Poll-The, B.T.

The EEG response to pyridoxine-IV neither identifies nor excludes pyridoxine-dependent epilepsy (Article)

2010-12-01T00:00:00Z

Purpose: Pyridoxine-dependent epilepsy (PDE) is characterized by therapy-resistant seizures (TRS) responding to intravenous (IV) pyridoxine. PDE can be identified by increased urinary alpha-aminoadipic semialdehyde (α-AASA) concentrations and mutations in the ALDH7A1 (antiquitin) gene. Prompt recognition of PDE is important for treatment and prognosis of seizures. We aimed to determine whether immediate electroencephalography (EEG) alterations by pyridoxine-IV can identify PDE in neonates with TRS. Methods: In 10 neonates with TRS, we compared online EEG alterations by pyridoxine-IV between PDE (n = 6) and non-PDE (n = 4). EEG segments were visually and digitally analyzed for average background amplitude and total power and relative power (background activity magnitude per frequency band and contribution of the frequency band to the spectrum). Results: In 3 of 10 neonates with TRS (2 of 6 PDE and 1 of 4 non-PDE neonates), pyridoxine-IV caused flattening of the EEG amplitude and attenuation of epileptic activity. Quantitative EEG alterations by pyridoxine-IV consisted of (1) decreased central amplitude, p < 0.05 [PDE: median -30% (range -78% to -3%); non-PDE: -20% (range -45% to -12%)]; (2) unaltered relative power; (3) decreased total power, p < 0.05 [PDE: -31% (-77% to -1%); -27% (-73% to -13%); -35% (-56% to -8%) and non-PDE: -16% (-43% to -5%); -28% (-29% to -17%); -26% (-54% to -8%), in delta-, theta- and beta-frequency bands, respectively]; and (4) similar EEG responses in PDE and non-PDE. Discussion: In neonates with TRS, pyridoxine-IV induces nonspecific EEG responses that neither identify nor exclude PDE. These data suggest that neonates with TRS should receive pyridoxine until PDE is fully excluded by metabolic and/or DNA analysis.

Is hearing loss a feature of Joubert syndrome, a ciliopathy? (Article)

2010-09-01T00:00:00Z

Objective: To assess if hearing loss is a feature of Joubert syndrome (JBS), one of the ciliopathies and therefore possibly associated with hearing loss. Design: Retrospective case series. Setting: University Children's Hospital. Patients: Dutch patients with JBS. Main outcome measures: Audiological data. Results: Data from 22 Dutch Joubert syndrome (JBS) cases (17 males, 5 females) aged 3-40 years were available. Audiological tests were successfully performed in 14 cases. Three cases (aged 17-26 years) showed very mild sensorineural hearing loss (SNHL) at different frequencies. Conductive hearing loss due to middle ear infections occurred frequently in young JBS children (6 out of 22 cases). In three cases (aged 3-13 years) the parents reported the child was hypersensitive to sound. Conclusion: We found no evidence for significant hearing loss in Joubert syndrome patients. However, given the compromised speech development in JBS, conductive hearing loss due to middle ear infections should be treated vigorously. SNHL at a later age cannot be excluded on the basis of our data, given the sample size. Three of the older cases showed discretely increased hearing thresholds. Analogous to the ciliopathy Bardet-Biedl syndrome, where hearing thresholds were reported to be subclinically increased in a group of adolescents patients, we recommend follow-up of JBS patients in view of the possibility of progressive, late-onset SNHL.

Neonatal cerebral sinovenous thrombosis from symptom to outcome (Article)

2010-07-01T00:00:00Z

Background and purpose: Cerebral sinovenous thrombosis is a rare disease with severe neurological sequelae. The aim of this retrospective multicenter study was to investigate the clinical course, possible risk factors, and outcome of a cohort of neonatal patients with sinovenous thrombosis and, second, to estimate the incidence in The Netherlands. Methods: From January 1999 to March 2009, a review of all neonatal patients with sinovenous thrombosis from 6 tertiary neonatal intensive care units was performed. Population characteristics, clinical presentation, (prothrombotic) risk factors, neuroimaging, interventions, and neurodevelopment were evaluated. An estimated incidence was calculated based on the Netherlands Perinatal Registry. Results: Fifty-two neonates were included (39 boys) with a median gestational age of 39 weeks (range, 30 to 42 weeks; 5 preterm). An assisted or complicated delivery occurred in 32 of 52. Presenting symptoms developed at a median postnatal age of 1.5 days (range, 0 to 28 days) and consisted mainly of seizures (29 of 52). All sinovenous thrombosis cases were confirmed with MRI/MR venography. Multisinus thrombosis was most common followed by superior sagittal sinus thrombosis. FII G20210A mutation was present in 2 of 18 tested neonates (11%). Anticoagulation therapy (in 22 of 52) did not result in hemorrhagic complications. At follow-up (median age, 19 months; range, 3 to 72 months), moderate to severe neurological sequelae were present in 38%. The mortality was 10 of 52 (19%). A variable, although high yearly incidence of 1.4 to 12 per 100 000 term newborns was found. Conclusions: Neonatal sinovenous thrombosis is a multifactorial disease. The estimated incidence in The Netherlands seems higher than reported elsewhere.

Glucose transporter-1 deficiency syndrome: The expanding clinical and genetic spectrum of a treatable disorder (Article)

2010-03-01T00:00:00Z

Glucose transporter-1 deficiency syndrome is caused by mutations in the SLC2A1 gene in the majority of patients and results in impaired glucose transport into the brain. From 2004-2008, 132 requests for mutational analysis of the SLC2A1 gene were studied by automated Sanger sequencing and multiplex ligation-dependent probe amplification. Mutations in the SLC2A1 gene were detected in 54 patients (41) and subsequently in three clinically affected family members. In these 57 patients we identified 49 different mutations, including six multiple exon deletions, six known mutations and 37 novel mutations (13 missense, five nonsense, 13 frame shift, four splice site and two translation initiation mutations). Clinical data were retrospectively collected from referring physicians by means of a questionnaire. Three different phenotypes were recognized: (i) the classical phenotype (84), subdivided into early-onset (<2 years) (65) and late-onset (18); (ii) a non-classical phenotype, with mental retardation and movement disorder, without epilepsy (15); and (iii) one adult case of glucose transporter-1 deficiency syndrome with minimal symptoms. Recognizing glucose transporter-1 deficiency syndrome is important, since a ketogenic diet was effective in most of the patients with epilepsy (86) and also reduced movement disorders in 48 of the patients with a classical phenotype and 71 of the patients with a non-classical phenotype. The average delay in diagnosing classical glucose transporter-1 deficiency syndrome was 6.6 years (range 1 month-16 years). Cerebrospinal fluid glucose was below 2.5 mmol/l (range 0.9-2.4 mmol/l) in all patients and cerebrospinal fluid: blood glucose ratio was below 0.50 in all but one patient (range 0.19-0.52). Cerebrospinal fluid lactate was low to normal in all patients. Our relatively large series of 57 patients with glucose transporter-1 deficiency syndrome allowed us to identify correlations between genotype, phenotype and biochemical data. Type of mutation was related to the severity of mental retardation and the presence of complex movement disorders. Cerebrospinal fluid: blood glucose ratio was related to type of mutation and phenotype. In conclusion, a substantial number of the patients with glucose transporter-1 deficiency syndrome do not have epilepsy. Our study demonstrates that a lumbar puncture provides the diagnostic clue to glucose transporter-1 deficiency syndrome and can thereby dramatically reduce diagnostic delay to allow early start of the ketogenic diet.

The unfolding clinical spectrum of POLG mutations (Article)

2009-11-01T00:00:00Z

Background: Mutations in the DNA polymerase-γ (POLG) gene are a major cause of clinically heterogeneous mitochondrial diseases, associated with mtDNA depletion and multiple deletions. Objective: To determine the spectrum of POLG mutations in our Dutch patient cohort, to evaluate the pathogenicity of novel mutations, and to establish genotype-phenotype correlations. Results: The authors identified 64 predominantly recessive mutations in 37 patients from a total of 232 patients, consisting of 23 different mutations. The substitution p.A467T was most frequently observed (n = 23), but was as frequent in childhood cases as in adult cases. Five new pathogenic recessive mutations, p.Lys925ArgfsX42, p.R275X, p.G426S, p.A804T and p.R869Q were identified. The known dominant chronic progressive external ophthalmoplegia (CPEO) mutation p.R943H was for the first time associated with premature ovarian failure as well. In 19 patients the authors identified only a single recessive mutation, or a sequence variant with unclear clinical significance. The data substantiate earlier observations that in POLG patients a fatal status epilepticus and liver failure can be triggered by sodium valproate. It is therefore important to exclude POLG mutations before administering this treatment. Conclusion: The clinical features of the patient are the most important features to select putative POLG mutation carriers and not the presence of mtDNA deletions or OXPHOS (oxidative phosphorylation) activity. The authors conclude that POLG mutations are an important cause of heterogeneous mitochondrial pathology and that more accurate genotype-phenotype correlations allow a more rapid genetic diagnosis and improved prognosis for mutation carriers.

The natural course of infantile Pompe's disease: 20 original cases compared with 133 cases from the literature (Article)

2003-01-01T00:00:00Z

OBJECTIVE: Infantile Pompe's disease is a lethal cardiac and muscular disorder. Current developments toward enzyme replacement therapy are promising. The aim of our study is to delineate the natural course of the disease to verify endpoints of clinical studies. METHODS: A total of 20 infantile patients diagnosed by the collaborative Dutch centers and 133 cases reported in literature were included in the study. Information on clinical history, physical examination, and diagnostic parameters was collected. RESULTS: The course of Pompe's disease is essentially the same in the Dutch and the general patient population. Symptoms start at a median age of 1.6 months in both groups. The median age of death is 7.7 and 6 months, respectively. Five percent of the Dutch patients and 8% of all reported patients survive beyond 1 year of age. Only 2 patients from literature became older than 18 months. A progressive cardiac hypertrophy is characteristic for infantile Pompe's disease. The diastolic thickness of the left ventricular posterior wall and cardiac weight at autopsy increase significantly with age. Motor development is severely delayed and major developmental milestones are generally not achieved. For the Dutch patient group, growth deviates significantly from normal despite start of nasogastric tube feeding. Levels of aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, creatine kinase, or creatine kinase-myocardial band isoenzyme are typically elevated, although aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase increase significantly with age. The patients have fully deleterious mutations. Acid alpha-glucosidase activity is severely deficient. CONCLUSIONS: Survival, decrease of the diastolic thickness of the left ventricular posterior wall, and achievement of major milestones are valid endpoints for therapeutic studies of infantile Pompe's disease. Mutation analysis and measurement of the alpha-glucosidase activity should be part of the enrollment program.