Jürgen Sperner

Mutations in the X-Linked Cyclin-Dependent Kinase–Like 5 (CDKL5/STK9) Gene Are Associated with Severe Neurodevelopmental Retardation

Recently, we showed that truncation of the X-linked cyclin-dependent kinase-like 5 (CDKL5/STK9) gene caused mental retardation and severe neurological symptoms in two female patients. Here, we report that de novo missense mutations in CDKL5 are associated with a severe phenotype of early-onset infantile spasms and clinical features that overlap those of other neurodevelopmental disorders, such as Rett syndrome and Angelman syndrome. The mutations are located within the protein kinase domain and affect highly conserved amino acids; this strongly suggests that impaired CDKL5 catalytic activity plays an important role in the pathogenesis of this neurodevelopmental disorder. In view of the overlapping phenotypic spectrum of CDKL5 and MECP2 mutations, it is tempting to speculate that these two genes play a role in a common pathogenic process.

Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes

Idiopathic focal epilepsy (IFE) with rolandic spikes is the most common childhood epilepsy, comprising a phenotypic spectrum from rolandic epilepsy (also benign epilepsy with centrotemporal spikes, BECTS) to atypical benign partial epilepsy (ABPE), Landau-Kleffner syndrome (LKS) and epileptic encephalopathy with continuous spike and waves during slow-wave sleep (CSWS). The genetic basis is largely unknown. We detected new heterozygous mutations in GRIN2A in 27 of 359 affected individuals from 2 independent cohorts with IFE (7.5%; P = 4.83 × 10−18, Fishers exact test). Mutations occurred significantly more frequently in the more severe phenotypes, with mutation detection rates ranging from 12/245 (4.9%) in individuals with BECTS to 9/51 (17.6%) in individuals with CSWS (P = 0.009, Cochran-Armitage test for trend). In addition, exon-disrupting microdeletions were found in 3 of 286 individuals (1.0%; P = 0.004, Fishers exact test). These results establish alterations of the gene encoding the NMDA receptor NR2A subunit as a major genetic risk factor for IFE.

Febrile infection–related epilepsy syndrome (FIRES): A nonencephalitic encephalopathy in childhood

Encephalitis is generally presumed, even when seizures follow banal febrile infection, and pathogen detection in cerebrospinal fluid fails. This retrospective multicenter case series reports on 22 previously healthy children aged 3–15 years (median 6.5 years) with prolonged or recurrent seizures occurring 2–14 days (median 5 days) after fever onset (19 children with respiratory or nonspecific infections). Cerebrospinal fluid studies revealed 2–42 cells/μl (median 5 cells/μl) and no pathogens. Electroencephalography showed diffuse slowing or multifocal discharges. Neuroimaging demonstrated normal findings in 10 children. Brain biopsies were performed in seven children showing gliosis but no inflammation. Anesthetic barbiturates were used in 14 children with refractory status epilepticus, and immunotherapy in 9. Two children died, eight remained in a state of impaired consciousness, eight developed therapy‐refractory epilepsies, two had behavioral disturbances, and two recovered. The lack of evidence for encephalitis suggests another infection‐related pathogenesis of this disastrous epileptic encephalopathy. Therefore, we propose the term “febrile infection–related epilepsy syndrome” (FIRES).

Deletions in 16p13 including GRIN2A in patients with intellectual disability, various dysmorphic features, and seizure disorders of the rolandic region

Seizure disorders of the rolandic region comprise a spectrum of different epilepsy syndromes ranging from benign rolandic epilepsy to more severe seizure disorders including atypical benign partial epilepsy/pseudo‐Lennox syndrome, electrical status epilepticus during sleep, and Landau‐Kleffner syndrome. Centrotemporal spikes are the unifying electroencephalographic hallmark of these benign focal epilepsies, indicating a pathophysiologic relationship between the various epilepsies arising from the rolandic region. The etiology of these epilepsies is elusive, but a genetic component is assumed given the heritability of the characteristic electrographic trait. Herein we report on three patients with intellectual disability, various dysmorphic features, and epilepsies involving the rolandic region, carrying previously undescribed deletions in 16p13. The only gene located in the critical region shared by all three patients is GRIN2A coding for the alpha‐2 subunit of the neuronal N‐methyl‐d‐aspartate (NMDA) receptor.

Cerebral proton magnetic resonance spectroscopy in infantile Alexander disease

Abstract. Alexander disease (AD) is a rare genetic disorder of the central nervous system due to a dysfunction of astrocytes. The most common infantile form presents as a progressive leukodystrophy with macrocephalus. Recently, heterozygous de novo mutations in the gene encoding glial fibrillary acidic protein (GFAP) have been demonstrated to be associated with AD. We used localized proton magnetic resonance spectroscopy (MRS) to assess metabolic abnormalities in grey and white matter, basal ganglia, and cerebellum of 4 patients with infantile AD and GFAP mutations. Strongly elevated concentrations of myo-inositol in conjunction with normal or increased choline-containing compounds in all regions investigated point to astrocytosis and demyelination. Neuroaxonal degeneration, as reflected by a reduction of N-acetylaspartate, was most pronounced in cerebral and cerebellar white matter. The accumulation of lactate in affected white matter is in line with infiltrating macrophages. Metabolic alterations demonstrated by in vivo proton MRS are in excellent agreement with known neuropathological features of AD.

The clinical outcomes of neonatal and childhood stroke: review of the literature and implications for future research

A detailed assessment of clinical outcomes after ischemic stroke in childhood is necessary to evaluate prognostic factors. Previous studies are difficult to compare because of differences in test instruments, study design, heterogeneity of cohorts and number of included cases. Depending on neurodevelopmental assessment methods, major and subtle/minor disabilities, especially in infants, may not have been detected. Most outcome studies reveal only limited information about behavioral changes and quality of life in children with ischemic stroke. Thus the assumption that children make a better recovery from stroke than adults due to the immature brains capacity to reorganize function is not evidence‐based. We systematically review the current literature with regard to the neurological and psychosocial development of affected children as well as their quality of life. Implications for future research strategies follow the review to encourage further clinical study of the neurobehavioral trajectory of childhood stroke.

Operative and technical complications of vagus nerve stimulator implantation.

BACKGROUND: The treatment of refractory epilepsy by vagus nerve stimulation (VNS) is a well-established therapy option for patients not suitable for epilepsy surgery and therapy refractory depressions. OBJECTIVE: To analyze surgical and technical complications after implantation of left-sided VNS in patients with therapy-refractory epilepsy and depression. METHODS: One hundred five patients receiving a VNS or VNS-related operations (n = 118) from 1999 to 2008 were investigated retrospectively. RESULTS: At the time of operation, 84 patients were younger than 18 years, with a mean age of 10.5 years. Twenty (19%) patients had technical problems or complications. In 6 (5.7%) patients these problems were caused by the operation. The device was removed in 8 cases. The range of surgically and technically induced complications included electrode fractures, early and late onset of deep wound infections, transient vocal cord palsy, cardiac arrhythmia under test stimulation, electrode malfunction, and posttraumatic dysfunction of the stimulator. CONCLUSION: VNS therapy is combined with a wide spread of possible complications. Technical problems are to be expected, including electrode fracture, dislocation, and generator malfunction. The major complication in younger patients is the electrode fracture, which might be induced by growth during adolescence. Surgically induced complications of VNS implantation are comparably low. Cardiac symptoms and recurrent nerve palsy need to be taken into consideration.

Life-long increase of substantia nigra hyperechogenicity in transcranial sonography

Transcranial ultrasound of the substantia nigra (SN) shows a distinct hyperechogenicity in the majority of patients with Parkinsons disease. Recent studies indicate a larger area of hyperechogenicity in elderly healthy adult subjects. The present study aimed to determine the size of the SN hyperechogenicity and of the mesencephalic brainstem in children and adults without evidence of movement disorders. The areas of echogenicity in the substantia nigra (aSN) and the area of the ipsilateral midbrain (aMid) were assessed in 121 healthy infants and children as well as in 64 healthy adults. Furthermore, the ratio of aSN and aMid was calculated (S/M ratio). We found a positive correlation between age and aSN and between age and the S/M ratio. The values for aSN and S/M ratio were smaller in infants and children compared to healthy adults (aSNmax 0.06+/-0.05 cm2 vs. 0.13+/-0.08 cm2). The aSN and S/M ratio grew with increasing age in an almost linear progression. The increase of SN hyperechogenicity over time suggests that the biological process underlying this ultrasound finding may be more dynamic and possibly progressive than previously thought.

Clinical and genetic features of myoclonus–dystonia in 3 cases: A video presentation†

Many cases of myoclonus–dystonia (M‐D) are caused by mutations in the ϵ‐sarcoglycan (SGCE) gene. We describe 3 children with a similar clinical picture of autosomal dominant M‐D and an SGCE mutation in only one of them, suggesting that M‐D is genetically heterogeneous.

Beneficial Prenatal Levodopa Therapy in Autosomal Recessive Guanosine Triphosphate Cyclohydrolase 1 Deficiency

OBJECTIVE To report the first prenatal dopaminergic replacement therapy in autosomal recessive (AR) guanosine triphosphate cyclohydrolase 1 (GTPCH) deficiency without hyperphenylalaninemia. DESIGN Case reports, literature review, and video presentation. SETTING University of Lübeck, Lübeck, Germany. PATIENTS Two boys from a consanguineous family. MAIN OUTCOME MEASURES Physical and mental development as a function of replacement initiation. RESULTS The older sibling presented with typical features of AR GTPCH deficiency due to a homozygous mutation in the GCH1 gene with proven pathogenicity. Levodopa treatment was initiated at age 10 months and resulted in a distinct motor improvement. However, mental development was delayed. In the younger sibling, prenatal replacement therapy was initiated after a prenatal diagnosis of AR GTPCH deficiency was made. At age 17 months, both motor and mental development were normal for his age. CONCLUSIONS This report highlights the importance of an early diagnosis, including prenatal diagnosis, of complex dopa-responsive extrapyramidal syndromes. Prenatally initiated dopaminergic replacement therapy is beneficial and thus justified in AR GTPCH deficiency, allowing prevention of significant impairment of mental abilities.