Effect and safety of treatment with ACE-inhibitor Enalapril and β-blocker metoprolol on the onset of left ventricular dysfunction in Duchenne muscular dystrophy - a randomized, double-blind, placebo-controlled trial

Background: X-linked Duchenne muscular dystrophy (DMD), the most frequent human hereditary skeletal muscle myopathy, inevitably leads to progressive dilated cardiomyopathy. We assessed the effect and safety of a combined treatment with the ACE-inhibitor enalapril and the β-blocker metoprolol in a German cohort of infantile and juvenile DMD patients with preserved left ventricular function. Methods, Trial design: Sixteen weeks single-arm open run-in therapy with enalapril and metoprolol followed by a two-arm 1:1 randomized double-blind placebo-controlled treatment in a multicenter setting. Inclusion criteria: DMD boys aged 10–14 years with left ventricular fractional shortening [LV-FS] ≥ 30% in echocardiography. Primary endpoint: time from randomization to first occurrence of LV-FS < 28%. Secondary: changes of a) LV-FS from baseline, b) blood pressure, c), heart rate and autonomic function in ECG and Holter-ECG, e) cardiac biomarkers and neurohumeral serum parameters, f) quality of life, and g) adverse events. Results: From 3/2010 to 12/2013, 38 patients from 10 sites were centrally randomized after run-in, with 21 patients continuing enalapril and metoprolol medication and 17 patients receiving placebo. Until end of study 12/2015, LV-FS < 28% was reached in 6/21 versus 7/17 patients. Cox regression adjusted for LV-FS after run-in showed a statistically non-significant benefit for medication over placebo (hazard ratio: 0.38; 95% confidence interval: 0.12 to 1.22; p = 0.10). Analysis of secondary outcome measures revealed a time-dependent deterioration of LV-FS with no statistically significant differences between the two study arms. Blood pressure, maximal heart rate and mean-NN values were significantly lower at the end of open run-in treatment compared to baseline. Outcome analysis 19 months after randomization displayed significantly lower maximum heart rate and higher noradrenalin and renin values in the intervention group. No difference between treatments was seen for quality of life. As a single, yet important adverse event, the reversible deterioration of walking abilities of one DMD patient during the run-in period was observed. Conclusions: Our analysis of enalapril and metoprolol treatment in DMD patients with preserved left ventricular function is suggestive to delay the progression of the intrinsic cardiomyopathy to left ventricular failure, but did not reach statistical significance, probably due to insufficient sample size. Clinical trial registration: DRKS-number 00000115, EudraCT-number 2009–009871-36

Spinal muscular atrophy with respiratory distress (SMARD1)

Die spinale Muskelatrophie mit Atemnot („respiratory distress“) Typ 1 (SMARD1, syn. DSMA1, MIM #604320) ist eine schwere neuromuskuläre Erkrankung des frühen Kindesalters, bei der es durch eine Lähmung des Zwerchfells zu einer akuten Ateminsuffizienz kommt. Außerdem entwickeln die Patienten aufgrund einer Degeneration der motorischen Vorderhornzellen im Rückenmark eine zunächst distal betonte, dann generalisierte Muskelschwäche und –atrophie. Mit Hilfe einer großen konsanguinen Familie konnten wir den Genort der SMARD1 auf Chromosom 11q13 lokalisieren und das der Erkrankung zugrunde liegende Gen, das IGHMBP2 (Immunoglobulin µ-bindendes Protein 2)- Gen identifizieren. Wir zeigten, dass IGHMBP2 eine aktive 5´-3´RNA/DNA-Helikase ist. Unterschiede im Schweregrad des Krankheitsverlaufs der SMARD1 konnten wir mit einer enzymatischen Restaktivität und mit der Höhe der vorhandenen IGHMBP2-Proteinmenge korrelieren. Anhand des korrespondierenden Mausmodells, der nmd-Maus zeigten wir, dass fehlendes IGHMBP2 noch keinen Einfluss auf die frühe embryonale Entwicklung der Motoneurone hat und diese erst nachdem sie schon einen Axon-Muskel-Kontakt hergestellt haben degenerieren. IGHMBP2 ist ein überwiegend zytoplasmatisches Protein, für das wir eine Assoziation mit Ribosomen nachwiesen und eine Rolle in der Translation postulieren.Spinal muscular atrophy with respiratory distress type 1 (SMARD1, DSMA1, MIM #604320) is a severe neuromuscular disorder of early infancy which leads to an acute respiratory insufficiency due to diaphragmatic paralysis. Patients develop a distal and then generalised muscular weakness and atrophy caused by a degeneration of alpha-motoneurons in the spinal cord. With the help of a large consanguineous family we located the gene locus for SMARD1 on chromosome 11q13 and identified the disease-causing gene IGHMBP2 (Immunoglobulin µ-binding protein 2). We demonstrated that IGHMBP2 is an active 5´-3´RNA/DNA helicase. Differences in disease severity of SMARD1 were correlated with enzymatic rest-activity and remaining IGHMBP2 levels. Examining the corresponding mouse model, the nmd mutant we found that lack of IGHMBP2 has no influence on early embryonic development of motoneurons which degenerate not before they have made contact with muscle cells. IGHMBP2 is a mainly cytoplasmic protein for which we demonstrated an association with ribosomes. We hypothesize that IGHMBP2 has a role in translation

A Paucisymptomatic Neuromuscular Disease Mimicking Type III 5q-SMA With Complex Rearrangements in the SMN Gene

Spinal muscular atrophy is an autosomal-recessive neuromuscular disorder, causing progressive proximal weakness and atrophy of the voluntary muscles. More than 96% of the spinal muscular atrophy patients show a homozygous absence of exons 7 and 8, or exon 7 only, in SMN1, the telomeric copy of the SMN gene. We report a young male patient with neurogenic symptoms and sparse muscle fiber atrophy, suggestive of a mild form of type III spinal muscular atrophy. He was found to be a carrier of intragenic mutations in both copies of the SMN gene, exhibiting a homozygous duplication of exons 7 and 8 in SMN1 and a homozygous deletion of exon 8 as well as a heterozygous deletion of exon 7 in SMN2. However, an intact full-length SMN1 complementary deoxyribonucleic acid was identified, and SMN protein levels in a muscle specimen were identical to that of a healthy control, formally excluding the diagnosis of spinal muscular atrophy III

Effect and safety of treatment with ACE-inhibitor Enalapril and β-blocker metoprolol on the onset of left ventricular dysfunction in Duchenne muscular dystrophy - a randomized, double-blind, placebo-controlled trial

Abstract Background X-linked Duchenne muscular dystrophy (DMD), the most frequent human hereditary skeletal muscle myopathy, inevitably leads to progressive dilated cardiomyopathy. We assessed the effect and safety of a combined treatment with the ACE-inhibitor enalapril and the β-blocker metoprolol in a German cohort of infantile and juvenile DMD patients with preserved left ventricular function. Methods Trial design Sixteen weeks single-arm open run-in therapy with enalapril and metoprolol followed by a two-arm 1:1 randomized double-blind placebo-controlled treatment in a multicenter setting. Inclusion criteria: DMD boys aged 10–14 years with left ventricular fractional shortening [LV-FS] ≥ 30% in echocardiography. Primary endpoint: time from randomization to first occurrence of LV-FS < 28%. Secondary: changes of a) LV-FS from baseline, b) blood pressure, c), heart rate and autonomic function in ECG and Holter-ECG, e) cardiac biomarkers and neurohumeral serum parameters, f) quality of life, and g) adverse events. Results From 3/2010 to 12/2013, 38 patients from 10 sites were centrally randomized after run-in, with 21 patients continuing enalapril and metoprolol medication and 17 patients receiving placebo. Until end of study 12/2015, LV-FS < 28% was reached in 6/21 versus 7/17 patients. Cox regression adjusted for LV-FS after run-in showed a statistically non-significant benefit for medication over placebo (hazard ratio: 0.38; 95% confidence interval: 0.12 to 1.22; p = 0.10). Analysis of secondary outcome measures revealed a time-dependent deterioration of LV-FS with no statistically significant differences between the two study arms. Blood pressure, maximal heart rate and mean-NN values were significantly lower at the end of open run-in treatment compared to baseline. Outcome analysis 19 months after randomization displayed significantly lower maximum heart rate and higher noradrenalin and renin values in the intervention group. No difference between treatments was seen for quality of life. As a single, yet important adverse event, the reversible deterioration of walking abilities of one DMD patient during the run-in period was observed. Conclusions Our analysis of enalapril and metoprolol treatment in DMD patients with preserved left ventricular function is suggestive to delay the progression of the intrinsic cardiomyopathy to left ventricular failure, but did not reach statistical significance, probably due to insufficient sample size. Clinical trial registration DRKS-number 00000115, EudraCT-number 2009–009871-36