The Natural Course of Infantile Spinal Muscular Atrophy With Respiratory Distress Type 1 (SMARD1)
Background: Only scarce information is available on the long-term outcome and the natural course of children with infantile spinal muscular atrophy with respiratory distress type 1 (SMARD1) due to mutations in the IGHMBP2 gene.
Objective: To describe the natural disease course, to systematically quantify the residual capacities of children with SMARD1 who survive on permanent mechanical respiration, and to identify markers predicting the disease outcome at the time of manifestation.
Methods: We conducted a longitudinal study of 11 infantile SMARD1 patients over a mean observational period of 7.8 (SD 3.2) years. Disease-specific features were continuously assessed by using a semiquantitative scoring system. Additionally, we analyzed the residual enzymatic activity of 6 IGHMBP2 mutants in our patients.
Results: After an initial rapid decline of the clinical score until the age of 2 years, residual capabilities reached a plateau or even improved. The overall clinical outcome was markedly heterogeneous, but clinical scores at the age of 3 months showed a positive linear correlation with the clinical outcome at 1 year and at 4 years of age. If expressed in an in vitro recombinant system, mutations of patients with more favorable outcomes retained residual enzymatic activity.
Conclusions: Despite their severe disabilities and symptoms, most SMARD1 patients are well integrated into their home environment and two thirds of them are able to attend kindergarten or school. This information will help to counsel parents at the time of disease manifestation.
- DSMA —
- distal spinal muscular atrophy
- DSMA1 —
- distal spinal muscular atrophy type 1
- IGHMBP2 —
- immunoglobulin μ-binding protein 2
- OMIM —
- Online Mendelian Inheritance of Man
- SMA —
- spinal muscular atrophy
- SMARD1 —
- spinal muscular atrophy with respiratory distress type 1
What Is Known On This Subject:
Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a progressive, inherited neuromuscular disease manifesting with diaphragmatic paralysis in the first year of life. All patients need mechanical ventilation.
What This Study Adds:
We describe the natural course of SMARD1, developed a scoring system, and defined prognostic values. The clinical outcome of the patients was heterogeneous, and residual enzymatic activity of the IGHMBP2 protein was associated with a more benign disease course.
Infantile spinal muscular atrophy with respiratory distress type 1 (SMARD1, OMIM 604320), also known as distal spinal muscular atrophy type 1 (DSMA1), is characterized by a sudden onset of respiratory distress within the first 13 months of life and initially distal and later generalized muscular weakness. One of the presenting symptoms is respiratory failure due to diaphragmatic paralysis. Other symptoms, albeit not always present, include intrauterine growth retardation, dysfunction of the autonomic nervous system (eg, excessive sweating, cardiac arrhythmia, arterial hypertension, or bladder dysfunction), and seizures.1–5
SMARD1 is caused by autosomal-recessive mutations in the gene encoding immunoglobulin μ-binding protein 2 (IGHMBP2, OMIM *600502).1 IGHMBP2 is a superfamily 1, 5′-3′ DNA/RNA-helicase that, in addition to its helicase domain, also contains a single-stranded nucleic acid binding domain of the R3H type and a zinc-finger motif.6 Similar to the survival motor neuron protein 1 (SMN1), which is absent or altered in classic spinal muscular atrophy (SMA), IGHMBP2 is also ubiquitously expressed and has a cell-type specific phenotype with motoneurons and myocytes being predominantly affected.7,8 In cell metabolism, IGHMBP2 has been found to be involved in nuclear processes such as regulation of transcription and tRNA processing.9–12 Additionally, it associates with ribosomes in the cytoplasm.13 Functional analysis of SMARD1-related mutants of IGHMBP2 revealed the importance of the helicase function for the pathogenesis of the disease, because most known missense mutations were localized in the helicase domain and disrupt RNA/DNA unwinding activity in vitro.2,13 However, the exact succession of pathologic events leading from a dysfunctional IGHMBP2 to the clinical manifestation of this disorder is still unknown.
Distal spinal muscular atrophy is a genetically heterogeneous disorder,14,15 and in addition to SMARD1/DSMA1, further clinical variants of DSMA with a later onset of symptoms have been described. DSMA2 was mapped on chromosome 9p21.1-p12.16 A third gene locus, causing DSMA3, has been mapped close to the IGHMBP2 gene locus, but the disease-causing gene is still elusive.17 DSMA4 is caused by mutations in the gene encoding Pleckstrin homology domain-containing protein, family G member 5 (PLEKHG5)18 and DSMA5 by mutations in the Glycyl-tRNA-synthetase gene (GARS).19 To clinically delineate the various early- and late-onset forms of distal spinal muscular atrophy from SMARD1, we have conducted a cluster analysis of clinical symptoms4 showing that the probability of finding mutations in IGHMBP2 in patients with respiratory distress and suspected SMARD1 can be predicted by the following items: (1) manifestation age of respiratory distress between 6 weeks and 6 months, (2) presence of diaphragmatic paralysis, (3) distal muscular weakness, and (4) intrauterine growth retardation. A late-onset form of SMARD1 (juvenile SMARD1) in 2 patients had been correlated with higher residual steady-state protein levels of functional IGHMBP2 protein.20
Approximately 60 cases with infantile SMARD1 have been published.1–4,14,15,21–27 So far, we have a detailed description of the clinical characteristics of SMARD1 at the time of disease manifestation. However, many open questions remain with regard to the natural course and the long-term clinical outcome of SMARD1 patients who receive continuous ventilatory support. Until now, only one report describes the clinical course in 6 patients between 4.5 and 11 years of age.21
Herein, we have conducted a prospective and partially retrospective long-term observational study in patients with IGHMBP2 mutations who survived on ventilator support. Additionally, we integrated biochemical and molecular findings to look for genotype-phenotype correlations. Our data from long-term observations will help parents, physicians, and health care professionals to make informed decisions regarding the management of this complex disorder.
The study was approved by the Institutional Ethic Review Board of the Charité, Berlin, Germany, on August 4, 2002. Inclusion criteria comprised the presence of pathogenic IGHMBP2 mutations and survival beyond the first year of life. We chose the “end of the first year of life” as an inclusion criterion because, at this age, parents and caregivers had decided in most cases in favor or against permanent mechanical ventilation (see Supplemental Table 4). We contacted the physicians or parents of 17 patients, asked them to participate in the study and to complete a follow-up questionnaire. Eleven parents gave their written informed consent according to the Declaration of Helsinki and returned a sufficiently completed questionnaire. The study investigators have revisited and physically examined 9 of the 11 patients (patients 5 and 8 were not visited personally).
Questionnaire and Quantification of Disease Severity
From all items in the questionnaire we considered for tabulation only those clinical features for which answers had been provided in >80% (Tables 1–3). For semiquantitative assessment of the clinical outcome we identified 10 items that changed during the observational period and thus may reflect important developmental stages in the clinical course of SMARD1. These were (1) onset of mechanical ventilation; (2) onset of muscle weakness, remaining antigravity movements in (3) arms and (4) legs, (5) sitting without support, (6) holding the head upright while in sitting position, (7) reduction in facial expression, (8) the ability to speak, (9) freedom from cerebral seizures, and (10) dysfunction of the autonomic nervous system. From these 10 items we calculated monthly sum scores (yes = 1/no = 0) at the first year of life and yearly thereafter. To take the normal development of children into account, we expressed the sum score obtained in each individual patient as a percentage of the sum score that would have been obtained by a normally developing child of the same age (Fig 1, Supplemental Fig 4). The images on Fig 2 illustrate the clinical course of 4 exemplary patients. Supplemental Table 4 provides clinical information on SMARD1 patients who died within the first 13 months of life.
Protein purification and biochemical investigations of ATPase and RNA helicase activity were performed as previously described.13 In brief, the mutations were introduced into pBluescript KSII(−)-cloning vector (Stratagene) containing the sequence of wild-type IGHMBP2 by site-directed mutagenesis followed by subcloning into expression plasmids and bacterial expression of the different constructs (Fig 3A). After purification, wild-type and mutant proteins were used for ATPase and RNA helicase assays using radiolabeled substrates (Fig 3B and 3C).13
In total, we investigated in recombinant proteins 6 IGHMBP2 mutations [p.H213R (c.638A>G), p.C241R (c.721T>C), p.L361P (c.1082T>C), p.D565N (c.1693G>A), p.L577P (c.1730T>C), and p.V580I (c.1738G>A)], all within the helicase domain and present in SMARD1 patients with different clinical outcomes. p.H213R had also been found in the homozygous state in a previously described SMARD1 patient (patient 2 in ref 1, patient 10 in ref 2, and patient 5 in ref 21). The enzymatic activity of the p.T493I variant (patient 8) had been investigated in detail before.13,20
Description of the Patient Cohort
Six female and five male patients between 2 and 14 years of age were observed over an average period of 7.8 (SD 3.2) years. Because IGHMBP2 mutations are typically identified between the first and second year of life, previous phenotypic data were collected retrospectively. The occurrence of SMARD1-characteristic clinical symptoms and the IGHMBP2 mutations for patients 1 to 11 are given in Table 1.
Evaluation of the Natural Course of SMARD1
As previously reported,2 we observed the most dramatic disease progression, that is, loss of independent breathing and muscle strength, between 2 and 9 months of life (Table 2). By 9 months, all patients were mechanically ventilated. Only 1 patient (patient 9) could be weaned from mechanical ventilation during the observation period. This girl was on permanent respiratory support between 9 months and 4 years of age. From 4 years onwards she regained independent breathing for about 8 hours per day. Now, at the age of 6.5 years, she is off the ventilator for about 12 hours per day and, despite her persisting complete diaphragmatic paralysis (verified by ultrasound), she is able to breathe using her accessory respiratory muscles. In all patients, loss of muscle strength went in parallel with diaphragmatic paralysis. In most cases, legs were affected earlier than arms, and in all children muscle weakness was more pronounced distally. No patient was able to walk with or without assistance, and all could be mobilized in a wheel chair. All children lived at home, with the exception of patient 2, who lived in a care facility and had contact with other children. We did not observe cardiomyopathy in 7 of 11 patients who were regularly investigated by cardiac ultrasound. Dysfunction of the autonomic nervous system, that is, excessive sweating, cardiac arrhythmia, or constipation, was observed in all patients, the latest beyond 9 years of age. At the end of the observational period 7 of 11 patients had normal facial expression, 4 of 11 were able to sit and hold the head, and 6 of 11 could speak or vocalize through a speech cannula or a leak in their tracheal cannula. Five of 10 children remained seizure-free (Supplemental Fig 4).
Overall, the prognosis of SMARD1 patients is poor. However, we observed a heterogeneous clinical course with marked differences in the disease outcome ranging between 10% and 70% of the maximum score achievable at the end of the observational period (Fig 1B). Seven of 11 patients showed an upward trend in terms of improving their clinical score between 1 and 3 years of age (Fig 1B).
In addition, we investigated whether an initial high or low score would predict a more or less favorable outcome. The plot of clinical scores at 3 months versus 12 and then 48 months (Fig 1C) revealed a high initial correlation of r2 = 0.79 (3 versus 12 months) which later declined to r2 = 0.52 (3 versus 48 months). However, patient 5 seemed to be an exception to this trend, because he started with a 100% score at 3 months and had an outcome of 10% at the age of 9 years. If aggregated, the data indicate that an initial high score might predict a more favorable disease course. To illustrate the different courses of SMARD1, clinical images of 4 children with different outcomes (10%, 40%, and twice 70% of the maximum score achievable) are shown in Fig 2.
We further reevaluated 11 children, in whom we had made the molecular diagnosis of SMARD1, but who had died in the meantime. As shown in Supplemental Table 4, the main cause of death in 9 of 11 SMARD1 patients before 1 year of age was respiratory failure after a decision against intubation or mechanical ventilation was withdrawn. Only 2 patients (patients 12 and 13) died of medical complications possibly related to mechanical ventilation (eg, sepsis, pneumonia). We therefore assume that SMARD1 patients who died during their first year of life did not have a priori a more severe disease phenotype than those who were mechanically ventilated.
Next, we investigated whether long-term outcome scores might correlate with the enzymatic activities of the mutant IGHMBP2 proteins. To address this question, we compared a selection of 6 mutant IGHMBP2-variants with the wild-type protein for ATPase and RNA unwinding activity. We chose to test missense mutations present in patients with different outcomes.
In the ATPase assay, the p.H213R and p.D565N mutants were still able to hydrolyze ATP similar to the wild-type protein (Fig 3B). However, when tested for helicase activity, only the p.H213R mutant was able to unwind RNA duplexes (Fig 3C). In summary, mutations p.C241R, p.L361P, p.L577P, and p.V580I cause a severe loss of enzymatic activity, whereas p.H213R displays no apparent reduction. The p.D565N mutation uncouples ATPase from helicase activity as previously described.13
This report and previous studies1–4,14,15,21–27 on the clinical syndrome of SMARD1 have shown that respiratory failure due to diaphragmatic paralysis is the first and most prominent clinical symptom. It often manifests in the first year of life as a life-threatening event. Muscle weakness progresses rapidly after the onset of respiratory distress. Hence, a “pro-life” decision to initiate mechanical ventilation is often made before SMARD1 can be genetically confirmed. However, this may be different in other children from families where the diagnosis had been established earlier and prenatal testing was performed.
In classic SMA types, clinical symptoms occur in a different order. In SMA1, proximal muscle weakness is the presenting symptom and respiratory function slowly declines thereafter because of progressive weakness of the accessory respiratory muscles. Therefore, the decision about permanent mechanical ventilation is made at a later age (8.6 ± 12.8 months).28 In SMARD1, however, sudden respiratory distress is often the manifesting symptom, and muscle weakness becomes clinically obvious only around the time or shortly after clinical manifestation. Disease manifestation is rather dramatic and has led to cases of sudden infant death syndrome in the past.2 The difference between the 2 disease entities becomes even more striking if SMARD1 is compared with SMA2. At the time when SMA2 patients are able to sit independently, they usually do not need ventilatory support yet, whereas all SMARD1 patients are ventilated well before they are able to sit unsupported. However, many SMARD1 children never reach the stage of sitting without support (Table 2, Supplemental Fig 4). Most SMA patients have some residual diaphragmatic function and can thus be treated with noninvasive positive pressure mask ventilation.29 Unfortunately, this does not seem to be an option for SMARD1 patients who, in most cases, completely lack any voluntary respiratory effort.
Infantile SMARD1 is a severe neuromuscular disorder with an overall poor outcome. A rapid worsening of the clinical condition within the first 2 years of life is typical for the disease and is followed by a disease plateau or even some clinical improvement. There are, however, remarkable differences in the natural course of SMARD1, which can already be predicted to a certain degree by the clinical condition at the age of 3 months. We did not anticipate how well most patients were able to take part in daily life activities. All patients had regular contact with other children and more than two thirds attended kindergarten or school. Approximately 70% of the patients had normal cognitive function if assessed subjectively by the parents and teachers. However, the cognitive and intellectual development of SMARD1 patients needs to be addressed in greater detail by a future study.
Some SMARD1 patients showed a transient or permanent improvement of muscular strength after the age of 2 years. This improvement might be because of the regeneration of muscle fibers; however, we were not able to test this hypothesis by repeated muscle biopsies. Interestingly, in nmd (neuromuscular degeneration) mice that carry a mutation in the murine Ighmbp2 gene, we were able to find regenerating muscle fibers in older homozygous mutant animals being most prominent in the diaphragm.7 It seems that in one of our patients (patient 9), such regenerating fibers were obviously sufficient to partially restore respiratory function of the accessory respiratory muscles of the chest, while her diaphragm remained completely paralyzed. Because, aside from respiratory failure, nmd mice also tend to die of dilated cardiomyopathy,30 we routinely assessed the cardiac function in our patients. Follow-up by cardiac ultrasound was possible in 7 patients, but no signs of cardiomyopathy were detected during the observational period. However, taking into account that cardiac problems might occur later in life, as seen in congenital myopathies or muscular dystrophies,31 cardiac function should continuously be monitored in SMARD1 patients.
All but one child (patient 2) have been discharged from hospital into a home care situation. The impact of home care on the parents and family life is immense, because all children are dependent on mechanical ventilation. All children required fulltime care, which could not always be provided by external home nursing services. In Germany, some parents were connected by a parent advocacy group (http://www.intensivkinder.de). Internationally, other forums can be found on the homepage of “Families of SMA” (http://www.fsma.org or http://www.jtsma.org.uk).
Three SMARD1 patients with an outcome score >50% (patients 4, 8, and 9) carried mutations that retained some catalytic activity. In vitro testing of mutant proteins revealed residual ATPase activity in p.D565N, p.T493I,13 and p.H213R, and even residual helicase activity in p.H213R and p.T493I. These findings corroborate our previous observation in a case of late-onset juvenile SMARD1 with high residual levels of functional IGHMBP2 protein.20 However, the notion that high residual IGHMBP2 enzymatic activity may delay disease progression or manifestation age must be handled with caution for mainly 2 reasons. (1) only the p.H213R mutation occurred in a homozygous state and all other mutations were compound heterozygotes; hence, the exact contribution of each mutation to the phenotype cannot be clearly defined. (2) This study only assesses the in vitro catalytic activity of recombinant mutant IGHMBP2 proteins and does not consider their actual tissue levels, which may depend on various factors such as mRNA expression levels, increased in vivo degradation of partially misfolded IGHMBP2 protein, or a potential disruption of protein interaction.
In conclusion, we report for the first time distinct variations in the long-term natural course and outcome of SMARD1 and relate it to residual IGHMBP2 enzymatic activity. Such information on the natural course of SMARD1 will considerably assist decision making by physicians and parents. Because not all SMARD1-related mutants could be tested for their enzymatic activity, the genotype-phenotype relations described here await confirmation in a larger cohort.
This work was funded by the Deutsche Forschungsgemeinschaft (HU 408/3-2,-3) and by a generous donation of the parents’ self support group “Helft dem muskelkranken Kind” Hamburg e.V. Dr von Au received a Rahel-Hirsch fellowship from the Charité. Dr Idkowiak received a long-term research fellowship from the European Society for Paediatric Endocrinology (ESPE). Dr Schuelke was supported by the Deutsche Forschungsgemeinschaft via the NeuroCure Cluster of Excellence (Exc 257).
We wish to thank all patients and their families for their participation in this study and the attending physicians and caregivers for their cooperation, among many others Prof. G. P. Comi (Milano, Italy), Dr. G. Schreiber (Kassel, Germany), and Prof. M. Albani / S. Schenk (Wiesbaden, Germany). We thank Dr S. Eichholz (Dresden, Germany) for providing us with a photograph of a patient.
- Accepted September 7, 2011.
- Address correspondence to Dr med Katja von Au, Department of Neuropediatrics, Charité, Universitätsmedizin Berlin, Campus Virchow Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany. E-mail:
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
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