Krankheitsverlauf der infantilen spinalen Muskelatrophie Typ I : Implikationen für zukünftige Therapiestudien und die genetische Beratung

The present work describes the disease course of 66 patients with infantile spinal muscular atrophy (SMA) type I. We examined several clinical and molecular genetic factors that may modify the disease course and affect the survival of the patients. This was done with the intention to define a historical control group for future clinical trials. Those patients were eligible who were diagnosed between 2000 and 2005 and whose diagnosis of SMA had been confirmed genetically in one of the participating laboratories (Aachen, Cologne, Würzburg) within six months of age. All patients had a homozygous deletion of the SMN1 gene. Recruitment was through pediatric facilities. Of the 174 patients who met the inclusion criteria, parents of 66 patients agreed to participate, completed questionnaires, and consented to the review of medical reports and further DNA studies. Using dosimetric methods (MLPA and real-time PCR), the SMN2 copy number of the patients was determined. Disease endpoint was defined by age at death or the age when either tracheostomy or permanent (>14 days) ventilation was performed. Kaplan-Meier survival analysis was calculated with SPSS version 13 for windows, the statistical comparison of survival course was performed with the log rank or Mantel-Haenszel test if applicable. A statistical analysis of the mean/median was performed using the Man-Whitney-U-test, and to identify correlations two-sided tests with Pearson correlation coefficient were applied. A p value of <0.05 was regarded as significant. Age at onset was within 4.5 months in all patients (median / mean 1.2 / 1.4 months). The majority (86.4%) of patients showed two SMN2 copies. In four patients (6.1%), only a single copy of SMN2 was seen. Five patients (7.6%) had three SMN2 copies. The clinical course oft the four unrelated single copy patients was most severe with prenatal onset of muscle weakness, congenital contractures and respiratory distress from birth. Three patients with a single SMN2 gene copy had congenital heart defects (atrial or ventricular septal defects) that were not explained by intrauterine muscle weakness, respiratory insufficiency at birth or other causes, suggesting a causal link between severe SMN deficiency and impaired cardiogenesis. Overall, the disease course depended on the SMN2 copy number. We investigated the effects of pneumonia, supportive treatment such as tube feeding or medication, the achievement of motor milestones, and of gender on disease progression. We found no significant increase or decrease of survival by the individual factors. Only the age at onset and the SMN2 copy number had an impact on survival. Still, the clinical course of children with two SMN2 copy numbers can be very different, for which other modifying factors are to blame. Ten children in this study received valproic acid (VPA), no positive effect could be proved. We also described the clinical course of eight patients who received mechanical ventilatory support for more than month before their death. Survival analysis in SMA I differed in previous studies depending on the in- and exclusion criteria used and were difficult to compare with or study or with each other. Cumulative death statistics according to age at onset groups in previous studies were similar to ours. We presented several possible historical control groups (two SMN2 copies, both with and without VPA treatment, with no respiratory problems at birth), which could be used for future clinical trials. In summary, this work represents an important further step towards the understanding of spinal muscular atrophy and possible treatment. In our study, we tried to reduce to a minimum any potential selection of cases that might be caused by either clinical or geographical factors. Unfortunately, the response rate was only 38%. To get a larger control group, this study should be extended to other countries.

Grantor dc:publisher

Publikationsserver der RWTH Aachen University

Year dc:date

2010

Author dc:creator

• Berg, Corinna Margarete

Contributors dc:contributor

• Rudnik-Schöneborn, Sabine

• info:eu-repo/classification/ddc/610
• Spinale Muskelatrophie
• Humangenetik
• Medizin
• SMA
• infantile spinal muscular atrophy

Statement dc:rights

• info:eu-repo/semantics/openAccess

Language dc:language

ger

Identifier

https://publications.rwth-aachen.de/search?p=id:%22RWTH-CONV-114054%22

OAI record oai:identifier

https://publications.rwth-aachen.de/oai2d?verb=GetRecord&metadataPrefix=oai_dc&identifier=oai%3Apublications.rwth-aachen.de%3A51802