Clinical and molecular characterization of an extended family with Fabry disease.

OBJECTIVE: To characterize clinical manifestations, biochemical changes, mutation of alpha-Galactosidase (alpha-Gal A) gene A (GLA), and functional capability of mutant protein. MATERIAL AND METHOD: Seventeen subjects from a family with a newly diagnosed patient with Fabry disease were enrolled in the present study. In each individual, clinical history, physical examination, leukocyte enzyme activity of alpha-Gal A, and mutation analysis were performed. Those with a mutation were further investigated by ophthalmological and audiological evaluations, electrocardiography, echocardiogram, urinalysis, and blood tests to determine renal insufficiency. Expression study of the mutant protein was performed using a Pichia pastoris expression system. RESULTS: Four affected males and five symptomatic female carriers were identified. Clinical manifestations included severe neuropathic pain, acroparesthesia, hypo-/hyper-hidrosis, frequent syncope, ischemic stroke, cardiac hypertrophy, corneal dystrophy and cart-wheel cataract, high frequency sensorineural hearing loss, periorbital edema and subcutaneous edema over hands and interphalangeal joints. None had angiokeratoma or renal symptoms. The authors identified a novel mutation, p.L106R, in the GLA gene. Recombinant expression of the mutant protein gave little or no enzyme activity compared to the normal protein. CONCLUSION: There were intrafamilial clinical variabilities, but consistent findings of the absence of angiokeratoma and renal symptoms, which could represent a unique feature of this particular mutation.

Convulsive status epilepticus in Thai children at Ramathibodi Hospital.

BACKGROUND: Convulsive Status Epilepticus (SE) is an emergency neurological condition with high morbidity and mortality. The outcome of this condition in children depends on the etiology and the duration of convulsion. There is no report of this condition in Thai children. OBJECTIVE: To study the etiology, clinical course and outcome in children with convulsive SE in a referral hospital in Thailand. MATERIAL AND METHOD: The medical records of infants and children aged between one month and 15 years with the diagnosis of SE who were admitted to the Department of Pediatrics, Ramathibodi Hospital, Bangkok from January 1st, 1981 to December 31st, 2000 were retrospectively reviewed. The demographic data, types of seizure, duration of seizure, underlying diseases, precipitating factors, laboratory results, treatment, clinical course and outcomes were collected for descriptive analysis. RESULTS: Thirty-two patients (15 boys, 17 girls) whose ages ranged from 2 months to 14.4 years (mean 6.5 years) were included Twenty-four patients had underlying epilepsy. Twelve patients had prior diagnosis of symptomatic and idiopathic/cryptogenic epilepsy. Seven patients had acute insults to the central nervous system leading to SE. One patient with acute lymphoblastic leukemia presented with SE without association to either the underlying disease or the treatment. Fever with or without specific infection was the most common precipitating factor observed in these patients. The mean duration of SE was 64.4 minutes. The mean duration from initiation of treatment to the cessation of seizure was 41.4 minutes. Twelve patients were lost to follow up. Of the two patients who died, one had severe infection and the other had renal failure. Twelve patients had severe neurological deficits and six had mild neurological deficits. Among the thirteen patients who had > or = 1 hour of convulsion, eleven had severe neurological deficits or died. CONCLUSION: Infantile SE occurred more frequently in children with pre-existing epilepsy or neurological disorder Acute febrile illness and infection were the most common precipitating causes in the present study. Early recognition and treatment of fever and infection in conjunction with prompt and appropriate termination of seizure in epileptic children may prevent the occurrence of SE and its morbidity.

Flunarizine for prophylactic treatment of childhood migraine.

OBJECTIVE: To determine the effectiveness of flunarizine for migraine prophylaxis in children. PATIENTS AND METHOD: Children aged between 7 and 15 years who had the indication for prophylactic treatment of migraine were recruited into a prospective study at the Department of Pediatrics, Ramathibodi Hospital, from January 1st to December 31st 1999. After verbal consent was obtained, flunarizine was administered either at 5-mg daily in those who had never received it or at 10-mg daily in those who previously took this drug within one year Serial evaluation for the severity of migraine including duration, intensity, and frequency of headache attacks was performed every 2 weeks for 6 months. RESULTS: Twenty-one children (10 boys, 11 girls) with a mean age of 11.3+/-2.48 years (range 7-15 years) were enrolled in the study. There were ten children who had migraine with aura. Initially, 5-mg daily and 10-mg daily of flunarizine were administered in 19 and 2 patients respectively. The dosage was increased to 10-mg daily after two weeks in 5 patients because of the unresponsiveness to the initial dose. Improvement was observed in 14 patients (66%) including 13 of 14 patients who received 5-mg daily and 1 of 7 patients who received 10 mg daily. Five patients (23%) had no recurrent attack. Nine patients (42%) had more than 50%-reduction of frequency of migraine and 3 of these had either shorter duration or less intensity of the attack. Clinical improvement was observed between 2 and 4 weeks after initiation of treatment. There was no adverse effect observed CONCLUSION: This is a preliminary result demonstrating that flunarizine is one of the effective drugs for migraine prophylaxis in children.

Magnetic resonance imaging of the brain in epileptic pediatric patients: review of the experience in Ramathibodi Hospital.

OBJECTIVE: To review a series of epileptic children referred for MR imaging and correlate the structural abnormalities from the MRI findings with clinical data and EEG. MATERIAL AND METHOD: Retrospective review of MRI of the brain performed in children, aged less than 15 years with epilepsy at Ramathibodi Hospital from January 1999 to December 2002 was done. There were 100 children (57 girls, 43 boys) with epilepsy, age range from one month to 14 years, mean 7 years and 5 months. Diagnosis of seizure type and epilepsy were classified according to clinical presentation and EEG. RESULTS: There were 16 children with primary generalized seizure, 79 children with partial or complex partial seizures with or without secondary generalization. The remaining 5 children had a specific syndrome. The most common etiology of all patients was congenital disease, especially cortical dysplasia. Among children with partial with or without generalization, cortical dysplasia was the most common finding (31%). Mesial temporal sclerosis and combined cortical dysplasia with mesial temporal sclerosis were found in 24% and 13.9%, respectively. Most of the disease categories showed significant concordance of the EEG to the MRI findings, except infectious disease. CONCLUSION: The most common etiology of epilepsy in children under 15 years old was cortical dysplasia. For children with partial or complex partial seizure, cortical dysplasia was the most common etiology followed by mesial temporal sclerosis and combined cortical dysplasia with mesial temporal sclerosis, respectively. MRI provides precise etiologic classifications of epilepsy.

Nonketotic hyperglycinemia in two siblings with neonatal seizures.

Seizures are a common problem in neonates. Differential diagnoses include infection, trauma, hypoxia and congenital metabolic disorders. Among these, congenital metabolic disorder is less familiar to general pediatricians. We report two patients with nonketotic hyperglycinemia (NKH), a rare and lethal congenital metabolic disease. Transient hyperammonemia and transient hypouricemia, uncommon features found in NKH, were detected in one patient. High doses of sodium benzoate and dextromethorphan failed to modify the clinical course. Neuropathology denoted characteristic diffuse vacuolization and changes in reactive and gliotic astrocytes. The clinical course, biochemical findings, diagnostic approaches and diagnostic tests are discussed in detail. Recent modalities of treatment are reviewed. Because of its rarity and rapidly progressive course, it maybe underdiagnosed resulting in death before being recognized. Awareness of the possibility of congenital metabolic disorder in early neonatal catastrophe will increase the diagnostic rate.

Isolated lissencephaly sequence with contiguous gene deletion detected by FISH analysis: a case report.

BACKGROUND: Lissencephaly is a clinically and genetically heterogeneous malformation of the brain, usually leading to a severe disabling condition and seizures. The recent discovery of molecular techniques and identification of lissencephaly genes (e.g. LISI and DCX) has allowed etiologic diagnosis of this disorder feasible. OBJECTIVE: To describe a patient with lissencephaly in whom fluorescence in situ hybridization (FISH) determined etiologic diagnosis, providing precise genetic counseling and possible prenatal diagnosis for the family. CLINICAL REPORT AND STUDY RESULTS: The authors report a 4 month-old girl who presented with intractable, generalized myoclonic seizures at I month of age. The patient was born at 37 weeks' gestation, to a G4P1A2 36-year-old woman. Chromosome analysis from amniotic fluid performed for advanced maternal age revealed normal karyotype. Pregnancy was complicated by polyhydramnios. Computed tomographic scan of the brain at age one month showed a total absence of gyral formation. FISH of the metaphase chromosome from the patient, using Smith-Magenis and Miller-Dieker/ILS probe showed two signals of Smith-Magenis probe but only one signal of Miller-Dieker/ILS probe, indicating a microdeletion of 17pl3.3 region including LIS1 gene. Hybridization of the ILS probe on the metaphase chromosome of both parents was normal. CONCLUSION: A confirmation of contiguous gene deletion in this patient lead to an etiologic diagnosis of lissencephaly. This information allowed precise genetic counseling, estimation of recurrent risk, and definite prenatal diagnosis available to the family. The authors suggest FISH 17p13.3 studies be performed in addition to a standard metaphase analysis in all patients with type I lissencephaly.

Serum diazepam levels after oral administration in children.

OBJECTIVE: To determine serum levels of diazepam after oral administration in children. PATIENTS AND METHOD: Forty six children admitted with febrile seizures were orally administered with 0.25 mg/kg/dose of diazepam six hourly for four doses. Trough (prior to the next dose) and peak (at 1 hour 20 minutes after the dose) serum levels of diazepam were analyzed. The patients were observed for adverse effects of the medication. RESULTS: The peak levels after 1st, 2nd, 3rd and 4th doses were above 0.15 microg/ml which is considered the therapeutic level in 93.5, 97.8, 97.7, and 100 per cent of the patients, respectively. The trough levels prior to the 2nd, 3nd, and 4th doses were greater than 0.15 microg/ml in 75.0, 84.0, and 91.3 per cent, respectively. Neither recurrent seizure nor serious adverse effects occurred in any of the patients. CONCLUSION: Serum concentrations above the therapeutic level were achieved after orally administered diazepam at 0.25 mg/kg/dose six hourly for four doses. Oral diazepam may be used as another method in the prevention of recurrent febrile seizures.