Three novel COLQ mutations and variation of phenotypic expressivity due to G240X.

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 epsilon 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.

Low serum 24,25 dihydroxyvitamin D in Duchenne muscular dystrophy.

Levels of serum 24,25(OH)2D3 (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)2D3 and 25(OH)D3 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)2D3 levels in DMD could be meaningful from the etiologic and therapeutic points of view.

Nemaline myopathy and a mitochondrial neuromuscular disorder in one family.

A family composed of parents and four children is reported. Two brothers presented from early infancy with hypotonia and non-progressive weakness. Muscle biopsy in both revealed numerous typical nemaline rods. The father, suffering from backache, had a slow MNCV of both common peroneal nerves. His muscle revealed variation in fiber size, splitting, type 1 atrophy and numerous pleomorphic mitochondria with crystalline inclusions. The mother's muscle showed type 2 atrophy, foci of myofibrillar degeneration, and lipofuscin bodies. In a 12-year-old daughter and a 5-year-old son the muscle revealed an excess of small, bizarre mitochondria and lipid droplets. The coexistence of nemaline myopathy and a mitochondrial neuromuscular disorder in one family has never been reported in the literature. It might be a coincidence of two rare muscle disorders in one family, or it might be the polymorphic expression of a single etiological factor causing a defect in protein synthesis.

Abnormal eye movements in hyperkinetic children with learning disability.

Eye movements were studied in 29 school children aged 6--12 years diagnosed as having Hyperactivity (HA) with Learning Disabilities (LD) and compared to an age matched control group of 32 children. The children had to track a moving target on a metronome and a canopy, to maintain eye fixation on a stationary target and to read a standard reading material. Accuracy, nystagmoid, reversal and overshoot movements were observed, as well as head movements and blinks. Persistence and deviations were monitored during fixation; duration, accuracy, number of fixations and reversals were monitored during reading. The tracking accuracy and fixation persistence were significantly inferior in the HA-LD children as compared to the control group in most items. This correlated well with the inferior performance on the reading task. This study supports the hypothesis that children with MBD and learning disabilities have primary defects in the motor control of eye movements which contribute significantly to their reading difficulties.