A de novo dominant mutation in ACTA1 causing congenital nemaline myopathy associated with a milder phenotype: expanding the spectrum of dominant ACTA1 mutations.

We describe the presentation and six-year follow up of a child with nemaline myopathy due to a de novo mutation in the skeletal muscle α-actin gene (ACTA1) characterized by dramatic improvement during the early childhood years. The presentation in this female patient was infantile-onset weakness in the facial, bulbar, respiratory and neck flexor muscles. A six-year follow-up revealed continued progressive improvement in her muscle strength. Based upon the histopathologic and ultrastructural features of nemaline rod disease, ACTA1 was sequenced. This revealed a mutation in exon 4 of ACTA1 (c.557A>G). Our report further expands the phenotypic spectrum associated with ACTA1 mutations. Although it is difficult to infer any genotype-phenotype correlation, this report stimulates the discussion regarding the pathophysiologic mechanism of the clinical improvement seen in some patients with ACTA1 mutations.

State-dependent hyperpolarization of voltage threshold enhances motoneurone excitability during fictive locomotion in the cat.

Experiments were conducted on decerebrate adult cats to examine the effect of brainstem-evoked fictive locomotion on the threshold voltage (Vth) at which action potentials were initiated in hindlimb motoneurones. Measurements of the voltage threshold of the first spike evoked by intracellular injection of depolarizing ramp currents or square pulses were compared during control and fictive locomotor conditions. The sample of motoneurones included flexor and extensor motoneurones, and motoneurones with low and high rheobase currents. In all 38 motoneurones examined, action potentials were initiated at more hyperpolarized membrane potentials during fictive locomotion than in control conditions (mean hyperpolarization -8.0 +/- 5.5 mV; range -1.8 to -26.6 mV). Hyperpolarization of Vth occurred immediately at the onset of fictive locomotion and recovered in seconds (typically < 60 s) following the termination of locomotor activity. The Vth of spikes occurring spontaneously without intracellular current injection was also reduced during locomotion. Superimposition of rhythmic depolarizing current pulses on current ramps in the absence of locomotion did not lower Vth to the extent seen during fictive locomotion. We suggest that Vth hyperpolarization results from an as yet undetermined neuromodulatory process operating during locomotion and is not simply the result of the oscillations in membrane potential occurring during locomotion.The hyperpolarization of Vth for action potential initiation during locomotion is a state-dependent increase in motoneurone excitability. This Vth hyperpolarization may be a fundamental process in the generation of motoneurone activity during locomotion and perhaps other motor tasks.

"Leukemic" pattern of in vitro growth in a patient with Down syndrome and transient myeloproliferative disorder.

Peripheral blood cells from a female infant with Down syndrome and over 60% circulating myeloblasts were cultured in soft agar. Growth was virtually restricted to cluster formation, and cluster-forming cells resided almost exclusively in the very light density fraction (SG less than 1.062). Morphological assessment of clusters revealed no evidence of cellular differentiation beyond the blast cell stage. Despite receiving no specific chemotherapy, the peripheral blood normalized within 2 months, and there was no evidence of leukemia when the patient died aged 1 year from cardiac pathology. The findings indicate that caution should be exercised when assessing prognosis on the basis of in vitro growth characteristics in such patients.

Occurrence of primary hepatocellular cancer and peliosis hepatis after treatment with androgenic steroids.

Three patients are reported in whom treatment of Fanconi's anaemia with androgenic steroids was complicated by the development of either primary hepatocellular cancer (PHC) or peliosis hepatis. The first, a White woman aged 34 years, was found to have PHC after receiving first methyltestosterone and then oxymetholone for a total period of 7 years. She died 4 months after the diagnosis was made. The other 2 patients were White children who presented with peliosis hepatis after receiving methyltestosterone and oxymetholone for 8 years and oxymetholone for 5 years, respectively. Both died from their primary diseases shortly after oxymetholone treatment was discontinued. Possible pathogenic mechanisms involved in the development of these serious complications are discussed and the therapeutic dilemma raised by their occurrence is emphasised.

Feto-maternal haemorrhage following successful and unsuccessful attempts at external cephalic version.

In the present study, 6 out of 100 patients who had an attempted or actual external cephalic version (ECV) showed significant feto-maternal haemorrhage, the amount being greatest in patients with "failed" external versions. Thus ECV may be a source of rhesus iso-immunization in a rhesus negative mother with a rhesus positive fetus and should not be performed unless the father is a rhesus negative. If, however, an ECV has been attempted, fetal cell counts should then be made and rhesus immunoprophylaxis administered if necessary.

Significance of tests of iron nutrition in pregnancy.

Tests of iron and folate nutrition have been carried out in early pregnancy and at delivery in 63 Bantu females. Accepted normal values for serum iron, and percentage saturation of transferrin, but not for unsaturated iron-binding capacity, for non-pregnant subjects were found to apply equally well in pregnancy. Concomitant folate deficiency in early pregnancy did not render tests of iron deficiency less valid. The unsaturated iron-binding capacity, percentage saturation, and marrow iron stores in early pregnancy all showed a significant correlation with the haemoglobin value at term. Patients with normal marrow iron stores and a percentage saturation of transferrin of 20 or more at or before the 24th week are unlikely to become anaemic from iron deficiency during pregnancy.