Virginia Wong

Absence of a Paternally Inherited FOXP2 Gene in Developmental Verbal Dyspraxia

Mutations in FOXP2 cause developmental verbal dyspraxia (DVD), but only a few cases have been described. We characterize 13 patients with DVD--5 with hemizygous paternal deletions spanning the FOXP2 gene, 1 with a translocation interrupting FOXP2, and the remaining 7 with maternal uniparental disomy of chromosome 7 (UPD7), who were also given a diagnosis of Silver-Russell Syndrome (SRS). Of these individuals with DVD, all 12 for whom parental DNA was available showed absence of a paternal copy of FOXP2. Five other individuals with deletions of paternally inherited FOXP2 but with incomplete clinical information or phenotypes too complex to properly assess are also described. Four of the patients with DVD also meet criteria for autism spectrum disorder. Individuals with paternal UPD7 or with partial maternal UPD7 or deletion starting downstream of FOXP2 do not have DVD. Using quantitative real-time polymerase chain reaction, we show the maternally inherited FOXP2 to be comparatively underexpressed. Our results indicate that absence of paternal FOXP2 is the cause of DVD in patients with SRS with maternal UPD7. The data also point to a role for differential parent-of-origin expression of FOXP2 in human speech development.

Spectrum of mutations in the MECP2 gene in patients with infantile autism and Rett syndrome

Editor—Rett syndrome (RTT, MIM 312750) is a progressive neurological disorder, occurring almost exclusively in females during their first two years of life . RTT is one of the most common causes of mental retardation in females, with an incidence of 1 in 10 000-15 000 female births. Patients with classical RTT appear to develop normally until 6-18 months of age, then gradually lose speech and purposeful hand use, and, eventually, develop microcephaly, seizures, autism, ataxia, hyperventilation, and stereotypic hand movements. After the initial regression, the clinical condition stabilises and patients usually survive into adulthood. Laboratory investigations have not shown any metabolic abnormalities in affected subjects.1 RTT is included in the differential diagnosis of autistic disorder in girls.1-3 Qualitative abnormalities in social and communicative development and stereotypic behaviour are typically present in RTT. Definitive diagnosis is often delayed until after the loss of purposeful hand movements and the relatively characteristic hyperventilation later in childhood,1 and earlier diagnosis would be desirable. The occurrence of a few familial cases with maternal inheritance suggests that RTT is an X linked dominant mutation with lethality in hemizygous males. Previous exclusion mapping studies using RTT families identified a locus in Xq28.4-6 Using a systematic gene screening approach, Amir et al 7and Wan et al 8 have identified mutations in the MECP2 gene, which encodes methyl-CpG binding protein 2, as the cause of some RTT cases. Most of the mutations are de novo and occur at a CpG dinucleotide. The cytosine in the CpG dinucleotide is a frequent site for DNA methylation and deamination of methylated cytosine to thymine causes the transition. The MeCP2 protein silences methylated chromatin by recruiting a histone deacetylase complex.9 Unlike most other transcriptional repressor proteins, however, the binding site of MeCP2 occurs frequently in genomic DNA …

Paroxysmal extreme pain disorder (previously familial rectal pain syndrome)

Objective: To describe the clinical phenotype of paroxysmal extreme pain disorder (previously called familial rectal pain syndrome), an autosomal dominant condition recently shown to be a sodium channelopathy involving SCN9A. Methods: An international consortium of clinicians, scientists, and affected families was formed. Clinical details of all accessible families worldwide were collected, including age at onset, features of attacks, problems between attacks, investigational results, treatments tried, and evolution over time. A validated pain questionnaire was completed by 14 affected individuals. Results: Seventy-seven individuals from 15 families were identified. The onset of the disorder is in the neonatal period or infancy and persists throughout life. Autonomic manifestations predominate initially, with skin flushing in all and harlequin color change and tonic attacks in most. Dramatic syncopes with bradycardia and sometimes asystole are common. Later, the disorder is characterized by attacks of excruciating deep burning pain often in the rectal, ocular, or jaw areas, but also diffuse. Attacks are triggered by factors such as defecation, cold wind, eating, and emotion. Carbamazepine is effective in almost all who try it, but the response is often incomplete. Conclusions: Paroxysmal extreme pain disorder is a highly distinctive sodium channelopathy with incompletely carbamazepine-sensitive bouts of pain and sympathetic nervous system dysfunction. It is most likely to be misdiagnosed as epilepsy and, particularly in infancy, as hyperekplexia and reflex anoxic seizures.

Epidemiological Study of Autism Spectrum Disorder in China

The object of this study was to investigate the epidemiologic pattern of autism spectrum disorder in Chinese children. An autism spectrum disorder registry has been established in Hong Kong since 1986 by collecting data in a single center (the only university-affiliated child assessment center in Hong Kong). Since 1997, inpatient data from all public hospitals under the Hospital Authority have been stored in a central computerized program and retrieved from the Clinical Data Analysis and Reporting System. Clinical data have also been retrieved through the Clinical Data Analysis and Reporting System to ensure the completion of the registry, and these suspected cases have undergone the same diagnostic evaluation for autism spectrum disorder, as some of the new autism cases might be hospitalized in the public hospital. The incidence and prevalence of autism spectrum disorder have been calculated for the period of 1986 to 2005 using the population statistics available in the government for children less than 15 years old in Hong Kong. This study has included 4 247 206 person-years from 1986 to 2005 for children less than 15 years old and 1 174 322 person-years for those less than 5 years old in Hong Kong. Altogether, 645 children 0 to 4 years old with diagnoses of autism spectrum disorder were identified from 1986 to 2005. The estimated incidence of autism spectrum disorder was 5.49 per 10 000. The prevalence was 16.1 per 10 000 for children less than 15 years old for the same period. The male to female ratio was 6.58:1. This is the first reported epidemiologic study of autism spectrum disorder in Chinese children. The incidence rate is similar to those reported in Australia and North America and is lower than Europeans.

Spinal Muscular Atrophy: Survival Pattern and Functional Status

Objective. Spinal muscular atrophy (SMA) is common. The prevalence of SMA in southern Chinese is 1 in 53 000. The clinical course is variable. The traditional classification of SMA includes age of onset, age of death, achievement of motor milestones, and ambulatory status as criteria. There was a lack of inclusion of the best lifetime functional status of any child with SMA. With the advances in medical care, the life expectancy and ambulatory status of patients with SMA have improved. The objective of this study was to assess the survival pattern, ambulatory status, and functional status of children with SMA. Methods. Patients with SMA were recruited from the neuromuscular clinic of the Duchess of Kent Childrens Hospital, which is a university-affiliated hospital, and the Families of SMA in Hong Kong. By September 2002, 102 SMA cases had been registered in the Duchess of Kent Childrens Hospital neuromuscular clinic and Families of SMA registry, and 83 patients were analyzed. Among them, 39 were recruited for the administration of Functional Independence Measure for Children (WeeFIM), an assessment tool for functional status that has been previously validated by us for Chinese children. The diagnosis of SMA was made from clinical history, serum muscle enzyme, electromyography, muscle biopsy, and, recently, by molecular studies. In Hong Kong, molecular tests of the survivor motor neuron gene was available since 1995. A total of 36 in our cohort of 83 patients had the diagnosis confirmed with molecular analyses. We adopted the classification of SMA from previous studies in which the criteria were based on the International SMA consortium (1992) with modifications according to the 59th European Neuromuscular Center International Workshops. As only SMA patients with childhood onset were studied, we did not include any type IV patients in our study. Parents were interviewed and records were reviewed for demographic and clinical data, including age of onset, gender, family history, motor milestones, disease progression, loss of motor function, and involvement of respiratory or bulbar muscles. We define the age of disease onset as the age in which the first abnormalities were obvious from the medical records or from the descriptions of the parents about the first signs of weakness, eg, age of achievement of certain motor milestones or loss of functions. For the ambulatory status, we define “being ambulatory” as having the ability to walk for 100 meters, either with assistance such as calipers or walkers or without assistance. Actuarial survival curves were obtained by using the Kaplan-Meier method for calculating survival probabilities and probabilities of remaining ambulatory. The parents or the chief caregivers were interviewed for functional status using WeeFIM at the last registered date in September 2002. The WeeFIM consists of 3 domains: 1) self-care, 2) mobility, and 3) cognition. The self-care domain consists of 8 items, namely eating, grooming, bathing, dressing (upper body), dressing (lower body), toileting, and bladder and bowel management. The mobility domain consists of 5 items: transfer from chair or wheelchair, transfer to toilet, transfer to tub or shower, walking/wheelchair/crawling distance, and moving up and down stairs. The cognition domain assesses comprehension, expression, social interaction, problem solving, and memory. A scoring scale from 1 to 7 was used (1 = total assistance, 2 = maximal assistance, 3 = moderate assistance, 4 = minimal contact assistance, 5 = supervision, 6 = modified independence, and 7 = complete independence). The maximum total WeeFIM score is 126, and the maximum score for self-care, mobility, and cognition are 56, 35, and 35, respectively. Results. For type I SMA (n = 22), the survival probabilities at 1, 2, 4, 10, and 20 years were 50%, 40%, 30%, 30%, and 30%, respectively. For type II SMA (n = 26), the survival probabilities at 1, 2, 4, 10, and 20 years were 100%, 100%, 100%, 92%, and 92%, respectively. Sixteen of the SMA I patients and 4 of the SMA II patients died of cardiorespiratory failure. The 5 surviving SMA I patients all were ventilator dependent. All SMA III patients were surviving at the time of study. The probability of remaining ambulatory at 2, 4, 10, and 20 years after onset was 100%, 100%, 81%, and 50% for type IIIa (age of onset <3 years) and 100%, 100%, 84%, and 68% for type IIIb (age of onset between 3 and 30 years), respectively. The interval between disease onset and inability to walk was 15.0 ± 10.9 years (mean ± standard deviation) and 21.2 ± 11.7 years for patients with SMA IIIa and IIIb, respectively. Only 39 patients participated in the WeeFIM interview as 20 had already died at the time of study and 24 refused participation. No difference could be found in the age of onset, gender, or types of SMA between those who participated (n = 39) and those who did not (n = 24). The mean total WeeFIM quotients were 24% for SMA type 1, 57% for SMA type 11, 75% for SMA type IIIa, and 78% for SMA type IIIb. For the self-care domain, 100% SMA type I and 73% SMA type II patients required assistance, whereas 55% and 63% of SMA types IIIa and IIIb patients achieved functional independence. Bathing and dressing (upper and lower body) were items with which most SMA children required help or supervision. For the mobility domain, assistance was needed in >90% of SMA types I, II, and IIIa and in 63% of SMA type IIIb patients. Stair management was the major obstacle for independence in achieving mobility for all types of SMA. For the cognition domain, performance was the best among the 3 domains, and 60% of SMA type II, 78% of SMA type IIIa, and 90% of SMA type IIIb patients achieved functional independence. However, except for SMA type IIIb, a significant proportion of patients still need assistance or supervision in the area of problem solving. Statistically significant differences were found in the WeeFIM scores between type I and type II and between type IIIa and IIIb patients. However, no significant difference could be observed between type II and type IIIa SMA patients in the overall WeeFIM scores or performance in any of the 3 domains. Conclusion. We found that there was improvement in survival in SMA patients as compared with other studies. Assistance or supervision was needed for the majority of SMA patients for both mobility and self-care domains. With improvement in survival as a result of medical advances, assessment of the most current or the best-ever functional status at a designated age might be an important criterion for classification of SMA.

Mercury Exposure in Children With Autistic Spectrum Disorder: Case-Control Study

Although mercury has been proven to be a neurotoxicant, there is a lack of data to evaluate the causal relationship between mercury and autism. We aim to see if there is increased mercury exposure in children with autistic spectrum disorder. We performed a cross-sectional cohort study over a 5-month period in 2000 to compare the hair and blood mercury levels of children with autistic spectrum disorder (n = 82; mean age 7.2 years) and a control group of normal children (n = 55; mean age 7.8 years). There was no difference in the mean mercury levels. The mean blood mercury levels of the autistic and control groups were 19.53 and 17.68 nmol/L, respectively (P = .15), and the mean hair mercury levels of the autistic and control groups were 2.26 and 2.07 ppm, respectively (P = .79). Thus, the results from our cohort study with similar environmental mercury exposure indicate that there is no causal relationship between mercury as an environmental neurotoxin and autism. (J Child Neurol 2004;19:431-434).

Association between ABCB1 C3435T polymorphism and drug-resistant epilepsy in Han Chinese.

There is accumulating evidence to suggest that overexpression of efflux drug transporters at the blood-brain barrier, by reducing antiepileptic drug (AED) accumulation in the seizure foci, contributes to drug resistance in epilepsy. P-glycoprotein, encoded by the ABCB1 gene, is the most studied drug transporter. There are conflicting data as to whether the CC genotype of the ABCB1 3435C>T polymorphism is associated with drug resistance in Caucasian patients with epilepsy. We investigated this association in ethnic Chinese. ABCB1 3435C>T was genotyped in 746 Han Chinese patients with epilepsy and 179 controls. Patients with drug-resistant epilepsy were more likely to have the TT genotype compared with those with drug-responsive epilepsy (16.7% vs 7.4%, odds ratio=2.5, 95% confidence interval=1.4-4.6, P=0.0009). Our results contrast with those of studies of Caucasians, and highlight the complexity of the possible role of this polymorphism in AED response in different ethnic populations.

Epilepsy in Children With Autistic Spectrum Disorder

A prospective study looking at the prevalence of epilepsy in 246 children with autistic spectrum disorder revealed that 7.6% of children satisfying the criteria of infantile autism and 5% of those with an autistic condition had epilepsy. The majority had onset of seizures before the age of 1 year. Boys predominated in both groups. There was no correlation between the age of onset of seizures, type of seizure, sex, mentality, and the outcome of epilepsy. There is an increased risk of epilepsy in autistic children compared to those with developmental dysphasia or Down syndrome. There might be some underlying defect of the brain in autistic children that causes different degrees of autistic manifestation with which epilepsy is associated, as part of the spectrum complex. (J Child Neurol 1993;8:316-322).

Summary of recommendations for the management of infantile seizures: Task Force Report for the ILAE Commission of Pediatrics

Evidence‐based guidelines, or recommendations, for the management of infants with seizures are lacking. A Task Force of the Commission of Pediatrics developed a consensus document addressing diagnostic markers, management interventions, and outcome measures for infants with seizures. Levels of evidence to support recommendations and statements were assessed using the American Academy of Neurology Guidelines and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. The report contains recommendations for different levels of care, noting which would be regarded as standard care, compared to optimal care, or “state of the art” interventions. The incidence of epilepsy in the infantile period is the highest of all age groups (strong evidence), with epileptic spasms the largest single subgroup and, in the first 2 years of life, febrile seizures are the most commonly occurring seizures. Acute intervention at the time of a febrile seizure does not alter the risk for subsequent epilepsy (class 1 evidence). The use of antipyretic agents does not alter the recurrence rate (class 1 evidence), and there is no evidence to support initiation of regular antiepileptic drugs for simple febrile seizures (class 1 evidence). Infants with abnormal movements whose routine electroencephalography (EEG) study is not diagnostic, would benefit from video‐EEG analysis, or home video to capture events (expert opinion, level U recommendation). Neuroimaging is recommended at all levels of care for infants presenting with epilepsy, with magnetic resonance imaging (MRI) recommended as the standard investigation at tertiary level (level A recommendation). Genetic screening should not be undertaken at primary or secondary level care (expert opinion). Standard care should permit genetic counseling by trained personal at all levels of care (expert opinion). Genetic evaluation for Dravet syndrome, and other infantile‐onset epileptic encephalopathies, should be available in tertiary care (weak evidence, level C recommendation). Patients should be referred from primary or secondary to tertiary level care after failure of one antiepileptic drug (standard care) and optimal care equates to referral of all infants after presentation with a seizure (expert opinion, level U evidence). Infants with recurrent seizures warrant urgent assessment for initiation of antiepileptic drugs (expert opinion, level U recommendation). Infantile encephalopathies should have rapid introduction and increment of antiepileptic drug dosage (expert opinion, level U recommendation). There is no high level evidence to support any particular current agents for use in infants with seizures. For focal seizures, levetiracetam is effective (strong evidence); for generalized seizures, weak evidence supports levetiracetam, valproate, lamotrigine, topiramate, and clobazam; for Dravet syndrome, strong evidence supports that stiripentol is effective (in combination with valproate and clobazam), whereas weak evidence supports that topiramate, zonisamide, valproate, bromide, and the ketogenic diet are possibly effective; and for Ohtahara syndrome, there is weak evidence that most antiepileptic drugs are poorly effective. For epileptic spasms, clinical suspicion remains central to the diagnosis and is supported by EEG, which ideally is prolonged (level C recommendation). Adrenocorticotropic hormone (ACTH) is preferred for short‐term control of epileptic spasms (level B recommendation), oral steroids are probably effective in short‐term control of spasms (level C recommendation), and a shorter interval from the onset of spasms to treatment initiation may improve long‐term neurodevelopmental outcome (level C recommendation). The ketogenic diet is the treatment of choice for epilepsy related to glucose transporter 1 deficiency syndrome and pyruvate dehydrogenase deficiency (expert opinion, level U recommendation). The identification of patients as potential candidates for epilepsy surgery should be part of standard practice at primary and secondary level care. Tertiary care facilities with experience in epilepsy surgery should undertake the screening for epilepsy surgical candidates (level U recommendation). There is insufficient evidence to conclude if there is benefit from vagus nerve stimulation (level U recommendation). The key recommendations are summarized into an executive summary. The full report is available as Supporting Information. This report provides a comprehensive foundation of an approach to infants with seizures, while identifying where there are inadequate data to support recommended practice, and where further data collection is needed to address these deficits.

Brainstem Auditory Evoked Potential Study in Children with Autistic Disorder.

Brainstem auditory evoked potentials were compared in 109 children with infantile autism, 38 with autistic condition, 19 with mental retardation, and 20 normal children. Children with infantile autism or autistic condition had significantly longer brainstem transmission time than normal (p<.001). Autistic features, rather than age, sex, or lower mentality, correlated with brainstem transmission time (p<.0001). The autistic characteristics may be related to dysfunction of the brainstem which affects the processing of the sensory input through the auditory pathway. The brainstem lesion may be part of a generalized process of neurological damage that accounts for the deviant language, cognitive, and social development in the spectrum of autistic disorder.