Severe Neurodevelopmental Delay Research Articles

MICrocephaly, disproportionate pontine and cerebellar hypoplasia syndrome: A clinico-radiologic phenotype linked to calcium/calmodulin-dependent serine protein kinase gene mutation

MICrocephaly, disproportionate pontine and cerebellar hypoplasia (MICPCH) syndrome, a rare X-linked disorder, generally seen in girls, is characterized by neurodevelopmental delay, microcephaly, and disproportionate pontine and cerebellar hypoplasia. It is caused by inactivating calcium/calmodulin-dependent serine protein kinase (CASK) gene mutations. We report a 2-year-old girl with severe neurodevelopmental delay, microcephaly, minimal pontine hypoplasia, cerebellar hypoplasia, and normal looking corpus callosum, with whom the conventional cytogenetic studies turned out to be normal, and an array-comparative genomic hybridization (a-CGH) analysis showed CASK gene duplication at Xp11.4. Our case highlights the importance of using clinico-radiologic phenotype to guide genetic investigation and it also confirms the role of a-CGH analysis in establishing the genetic diagnosis of MICPCH syndrome, when conventional cytogenetic studies are inconclusive.

1034 A Hypotonic Infant with Methylene Tetrahydrofolate Reductase (MTHFR) Deficiency; Homozygous Mutation of C.1015T>G in Mtfhr Gene

BackgroundMethylene tetrahydrofolate reductase (MTHFR) deficiency is a rare autosomal recessive disorder, caused by mutated alleles of the MTHFR gene. Since this enzyme catalyzes the conversion of 5.10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, its...

Epileptic Encephalopathy in Children with Risk Factors for Brain Damage

In the study of 887 new born infants with prenatal and perinatal risk factors for brain damage, 11 children with West syndrome that progressed into Lennox-Gastaut syndrome and another 4 children with Lennox-Gastaut syndrome that had not been preceded by West syndrome were found. In this study we present the main findings of these 15 subjects. In all infants multifactor antecedents were detected. The most frequent risk factors were prematurity and severe asphyxia; however placenta disorders, sepsis, and hyperbilirubinemia were also frequent. In all infants MRI direct or secondary features of periventricular leukomalacia were observed. Followup of all infants showed moderate to severe neurodevelopmental delay as well as cerebral palsy. It is concluded that prenatal and perinatal risk factors for brain damage are very important antecedents that should be taken into account to follow up those infants from an early age in order to detect and treat as early as possible an epileptic encephalopathy.

Griscelli syndrome types 1 and 3: analysis of four new cases and long-term evaluation of previously diagnosed patients

Griscelli syndrome (GS) is a rare autosomal recessive disorder characterized by partial albinism. Three different types are caused by defects in three different genes. Patients with GS type 1 have primary central nervous system dysfunction, type 2 patients commonly develop hemophagocytic lymphohistiocytosis, and type 3 patients have only partial albinism. While hematopoietic stem cell transplantation is life saving in type 2, no specific therapy is required for types 1 and 3. Patients with GS types 1 and 3 are very rare. To date, only 2 patients with type 3 and about 20 GS type 1 patients, including the patients described as Elejalde syndrome, have been reported. The neurological deficits in Elejalde syndrome were reported as severe neurodevelopmental delay, seizures, hypotonia, and ophthalmological problems including nystagmus, diplopia, and retinal problems. However, none of these patients' clinical progresses were reported. We described here our two new type 1 and two type 3 patients along with the progresses of our previously diagnosed patients with GS types 1 and 3. Our previous patient with GS type I is alive at age 21 without any other problems except severe mental and motor retardation, patients with type 3 are healthy at ages 21 and 24 years having only pigmentary dilution; silvery gray hair, eye brows, and eyelashes. Since prognosis, treatment options, and genetic counseling markedly differ among different types, molecular characterization has utmost importance in GS.

Long-term cognitive and cardiac outcomes after prenatal exposure to chemotherapy in children aged 18 months or older: an observational study

Chemotherapy for the treatment of maternal cancers during pregnancy has become more acceptable in the past decade; however, the effect of prenatal exposure to chemotherapy on cardiac and neurodevelopmental outcomes of the offspring is still uncertain. We aimed to record the general health, cardiac function, and neurodevelopmental outcomes of children who were prenatally exposed to chemotherapy. We did an interim analysis of a multicentre observational cohort study assessing children who were prenatally exposed to maternal cancer staging and treatment, including chemotherapy. We assessed children at birth, at age 18 months, and at age 5-6, 8-9, 11-12, 14-15, or 18 years. We did clinical neurological examinations, tests of the general level of cognitive functioning (Bayley or intelligence quotient [IQ] test), electrocardiography and echocardiography, and administered a questionnaire on general health and development. From age 5 years, we also did audiometry, the Auditory Verbal Learning Test, and subtasks of the Children's Memory Scale, and the Test of Everyday Attention for Children, and we also completed the Child Behavior Checklist. This study is registered with ClinicalTrials.gov, number NCT00330447. 236 cycles of chemotherapy were administered in 68 pregnancies. We assessed 70 children, born at a median gestational age of 35·7 weeks (range 28·3-41·0; IQR 3·3; 47 women at <37 weeks), with a median follow-up period of 22·3 months (range 16·8-211·6; IQR 54·9). Although neurocognitive outcomes were within normal ranges, cognitive development scores were lower for children who were born preterm than for those born at full term. When controlling for age, sex, and country, the score for IQ increased by an average 11·6 points (95% CI 6·0-17·1) for each additional month of gestation (p<0·0001). Our measurements of the children's behaviour, general health, hearing, and growth corresponded with those of the general population. Cardiac dimensions and functions were within normal ranges. We identified a severe neurodevelopmental delay in both members of one twin pregnancy. Fetal exposure to chemotherapy was not associated with increased CNS, cardiac or auditory morbidity, or with impairments to general health and growth compared with the general population. However, subtle changes in cardiac and neurocognitive measurements emphasise the need for longer follow-up. Prematurity was common and was associated with impaired cognitive development. Therefore, iatrogenic preterm delivery should be avoided when possible. Research Foundation-Flanders; Research Fund-K U Leuven; Agency for Innovation by Science and Technology; Stichting tegen Kanker; Clinical Research Fund-University Hospitals Leuven; and Belgian Cancer Plan, Ministery of Health.

Central Nervous System Infection by HIV-1: Special Emphasis to NeuroAIDS in India

Advent of combinatorial antiretroviral therapy has widely declined the number of HIV related deaths. It has however resulted in an increase in number of people living with HIV, and their morbidity in terms of their compromised brain functions, thereby worsening the overall scenario in the form of HIV associated neurocognitive impairment that are studied under the umbrella of neuroAIDS. Productively infected macrophages “hijack” brain parenchyma, resulting in slow neurodegeneration especially in the basal ganglia, hippocampus, prefrontal cortex and white matter. Although not directly infected, neurons undergo apoptosis via different pathways as discussed in the review. In addition, more devastating is the condition when HIV synergizes with drugs of abuse and brings in oxidative stress, elevation of inflammatory cytokines and increased calcium waves ultimately leading to augmented excitotoxicity. Mother to child transmission has been another important risk factor in the field of HIV rendering the neonates afflicted with severe neurodevelopmental delays and reduced immune response. Increase in several cytokines and other molecules have been promising in early diagnosis of the syndrome, but search for a biomarker is still on. In this review, we have outlined the recent developments in the field, practical challenges in neuroAIDS research and possible future directions that may help in better management of the disease.

Severe Hunter Syndrome (Mucopolysaccharidosis II) Phenotype Secondary to Large Deletion in the X Chromosome EncompassingIDS,FMR1, andAFF2(FMR2)

A 2-year-old boy with an initial diagnosis of Hunter syndrome (mucopolysaccharidosis II) had a more severe phenotype than expected, which warranted further evaluation. The patient had severe infantile global neurodevelopmental delays, macrocephaly with a prominent forehead, coarse facial features with clear corneas, chronic congestion with snoring, wide-spaced teeth, short thick neck, hepatomegaly, an inguinal hernia repaired, early clawhand deformities, and severe generalized hypotonia. X chromosome microarray revealed a large deletion encompassing the genes IDS, FMR1, and AFF2 (FMR2) confirming the diagnoses of both Hunter and fragile X syndromes. This case is also a reminder to clinicians that for optimum patient care, further diagnostic testing is warranted if there is concern that a patient's phenotype is more severe or complex than would be expected for the initial neurogenetic diagnosis.

Neurodevelopmental outcome in full‐term newborns with refractory neonatal seizures

This retrospective study describes the prognosis of full-term newborns with refractory neonatal seizures, comparing the need for treatment with two versus three or more antiepileptic drugs. We reviewed our database (January 2002-December 2007) to include newborns with refractory neonatal seizures and abnormal electroencephalogram. Group A consisted of 17 newborns with two antiepileptic drugs. Group B consisted of 29 newborns with three or more antiepileptic drugs. Outcome was determined at 2 years of age using the Dutch Bayley Scales of Infant Development or a neurodevelopmental classification scheme. Group A and group B were comparable regarding to a variety of demographic and aetiologic factors. Thirteen newborns died before 2 years of age and one was lost to follow-up. Normal development at 2 years of age was found in 50% and 5% for group A and B, respectively. Severe neurodevelopmental delay at 2 years of age was found in 30% and 68% for group A and B, respectively. The number of antiepileptic drugs probably reflects increased seizure burden and is--in that way--related to poor outcome. This may be useful information for early prediction of adverse neurological outcome in the first days of life.

Creatine deficiency syndromes and the importance of creatine synthesis in the brain

Creatine deficiency syndromes, due to deficiencies in AGAT, GAMT (creatine synthesis pathway) or SLC6A8 (creatine transporter), lead to complete absence or very strong decrease of creatine in CNS as measured by magnetic resonance spectroscopy. Brain is the main organ affected in creatine-deficient patients, who show severe neurodevelopmental delay and present neurological symptoms in early infancy. AGAT- and GAMT-deficient patients can be treated by oral creatine supplementation which improves their neurological status, while this treatment is inefficient on SLC6A8-deficient patients. While it has long been thought that most, if not all, of brain creatine was of peripheral origin, the past years have brought evidence that creatine can cross blood-brain barrier, however, only with poor efficiency, and that CNS must ensure parts of its creatine needs by its own endogenous synthesis. Moreover, we showed very recently that in many brain structures, including cortex and basal ganglia, AGAT and GAMT, while found in every brain cell types, are not co-expressed but are rather expressed in a dissociated way. This suggests that to allow creatine synthesis in these structures, guanidinoacetate must be transported from AGAT- to GAMT-expressing cells, most probably through SLC6A8. This new understanding of creatine metabolism and transport in CNS will not only allow a better comprehension of brain consequences of creatine deficiency syndromes, but will also contribute to better decipher creatine roles in CNS, not only in energy as ATP regeneration and buffering, but also in its recently suggested functions as neurotransmitter or osmolyte.

Malformations of cortical development: current concepts and advanced neuroimaging review

Malformations of cortical development (MCD) result from disruptions in the complex process of the human brain cortex formation and are highly associated to severe epilepsy, neurodevelopmental delay and motor dysfunction. Nowadays, magnetic resonance imaging (MRI) is the cornerstone of the work-up of patients with epilepsy and modern advanced imaging techniques have improved not only our ability to detect and characterize cortical malformations, but also in identifying associated functional abnormalities that are far beyond the structural visualized lesions. Herein, we address the most currently used classifications of MCD and make a concise review of the embryological process of cortical development. Our main goal is to summarize recent advances and new trends in diagnostic imaging techniques concerning MCD. Thereafter, follows a brief discussion of specific disorders and their radiological features.

Neurodevelopmental Outcome Following Congenital Cytomegalovirus Infection in Preterm Infants with Twin-to-Twin Transfusion Syndrome: A Case Report

Twin-to-twin transfusion syndrome and conital cytomegalovirus infection bear the risk of brain damage. In the 27th week of gestation of a twin pregnancy a Caesarean section was performed because of pathological cardiotocogram and Doppler ultrasonography of the second twin (recipient). Both infants presented with severe, persistent thrombocytopenia, elevated liver enzymes and direct hyperbilirubinemia. Primary congenital CMV infection was diagnosed. Both twins showed severe neuropathological symptoms, pathological aEEG with seizure activity and severe neurodevelopmental delay at corrected age of 12 months. The severity of brain pathology, the complex etiology, its consequence for neurotion with extreme prematurity make this case of special interest.

Partial atrioventricular septal defect in the fetus: diagnostic features and associations in a multicenter series of 30 cases

To assess the anatomical features and the associations of partial atrioventricular septal defect (pAVSD) in the fetus. This was a retrospective multicenter study of 30 cases of confirmed pAVSD seen since 1996 at two referral centers. The following variables were available for analysis in all cases: indications for fetal echocardiography, diagnostic features, associated cardiac, extracardiac and chromosomal anomalies and fetoneonatal outcome. At fetal echocardiography, the echocardiographic features deemed indicative of pAVSD were: 1) ostium primum atrial septal defect and 2) loss of the normal offset appearance of the atrioventricular valves. Eighteen of the 30 (60%) cases were diagnosed before 24 weeks of gestation and 12 were diagnosed later. Suspicion of congenital heart disease and known aneuploidy (trisomy 21) accounted for 60% of the referral indications. The two anatomical landmarks deemed indicative of pAVSD were detected in all cases at echocardiography. Twelve cases were isolated (one with increased nuchal transluceny at the 12-week scan, one with polyhydramnios, one with fetal growth restriction) including four that were detected on routine ultrasound examination by the authors. Additional cardiac anomalies were present in five (17%) cases, four of which involved aortic coarctation. There were associated chromosomal anomalies in 13 (43%); however, excluding the six cases referred because of known Down syndrome, the adjusted association rate with aneuploidy was 29.2% (7/24). Extracardiac anomalies, including non-chromosomal syndromes, were present in 10 cases (33.3%). Regarding fetoneonatal outcome, there were 13 terminations of pregnancy, one early neonatal death and 16 survivors, including four with mild to severe neurodevelopmental delay due to associated syndromic conditions. We describe the key echocardiographic features of pAVSD in the fetus. In addition, we have confirmed that the association with trisomy 21 holds also for pAVSD, though to a lesser extent, with a 12.5% association rate in this series. In the fetus, pAVSD seems to be associated with a high rate of chromosomal/non-chromosomal syndromic conditions, including skeletal dysplasias. Inutero, aortic coarctation represents the most frequently associated cardiac lesion (13.3%).

Early Systemic Hypotension and Vasopressor Support in Low Birth Weight Infants: Impact on Neurodevelopment

The duration and severity of systemic hypotension have been related with altered neurodevelopment. Cerebral circulation is pressure-passive in low birth weight infants with early systemic hypotension who receive cardiovascular support. The treatment of early systemic hypotension is controversial, because it has been associated with short-term and long-term morbidity in retrospective studies. However, there has been no prospective information on cardiovascular support for hypotension and morbidity. Our goal for this prospective study was to evaluate the effect on neurodevelopment resulting from the use of vasopressors/inotropes for early systemic hypotension. Low birth weight infants with early systemic hypotension (<24 hours of life; study group) were assigned randomly to receive dopamine (2.5-10 microg/kg per minute) or epinephrine (0.125-0.5 microg/kg per minute) in progressively larger doses until target blood pressure was attained (treatment-success subgroup). Hemodynamically stable patients who did not receive cardiovascular support were the control group. Outcome measures were serial cranial ultrasound up to 40 weeks, structured neurologic evaluation (every 3 months), and neurodevelopmental test at 2 to 3 years of age. One hundred thirty patients were included (study = 60; treatment success = 38; controls = 70). Study-group patients had lower birth weight, gestational age, and 5-minute Apgar score, higher rates of premature rupture of membranes, need for cardiorespiratory resuscitation at birth, and sickness shortly after birth than the control group. The patients in the study group also had significantly higher serum troponin I levels at birth. Initial cranial ultrasound findings did not differ between groups, but the final cranial ultrasounds revealed higher rates of severe periventricular hemorrhage in the study group and higher rates of normal cranial ultrasounds in the control group. Only the latter remained when the treatment-success subgroup and control group were compared. Multivariate analysis did not detect any association between final cranial ultrasounds and the use of vasopressors/inotropes. Sixteen infants died and 103 were followed up (90% survival rate). No differences between groups were found in the rates of abnormal neurologic status, developmental delay, or combined adverse outcome (death or cerebral palsy or severe neurodevelopmental delay). Cautious use of cardiovascular support to treat early systemic hypotension in low birth weight infants seems to be safe. The question of whether raising systemic blood pressure to within a normal range will improve outcome should be examined by using appropriate study designs.

Creatine synthesis and transport during rat embryogenesis: spatiotemporal expression of AGAT, GAMT and CT1.

BackgroundCreatine (Cr) is synthesized by a two-step mechanism involving arginine:glycine amidinotransferase (AGAT) and guanidinoacetate methyltransferase (GAMT), and is taken up by cells through a specific Cr transporter, CT1. Recently, genetic defects of this pathway have been described, that lead to Cr deficiency, neurological symptoms in early infancy and severe neurodevelopmental delay. To investigate the involvement of Cr synthesis and uptake pathways during embryonic development, we determined the spatiotemporal expression of AGAT, GAMT and CT1 during the rat embryogenesis, at the mRNA and protein level.ResultsWe show that AGAT and GAMT are expressed in hepatic primordium as soon as 12.5 days, then progressively acquire their adult pattern of expression, with high levels of AGAT in kidney and pancreas, and high levels of GAMT in liver and pancreas. AGAT and CT1 are prominent in CNS, skeletal muscles and intestine, where they appear earlier than GAMT. High levels of CT1 are found in epithelia.ConclusionOur results suggest that de novo synthesis of Cr by AGAT and GAMT, as well as cellular Cr uptake by CT1, are essential during embryonic development. This work provides new clues on how creatine can be provided to developing tissues, and suggests that Cr deficiencies might induce irreversible damages already in utero, particularly on the nervous system.

OC125: Ultrasound dating at 12–14 weeks of gestation. Which dating formula is best?

Objective: To evaluate the incidence, risk factors and consequences of intrauterine death of one twin, in TTTS treated by laser. Methods: All pregnancies with TTTS treated by laser coagulation of chorionic anastomoses between 1999 and 2004 with IUFD of one twin not related to PROM or preterm delivery were analysed. Staging of the disease, estimated fetal weight, fetal Doppler, placental insertion, interval from procedure to IUFD, surgical complications, intrauterine transfusions and neonatal outcomes were reviewed. Results: 120 cases of TTTS were treated by laser between 1999 and 2004. IUFD of one twin occurred in 45 cases (33%) 8 hours to 85 days after the procedure. These were 29 donors and 21 recipients. This occurred within 24 hours of the procedure in 60% of the cases and within a week in 75%. The second twin also died in utero in 5 cases (11%) within 24 hours following the death of the first twin. 17 of the 22 (77%) donors that died had severe IUGR and 14 of the 45 fetuses (31%) that died had abnormal ductus venosus and/or umbilical artery Doppler. Late miscarriage occurred in 2 cases (5%) within 2 weeks. Brain lesions developed in 2 survivors and termination of pregnancy was carried out. The surviving twin was anaemic and intrauterine transfusion was given in 5 cases within 24 hours of the death of one twin. There were 2 neonatal deaths. 2 babies had severe and moderate neurodevelopmental delay at 36 months and at 1 year of life respectively. 32 of 36 liveborn babies are neurologically normal at 1 to 44 months of life. Conclusion: IUFD of one or both twins occurred in 45 of 120 cases of severe TTTS treated by laser at a mean gestation of 20 weeks and 5 days. The prognosis of the co-twin was poor in 8/40 (20%) of the cases. Separation of the 2 placental circulations was incomplete in at least 10 cases (25%) where the co-twin either died, developed in utero cerebral lesions or was anaemic following the death of its co-twin.

OC124: Intrauterine fetal demise (IUFD) following laser treatment in twin to twin transfusion syndrome (TTTS)

To evaluate the incidence, risk factors and consequences of intrauterine death of one twin, in TTTS treated by laser. All pregnancies with TTTS treated by laser coagulation of chorionic anastomoses between 1999 and 2004 with IUFD of one twin not related to PROM or preterm delivery were analysed. Staging of the disease, estimated fetal weight, fetal Doppler, placental insertion, interval from procedure to IUFD, surgical complications, intrauterine transfusions and neonatal outcomes were reviewed. 120 cases of TTTS were treated by laser between 1999 and 2004. IUFD of one twin occurred in 45 cases (33%) 8 hours to 85 days after the procedure. These were 29 donors and 21 recipients. This occurred within 24 hours of the procedure in 60% of the cases and within a week in 75%. The second twin also died in utero in 5 cases (11%) within 24 hours following the death of the first twin. 17 of the 22 (77%) donors that died had severe IUGR and 14 of the 45 fetuses (31%) that died had abnormal ductus venosus and/or umbilical artery Doppler. Late miscarriage occurred in 2 cases (5%) within 2 weeks. Brain lesions developed in 2 survivors and termination of pregnancy was carried out. The surviving twin was anaemic and intrauterine transfusion was given in 5 cases within 24 hours of the death of one twin. There were 2 neonatal deaths. 2 babies had severe and moderate neurodevelopmental delay at 36 months and at 1 year of life respectively. 32 of 36 liveborn babies are neurologically normal at 1 to 44 months of life. IUFD of one or both twins occurred in 45 of 120 cases of severe TTTS treated by laser at a mean gestation of 20 weeks and 5 days. The prognosis of the co-twin was poor in 8/40 (20%) of the cases. Separation of the 2 placental circulations was incomplete in at least 10 cases (25%) where the co-twin either died, developed in utero cerebral lesions or was anaemic following the death of its co-twin.

Necrotizing enterocolitis and neurodevelopmental outcome in extremely low birth weight infants

To determine the growth and neurodevelopmental outcome, as well as predictors of the latter in extremely low-birth-weight (ELBW) infants with definitive necrotizing enterocolitis (NEC). Case - control analysis. In all, 17 ELBW infants <1000 g with Stage 2 or 3 NEC were matched to 51 control infants without NEC. Demographics, clinical course, growth, and neurodevelopmental outcome were compared. Demographic and clinical characteristics of both groups were similar except that NEC infants had more culture-proven sepsis (59 vs 24%, p=0.02), longer intubation (36 vs 16 days, p=0.003) and longer hospital stay (134 vs 86 days, p<0.001). At 18 to 22 months corrected age BSID-II mental scores (MDI) were similar between groups (74+/-14 vs 81+/-13, p=0.2). However, the psychomotor index (PDI) (66+/-18 vs 88+/-14), the proportion with abnormal neurologic examination (54 vs 9%), subnormal height (38 vs 3%) and head circumference (23 vs 0%) were significantly higher in NEC infants (p<0.05). A logistic model identified NEC and chronic lung disease as predictors for abnormal PDI and MDI, respectively. NEC and its comorbidities are associated with severe neurodevelopmental and growth delay in ELBW infants.

Prader-Willi syndrome with an unusually large 15q deletion due to an unbalanced translocation t(4;15)

Prader-Willi syndrome (PWS) is a neurobehavioral disorder caused by deletions in the 15q11-q13 region, by maternal uniparental disomy of chromosome 15 or by imprinting defects. Structural rearrangements of chromosome 15 have been described in about 5% of the patients with typical or atypical PWS phenotype. An 8-year-old boy with a clinical diagnosis of PWS, severe neurodevelopmental delay, absence of speech and mental retardation was studied by cytogenetic and molecular techniques, and an unbalanced de novo karyotype 45,XY,der(4)t(4;15)(q35;q14),-15 was detected after GTG-banding. The patient was diagnosed by SNURF-SNRPN exon 1 methylation assay, and the extent of the deletions on chromosomes 4 and 15 was investigated by microsatellite analysis of markers located in 4qter and 15q13-q14 regions. The deletion of chromosome 4q was distal to D4S1652, and that of chromosome 15 was located between D15S1043 and D15S1010. Our patient’s severely affected phenotype could be due to the extent of the deletion, larger than usually seen in PWS patients, although the unbalance of the derivative chromosome 4 cannot be ruled out as another possible cause. The breakpoint was located in the subtelomeric region, very close to the telomere, a region that has been described as having the lowest gene concentrations in the human genome.

Neurological Presentation in Pediatric Patients with Congenital Disorders of Glycosylation Type Ia

Congenital disorders of glycosylation (CDG), formerly called carbohydrate-deficient glycoprotein syndromes, constitute a newly identified group of multisystem disorders characterized by defective glycosylation of N-glycosylated proteins. The objective of this work was to describe precisely neurological findings in patients with type Ia CDG (CDG-Ia) and to compare our results with the literature. We retrospectively reviewed neurological and neurodevelopmental, neuroimaging, and genetic features in ten patients with CDG-Ia who mainly presented with neurological abnormalities during childhood and therefore were referred to a neuropediatrician or a neurogeneticist. Neurological manifestations had a static clinical course, dominated by mental retardation and cerebellar dysfunction, and acute episodes: stroke-like episodes and seizures. However, microcephaly, retinopathy, and polyneuropathy were progressive. All patients had severe global neurodevelopmental delay: only one was able to walk alone at ten years of age and only one could read. Marked heterogeneity in manifestations and delay of diagnosis was noted across the patients. Cerebellar hypoplasia was found by magnetic resonance imaging in all ten patients and olivopontocerebellar hypoplasia in four patients. As in the literature, there was no clear phenotype-mutation correlation. Our findings confirm the importance of a precise and complete description of the neurological and neuroradiological phenotype delineating the phenotype of CDG-Ia to increase the likelihood of diagnosing the disease.

Relationship between encephalopathy and abnormal neuronal activity in the developing brain

Infantile spasms represent a unique age-specific epileptic syndrome that is often associated with a focal or diffuse encephalopathy and can result in severe neurodevelopmental delay and retardation. The behavioral and electroencephalogram (EEG) phenotype of infantile spasms is similar, despite its association with multiple neurological disease states. The stereotypy suggests that the spasms originate from a highly age-specific hyperexcitable network. Treatment strategies for infantile spasms remain largely empirical due to the lack of understanding of the underlying neurochemistry and circuitry. This chapter reviews experimental evidence for the presence of unique developmental factors that appear to promote hyperexcitability in the immature brain and that may play a role in the generation of infantile spasms. In addition, this chapter evaluates the potential interplay between an associated developmental encephalopathy and enhanced neuronal hyperexcitability in infantile spasms.