Efficacy of nusinersen in type 1, 2 and 3 spinal muscular atrophy: Real world data from Hungarian patients.

INTRODUCTION: Spinal muscular atrophy (SMA) is an autosomal recessive disorder caused by a homozygous deletion of the survival motor neuron (SMN) 1 gene. Nusinersen is an antisense oligonucleotide enhancing the production of the SMN protein. It has received approval by the European Medicines Agency (EMA) in 2017, based on the clinical trials demonstrating the effectiveness of nusinersen in several types of SMA. In Hungary, the first patient received nusinersen treatment in April 2018. Our aim is to summarize our experience regarding the efficacy, safety and tolerability of nusinersen in our patients. METHODS: Data were collected retrospectively in all types of SMA patients (type 1-3) starting treatment with nusinersen in Hungary between April 2018 and December 2019. Motor functions were evaluated at baseline, at the fourth and all following injections. RESULTS: By 31st December 2019, nusinersen therapy was initiated in 54 patients at either of the two Hungarian treatment centres. Mean age of the patients at the start of the treatment was 6.3 years (±5,4 range 0.4-17.9). 13 patients are type 1 (mean 0.78 ± 0.27, range 0.4-1.5 yrs), 21 patients are type 2 (mean 4.5 ± 3.3, range 1.3-12 yrs), 23 patients are type 3 (mean 10.9 ± 5.2, range 2.9-17.9 yrs). Fourteen patients had severe scoliosis, four of them underwent spine stabilizing surgery. During the study period 340 injections were administered without any new safety concerns emerging. The data of 38 patients, who had completed the first six treatments, were included in the final statistical analysis. Motor function has improved in most of the children. By the 307th day visit, on average, a 14.9 (±5,1) point improvement was measured on the CHOP INTEND scale in type 1 patients (p = 0.016). All patients with type 1 SMA who performed the motor evaluation (7/10) have improved by more than four (7-21) points. Regarding type 2 patients, a 7.2 (range -2- 17) point increase from baseline (p < 0.001) on the Hammersmith Functional Motor Scale Expanded (HFMSE) and 4.3 (range: 2-9) point increase (p = 0.031) on the Revised Upper Limb Module (RULM) were found. The distance of the 6 min walk test also increased by 33.9 m on average (range -16 - 106), in type 3 patients. CONCLUSION: According to our results nusinersen has the same safety and tolerability profile as in the clinical trials. In a heterogenic patient population of SMA type 1 and 2, nusinersen showed similar efficacy as seen in the pivotal studies. A clinically and statistically significant improvement of motor functions was also detectable in type 3 patients with heterogeneous age distribution.

The use of drugs in mothers of offspring with neural-tube defects.

OBJECTIVE: To study the risk of maternal drugs use during pregnancy in the origin of isolated neural-tube defects (NTD). MATERIALS AND METHODS: 1202 cases with NTD, 38,151 population controls without any defects and 22,475 patient controls with other defects were compared in the population-based data set of the Hungarian Case-Control Surveillance of Congenital Abnormalities (HCCSCA), 1980-1996. The HCCSCA contains 542 drugs, however only those drugs were evaluated which included five or more mothers in the NTD group. Drugs with the same chemical structures were combined. In addition, only drug use in the second month of pregnancy was evaluated because it is the critical period for NTD. Of course, it is necessary to exclude different biases, mainly recall bias at the evaluation of these drugs. Of 121 chemicals, only oxytetracycline, carbamazepine and valproic acid had some association with NTD. High doses of exogenous oestrogens, clomiphene, chorionic gonadotropin, lynesterol and ergotamine also seemed to have some indirect association with NTD because their exposures occurred more frequently before the critical period of NTD due to maternal infertility. CONCLUSION: Our findings suggest that drugs used during pregnancy do not appear to substantially contribute to the occurrence of isolated NTD but some drugs have a role in the origin of these defects.

Parental employment status and neural-tube defects and folic acid/multivitamin supplementation in Hungary.

OBJECTIVE: To study the role of parental employment status as indicator of socio-economic status (SES) in the origin of neural-tube defect (NTD) and in the use of periconceptional folic acid/multivitamin supplementation. MATERIALS AND METHODS: One thousand two hundred and two cases with neural-tube defects, 38,151 population controls without any defects and 22,475 patient controls with other defects were compared in the population-based data set of the Hungarian case-control surveillance of congenital abnormalities, 1980-1996. RESULTS: The proportion of professionals was lower, while the proportion of semi- and unskilled workers was higher in the neural-tube defect group compared with the population control group. However, the comparison of neural-tube defect and patient control groups showed a lower socio-economic status in the patient control group. In addition, the socio-economic status of fathers in the neural-tube defect group seemed to be better than in the population and patient control groups. The higher periconceptional folic acid supplementation and the higher use of multivitamins during pregnancy occurred in the professional and managerial categories in all the three study groups. CONCLUSION: The occurrence of neural-tube defect shows a slight socio-economic dependence in the mothers at the comparison with population control group, however, patient control group had the lowest socio-economic status. The higher maternal education goes together with a higher proportion of periconceptional folic acid supplementation.

An evaluation of maternal illnesses in the origin of neural-tube defects.

OBJECTIVE: The objective of the study was to estimate risk of acute and chronic maternal diseases during pregnancy in the origin of neural-tube defects. MATERIALS AND METHODS: Mothers with neural-tube defect fetuses/newborns (the NTD group), controls without any congenital defects (the normal control group) and controls with other defects (the other CA control group) were compared in the population-based data set of the Hungarian Case-Control Surveillance of Congenital Abnormalities, 1980-1996. Of 1,202 cases with neural tube defects, 559 (49.8%) and 229 (19.1%) had mothers with one or more acute and chronic diseases, respectively. Of 38,151 mothers in the normal control group 14,004 (36.7%) and 8,328 (21.8%) had mothers with one or more acute or chronic diseases, respectively. Of 22,475 mothers in the other CA control group, 8,999 (40.0%) and 3,793 (16.9%) were affected with one or more acute or chronic maternal diseases, respectively. The prevalence of these diseases was evaluated in the 2nd months of gestation, however, if diseases occurred in the 1st month and continued in the 2nd month were also included. RESULTS: There was a potential recall bias between the NTD group and the normal control group, but not between the NTD group and the other CA control group. CONCLUSIONS: We suggest that maternal fever is a possible cause of neural-tube defects. Thus, these fevers should be treated with antipyretics during pregnancy. Among chronic maternal diseases, the possible association of migraine-headache, on the one hand and neural tube defects (particularly anencephaly) on the other hand cannot be excluded.

Periconceptional multivitamin supplementation and multimalformed offspring.

OBJECTIVE: To study the human teratogenic risk of a folic acid-containing multivitamin. METHODS: We evaluated the data set of two Hungarian intervention studies: a randomized double-blind, controlled trial and a two-cohort, controlled study of the same folic acid-containing multivitamin in participants of the Hungarian periconceptional service. RESULTS: Of 2471 supplemented and 2391 unsupplemented women, 18 and 21, respectively, had multiple congenital abnormalities in the randomized, controlled trial. Of 3056 supplemented and unsupplemented pairs in the two-cohort, controlled study, 33 and 32, respectively, were affected with multiple congenital abnormalities. After the combination of two data sets, the number of cases with multiple congenital abnormalities was 51 in the supplemented group and 53 in the unsupplemented group (odds ratio 0.89; 95% confidence interval 0.45, 1.68). In addition, there was no difference in the occurrence of specified multiple congenital abnormality entities or of unidentified multimalformed informative offspring. CONCLUSION: We found no evidence that periconceptional folic acid-containing multivitamin supplementation either prevents or induces multiple congenital abnormalities.