Hypoglycaemia in spinal muscular atrophy

Repeated episodes of hypoglycaemia were observed in two girls with spinal muscular atrophy. During a 12 h fast blood glucose fell to 3.4 and 2.7 mmol/L, respectively. One girl developed hypoglycaemia and ketonuria. Reduced gluconeogenesis was probably the cause of hypoglycaemia in these patients who had a muscle mass of about 10% of bodyweight (normal 30-40%). Hypoglycaemia must be suspected and treated when patients with severe muscle wasting due to chronic neuromuscular disorders are admitted comatose. In our experience this condition is often regarded as respiratory insufficiency.     

The prenatal diagnosis of spinal muscular atrophy

Trimethyltin (TMT) causes prominent neuronal damage and enhanced expression of neuropeptide Y in the hippocampus. We investigated expression of neuropeptide Y Y2 receptors after TMT intoxication. Markedly elevated (by 470%) concentrations of Y2 receptor mRNA were found in the suprapyramidal blade of the dentate granule cell layer after 5 days. Increases in the infrapyramidal blade were less prominent (by 198%). After 16 days, mRNA levels in both blades of the granule cell layer showed no significant difference from those in controls. Quantification of Y2 receptor-specific binding revealed no significant change at both 5 and 16 days after TMT intoxication. It is suggested, together with a previous report describing a similar increase of neuropeptide Y expression, that a transient expression of Y2 receptors in the dentate gyrus in the initial phase of TMT intoxication may be involved in mediating TMT-induced hippocampal damage.     

Axonal neuropathy and predominance of type II myofibers in infantile spinal muscular atrophy

Two affected siblings with infantile spinal muscular atrophy (SMA I) presented with generalized muscular hypotonia, which progressed to early death. Quadriceps muscle biopsy did not show the typical neurogenic pattern of spinal muscular atrophy. The histochemical fiber type determination revealed a predominance of type II fibers without type I hypertrophy, an unprecedented finding in spinal muscular atrophy. Sural nerve biopsy exhibited findings typical for axonal neuropathy. In one patient, electrical stimulation of peripheral nerves showed an inexcitability of motor and sensory nerves. Genetic studies revealed homozygous deletions of the telomeric survival motor neuron (SMN) gene and the neuronal apoptosis inhibitory protein (NAIP) gene in the affected children. This is the second case report of molecular genetically proven spinal muscular atrophy associated with axonal neuropathy. We conclude atypical findings on muscle biopsy and evidence of axonal neuropathy are compatible with the diagnosis of infantile spinal muscular atrophy.     

Mapping of the spinal muscular atrophy (SMA) gene to a 750-kb interval flanked by two new microsatellites

The gene for autosomal recessive proximal spinal muscular atrophy (SMA) has recently been mapped between D5S629 and D5S557. We report here a new single-locus microsatellite A31 (D5S823) and two multicopy microsatellites 97T-CA and 95/23-CA. The marker A31 maps to the region of overlap between YACs y116, y55 and y122, distal to D5S629; 97T-CA originates from a cosmid corresponding to the STS 97T, localized distally to A31, while 95/23-CA derives from a cosmid corresponding to the STS 97U, localized proximally to D5S557. We tested all our key recombinant families with these markers. In one type I/II SMA family, a recombinant was found that placed the SMA locus distal to D5S823. Homozygosity mapping in a consanguineous type I SMA family indicates that the SMA gene lies proximal to 95/23-CA. Thus, the two new markers, A31 and 95/23-CA further refine the SMA gene to an approximately 750-kb interval.     

Infantile spinal muscular atrophy. An unusual disease with various differential diagnoses

Patients with human immunodeficiency virus (HIV) infection are prone to severe drug reactions, mainly from sulfonamides. We report the case of a 33-year-old male patient with HIV infection (group IV C-2 of CDC staging system) that developed a toxic epidermal necrolysis (TEN) affecting more than 70% of the body surface area and severe mucosal involvement after starting fluconazole for a recurrent oral thrush with dysphagia. This is to our knowledge the first reported case of TEN due to fluconazole.     

Spinal pathology in spinal muscular atrophy in comparison with amyotrophic lateral sclerosis

We analyze neuronal cytopathology and secondary reactions in spinal-muscular atrophy (SMA) in comparison with amyotrophic lateral sclerosis (ALS). In a series of SMA and ALS cases, immunohistochemistry was performed on spinal cord sections for neuronal, astroglial and microglial antigens, ubiquitin and tau proteins. Swollen motoneurons staining for phosphorylated neurofilament proteins are seen in most SMA but few ALS cases. Ubiquitinated inclusions are found only in ALS. In SMA, glial bundles are prominent in anterior roots, to lesser extent in posterior roots. In ALS, glial bundles are seen only in some cases. While basic histopathologies are similar in both types of motor neurone diseases, neuronal cytoskeletal pathology is more prominent in SMA, possibly reflecting a more acute degenerative process. The presence of axon spheroids and glial bundles also in posterior horns/roots of both types of motor neurone disease suggests spread of degenerative pathology beyond the motor system.     

Congenital axonal neuropathy caused by deletions in the spinal muscular atrophy region

Three newborn siblings presented with generalized weakness, asphyxia, facial diplegia, and external ophthalmoplegia. Electrophysiological testing showed inexcitability of motor and sensory nerves and myographic signs of denervation. Nerve biopsies and postmortem examination showed loss of myelinated fibers and axonal damage in sensory and mixed nerves. Many spinal motor neurons were chromatolytic although their number was normal. Molecular genetic investigations revealed a homozygous deletion of the survival motor neuron (SMN) gene and a loss of markers Ag1-CA and C212 in the paternal haplotype. These findings are consistent with the diagnosis of an unusually severe type of spinal muscular atrophy. Given the large extent of the deletion, it must be considered that the unusual severe phenotype with involvement of brainstem nuclei and afferent nerves might also be due to changes of yet unknown genes neighboring the SMN gene.     

De novo deletions in spinal muscular atrophy: implications for genetic counselling

We monitored 12 patients undergoing major abdominal surgery using a pulse oximeter (Nellcor N-200) and a transcutaneous oxygen tension monitor (TINA, Radiometer A/S) on the second or third night after operation. Of the shortest hypoxaemic episodes measured with the pulse oximeter (< or = 30 s duration), 78% also occurred in the transcutaneous oxygen tension measurement. Episodes of longer duration (> or = 1 min duration on the pulse oximeter) were, in 95% of cases, reflected in the transcutaneous oxygen tension measurement also. Thus postoperative episodic desaturations lasting > or = 1 min are at least 95% likely to be a real phenomenon.     

The distribution of SMN protein complex in human fetal tissues and its alteration in spinal muscular atrophy

Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder characterized by degeneration of motor neurons of the spinal cord and muscular atrophy. SMA is caused by alterations to the survival of motor neuron (SMN) gene, the function of which has hitherto been unclear. Here, we present immunoblot analyses showing that normal SMN protein expression undergoes a marked decay in the postnatal period compared with fetal development. Morphological and immunohistochemical analyses of the SMN protein in human fetal tissues showed a general distribution in the cytoplasm, except in muscle cells, where SMN protein was immunolocalized to large cytoplasmic dot-like structures and was tightly associated with membrane-free heavy sedimenting complexes. These cytoplasmic structures were similar in size to gem. The SMN protein was markedly deficient in tissues derived from type I SMA fetuses, including skeletal muscles and, as previously shown, spinal cord. While our data do not help decide whether SMA results from impaired SMN expression in spinal cord, skeletal muscle or both, they suggest a requirement for SMN protein during embryo-fetal development.     

Body composition determined with MR in patients with Duchenne muscular dystrophy, spinal muscular atrophy, and normal subjects

OBJECTIVE: To examine the feasibility of using spectral analysis techniques to identify potential biomarkers of diminished postural control in elderly individuals. DESIGN: Data from spectral signatures (derived from postural sway) of 21 young adults and 42 elderly individuals classified as "high" or "low" risk with regard to functional balance capacity were analyzed using Risk Category (3) x Sensory Condition (3) multivariate analyses of variance. Postural control was challenged by varying the visual conditions under which individuals stood on a measurement platform. RESULTS: Results indicated that measures of central tendency and dispersion of the spectral frequency distribution from medial-lateral components of sway (but not antero-posterior sway) clearly differentiated between "high" and "low" risk elderly. Low risk elderly were not different from young adults. High risk elderly exhibited greater dispersion and lower mean frequency than other groups. CONCLUSIONS: Differences in spectral characteristics of medial-lateral components of sway were more related to risk category than to age. Elderly persons with high functional balance capacity displayed characteristics similar to those of young adults. Thus, spectral frequency analysis techniques may be a clinically useful tool for identifying individuals potentially at risk of falling.     

Successful pregnancies in the presence of spinal muscular atrophy: two case reports

We report two cases of successful pregnancy in women with chronic, infantile onset, or type II spinal muscular atrophy, both of whom delivered healthy, unaffected babies. The patients required concurrent management by a physiatrist, pulmonologist, and perinatologist throughout the pregnancy. Complications included recurrent urinary tract infections, dyspnea and worsening of pulmonary function, wheelchair seating and positioning problems, and musculoskeletal and low back pain. These problems resolved postpartum. One woman had vaginal delivery, the other had caesarean section, both of which were well-tolerated. Because of severe musculoskeletal deformity, pelvic assessment is necessary to determine the mode of delivery. The uterus has normal contractility and effective labor patterns can be established. Spinal/epidural anesthesia may be contraindicated because of spine deformity. The pregnancies had no deleterious effect on the progression of the disease in our patients, both of whom reported a positive experience with great personal fulfillment.     

Disturbances of neuromuscular interaction may contribute to muscle weakness in spinal muscular atrophy

During a critical period of development, motoneurones and muscles are dependent on functional interaction with each other for their survival. In certain neuromuscular disorders such as spinal muscular atrophy (SMA), motoneurones die and muscle development is seriously affected. Recently advances have been made towards understanding the genetic basis of this disease, and a particular gene, i.e. the survival motoneurone gene (SMN), has been identified and found missing in SMA patients. Nevertheless the function of this gene is not clear, it may be involved in the control of the development of either the motoneurone or the muscle. Here we report that disrupting neuromuscular interaction during the early postnatal period has similar consequences on the development of muscles and motoneurones to those seen in patients with SMA, in that there is a loss of motoneurones and muscle function is severely impaired. In view of this, we discuss the possibility that these symptoms in SMA patients may be due to a disturbance of neuromuscular interaction during a critical stage of development.     

Kinematic analysis of patients with spinal muscular atrophy during spontaneous breathing and mechanical ventilation

Dinoseb is a herbicide known to inhibit photosystem II electron transfer like DCMU, triazine and phenolic-type herbicides. The mutant Din7 of the cyanobacterium Synechocystis sp. PCC 6803, selected for resistance to dinoseb, and the mutant Ins2, constructed by the insertion of the kanamycin resistance cassette into the drgA gene, were cross-resistant to other nitrophenolic herbicides (DNOC, 2,4-dinitrophenol) and to the cell inhibitor metronidazole but not to the photosystem II inhibitors DCMU or ioxynil. The Din7 mutant had the same characteristics of photosystem II inhibition by dinoseb as the wild type. This result suggested the existence of another site for dinoseb inhibition. The wild type cells modified dinoseb to a non-toxic product that gave an absorption spectrum similar to that of dithionite treated dinoseb containing reduced nitro groups. In contrast, the Din7 mutant did not modify dinoseb. These phenomena were controlled by the drgA gene encoding a protein which showed similarity to several enzymes having nitroreductase activity. The addition of superoxide dismutase to the medium relieved the toxic effect of dinoseb in wild type cells but not in Din7. It is proposed that in wild type cells of Synechocystis sp. PCC 6803 the DrgA protein is involved in detoxification of dinoseb via the reduction of the nitro group(s) and this process is accompanied by the formation of toxic superoxide anions. Mutations blocking the activity of the DrgA protein lead to the development of resistance to nitrophenolic herbicides and metronidazole.     

Refined linkage map of chromosome 5 in the region of the spinal muscular atrophy gene

The genetic map in the region of human chromosome 5 that harbors the gene for autosomal recessive forms of spinal muscular atrophy (SMA) has been refined by a multilocus linkage study in 50 SMA-segregating families. Among six markers spanning 8 cM for combined sexes, four were shown to be tightly linked to the SMA locus. Multipoint linkage analysis was used to establish the best estimate of the SMA gene location. Our data suggest that the most likely location for the SMA locus is between blocks AFM114ye7 (D5S465)/EF5.15 (D5S125) and MAP-1B/JK53 (D5S112) at a sex-combined genetic distance of 2.4 and 1.7 cM, respectively. Thus the SMA gene lies in the 4-cM region between these two blocks. This information is of primary importance for designing strategies for isolating the SMA gene.     

Contribution of the electromyogram in the diagnosis of infantile spinal muscular atrophy in the neonatal period

Iodide inhibits several thyroid parameters through an organic intermediate, and this process has been related to thyroid autoregulation. The aim of this study was to determine the effect of iodine on thyroglobulin (Tg) synthesis in the rat thyroid cell line FRTL-5. TSH stimulated amino acid incorporation into the cells by 400% and iodine had no effect on this parameter. No effect of TSH or iodide on [35S] methionine incorporation into protein was found under our experimental conditions (approximately 80% of total [35S]methionine incorporated was found in TCA-precipitable material). TSH caused an increase in Tg synthesis, after 1 h, while iodide partially blocked the effect of TSH (control 6.4% of TCA precipitable radioactivity; TSH 10.7%; iodide 8.4%). After 24 h, the protein released into the medium was measured. TSH stimulated total protein liberation and iodide inhibited this parameter. TSH stimulated total RNA content, and iodide caused an inhibition. Northern analysis did not show inhibition by iodide of TSH-stimulated Tg mRNA levels. The present results show an inhibitory effect of excess iodide on TSH-stimulated thyroglobulin biosynthesis in FRTL-5 cells.     

Parapapillary chorioretinal atrophy in patients with ocular hypertension. II. An evaluation of progressive changes

OBJECTIVE: To determine whether parapapillary chorioretinal atrophy in patients with ocular hypertension remained stationary or progressed along with glaucomatous optic nerve damage. METHODS: The morphometric parameters and progression of parapapillary atrophy were retrospectively investigated, using serial photographs, in 350 eyes of 175 patients with ocular hypertension. The association of parapapillary atrophy progression with subsequent glaucomatous conversion and with other baseline patient- and eye-specific characteristics was analyzed. RESULTS: Progression in the area and extension of parapapillary atrophy before noticeable optic disc or visual field changes was observed in 48 (49.0%) of 98 eyes that converted to glaucoma, while parapapillary atrophy progression was noted in 25 (9.9%) of 252 ocular hypertensive eyes that did not develop glaucomatous damage (P<.001). The predictive sensitivity and specificity of this observation were 49% and 90%, respectively. In a logistic multiple regression model, the progression of parapapillary atrophy was associated with a family history of glaucoma (odds ratio, 2.7) and the initial size of zone beta (odds ratio, 1.64, for an increase of 0.10 of the zone beta area-disc area ratio). CONCLUSION: The progression of parapapillary chorioretinal atrophy may be an early glaucomatous finding in some patients with ocular hypertension.     

The spinal muscular atrophy gene region at 5q13.1 has a paralogous chromosomal region at 6p21.3

We have examined acetaminophen (paracetamol) dosing for outpatient management of posttonsillectomy pain in children. Forty children, 5-15 years of age, undergoing tonsillectomy and their parents were randomly assigned to use a scheduled administration of acetaminophen in weight appropriate doses, 60 mg.kg-1.24h-1 orally, 90 mg.kg-1.24h-1 rectally, or to use acetaminophen 'as needed' according to present standards (control group). Postoperative pain was assessed by the child using the poker chip tool for the first three days after discharge. The prevalence of pain amongst all the children was high. The second day after discharge 22%-64% of the children in the study group and 36%-73% of the children in the control group rated severe pain. Recommended dose ranges of acetaminophen do not provide sufficient pain relief in children following tonsillectomy. Further studies are required to determine, whether higher doses of acetaminophen or analgesics with different analgesic properties will lead to improved analgesia in children following tonsillectomy.