If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Spinal muscular atrophy is a rare genetic disease with devastating neurodegenerative consequences. Timing of diagnosis is crucial for spinal muscular atrophy because early diagnosis may lead to early supportive care and reduction in patient and caregiver stress. The purpose of this study was to examine the published literature for diagnostic delay in spinal muscular atrophy.
Methods
A systematic literature search was conducted in the PubMed and Web of Science databases for studies published between 2000 and 2014 that listed any type of spinal muscular atrophy and without molecular, mouse, or pathology in the keywords. Mean and/or median age of onset and diagnosis and delay in diagnosis was extracted or calculated. All estimates were weighted by the number of patients and descriptive statistics are reported.
Results
A total of 21 studies were included in the final analysis. The weighted mean (standard deviation) ages of onset were 2.5 (0.6), 8.3 (1.6), and 39.0 (32.6) months for spinal muscular atrophy types I, II, and III, respectively, and the weighted mean (standard deviation) ages of confirmed spinal muscular atrophy genetic diagnosis were 6.3 (2.2), 20.7 (2.6), and 50.3 (12.9) months, respectively, for types I, II, and III. For studies reporting both age of onset and diagnosis, the weighted diagnostic delay was 3.6, 14.3, and 43.6 months for types I, II, and III, respectively.
Conclusions
Diagnostic delay is common in spinal muscular atrophy. The length of delay varied by severity (type) of spinal muscular atrophy. Further studies evaluating this delay and tools such as newborn screening are warranted to end the diagnostic delay in spinal muscular atrophy.
Spinal muscular atrophy (SMA) is a neuromuscular disease that affects approximately 1 in 6000 to 1 in 11,000 live births in the United States with a high carrier frequency of 1 in 40 to 60.
SMA is an autosomal recessive disorder caused by mutations in the survival motor neuron (SMN) 1 gene and is characterized by degeneration of the motor neurons in the spinal cord, which results in progressive muscular atrophy and weakness.
It has been shown that another gene, SMN2, codes for a protein similar to that encoded by the SMN1 gene and multiple copies of SMN2 can somewhat compensate for the loss of the SMN1 gene and alleviate the severity of clinical symptoms observed.
Correlation between SMN2 copy number and clinical phenotype of spinal muscular atrophy: three SMN2 copies fail to rescue some patients from the disease severity.
Approximately 50% of patients diagnosed with SMA have type I, which has an early onset; these infants usually do not survive beyond the first 2 years without intervention.
Type I patients have the most severe form of SMA with extensive muscle weakness, are never able to sit without support, and have increasing difficulty over time with swallowing and feeding, and respiratory difficulties.
In type II SMA, the onset of symptoms occurs slightly later than in type I and, although type II children are generally able to sit without support and some may stand, they are never able to walk independently. Type II SMA patients can present with varying severity of bone weakness (such as scoliosis), weakness in swallowing or chewing, and respiratory problems.
Patients with type III SMA have less severe symptoms and are able to walk and reach the major motor milestones, but often lose the ability to walk over time as the disease progresses.
Although awareness of SMA is increasing, diagnostic delay is common as SMA symptoms can vary widely in onset and severity and can resemble other diseases.
This also may be due to the potential lack of expertise in this area for many health care professionals who may often rule out other diagnoses before considering SMA. Data on the frequency and extent of the diagnostic delay in SMA are limited. The objective of this systematic review was to evaluate the diagnostic delay in SMA and to identify potential factors for this delay based on the published literature.
Materials and Methods
A systematic review of the literature was conducted using the PubMed and Web of Science databases. Articles in English that were published between January 1, 2000, and August 21, 2014, were identified using the search terms: (“spinal muscular atrophy” OR “Werdnig-Hoffmann”) AND (“type 1” OR “type I” OR infantile) NOT (pathology OR molecular OR mouse OR mice) for SMA type I; and “spinal muscular atrophy” AND (“type 2” OR “type II” OR “type 3” OR “type III”) NOT (pathology* OR molecule* OR mouse OR mice) for SMA types II and III. This time frame was chosen because the genetic test for SMN1 became available in the late 1990s.
Included in the analysis were articles that reported age of first symptom onset and/or age of confirmed SMA genetic diagnosis. Studies with a prenatal SMA diagnosis, no confirmed genetic case, or adult onset patients (≥18 years of age) and publications of case reports or case series were excluded.
Age of symptom onset, age of diagnosis as confirmed by genetic testing, and diagnostic delay were evaluated across studies. Age of onset was defined as the age of the patient when the first symptom was observed as reported by parents or caregivers using questionnaires or collected from medical charts in chart review studies. The age of diagnosis was defined as the age of the patient when SMA diagnosis was confirmed with genetic testing. Diagnostic delay was defined as the time between the age of onset and age of confirmed diagnosis and was calculated directly if both age of onset and diagnosis were reported in the same study. The mean and standard deviation (SD) of age of onset, confirmed diagnosis, and diagnostic delay for studies that reported mean ages were weighted by the number of patients in each study. The weight for each study was the proportion of patients in that study among all patients with the available age information. For example, the weight for Harada et al.
Correlation between SMN2 copy number and clinical phenotype of spinal muscular atrophy: three SMN2 copies fail to rescue some patients from the disease severity.
Correlation between SMN2 copy number and clinical phenotype of spinal muscular atrophy: three SMN2 copies fail to rescue some patients from the disease severity.
; Table 1) divided by the total number of patients. The weighted mean age was then calculated as the sum of the product of ages reported in the study and the associated weights for the study. For studies that only reported median ages, the range of the medians was extracted. If both median and mean were reported, the mean was used in the analysis. As a sensitivity analysis, studies that reported median ages were analyzed and reported separately. An analysis of potential overlap in study populations in publications using the same dataset also was conducted. Age of onset and diagnosis also were examined by type of SMA, region (North America, Europe, and Asia Pacific), and year of publication.
Table 1Characteristics and Findings for Included Studies: Studies Reporting Means
Included in both Tables 1 and 2 because the study reported mean age of onset for type II patients and median age of onset for part of type III patients.
Poland, Germany
Retrospective chart review with questionnaire survey
II
175
NR
Normal sitters, n = 128: 6.6 (2.3) Delay sitters, n = 47: 9.6 (2.7)
NR
57 type II and 186 type III patients genetically confirmed
Correlation between SMN2 copy number and clinical phenotype of spinal muscular atrophy: three SMN2 copies fail to rescue some patients from the disease severity.
A genetic and phenotypic analysis in Spanish spinal muscular atrophy patients with c.399_402del AGAG, the most frequently found subtle mutation in the SMN1 gene.
1 copy = 1 type I and 1 type II patient; 2 copies = 2 type III patients; 3 copies = 2 type II and 2 type III patients 5 patients without SMN1 deletion excluded
Natural course of scoliosis in proximal spinal muscular atrophy type II and IIIa: descriptive clinical study with retrospective data collection of 126 patients.
Retrospective chart and registry review with questionnaire survey
I
107
61 M, 46 F
3.1 (2.7)
9.0 (12.8)
II
105
62 M, 43 F
8.7 (3.8)
23.0 (15.0)
III
25
17 M, 8 F
21.1 (11.7)
64.7 (49.3)
Abbreviations:
F = Female
M = Male
NR = Not reported
SD = Standard deviation
SMN = Survival motor neuron
∗ Included in both Tables 1 and 2 because the study reported mean age of onset for type II patients and median age of onset for part of type III patients.
† Excluded one adult-onset patient.
‡ Number of patients based on participants' reported age of onset and/or diagnosis.
The initial search and screening by title resulted in 355 publications (Fig 1). After reviewing the abstract, 204 publications were excluded because they did not meet the search criteria. The remaining 151 publications were reviewed in detail and an additional 130 were excluded because they did not meet the inclusion criteria. After excluding case reports, case series, and publications with only adult onset patients, a total of 21 publications were included in the final analysis (Table 1, Table 2, Fig 1). Of these, 11 articles reported only age of onset, five reported only age of confirmed diagnosis, and five reported both age of onset and confirmed diagnosis (Table 1, Table 2). Although some publications included mean age information on more than one type of SMA, 11 articles studied SMA type I, 11 studied SMA type II, and 7 studied SMA type III (Table 3). Evaluation of potential overlap in patients from publications reporting data from the same dataset revealed no double counting of patients in the studies. Clinical research studies were the most common type of study (12; 57.1%), followed by retrospective chart review and registry review (six; 28.6%), and retrospective chart review with questionnaire survey (three; 14.3%). Six studies were conducted in North America, eight in Europe, five in Asia, one in Turkey, and one in Australia (Table 1, Table 2).
Figure 1Selection of studies for review. SMA, spinal muscular atrophy.
Included in both Tables 1 and 2 because the study reported mean age of onset for type II patients and median age of onset for part of type III patients.
Poland, Germany
Retrospective chart review with questionnaire survey
II
175
NR
NA
NR
57 type II and 186 type III patients genetically confirmed
III
266
8 for delayed walking (walked after 18 month of age, n = 27)
2 copies = 23 type I and 2 type II patients; 3 copies = 9 type I and 43 type II patients
II
45
18 M, 27 F
IIa: 11.0 (IQR 7-12) IIb: 8.5 (IQR 6-12)
IIa: 11.5 (IQR 9-14) IIb: 13.0 (IQR 10-18)
Abbreviations:
F = Female
IQR = Interquartile range
M = Male
NA = Not applicable
NR = Not reported
SD = Standard deviation
SMN = Survival motor neuron
∗ Included in both Tables 1 and 2 because the study reported mean age of onset for type II patients and median age of onset for part of type III patients.
Numbers are not mutually exclusive because one study could have reported on more than one type of SMA. Only studies with mean ages available are included (Table 1).
Total no. of studies included in the analysis
11
11
7
No. of studies only reporting age of onset
7
7
4
No. of studies only reporting age of confirmed diagnosis
1
3
2
No. of studies reporting both age of onset and age of confirmed diagnosis
Numbers are not mutually exclusive because one study could have reported on more than one type of SMA. Only studies with mean ages available are included (Table 1).
Retrospective chart review and registry review
4
1
0
Retrospective chart review with questionnaire survey
2
2
1
Clinical research
5
8
6
Abbreviation:
SMA = Spinal muscular atrophy
∗ Numbers are not mutually exclusive because one study could have reported on more than one type of SMA. Only studies with mean ages available are included (Table 1).
The weighted mean ± SD age of onset was 2.5 ± 0.6 months (range 1.0-11.0 months; number of patients, n = 420) for SMA type I, 8.3 ± 1.6 months (range 2.0-18.0 months; n = 357) for SMA type II, and 39.0 ± 32.6 months (range 5.0-192.0 months; n = 63) for SMA type III (Table 4, Fig 2). Weighted mean ± SD age of confirmed diagnosis was 6.3 ± 2.2 months (range 0.6-9.0 months; n = 271), 20.7 ± 2.6 months (range 1.2-72.0 months; n = 219), and 50.3 ± 12.9 months (range 3.0-82.8 months; n = 63) for SMA types I, II, and III, respectively (Table 4, Fig 2).
Table 4Weighted Mean Age of Onset, Confirmed Diagnosis, and Diagnostic Delay
Case reports and studies reporting only median age were excluded; data weighted by total number of patients evaluated in studies that met the search criteria.
∗ Case reports and studies reporting only median age were excluded; data weighted by total number of patients evaluated in studies that met the search criteria.
Figure 2Age of onset and diagnoses by type of SMA. SMA, spinal muscular atrophy. (The color version of this figure is available in the online edition.)
For the subset of studies that reported both age of onset and age of diagnosis, SMA type III patients had the longest delay (43.6 months; n = 25), followed by type II (14.3 months; n = 105), and type I had the shortest delay in diagnosis (3.6 months; n = 264; Table 4). For SMA type I, the difference between the weighted mean age of confirmed diagnosis (6.3 months) and the weighted mean age of onset (2.5 months) was 3.8 months, which was similar to the diagnostic delay measured in the subset of studies that included both age of confirmed diagnosis and mean age of onset (3.6 months; Table 4). Similarly, for SMA type II, the difference of 12.4 months was comparable to the delay in diagnosis observed in the subset of studies that included both age of confirmed diagnosis and mean age of onset (14.3 months). However, in SMA type III the difference between mean age and age of onset was 11.3 months versus 43.6 months from studies that evaluated both of these outcomes. In the studies that reported only medians (n = 6), the range of reported median age of onset was 1.2-3.0 months for SMA type I, 7.5-15.0 months for type II, and 8.0-24.0 months for type III (Table 5). The median age of diagnosis was 2.3-6.0 months for SMA type I, 11.5-13.2 months for type II, and 42.0 months for type III (Table 5).
Table 5Range of Median Age of Onset, Diagnosis, and Diagnostic Delay in SMA
A subgroup analysis by region (data not shown) indicated that patients in North America appeared to have been diagnosed earlier than those in Europe or the Asia Pacific region. The weighted mean age of onset was greatest for SMA type III in North America compared with those in Europe and the Asia Pacific region. An analysis of delay in diagnosis by year of publication did not show any clear trends (data not shown). A further analysis of age of onset by SMN2 copy number also was inconclusive due to the small number of studies (n = 3) reporting SMN2 copy numbers and mean age of diagnosis (data not shown).
Discussion
This is the first extensive systematic literature review to study the diagnostic delay in SMA. Our review included a wide range of studies from several regions and our results show that there is an apparent delay between when a patient with SMA shows symptoms to when the diagnosis is confirmed. From the results of this review, the only factor directly related to the length of delay in diagnosis was the type of SMA. The shortest delay in diagnosis was observed for SMA type I patients and the longest delay was for type III patients, indicating that severity of disease has an impact on time to diagnosis. Although we analyzed delay of diagnosis by geographic region and year of study publication, we did not find a clear correlation between delay in diagnosis and these factors, likely due to the small sample size.
It has been noted that the delays in diagnosis of SMA resulted from patient visits to multiple health care professionals to rule out the possibility of other illnesses before genetic testing for SMA was performed and a confirmed diagnosis was obtained.
This “diagnostic odyssey” from the time first symptoms are noticed to a confirmed genetic diagnosis of SMA puts patients and caregivers through physical and mental stress.
Although it is not clear what kind of functional loss occurs during the delay, a later diagnosis may result in a missed opportunity for optimal early intervention for SMA. Early diagnosis and care of SMA also can lead to lower patient and caregiver burden; therefore, tools for improving the appropriate and early detection of SMA, such as newborn screening, may be warranted.
Regular newborn screening is currently not standard practice in the United States, although the SMA-determining gene was identified in 1995 and the test is available.
Newborn blood spot screening test using multiplexed real-time PCR to simultaneously screen for spinal muscular atrophy and severe combined immunodeficiency.
A long delay to diagnosis has been noted in other pediatric diseases as well. For example, a median delay of 1.4 months to 12.6 years from symptom onset to diagnosis has been noted in patients with Pompe disease,
It is important to identify ways to reduce these delays to diagnosis for all pediatric diseases to provide earlier intervention for disease management or appropriate treatment. As shown in other childhood diseases,
earlier treatment has been associated with better outcomes and suggests that in a neurodegenerative condition such as SMA, an earlier diagnosis, particularly for type I and II patients, will be immensely helpful to increase the chance of survival using optimal care and supportive interventions.
A strength of this study is the application of stringent criteria by including only those publications that based diagnosis on confirmed genetic testing and excluding any case studies or case series. These criteria allowed us to obtain robust estimates (i.e., less affected by special cases in case report studies) for patients that were properly diagnosed with current technology, such as genetic testing. Moreover, the weighted mean age of onset and weighted mean age of diagnosis appeared to match between studies that reported only the age of onset or age of confirmed diagnosis and those that reported both age of onset and confirmed diagnosis, which indicates the validity of the findings. However, this study has a few limitations. The number of publications evaluated overall is small, and of these only a few focused on SMA type III; therefore, it is difficult to draw any conclusions for type III. Also, the age of onset may be affected by parental recall bias and could be more common in SMA type III patients because of the longer diagnostic delay. Therefore, more studies on age of onset and diagnosis of SMA, particularly type III, are needed to provide a reliable estimate of the diagnostic delay in these patients.
Conclusions
This systematic review clearly indicates that there is a delay in diagnosis of SMA and that the length of delay varies by the severity (type) of SMA. Based on the publications examined for this review, it is difficult to conclude if other factors are related to the delay. Newborn screening, which has resulted in improved outcomes for pediatric patients with other diseases such as cystic fibrosis,
may provide an opportunity for earlier diagnosis of SMA and could be the most effective solution to end this SMA diagnostic odyssey. Future studies are necessary to confirm the observations in this report, to examine the extent of functional decline during the prediagnosis period, and to evaluate the potential negative impact the process of obtaining an appropriate diagnosis has on patients and families of patients with SMA.
Biogen provided funding for this review and for editorial support in the development of this paper; Aruna Seth, PhD, from Excel Scientific Solutions wrote the first draft of the manuscript based on input from authors, and Elizabeth Cassell from Excel Scientific Solutions copyedited and styled the manuscript per journal requirements. Biogen reviewed and provided feedback on the paper to the authors. The authors had full editorial control of the paper and provided their final approval of all content.
Conflict of interest: C-W.L. was an intern at Biogen when this study was conducted. S.K. and W-S.Y. are full-time employees of Biogen.
Correlation between SMN2 copy number and clinical phenotype of spinal muscular atrophy: three SMN2 copies fail to rescue some patients from the disease severity.
A genetic and phenotypic analysis in Spanish spinal muscular atrophy patients with c.399_402del AGAG, the most frequently found subtle mutation in the SMN1 gene.
Natural course of scoliosis in proximal spinal muscular atrophy type II and IIIa: descriptive clinical study with retrospective data collection of 126 patients.
Newborn blood spot screening test using multiplexed real-time PCR to simultaneously screen for spinal muscular atrophy and severe combined immunodeficiency.
00275-1&id=gr1.jpg){kind=link}
00275-1&id=gr2.jpg){kind=link}