[The usefulness of tizanidine. A one-year follow-up of the treatment of spasticity in infantile cerebral palsy]. / Utilidad de la tizanidina. Seguimiento de un ano en el tratamiento de la espasticidad en la paralisis cerebral infantil.

INTRODUCTION: The cerebral palsy has the first place of physical handicap in children (type spastic, 88%). Tizanidine imidazole derivative is centrally acting as a a2-adrenergic agonist. AIM: To demonstrate clinically the effectiveness of tizanidine in the decrease of the spasticity. PATIENTS AND METHODS: We assigned randomly in a double blind study 10 children treated with tizanidine (0.05 mg/kg/day) and 30 with placebo for a 6-month period, after which they were unified in the group of tizanidine. The dependent variables were spasticity, Ashworth scale, posture tone scale, reflex scale and liver function test. RESULTS: The spasticity and the reflex decreased in the group of tizanidine an 78.85% in comparison with a 7.64% in the group of placebo (p = 0.0001); in the monitoring of 6 months 35 patients reduced this to 78.2% (p= 0.0001). The duration of effectiveness of tizanidine in four patients was two months and they never returned to their appraisal basal. Without reported adverse effects, the liver function test remains normal. CONCLUSION: Tizanidine produces a significant reduction of the spasticity in children without adverse effects, having a high percentage of acceptance to the prescribe dose.

Combined pituitary hormone deficiency caused by a novel mutation of a highly conserved residue (F88S) in the homeodomain of PROP-1.

Mutations in the pituitary-specific paired-like homeodomain transcription factor, PROP-1, result in combined pituitary hormone deficiency. We studied a Brazilian girl, offspring of first cousins, who presented with short stature and deficiencies of GH, TSH, PRL, LH, and FSH. Her cortisol response to hypoglycemia was determined at age 4.9, 10.7, and 14.1 yr and remained normal. Magnetic resonance imaging at the age of 9 yr revealed an anterior pituitary lobe of diminished height (3 mm; normal, 4.5 +/- 0.6), but radiography revealed a sella turcica volume above the normal mean. Direct sequencing of the PROP-1 gene revealed homozygosity for a novel 263T>C transition that results in the replacement of a highly conserved phenylalanine by serine at codon 88 (F88S). F88 constitutes the hydrophobic core of the first helix of the homeodomain of PROP-1, and the substitution by the polar residue serine is expected to alter the secondary structure and impair binding of the mutated PROP-1 to DNA target sequences. The F88S mutation (which corresponds to murine F85S) was introduced into the murine Prop-1 complementary DNA and its consequences on DNA binding and trans-activation were assessed in vitro. In contrast to wild-type Prop-1, the F88S mutant showed no significant DNA binding to a PRDQ9 Prop-1 response element in gel shift assays. Transcriptional activation of a luciferase reporter gene containing a PRDQ9 site upstream of a simian virus 40 promoter was reduced to approximately 34% compared with that of wild-type Prop-1 in transiently transfected TSA-201 human embryonic kidney cells. The F88S mutation further expands the repertoire of mutations in PROP-1.

The PROP1 2-base pair deletion is a common cause of combined pituitary hormone deficiency.

Combined pituitary hormone deficiency (CPHD) has an incidence of approximately 1 in 8000 births. Although the proportion of familial CPHD cases is unknown, about 10% have an affected first degree relative. We have recently reported three mutations in the PROP1 gene that cause CPHD in human subjects. We report here the frequency of one of these mutations, a 301-302delAG deletion in exon 2 of PROP1, in 10 independently ascertained CPHD kindreds and 21 sporadic cases of CPHD from 8 different countries. Our results show that 55% (11 of 20) of PROP1 alleles have the 301-302delAG deletion in familial CPHD cases. Interestingly, although only 12% (5 of 42) of the PROP1 alleles of our 21 sporadic cases were 301-302delAG, the frequency of this allele (in 20 of 21 of the sporadic subjects given TRH stimulation tests) was 50% (3 of 6) and 0% (0 of 34) in the CPHD cases with pituitary and hypothalamic defects, respectively. Using whole genome radiation hybrid analysis, we localized the PROP1 gene to the distal end of chromosome 5q and identified a tightly linked polymorphic marker, D5S408, which can be used in segregation studies. Analysis of this marker in affected subjects with the 301-302delAG deletion suggests that rather than being inherited from a common founder, the 301-302delAG may be a recurring mutation.

Longitudinal hormonal and pituitary imaging changes in two females with combined pituitary hormone deficiency due to deletion of A301,G302 in the PROP1 gene.

Genomic DNA from 18 patients with combined pituitary hormone deficiency was screened for 2-bp deletion (A301,G302) in PROP1 gene by BcgI restriction endonuclease analysis of PCR-amplified exon 2 gene fragments. Two unrelated female patients were homozygous for this 2-bp deletion. Patient 1 presented at 8.8 yr with severe short stature (-2.9 SD score), slightly enlarged sella turcica at x-rays, and diffusely enlarged pituitary gland (height, 8 mm vs. 4.5 +/- 0.6 mm in matched controls) with hyperintense enhanced signal at T1 weighted image at coronal and sagittal views at magnetic resonance imaging (MRI). MRI repeated at age 15 yr revealed a marked reduction of pituitary height (2 mm vs. 5.3 +/- 0.8 mm in matched controls). Patient 2 presented at 27 yr with short stature (-5.5 SD score) without pubertal development, normal sella turcica, and a pituitary gland of reduced size (height, 5 mm vs. 6.1 +/- 0.3 mm in matched controls) of normal intensity at MRI. Both patients had normal pituitary stalk and normally located neurohypophysis. Hormonal features were characterized by GH, TSH, PRL, LH, and FSH deficiencies. Patient 1 had normal cortisol secretion at 8.8 yr, and at 16.6 yr had developed partial cortisol deficiency, whereas patient 2 maintained normal cortisol secretion at 28.4 yr. We conclude that 1) a large sella turcica and an enlarged pituitary anterior lobe with hyperintense enhanced signal at T1 at MRI can be suggestive of PROP1 deficiency; 2) pituitary morphology can change during follow-up of patients with PROP1 gene mutation; and 3) hormonal deficiencies could include the adrenal axis.

Clinical and molecular characterization of Brazilian patients with growth hormone gene deletions.

Genomic DNA from 23 patients with isolated growth hormone (GH) deficiency (12 males and 11 females: heights -4.9 +/- 1.4 SDS) was screened for GH gene deletions by restriction endonuclease analysis of polymerase chain reaction amplification products. Three unrelated patients had typical features of severe GH deficiency and deletions (6.7 kb in two and 7.6 kb in one) of the GH gene. The two patients with 6.7-kb deletions developed growth-attenuating anti-GH antibodies whereas the patient with the 7.6-kb deletion continued to grow with GH replacement therapy. Our finding that 3/23 (approximately 13%) Brazilian subjects had GH gene deletions agrees with previous studies of severe isolated GH deficiency subjects in other populations. Two of three subjects (67%) with deletions developed blocking antibodies despite administration of exogenous GH at low doses. Interestingly, only 1/10 of cases with affected relatives or parental consanguinity had GH-1 gene deletions.

Insulin-like growth factor-I treatment in two children with growth hormone gene deletions.

Two unrelated Brazilian patients had homozygous 6.7 kb deletions in the GH-1 gene (girl and boy, 1.8 and 3.3 yr, heights -7.9 and -6.0 SDS, respectively). Desensitization using small amounts of exogenous GH (0.033 IU/kg body weight/week, divided into daily s.c. injections) was attempted, but anti-GH antibodies appeared. Replacement with usual doses of hGH induced only transient increase in growth. IGF-I therapy with increasing doses resulted in catch-up growth without side-effects. Growth velocity was 7.5 cm/yr in the first year and 8.4 cm/yr in the next 6 months in patient 1, and 6.7 cm/yr in the first year, 5.9 cm/yr in the second year and 7.9 cm/yr in the third year of IGF-I treatment in patient 2, when the daily dose of 240 micrograms/kg was divided into three injections. IGFBP-3 levels were low (0.55 and 0.40 mg/I) and did not increase after IGF-I treatment, suggesting that this GH effect is not mediated by IGF-I, and injected IGF-I had a rapid disappearance rate. We conclude that IGF-I promotes growth by endocrine mechanisms and constitutes an effective treatment for patients with GH insensitivity secondary to GH antibodies.

Lack of reduction in body fat after treatment with insulin-like growth factor-I in two children with growth hormone gene deletions.

Two patients with growth hormone (GH) gene deletions were treated with recombinant insulin-like growth factor-I (IGF-I) (80-240 (microg/kg/day) and the effects on bone mass and body composition were compared to administration of GH (0.075 U/kg/day) to 8 patients with idiopathic GH deficiency. Bone mass and body composition were measured by dual photon X-ray absorptiometry (DEXA ) before and 3 and 6 months after treatment with GH or IGF-I. Similar increases in growth velocities were observed after GH and IGF-I treatment. Treatment with GH resulted in prompt and significant reduction in body fat percentage (basal, 3 and 6 months: 22+/-10, 17+/-9, and 16+/-9%) whereas body fat percentage remained unchanged after IGF-I therapy (basal, 3 and 6 months: 49, 52 and 48% in patient 1 and 45, 42 and 43% in patient 2, respectively). Fat percentage remained elevated after 18 months of IGF-I treatment in patients 1 (51%) and 2 (44%), respectively. Lean mass and bone mineral content increased with GH and IGF-I therapies. We conclude that reduction of body fat measured by DEXA, observed after administration of GH but not after IGF-I treatment in these children with GH deficiency, suggests that the GH effect on body fat mass is not mediated by circulating IGF-I.

Utilidad de la tizanidina. Seguimiento de un año en el tratamiento de la espasticidad en la parálisis cerebral infantil / The usefulness of tizanidine. A one-year follow-up of the treatment of spasticity in infantile cerebral palsy

Introducción. La parálisis cerebral infantil ocupa el primerlugar de discapacidad (tipo espástico, 88%). La tizanidina es unimidazólico de acción central y agonista que actúa como α2-adrenérgico.Objetivo. Demostrar clínicamente la efectividad de la tizanidinaen la disminución de la espasticidad. Pacientes y métodos.Por asignación aleatoria en estudio doble ciego, se trataron durante6 meses 10 niños con tizanidina (0,05 mg/kg/día) y 30 con placebo,los cuales posteriormente se unificaron en el grupo de la tizanidina.Las variables dependientes fueron la espasticidad, la escalade Ashworth, la escala del tono postural, los reflejos y las pruebasde funcionamiento hepático. Resultados. La espasticidad y los reflejosfueron sistemáticamente menores en el grupo de la tizanidina, demanera que la espasticidad se redujo en un 78,85% frente al 7,64 %con el placebo (p = 0,0001); en el seguimiento de seis meses de los35 pacientes se redujo un 78,2% (p = 0,0001). La duración de laefectividad de la tizanidina en cuatro pacientes fue de dos meses yéstos nunca regresaron a su valoración basal. No se observaron efectosadversos ni la elevación de enzimas hepáticas. Conclusiones. Latizanidina produce una reducción significativa de la espasticidad enniños, sin efectos adversos y con un alto porcentaje de aceptaciónen las dosis prescritas

Introduction. The cerebral palsy has the first place of physical handicap in children (type spastic, 88%). Tizanidineimidazole derivative is centrally acting as a α2-adrenergic agonist. Aim. To demonstrate clinically the effectiveness oftizanidine in the decrease of the spasticity. Patients and methods. We assigned randomly in a double blind study 10 childrentreated with tizanidine (0.05 mg/kg/day) and 30 with placebo for a 6-month period, after which they were unified in the groupof tizanidine. The dependent variables were spasticity, Ashworth scale, posture tone scale, reflex scale and liver function test.Results. The spasticity and the reflex decreased in the group of tizanidine an 78.85% in comparison with a 7.64% in the groupof placebo (p = 0.0001); in the monitoring of 6 months 35 patients reduced this to 78.2% (p= 0.0001). The duration ofeffectiveness of tizanidine in four patients was two months and they never returned to their appraisal basal. Without reportedadverse effects, the liver function test remains normal. Conclusion. Tizanidine produces a significant reduction of thespasticity in children without adverse effects, having a high percentage of acceptance to the prescribe dose