Yoram Nevo

Mutant mitochondrial thymidine kinase in mitochondrial DNA depletion myopathy

The mitochondrial deoxyribonucleotide (dNTP) pool is separated from the cytosolic pool because the mitochondria inner membrane is impermeable to charged molecules. The mitochondrial pool is maintained by either import of cytosolic dNTPs through dedicated transporters or by salvaging deoxynucleosides within the mitochondria; apparently, enzymes of the de novo dNTP synthesis pathway are not present in the mitochondria. In non-replicating cells, where cytosolic dNTP synthesis is down-regulated, mtDNA synthesis depends solely on the mitochondrial salvage pathway enzymes, the deoxyribonucleosides kinases. Two of the four human deoxyribonucleoside kinases, deoxyguanosine kinase (dGK) and thymidine kinase-2 (TK2), are expressed in mitochondria. Human dGK efficiently phosphorylates deoxyguanosine and deoxyadenosine, whereas TK2 phosphorylates deoxythymidine, deoxycytidine and deoxyuridine. Here we identify two mutations in TK2, histidine 90 to asparagine and isoleucine 181 to asparagine, in four individuals who developed devastating myopathy and depletion of muscular mitochondrial DNA in infancy. In these individuals, the activity of TK2 in muscle mitochondria is reduced to 14–45% of the mean value in healthy control individuals. Mutations in TK2 represent a new etiology for mitochondrial DNA depletion, underscoring the importance of the mitochondrial dNTP pool in the pathogenesis of mitochondrial depletion.

Epidemiology of epilepsy in childhood: A cohort of 440 consecutive patients

This study analyzes the relative frequency and age of onset of the different seizure types in a 20-year cohort of a pediatric neurology outpatient clinic of an urban hospital that serves the majority of the citys population (Tel Aviv Medical Center). Only patients with two or more unprovoked seizures were included. Neonatal seizures were excluded from the analysis. The different seizure types in descending order of frequency were: partial seizures secondarily generalized (20.6%), complex partial seizures (12.5%), West syndrome (9%), simple partial seizures (8.6%), benign rolandic epilepsy of childhood (8%), absence seizures (7%), generalized tonic-clonic seizures (6.6%), generalized tonic seizures (5%), myoclonic seizures (2.2%), benign occipital epilepsy of childhood (2%), mixed type seizures (1.8%), Lennox-Gastaut syndrome (1.5%), juvenile myoclonic epilepsy (0.9%), atypical absence (0.6%), Landau-Kleffner syndrome, Ohtahara syndrome, myoclonic astatic epilepsy, electrical status epilepticus in sleep and startle epilepsy (0.2% each), and unclassified seizures (12%). The findings of this study confirm that there are more pediatric patients with partial seizures (52%) than primary generalized seizures (33%) and that partial seizures secondarily generalized is the most frequent seizure type in this age group.

The value of EEG in children with chronic headaches

To establish the usefulness of electroencephalography (EEG) as a diagnostic tool in the evaluation of headaches in children, we retrospectively reviewed the records of all children referred to our outpatient neuropediatric clinic because of recurrent headaches. Of 312 children, 257 (82%) underwent EEG tracings: 143 of the children who had had EEG recordings were diagnosed as migraineurs. In 31 (12%) of the children, the EEG revealed epileptic activity. The highest incidence of epileptic EEG activity was found amongst the children with very brief headaches. In 22 (8.6%) of the children, diffuse or focal slowing was detected. The group with migraine headache had a significantly higher incidence of slowing than the group with other types of headaches. There was no correlation between focal EEG abnormalities and brain radioimaging studies or clinical course. We conclude that despite the high incidence of epileptic abnormalities, the contribution of EEG to diagnosis and treatment in children with chronic headache is minimal, and should not be routinely prescribed in these children.

Childhood macrophagic myofasciitis—consanguinity and clinicopathological features

Macrophagic myofasciitis has been almost exclusively detected in adults only. We describe six children of Arab Moslem origin with this disorder. Three presented with hypotonia, developmental delay and seizures and were evaluated for a mitochondrial disorder. The other three children had hypotonia and predominantly motor delay. Five of the six families were consanguineous. A massive collection of macrophages was present in the fascia and adjacent epimysium in all biopsies. The macrophages were periodic-acid-Schiff positive and immunoreactive for CD68. One biopsy which was evaluated by electron microscopy and energy-dispersive X-ray microanalysis showed crystalline structures containing aluminum in macrophages. Two children with motor delay and hypotonia were treated with oral prednisone for 3 months with no clinical improvement. Genetic predisposition probably accounts for the variability in the prevalence of macrophagic myofasciitis in different populations. At least in childhood, there seems to be no connection between macrophagic myofasciitis as a pathological entity and the clinical symptoms and signs.

Childhood chronic inflammatory demyelinating polyneuropathy

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a chronic disorder of the peripheral nervous system with sensory and motor involvement, and insidious onset over a period of months. In children and adults, both proximal and distal muscles are affected. Muscle stretch reflexes are absent or depressed. Laboratory findings include elevated cerebrospinal fluid protein with no increase of mononuclear cells. Electrophysiological and pathological studies show evidence of demyelination. No control studies of the efficacy of immunomodulating therapy in childhood CIDP are available. However, several studies have indicated clinical improvement after treatment with prednisolone, plasmapheresis and intravenous immunoglobulin, but disappointing results with other immunosuppressive agents. While some children have a monophasic course, with complete recovery, others have a protracted course, with either a slowly progressive or a relapsing-remitting course, resulting in prolonged morbidity and disability.

Electromyography (EMG) Accuracy Compared to Muscle Biopsy in Childhood

Reports show wide variability of electromyography (EMG) in detecting pediatric neuromuscular disorders. The studys aim was to determine EMG/nerve conduction study accuracy compared to muscle biopsy and final clinical diagnosis, and sensitivity for myopathic motor unit potential detection in childhood. Of 550 EMG/nerve conduction studies performed by the same examiner from a pediatric neuromuscular service, 27 children (ages 6 days to 16 years [10 boys; M:F, 1:1.7]) with muscle biopsies and final clinical diagnoses were compared retrospectively. Final clinical diagnoses were congenital myopathies (5 of 27,18%), nonspecific myopathies (biopsy myopathic, final diagnosis uncertain; 6 of 27, 22%), congenital myasthenic syndrome (3 of 27, 11%), juvenile myasthenia gravis (1 of 27, 4%), arthrogryposis multiplex congenita (2 of 27, 7%), hereditary motor and sensory neuropathy (1 of 27, 4%), bilateral peroneal neuropathies (1 of 27, 4%), and normal (8 of 27, 30%). There were no muscular dystrophy or spinal muscular atrophy patients. EMG/nerve conduction studies had a 74% agreement with final clinical diagnoses and 100% agreement in neurogenic, neuromuscular junction, and normal categories. Muscle biopsies concurred with final diagnoses in 87%, and 100% in myopathic and normal categories. In congenital myasthenic syndrome, muscle biopsies showed mild variation in fiber size in 2 of 3 children and were normal in 1 of 3. EMG sensitivity for detecting myopathic motor unit potentials in myopathies was 4 of 11 (36%), greater over 2 years of age (3 of 4, 75%), compared to infants less than 2 years (1 of 7, 14%), not statistically significant (P = .0879). EMGs false-negative for myopathy in infants < 2 years of age were frequently neurogenic (3 of 6, 50%). In congenital myopathies EMG detected myopathic motor unit potentials in 40%, with false-negative results neurogenic (20%) or normal (40%). Because our study has no additional tests for active myopathies, for example Duchenne muscular dystrophy genetic testing, our sensitivity for myopathies is lower than if we used a more global view. In conclusion, EMG detection rate of myopathic motor unit potentials at a young age was low, improving in children over 2 years of age. In neurogenic and neuromuscular junction disorders, the EMG has a very high detection rate. In children with mild to moderate neurogenic EMG findings and normal nerve conduction, a myopathy should always be considered.

Neuroimaging of children with partial seizures

The predictive value of abnormal neurological findings on neuroimaging (NI) of children with partial seizures (PS) was studied. The sample comprised 143 children and adolescents with PS from 1979 to 1996. Fifty patients had the following abnormal NI findings: diffuse atrophy and porencephalic cyst (5.6% each), hemiatrophy, tumors, neurocutaneous syndrome brain lesions, and dysgenesis (4.2% each), and arachnoid cyst and hydrocephalus (2.1% each). There were significantly more NI abnormalities among those with simple PS than among the other groups of complex PS or PS with secondary generalization. All cases of porencephalic cyst (n = 8), and hemiatrophy (n = 6) were in the hemiparetic group, all cases of tumor (n = 6) were in the normal group, while most cases of diffuse atrophy were in the mentally retarded group. Patients with abnormal NIs had a significantly earlier age of seizure onset than the others. The chance of finding a treatable abnormality in neuroimaging was 5% for tumors and 2% for arachnoid cysts in the group of patients with PS and normal neurological findings. Neither an abnormality detected in a neurological examination nor the type of seizure are predictive parameters for suggesting the presence of a resectable brain tumor. All patients with newly diagnosed PS should undergo an MRI.

Characterization and comparison of autistic subgroups: 10 years' experience with autistic children

To summarize our 10‐year experience with autistic children at the Tel Aviv Child Development Center, the files of all 55 children with autism treated at our center over a 10‐year period were retrospectively reviewed. Particular attention was addressed to the value of the medical work‐up in detecting the etiology of autism and to factors differentiating infantile autism (IA) from autistic‐like behavior (ALB). Twenty‐four subjects (44%) had IA and 31 (56%) had ALB. These subgroups were compared for demographic, perinatal, familial, neurological, and psychological findings, and outcome at discharge. Associated medical conditions and the yield of metabolic work‐up and neuroimaging and electroencephalography studies are discussed. The two subgroups differed only in severity of autistic symptoms and cognitive function (P<0.05), but not in demographic or neurobiological findings. It was concluded that IA and ALB are similar conditions, and autism has a wide continuum of clinical expressions.

Clinical Characteristics and Muscle Pathology in Myopathic Mitochondrial DNA Depletion

Four nonrelated children with myopathic mitochondrial DNA depletion are described. Two of them initially had normal motor development and two had mild motor delay. Motor arrest and regression started at age 6 to 21 months. All four had mitochondrial DNA:nuclear DNA ratios reduced to 16 to 22% of the control mean and mutations in their mitochondrial thymidine kinase 2. Muscle pathology was genotype related: homozygosity for a missense mutation at position 181 was associated with severe myopathic changes, including marked variation in muscle fiber size, myofiber necrosis, regeneration, and interstitial fibrosis, whereas homozygosity for a missense mutation at position 90 was associated with essentially normal muscle histology. No ragged red fibers were detected in any study child. Mitochondrial DNA depletion should be considered in children with myopathy, worsening hypotonia, motor regression, and death during infancy or early childhood. The severity of pathologic findings on muscle biopsy is variable and may correlate with specific mutations and thymidine kinase 2 protein residual activity. (J Child Neurol 2002;17:499-504).

Carbamazepine versus Sulthiame in Treating Benign Childhood Epilepsy With Centrotemporal Spikes

We compared the therapeutic efficacy of carbamazepine versus sulthiame in patients with benign childhood epilepsy with centrotemporal spikes. Drug efficacy was evaluated only in those patients who initiated treatment with any drug after at least three seizures. Thirty-eight patients who received carbamazepine and 18 patients who received sulthiame were included in the analysis. Cessation of seizures was observed in 73.6% of the former and in 66.7% of the latter (P = not significant). Five of eight patients who were switched to sulthiame after failing carbamazepine became seizure free, whereas none of the three patients who failed sulthiame became seizure free after being switched to carbamazepine. The rate of drug discontinuation owing to adverse reaction was 15% in carbamazepine and 14.3% in sulthiame. Normalization of interictal epileptiform activity on electroencephalography was seen more often following treatment with sulthiame (71%) than with carbamazepine (42%) (P = not significant). No significant differences between these two medications were found in the treatment of benign childhood epilepsy with centrotemporal spikes in this small patient sample. (J Child Neurol 2002;17:913—915).