromosomal microarray results showed a 4.2 Mb deletion of Xp21.3p21.1 (29296579-33551038) including complete copies of GK, DMD, and NR0B1 genes as well as multiple exons of IL1RAPL1. This confirmed his GKD as part of the Xp21 continuous gene deletion syndrome. Elevated triglycerides were then recognized as pseudo-hypertriglyceridemia after the diagnosis. Mild glyceroluria is also observed in the younger sister of this patient. Discussion and Conclusion This case highlights the importance recognizing pseudo-hypertriglyceridemia and diagnostic challenges. Earlier identification through urine organic acid analysis could have been made. The combination of clinical presentations and increased glycerol should cause suspicion for GKD. Female carriers of this X-linked disorder need to be evaluated for intellectual disability, as seen in this patient's mother and younger sister.

EPID-03MENINGIOANGIOMATOSIS ASSOCIATED WITH MICROCEPHALY AND DEVELOPMENTAL DELAY IN A PEDIATRIC PATIENT

BACKGROUND: Meningioangiomatosis is a rare benign lesion of the central nervous system characterized by focal leptomeningeal and meningovascular proliferation most commonly in the frontal and temporal cerebral cortex. Typically meningioangiomatosis presents with seizures and much less commonly headache, visual disturbance, limb weakness and personality change. Genetic mutations in Microcephalin1 (MCPH1) and ASPM (abnormal spindle like microcephaly) cause primary microcephaly and their role in carcinogenesis is being elucidated. CASE REPORT: A boy with global developmental delay due to microcephaly of undetermined etiology and vesicoureteral reflux presented with a new onset generalized tonic clonic seizure. He had a family history of developmental delay in male relatives (maternal uncle and brother) and a family history (maternal) of malignancy in female relatives (breast, mesothelioma, ovarian and uterine cancer). He had large low set ears, prominent jaw and normal testicles. MRI demonstrated a minimally enhancing vascular 1.9 x 1.9 x 1.5 cm lesion in the mesial right inferior frontal lobe predominantly in the superficial cortical gray matter. The lesion had a low intensity T2 signal and dense calcification along the periphery and a central zone of linear vascular enhancement. There was no associated vasogenic edema or any other abnormal MRI findings. The lesion was totally resected under image guidance. Histopathological examination showed meningoendothelial proliferation without atypical features. Intervening neurons immunoreactive with synaptophysin, GFAP and NeuN were seen. The final diagnosis was frontal lobe meningioangiomatosis. Fragile X syndrome testing was negative (FMR gene CGG repeat number: 32) and chromosomal microarray analysis was normal. Follow up MRIs have not demonstrated recurrence of the meningioangiomatosis and he has been seizure free on Levetiracetam/Topiramate therapy. CONCLUSION: We speculate that there is a genetic basis to the microcephaly and meningioangiomatosis in our patient perhaps involving genes in the X chromosome, MPCH1 or ASPM genes. Further testing is warranted.

Spinal muscular atrophy: Clinical spectrum and genetic mutations in Pakistani children

In Pakistan the rate of consanguineous marriages is high, thus, the chance of incidence of autosomal recessive disorders is likely to be high. The aim of this study is to investigate the clinical characteristics and genetics of spinal muscular atrophy (SMA) in children who presented to Aga Khan University, Karachi. This study was a retrospective review of the medical charts of children (neonate: 15 years) with discharge diagnosis of SMA during last 10 years. Demographic features, consanguinity, and diagnostic analysis (including genetic analysis) were noted. During the study period 67 children had a discharge diagnosis of SMA. Werdnig Hoffman disease (SMA type I) was the commonest variant seen in 37 (56%) children. Overall 68% were infants. High parental consanguinity was observed in 68% of the study cohort. The history of delayed development and undiagnosed early death was observed in the families of 19 children. Genetic testing was performed in 22 (33%) children. Survival motor neuron (SMN) 1 gene deletion was found in 19 (86%) of the 22 patients in whom the gene analysis was done and 13 (68%) were also positive for neuronal apoptosis inhibitory proteins (NAIP) deletion. SMA is not an uncommon neurodegenerative disorder in Pakistan and SMA type I was the most common type. SMN1 gene deletion was the most common genetic deletion found in this study. In addition, family history of developmental delay and frequent early deaths highlights the need for implementation of prenatal diagnosis for early detection, effective control, and management of this disorder in Pakistan.

Algorithmic Approach for Methyl-CpG Binding Protein 2 (MECP2) Gene Testing in Patients With Neurodevelopmental Disabilities

Methyl-CpG binding protein 2 gene (MECP2) testing is indicated for patients with numerous clinical presentations, including Rett syndrome (classic and atypical), unexplained neonatal encephalopathy, Angelman syndrome, nonspecific mental retardation, autism (females), and an X-linked family history of developmental delay. Because of this complexity, a gender-specific approach for comprehensive MECP2 gene testing is described. Briefly, sequencing of exons 1 to 4 of MECP2 is recommended for patients with a Rett syndrome phenotype, unexplained neonatal encephalopathy, an Angelman syndrome phenotype (with negative 15q11-13 analysis), nonspecific mental retardation, or autism (females). Additional testing for large-scale MECP2 deletions is recommended for patients with Rett syndrome or Angelman syndrome phenotypes (with negative 15q11-13 analysis) following negative sequencing. Alternatively, testing for large-scale MECP2 duplications is recommended for males presenting with mental retardation, an X-linked family history of developmental delay, and a significant proportion of previously described clinical features (particularly a history of recurrent respiratory infections).

Prevalence of Pervasive Developmental Disorders in Preschool Children in the UAE

Available evidence from the literature suggests that the prevalence of autistic disorder may be on the rise world wide, but no prevalence studies have been carried out till date in the Arabian Gulf region. A representative random sample of 694 three-year-old United Arab Emirates national children was evaluated in a two-stage study in the community. In the first stage, using Autism Screening Questionnaire, 58 per 10,000 children were noted to have autistic features. In the second stage using clinical interview, the weighted prevalence was estimated to be 29 per 10,000 for a DSM-IV diagnosis of pervasive developmental disorder (PDD). However, none of these children had been diagnosed prior to the study. Presence of autistic features was associated with male gender, presence of behavioural problems and a family history of developmental delay. The rate of PDD observed in the UAE is comparable with that reported from western countries. However, the lack of recognition of these disorders suggests the need for a comprehensive screening program, as early diagnosis can open the door for early intervention which in turn may improve the prognosis.

Pattern of Childhood Epilepsies With Neuronal Migrational Disorders in Oman

Neuronal migrational disorders form a significant cause of psychomotor delay and intractable epilepsy in children. Pediatric neurology services are available at Sultan Qaboos University Hospital, Muscat, Oman, which is a tertiary care hospital for the whole country. The children undergoing evaluation for developmental delay and epilepsy formed the subjects of the study. Data were analyzed from children found to have neuronal migrational disorders on imaging (computed tomography [CT] or magnetic resonance imaging [MRI]). There were 40 cases of neuronal migrational disorders. Corpus callosum agenesis and lissencephaly or pachygyria formed the major group. There were 22 cases of corpus callosum agenesis, 12 of lissencephaly or pachygyria, 2 of schizencephaly, and 1 each of polymicrogyria, holoprosencephaly, hydranecephaly, and hemimegalencephaly. Nineteen of these 40 (47.5%) cases of neuronal migrational disorders had epilepsy. The break-down was 8 of 22 cases of corpus callosum agenesis (36%), 7 of 12 (58.3%) cases of lissencephaly or pachygyria, and 1 each of polymicrogyria, hydranencephaly, and hemimegalencephaly. The family history of developmental delay, similar to the index case, was present in two children with lissencephaly. However, the brain imaging did not reveal the abnormality. The types of seizures were infantile spasms in five, tonic-clonic in nine, myoclonic in two, partial in one, and mixed in five. Nineteen of 40 cases of neuronal migrational disorders had epilepsy. Only 2 of 19 (10.5%) with epilepsy had good seizure control. This raises the possibility of more and more surgical intervention in the management of such cases. Neuronal migrational disorders are related to exogenous and genetic factors from the 6th to 26th weeks of gestation. Molecular and genetic research is defining the mechanism of these disorders. This could help in early diagnosis, prevention, and eventual gene therapy in such conditions.

In Utero Effects of AEDs.

Long-term Health and Neurodevelopment in Children Exposed to Antiepileptic Drugs Before Birth Dean JC, Hailey H, Moore SJ, Lloyd DJ, Turnpenny PD, Little J. J Med Genet 2002;39:251–259 Objective To investigate the frequency of neonatal and later childhood morbidity in children exposed to antiepileptic drugs in utero. Design Retrospective population-based study. SETTING: Population of the Grampian region of Scotland. Participants Mothers taking antiepileptic drugs in pregnancy between 1976 and 2000 were ascertained from hospital obstetric records, and 149 (58% of those eligible) took part. They had 293 children whose health and neurodevelopment were assessed. Main outcome measures: Frequencies of neonatal withdrawal, congenital malformations, childhood-onset medical problems, developmental delay, and behaviour disorders. Results Neonatal withdrawal was seen in 20% of those exposed to antiepileptic drugs (AEDs). Congenital malformations occurred in 14% of exposed pregnancies, compared with 5% of nonexposed sibs, and developmental delay in 24% of exposed children, compared with 11% of nonexposed sibs. After excluding cases with a family history of developmental delay, 19% of exposed children and 3% of nonexposed sibs had developmental delay, 31% of exposed children had either major malformations or developmental delay, 52% of exposed children had facial dysmorphism compared with 25% of those not exposed, 31% of exposed children had childhood medical problems (13% of nonexposed sibs), and 20% had behaviour disorders (5% of nonexposed). Conclusion Prenatal AED exposure in the setting of maternal epilepsy is associated with developmental delay and later childhood morbidity in addition to congenital malformation.

Long term health and neurodevelopment in children exposed to antiepileptic drugs before birth

Objective: To investigate the frequency of neonatal and later childhood morbidity in children exposed to antiepileptic drugs in utero. Design: Retrospective population based study. Setting: Population of the Grampian region...