SUMMARY A regional population‐based survey identified six patients with pyridoxine dependency. Four presented on the first day of life and the other two at 1 and 8 months of age. Apart from multiple seizure types, other presenting features included jitteriness; encephalopathy, at first thought to be hypoxic‐ischaemic; hepatomegaly, and abdominal distension with bilious vomiting. Later problems included break‐through fits with fever; transient visual agnosia; squint; severe articulatory apraxia; motor delay with later dyspraxia; macrocephaly. and post‐haemorrhagic hydrocephalus. Magnetic resonance imaging showed variable structural abnormalities in all the early onset cases. Psychometric assessment revealed a stereotyped pattern of intelligence scale subtest scores, with a specific impairment of expressive verbal ability. In a prospective open study over one year, an.‐ increased dose of pyridoxine was associated with an improvement in IQ, particularly in performance subtests. Pyridoxine dependency is more common than has been thought. It has a wider range of clinical features than the classical neonatal seizures and causes specific impairments of higher function, some of which may be reversible. The dosage of pyridoxine should be optimal for IQ as well as seizure control. RÉSUMÉ Comitialité pyridoxine‐dépendaiite Caractéristiques déinograpliiques, cliniques. IRM et psychométriques. Effet de dose sur le Ql Une étude de population régionale identifia six patients pyridoxine‐dépendants. Quatre cas se révélèrent le jour de la naissance, et les deux autres à I et 8 mois d'âge. En dehors d'une comitialité d'aspect variable, les autres caractéristiques présentes incluaicnt le sautillement permanent; une encéphalopathie rattachée initialement a une origine hypoxique‐ischémique; une hépatomégalie, et une distension abdominalc et vomisserrients biljaires. Les problèmes ultérieurs incluaienl des crises hyperthermiques soudaines; une agnosie visuelle transitoire; un strabisme; une apraxic articulatoire sévère; un retard motcur avec dyspraxic ultérieure; unc macrocéphalie, et une hydrocéphalic post‐hémorragique. L'imageric de résonance magnétique révélait des anomalies structurales variables dans tous les cas à début précoce. L'évaluation psychométrique révélait un groupement stéréotypé des scores aux subtests d'échellc d'intelligence, avec un trouble spécifique de l'aptitudc a l'expression verbale. Lors d'une etude prospective ouvertc sur un an. une dose accrue de pyridoxine se traduisit par un progrès du Ql, particulièrement dans les subtests de performance. La dépéndance à la pyridoxine est plus fréquente qu'il n'a été pense. La variété des manifestations cliniqucs déborde les classiques crises néonatales et cause des altérations spécifiques des fonctions supérieurcs, certaines étant réversibles. Le dosage de la pyridoxine doit etre maintenu optimal pour le Ql aussi bien que pour le contrôle des crises. ZUSAMMENFASSUNG Pyridoxin abháuingige Anfälle: denwgntphische, klinische. MRl bezogene ttnd psychomeirische Merkmale. Einf...

We have correlated a detailed clinical assessment of 67 patients with proven Becker muscular dystrophy with the results from genetic and protein analyses. There was an overall deletion frequency of 80%, rising to 92.6% in the large group of patients defined on clinical grounds as being of "typically" mild severity. The deletions in this group were all clustered in the region of the gene between exons 45 and 59; the most common deletion was of exons 45-47 and all but one started at exon 45. No similar deletions were seen in the patients with more severe disease, in whom the diverse genetic defects included a duplication and a very large deletion. Dystrophin patterns in the "typical" group were also very characteristic, and in both groups were as predicted from the genetic defect, the size of deletions being inversely proportional to the size of the protein produced.

The properties of neuromuscular junctions (NMJs) were studied in motor-point biopsy samples from eight patients with congenital myasthenic syndromes affecting primarily proximal limb muscles ['limb-girdle myasthenia' (LGM)]. All had moderate to severe weakness of the proximal muscles, without short-term clinical fatigability but with marked variation in strength over periods of weeks or months, with little or no facial weakness or ptosis and no ophthalmoplegia. Most had a characteristic gait and stance. All patients showed decrement of the compound muscle action potential (CMAP) on repetitive stimulation at 3 Hz, and increased jitter and blocking was detected by SFEMG, confirming the presence of impaired neuromuscular transmission. None of the patients had serum antibodies against acetylcholine receptors (AChRs). Two of the patients had similarly affected siblings. Intracellular recording from isolated nerve-muscle preparations revealed that the quantal content (the number of ACh quanta released per nerve impulse) was only approximately 50% of that in controls. However, the quantal size (amplitude of miniature end-plate currents) and the kinetic properties of synaptic potentials and currents were similar to control values. The area of synaptic contact and extent of post-synaptic folding were approximately 50% of control values. Thus, the quantal content per unit area of synaptic contact was normal. The number of AChRs per NMJ was also reduced to approximately 50% of normal, so the local AChR density was normal. Immunolabelling studies revealed qualitatively normal distributions and abundance of each of 14 proteins normally concentrated at the NMJ, including components of the basal lamina, post-synaptic membrane and post-synaptic cytoskeleton. DNA analysis failed to detect mutations in the genes encoding any of the following proteins: AChR subunits, rapsyn, ColQ, ChAT or muscle-specific kinase. Response of these patients to treatment was varied: few showed long-term improvement with pyridostigmine and some even deteriorated with treatments, while others had intolerable side-effects. Several patients showed improvement with 3,4-diaminopyridine, but this was generally only transient. Ephedrine was helpful in half of the patients. We conclude that impaired neuromuscular transmission in these LGM patients results from structural abnormalities of the NMJ, including reduced size and post-synaptic folding, rather from any abnormality in the immediate events of neuromuscular transmission.

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