Areas of improvement in the medical care of SMA: evidence from a nationwide patient registry in Germany

Spinal muscular atrophy (SMA) is a genetic neurodegenerative disease of the second motoneuron that causes progressive impairment of motor skills. Inheritance of SMA is autosomal recessive due to mutations of the survival motor neuron (SMN1) gene. Yet, depending on the expression of the paralougous SMN2 gene, there is considerable variability in disease onset, morbidity, and life expectancy [1, 2].

SMA is traditionally classified into four subtypes according to age at onset of clinical symptoms and highest motor function milestone achieved. In SMA type 1 (SMA1), disease onset occurs in the first six months of life with impaired head control and progressive weakness of the respiratory muscles, so that most children require invasive ventilation or die before 2 years of age. In SMA type 2 (SMA2), the disease begins before 18 months of age, children show motor developmental delay, with sitting being the highest motor milestone achieved, which some lose over time into adulthood. In SMA type 3 (SMA3), all patients are able to walk, and two subtypes are distinguished: type 3a, with disease onset before 3 years of age and tendency to lose the ability to walk in adulthood, and type 3b, with disease onset beyond 3 years of age [2]. Until now, adult SMA frequently included patients who had previously been classified as SMA4, since they only were diagnosed in adulthood when symptoms of motor involvement became more disabling. However, careful exploration of the medical history often point towards an earlier onset in late childhood or adolescence, and the majority of patients also harbor 3–4 SMN2 copies, same as seen in patients with SMA3, so the existence and frequency of a SMA type 4 (SMA4) phenotype is controversial [3].

In recent years, the introduction of several novel treatments that target SMN2 splicing to increase SMN protein expression (e.g., nusinersen and risdiplam) has dramatically transformed the prognosis of SMA [4, 5]. As a result, it is therefore now possible to modify the natural history of the disease, resulting in new phenotypes that are challenging to classify [6]. However, in most geographical areas, including Germany, little is known about the uptake and impact of these therapies in real-world clinical practice [7‐10].

The objective of this study was to describe current motor function, need of assistive devices, and therapeutic and supportive interventions provided by the healthcare system, as well as the socioeconomic situation of children and adults with different SMA phenotypes. Our aim was to identify areas of improvement in the current medical management of SMA in Germany.

In this study, we examined demographic, clinical, and socioeconomic characteristics, as well as therapeutic and supportive interventions, among German children and adults with SMA identified via a nationwide disease-specific registry. Our findings reveal a change in the natural history of the disease, where all children with SMA1 acquired the ability to sit, and one child with SMA2 was able to walk. Natural history reports on SMA1 reveal that patients never achieve the ability to sit independently, and typically die because of respiratory failure at a median age of between 7 and 13 months [11, 12]. For patients with SMA2, natural history reports show that children achieve the ability to sit independently; yet, without specific therapy they never will be able to walk and over time some of them may lose the ability to sit independently [11, 13]. At the same time, our results are also indicative of the detrimental, progressive nature of SMA, where the majority of adults with SMA3 already had lost their ability to walk. Taking into account the age of our study population, this finding is in line with natural history reports [11, 13, 14]. We also found that impairment in upper limb function, scoliosis, and bulbar dysfunction were more common in patients with poor lower limb and trunk function, which again supports previous observations [15, 16]. Given the availability of novel, highly efficacious, and potentially curative therapeutic options and newborn screening programs ensuring timely identification and intervention, there is undoubtedly the potential for major phenotype shifts within the traditional SMA subtypes. The approach of classifying SMA according to the patient’s current level of motor function (i.e., non-sitter, sitter, walker) can thus help the medical community to monitor disease progress more accurately and to inform and improve appropriate medical care.

In total, 55% of all participants in this study were treated with nusinersen. This was in line with our expectations, as nusinersen was the first disease-specific treatment marketed in Germany for SMA (made available in 2017). However, a change in treatment preference in adults towards risdiplam was observed in those with decreasing lower limb motor function and higher scoliosis prevalence. Nevertheless, 22% of all participants still did not receive any specific therapy. In particular, this was most common among patients with SMA3 and sitters. Accordingly, there still seems to be some hesitation in, or barriers to, initiating specific treatment in this patient population in Germany. Possible explanations include lack of awareness of existing therapy options, disadvantages due to intrathecal application, and/or possible side-effects, especially in patients with slow disease progress or severe scoliosis [14, 17, 18].

We also identified notable deficiencies in the rehabilitation treatment of patients with SMA. For example, less than 25% of our cohort reported using orthoses and physiotherapy support among adults with SMA3b or walkers was also relatively infrequent. Indeed, orthoses can be helpful in SMA patients with impaired walking ability, regardless of motor subgroups, to support lower and upper limb function, and physiotherapy is recommended not only in children to improve motor development, but also in the adult population to promote function and mobility, as well as aerobic and general conditioning training [19]. Although impaired upper limb function is a potential limitation in everyday life, it is surprising that only a minority of participants receive functional rehabilitation treatment to improve hand skills. Therefore, awareness should be improved to facilitate access to physiotherapy and occupational therapy in SMA. Similarly, coverage of speech therapy in non-sitters and sitters, which can help provide more endurance and safe swallowing, was limited. Greater awareness of such symptoms (e.g. through proactive questioning) is recommended to ensure optimum supportive treatment [16, 20‐23]. Similarly, with an overall prevalence of NIV of over 20%, we would also expect cough support to be used in all patients requiring NIV (at a minimum) [23]. Possible explanations for the identified gaps in rehabilitation care include lack of awareness of the need for rehabilitation treatment, limited availability of qualified therapists locally, difficulties in obtaining a prescription, or refusal by the patients themselves due to time constraints or low appreciation of the potential benefits [14]. Yet, this topic warrants further study to help improve prognosis and quality of life as better awareness of disease symptoms is needed to improve lung function and reduce respiratory impairment.

We found differences in relationship status of adults with SMA, where all walkers lived in marriage/relationship with their own family compared to sitters and non-sitters. In line with previous research, these findings suggests that motor skill impairment and disease comorbidity play a role in family planning [24‐28].

Among adults with SMA, 60% had a high school diploma or other higher education entrance qualification and 36% had a university degree. These rates are almost twice as high as those derived for the German general population (34% and 18%, respectively) [29]. On the other hand, a significantly greater proportion of adults with SMA2 did not finish a vocational training (i.e., had not learned a profession) compared to SMA3. Although we cannot rule out that patients with academic education are more interested and willing to participate in research, this result could be an indication that the impact of the disease on motor functions at a young age encourages patients to opt for more academic education, as impairment of motor skills may discourage the choice of an apprenticeship.

The proportion of unemployed adults, 41% in all subgroups, was seven times higher than the German average (5.6%), which is somewhat surprising given their above-average education level [30]. Adults from the walker subgroup were less often unemployed than adults from the sitter and non-sitter groups, but still clearly above the German average. It seems reasonable to think that not only reduced motor function contributes to the high unemployment rate, but that the labour market generally is not sufficiently inclusive for people with chronic diseases, regardless of their vocational training. Therefore, future studies should investigate the reasons for the higher unemployment rate and support programs need to be developed to facilitate and improve vocational training and access to the labour-market for patients with SMA.

The main limitation of our study concerns external validity. Patients were recruited through a nationwide SMA registry for which participation is voluntary and patient/family-initiated. The response rate was only 21%. We therefore cannot rule out a degree of selection bias. Another limitation concerns information bias due to incorrect reporting. We tried to alleviate this problem by specifying recall periods in accordance with standard SMA care (based on our clinical experience and expertise of treating patients with SMA) and by including help texts, as well as logical tests and skip patterns to ensure that the collected data was accurate and complete. However, since patients also stated their type of SMA, this potential bias might also have impacted our comparison across SMA types.

We show that the natural history of disease has changed in Germany following improvements in SMA care and the introduction of novel therapies. Yet, a non-trivial proportion of patients remain untreated. We also identified considerable limitations in rehabilitation and respiratory care, as well as low labour-market participation among adults with SMA, calling for action to improve the current situation.

This was a cross-sectional, observational study of children and adults with SMA and one their caregivers in Germany. Study data was recorded directly from patient-caregiver pairs through a study questionnaire.