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The objective of the study was to evaluate the epidemiology of patients with congenital myasthenic syndrome (CMS) in Israel. Targeted mutation analysis was performed based on the clinical symptoms and electrophysiological findings for known CMS. Additional specific tests were performed in patients of Iranian and/or Iraqi Jewish origin. All medical records were reviewed and clinical data, genetic mutations and outcomes were recorded. Forty-five patients with genetic mutations in known CMS genes from 35 families were identified. Mutations in RAPSN were identified in 13 kinships in Israel. The most common mutation was c.-38A>G detected in 8 patients of Iranian and/or Iraqi Jewish origin. Four different recessive mutations in COLQ were identified in 11 kinships, 10 of which were of Muslim-Arab descent. Mutations in CHRNE were identified in 7 kinships. Less commonly detected mutations were in CHRND, CHAT, GFPT1 and DOK7. In conclusion, mutations in RAPSN and COLQ are the most common causes of CMS in our cohort. Specific mutations in COLQ, RAPSN, and CHRNE occur in specific ethnic populations and should be taken into account when the diagnosis of a CMS is suspected.

SUMMARY Ten babies with cerebral palsy of varying types and degrees (age-range 10 to 27 months) participated in an initial exploratory study designed to determine the effectiveness of an automated, two-choice audio feedback system (‘Playtest’) for evaluation of the auditory perception and processing capabilities of neurologically impaired infants. The major components of the ‘Playtest’ are a master control unit and two toy-like switches which are attached to the baby's crib. By playing with the ‘toys’, the baby is able to listen to one of two pre-recorded audio stimuli, music or a monotone hum. Frequency and duration of the baby's self-selected listening responses are automatically recorded on meters inside the control unit and provide a precise numerical record over an extended period of time. In this study the handicapped infants were physically able to operate the apparatus and demonstrated highly significant preferential listening. Comparison of the recorded data from the study infants with those from normal infants showed no significant difference between the performances of the two groups. The findings suggest that the ‘Playtest’ technique could be successfully applied to the objective assessment of auditory perception and processing abilities of neurologically impaired infants, whose handicaps often prevent them from effectively participating in other standardised test procedures. The principal advantages of the technique are that testing is done in the child's most familiar environment—his own crib at home—without the intrusion of other people, and the evaluation of hearing competence is a function of the baby's spontaneous self-selected responses to sound variables, and hence of his auditory discrimination. RESUME Application d'un procede de reponse automalique operatoire a l'etude de la perception auditive et des possibilites de progres des nourrissons neurologiquement leses L'article decrit une experience mise en place pour apprecier 1'efficacite potentielle d'une technique d'analyse comportementale (Playtest) dans 1′evaluation de la perception auditive et des capacites de developpement chez les nourrissons IMC. 10 nourrissons de 10 a 27 mois IMC et presentant des degres varies de handicap ont eteetudies. Le materiel ‘Playtest’ comprend un enregistreur central et deux interrupteurs en forme de jouet attaches au berceau du nourrisson. En s'amusant avec ces ‘jouets’, le nourrisson peut ecouter un ou deux stimuli pre-enregistres. La frequence et la duree des reponses d'ecoute etablies par l'enfant sont enregistrees automatiquement dans l'appareil central. L'un des principaux buts de l'experience etait de determiner si des nourrissons atteints neurologiquement etaient physiquement capables de faire fonctionner le dispositif'Playtest' et s'il le pouvait, de voir s'il etait possible de recueillir des donnees quantitatives suffisantes de leur comportement d'ecoute pour permettre une analyse. Les resultats cnt montre qu'un handicap n'empeche pas le nourrisson d'utiliser les interrupteurs et une preference d'ecoute hautement significative a pu etre demontree. La comparaison des donnees obtenues chez les nourrissons IMC et chez les nourrissons normaux n'a pas montre de difference significative entre les performances des deux groupes. Ces fails suggerent que la technique ‘Playtest’ peut etre utilisee avec succes pour appreciation objective de la perception auditive et des possibilites de developpement de nourrissons atteints de lesions neurologiques, dont les handicaps les empechent souvent de participer avec efficacite dans les epreuves standardisees habituelles. L'un des avantages du dispositif ‘Playtest’ est que l'exploration peut etre faite a la maison du nourrisson et sans presence etrangere. ZUSAMMENFASSUNG Die Anwendung eines automatischen Antwortsystems zur Untersuchung der akustischen Erfassung und der Handlungsfahigkeit neurologisch geschadigter Kinder Diese Arbeit beschreibt eine Versuchsanordnung, die entwickelt wurde, die mogliche Effektivitat einer Verhaltensanalysetechnik (‘Playtest’) zur Beurteilung der akustischen Erfassung und Handlungsfahigkeit bei Kindern mit Cerebralparese einzuschatzen. 10 Kinder im Alter von 10 bis 27 Monaten mit Cerebralparese und unterschiedlich ausge-pragter Behinderung wurden untersucht. Die Spieltestausrustung besteht aus einer Hauptkontrolleinheit und zwei Spielzeug ahnlichen Schaltern, die am Bett der Kinder angebracht sind. Im Spiel mit diesen ‘Spielzeugen’ ist das Kind in der Lage, auf einen von zwei vorher wahrgenommenen Reize zu horen. Haufigkeit und Dauer der von den Kindern selbst bestimmten Horreaktion werden automatisch aufgezeichnet auf Mesgeraten des Kontrollgerates. Es war eines der Hauptziele dieses Experimentes festzustellen, ob die neurologisch behinderten Kinder physisch in der Lage waren, den ‘Playtest’ Apparat zu bedienen und wenn, ob quantitativ suffiziente Daten uber ihr Horreationsverhalten erzielt werden konnten, um eine Analyse durchzufuhren. Die Ergebnisse zeigen, das eine Behinderung die Kinder nicht am Gebrauch der Sehalter hindert und es konnte eine hoch signifikante Bevorzugung einer akustischen Wahrnehmung nachgewiesen werden. Ein Vergleich der Daten der Kinder mit Cerebralparese mit denen normaler Kinder zeigte keinen signifik-anten Unterschied in den Testausfuhrungen der beiden Gruppen. Die Befunde lassen vermuten, das die ‘Playtest’ Methode zur objektiven Bewertung der akustischen Erfassung und Handlungsfahigkeit neurologisch behinderter Kinder erfolgreich eingesetzt werden kann, wogegen die Kinder durch ihre Behinderungen haufig nicht in der Lage sind, an den gelaufigen standardisierten Testmethoden teilzunehmen. Ein Vorteil der Playtest Methode besteht darin, das der Test bei den Kindern zu Hause und ohne Anwesenheit einer fremden Person durchgefuhrt werden kann. RESUMEN Aplicacion de un procedimiento a base de respuesta automatica operante en el estudio de la percepcion auditiva y en la habilidad procesiva de ninos con alteracion neurologica Esta comunicacion describe un experimento ideado para evaluar la eficacia potential de una tecnica de analisis de comportamiento (‘Playtest’) para la evaluacion de la percepcion auditiva y de las habilidades procesivas en ninos con paralisis cerebral. Participaron 10 ninos (de 10 a 27 meses de edad) con paralisis cerebral y diversos grados de minus-valencia. El equipo Playtest consiste en una unidad de control principal y dos interruptores semejantes a juguetes que estan fijados a la cuna, del nino. Jugando con estos ‘juguetes’ el nino es capaz de escuchar uno o dos estimulos pre-grabados. La frecuencia y la duration de las respuestas de escucha autoseleccionada del nino son registradas automaticamente en la unidad de control. Una de las principales finalidades del experimento era determinar si los ninos con alteracion neurologica serfan fisicamente capaces de manipular el aparato del ‘Playtest’, y en caso afirmativo si se podrian obtener suficientes datos cuantitativos a partir de los comportamientos de escucha para hacer posible el analisis. Los resultados sugieren que una minusvalencia no impide a un nino el uso de interruptores y se demostro una preferencia altamente significativa en la escucha. La comparacion de datos obtenidos de ninos con paralisis cerebral, con los de ninos normales, no mostro ninguna diferencia significativa entre las realizaciones de ambos grupos. Los hallazgos sugieren que la tecnica del ‘Playtest’ puede ser utilizada con exito para la estimation objetiva de la perception auditiva y habilidades procesivas de ninos con alteraciones neurologicas, cuyos handicaps con frecuencia les impide el participar eficaz-mente en tests corrientemente standardizados. Una ventaja de la aplicacion del Playtest es que puede ser aplicado en la misma casa del nino sin la presencia de una segunda persona.

The objective of the present study was to analyze the diagnostic indications that most often prompt the referral of children and adolescents in the outpatient clinical pediatric practice for electroencephalographic evaluation and to check its utility in these clinical conditions. The electroencephalographic records of 547 consecutive children and adolescents (5-16 years of age) referred to a single community laboratory for the evaluation of various neurologic disorders were prospectively read by a single blinded investigator. Common diagnostic indications included the following: clinical seizures (42%), attention-deficit-hyperactivity disorder (23%), headaches (10.4%), syncope (9.9%), and tic disorder (4.9%). Overall, 76% of records were normal. Slowing of electroencephalographic activity was noted in 1% (attention-deficit-hyperactivity disorder) to 26% (probable epilepsy), and epileptiform activity in 53% of the probable and 29% of the clinically possible epileptics. Epileptiform activity was rarely found in the nonepileptic patients. The results of the present study demonstrate that standard interictal electroencephalogram is being overused during evaluation of various neurologic disorders in children and adolescents, suggesting that its use should be reserved for supporting the diagnosis in those cases in which epilepsy is a reasonable clinical possibility.

Objective: To determine the molecular basis and consequences of endplate (EP) acetylcholinesterase (AChE) deficiency. Background: The EP species AChE is an asymmetric enzyme consisting of a tail subunit composed of three collagenic strands (ColQ), each attached to a tetramer of catalytic subunits. The tail subunit is essential for insertion of AChE into the synaptic basal lamina. Human EP AChE deficiency is caused by mutations in COLQ . The authors report three novel COLQ mutations in eight kinships. Methods: Immunocytochemistry, electron microscopy, microelectrode recordings, mutation analysis, and expression studies in COS cells were employed. Results: Two mutations (275insC and Q211X) were heterozygous in one patient. EP studies in this patient revealed no EP AChE, small nerve terminals, reduced presynaptic membrane length, as well as abnormally low-evoked quantal release. The third mutation (G240X) was homozygous in six Palestinian Arab families of the same tribe and in an Iraqi Jewish patient. Expression studies of the three mutations in COS cells indicate that each abrogates formation of insertion competent asymmetric AChE. Although the three mutations have identical predicted consequences at the EP, their phenotypic expressivity varies as regards age at onset, rate of progression, and severity of symptoms. Conclusions: 1) After mutations in the AChR e subunit, mutations in COLQ are emerging as second most common cause of congenital myasthenic syndromes. 2) A founder effect is likely for G240X in the Palestinian Arab families. 3) That mutations predicting total absence of AChE from the EP have variable phenotypic expressivity suggests that modifying genes or environmental factors can partially compensate for EP AChE deficiency.

A series of 9 infants, ranging in age from 3 months to 5 years (average: 2 years), suffered from idiopathic myopathic carnitine deficiency presenting as hypotonia and motor delay. Secondary carnitine deficiency was eliminated by appropriate tests. Muscle carnitine concentration ranged from 2.3–7.1 nmol/mg non-collagen protein (NCP; average: 4.87 nmol/mg NCP; normal: 22 ± 6 nmol/mg NCP). Lipid accumulation in muscle was observed in 2 of 8 patients. Therapy with l-carnitine (100 mg/kg/day in most patients) was given with clinical and laboratory follow-up 6 months later. In 7 of 9 patients, muscle tone and motor function improved. Muscle carnitine concentration increased to a range of 2.7–23.4 nmol/mg (average: 12.27 nmol/mg). In some patients the muscle carnitine content multiplied by a factor of 3–4, but carnitine concentration reached the normal range in only 2 patients. Most infants with idiopathic carnitine deficiency did benefit from 6 months of therapy; however, in order to achieve full recovery the duration of therapy should probably continue for longer periods, with a dose of not less than 100 mg/kg/day.

Objective: Defects in glycosylation of -dystroglycan are associated with several forms of muscular dystrophy, often characterized by congenital onset and severe structural brain involvement, collectively known as dystroglycanopathies. Six causative genes have been identified in these disorders including fukutin. Mutations in fukutin cause Fukuyama congenital muscular dystrophy. This is the second most common form of muscular dystrophy in Japan and is invariably associated with mental retardation and structural brain defects. The aim of this study was to determine the genetic defect in two white families with a dystroglycanopathy. Methods: The six genes responsible for dystroglycanopathies were studied in three children with a severe reduction of -dystroglycan in skeletal muscle. Results: We identified pathogenic fukutin mutations in these two families. Affected children had normal intelligence and brain structure and shared a limb girdle muscular dystrophy (LGMD) phenotype, had marked elevation of serum creatine kinase, and were all ambulant with remarkable steroid responsiveness. Interpretation: Our data suggest that fukutin mutations occur outside Japan and can be associated with much milder phenotypes than Fukuyama congenital muscular dystrophy. These findings significantly expand the spectrum of phenotypes associated with fukutin mutations to include this novel form of limb girdle muscular dystrophy that we propose to name LGMD2L. Ann Neurol 2006;60:603– 610

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.

Harris first reported transient idiopathic trigeminal sensory neuropathy in 1935, although it later appeared that, in some of his patients, this condition evolved to typical chronic and painful trigeminal neuralgia. The patients who were later described by Hill and Hughes suffered a combined motor-sensory Vth cranial nerve dysfunction, and most cases reported by Spillane and Wells developed sustained permanent trigeminal neuropathy. The largest reported series of pure trigeminal sensory neuropathy includes 10 adults with varying degrees of sensory disturbance confined to all three nerve divisions. These patients experienced no facial pain or motor deficit, and 5 (50%) recovered completely within a few months. It is estimated that typical trigeminal neuralgia occurs in about 1 in 25,000 of the population and is uncommon prior to the third decade, with 1% of the cases occurring before the age of 20 years. To our knowledge, we present the first clinical report of idiopathic trigeminal sensory neuropathy occurring in childhood.

LEMS is a presynaptic neuromuscular junction disorder typically associated with small cell lung carcinoma. The characteristic electrophysiological abnormality is a low amplitude compound muscle action potential that shows a marked increment after short maximal contraction or brief tetanic nerve stimulation. Here we describe 3 patients who had LEMS in association with lymphoproliferative disorder. The first patient had Castleman's syndrome with typical clinical and electrophysiological features of LEMS, which responded partially to treatment with 3-4-diaminopyridine. The second patient was a 7-year-old boy who had an unusual acute onset of LEMS associated with relapse of his Burkitt's leukemia. The third patient was a 60-year-old woman with non-Hodgkin's lymphoma. These 3 patients (together with 6 additional patients identified in the literature) lead us to suggest that lymphoproliferative diseases are another, hitherto unrecognized, type of malignancy associated with LEMS. Thus, any patient with these malignancies and unexplained muscle weakness should have electrophysiological evaluation for LEMS.

The present study describes the use of simple video games for a 5-week regimen of respiratory muscle training in 15 patients with Duchenne muscular dystrophy (DMD) at various stages of the disease. The games were re-arranged to be operated and driven by the respiratory efforts of the patient and to incorporate accurate ventilation and time measurements. Improvement in respiratory performance was determined by maximum voluntary ventilation (MVV), maximal achieved ventilation (VEmax) during a progressive isocapnic hyperventilation manoeuvre (PIHV) and the PIHV duration. The actual training period was 23 +/- 4 days (mean +/- S.D.) at ventilatory effort of 46 +/- 6% MVV, for 10 +/- 3 min day-1. Patients with moderate impairment of lung function tests (LFT) showed an improvement in MVV, VEmax, and duration of PIHV of 12 +/- 7% (p < 0.02), 53 +/- 25% (p < 0.001) 57 +/- 21% (p < 0.01), respectively. Improvements correlated with actual training time and ventilation level, %MVV, but negatively correlated with years of immobilization and with the initial MVV. We conclude that computerized respiratory games may be applied for breathing exercises and may improve respiratory performance in recently immobilized children with DMD who have moderate impairment of LFT.

An infant girl of consanguinous Bedouin parents suffered from fatal early onset of progressive generalized muscle weakness. Her older brother suffered from similar weakness and cardiomyopathy, which led to his death at the age of 21 months. A muscle biopsy performed on the propositus at the age of 9 months was PAS-negative, and showed nonspecific myopathic changes. A second muscle biopsy, performed at 21 months of age, a few days before her death, and postmortem study of heart and liver, disclosed excessive extralysosomal glycogen storage and reduced phosphofructokinase-1 (PFK-1) activity. Because the genes encoded for PFK-1 in liver and muscle are located on separate chromosomes, the reduced enzyme activity in both tissues could not be related to a single mutation for this enzyme. Activity of 6-phosphofructose-2-kinase (PFK-2), a recently discovered physiological activator to all PFK-1 isozymes, was normal in the liver. The possibility that this multisystem PFK-1 deficiency may be related to the absence of a yet unknown activator, common to all PFK-1 isozymes, is discussed.

A 15-month-old boy, thought to have a congenital myopathy, was subsequently diagnosed as having mucolipidosis type IV, with typical membranous inclusions in muscle fibers. Involvement of skeletal muscle in this lysosomal storage disease may explain the motor delay and hypotonia that are its most common presenting signs.

Acute disseminated encephalomyelopathy and Guillain-Barré syndrome are both immunologically mediated para-infectious demyelinating disorders, the former affecting the central nervous system and the latter affecting the peripheral nervous system. The term encephalo-myelo-radiculo-neuropathy was introduced to describe cases in which major involvement of one system, most commonly the peripheral, was associated with mild involvement of the other. We present a case of acute severe demyelination simultaneously affecting both the central and the peripheral nervous systems in a 10-year-old female. This clinical picture combines acute disseminated encephalomyelopathy and Guillain-Barré syndrome, both of which are extremely severe.

An infant presented with congenital hypotonia, poor sucking, apathy, and areflexia. Muscle biopsy at two months of age revealed numerous nemaline rods, suggesting congenital nemaline myopathy. During the ensuing months, familial dysautonomia was suggested by recurrent pulmonary infections, dysphagia, alacrima, hyperhydrosis, emotional lability, and unexplained episodes of hyperthermia and breath-holding spells. The diagnosis was confirmed by positive intradermal histamine and ocular mecholyl tests. The finding of nemaline rods adds a new facet to the recognized polymorphic presentation of familial dysautonomia.

Vitamin E levels were measured in the plasma of infants and children with various neuromuscular disorders. Seven of 8 infants with Werdnig-Hoffmann disease (WHD) had a significantly lower plasma vitamin E level (p less than 0.01) than age-matched normal controls, children with congenital myopathies, or children with muscular dystrophy. Vitamin E deficiency in WHD is not caused by malabsorption. A therapeutic trial of vitamin E in 3 patients with WHD did not change the natural course of the disease. Vitamin E deficiency may play a role in the pathogenesis of WHD.

SYNOPSIS A case of transient global amnesia in a nine year old child with a history of recurrent episodes of vertigoand a family history of migraine headache is described. The possibility that acute confusional state inchildren, presenting as transient global amnesia may represent a variant of basilar migraine is discussed.

• In a muscle biopsy specimen from a baby girl with hypotonia, there was the ultrastructural finding of selective myosin degeneration in some myofibers. The sarcomeres were either well aligned or completely distorted. Excessive glycogen, fiber and fibril splitting, and occasional aggregates of vesicles were the other abnormalities present.

To the Editor.— In the February 1977Archives(34:114-115, 1977), we described an infant who had severe generalized congenital hypotonia, in whom selective myosin degeneration was found in a muscle biopsy specimen. During the following year, we reexamined the girl and performed another biopsy on her contralateral quadriceps femoris muscle. We would like to report here the benign course of this disorder. During the second year of life, the infant showed great improvement in motor performance. At 1 year of age, she was able to stand against the wall and walk with assistance. At 15 months of age, she learned to roll over and to sit up. At 18 months of age, she was able to get up from the floor and walk unassisted. At 27 months of age, she still had a positive Gowers' maneuver and tired easily. The results of a Bayley development test showed a two-month delay

Levels of serum 24,25(OH) 2 D 3 (0.69 ± 0.17 ng/ml) were lower in DMD patients than in age-matched controls (2.13 ± 0.15 ng/ml). Circulating levels of 1,25(OH) 2 D 3 and 25(OH)D 3 were within the accepted normal range. Bearing in mind the proposed pathophysiologic role of calcium in DMD and the influence of vitamin D metabolites on muscle ATP and protein synthesis, as well as on sarcoplasmic reticulum calcium transport and muscle mitochondrial calcium content, the above findings of low or deficient 24,25(OH) 2 D 3 levels in DMD could be meaningful from the etiologic and therapeutic points of view.