Efo/proximal Spinal Muscular Atrophy Type 3

1. Disease Summary:

Proximal spinal muscular atrophy type 3 (SMA3), also known as Kugelberg-Welander disease, is a genetic neuromuscular disorder characterized by the degeneration of motor neurons in the spinal cord, leading to progressive muscle weakness and atrophy. Patients typically present with muscle fatigue and weakness in the proximal muscles, particularly in the lower limbs, after achieving independent ambulation. While individuals with SMA3 often have a normal lifespan, they may experience significant functional decline over time, including loss of ambulation and increased dependency on caregivers.

2. Global Prevalence and Disease Burden:

SMA has an estimated prevalence of approximately 1 in 10,000 live births, with SMA3 being one of the less severe forms of the disease. The economic burden of SMA is substantial, encompassing direct medical costs (hospitalizations, treatments, and therapies) and indirect costs (loss of productivity, caregiver burden). A study indicated that the overall cost of care for SMA patients can exceed $1 million over a patient's lifetime, depending on the severity of the disease and the age of onset (source: Cure SMA). The disease significantly impacts the quality of life for both patients and their families, leading to emotional and psychological challenges.

3. Unmet Medical Need:

Despite advancements in treatment, several unmet needs persist for patients with SMA3:

Comprehensive Care: There is a critical need for multidisciplinary care that includes not only neurology but also respiratory therapy, physical therapy, occupational therapy, and psychological support. Many patients report inadequate access to these services, particularly post-surgery (source: PMID 39233378).
Mental Health Support: Mental health care is often overlooked, yet it is a significant unmet need. Patients frequently experience feelings of isolation, anxiety, and depression due to the progressive nature of the disease and the associated loss of function (source: Getting ready for the adult world).
Access to Therapies: While new therapies like Risdiplam and Onasemnogene Abeparvovec have shown promise, access remains a challenge, particularly in low- and middle-income countries. There is a need for more equitable access to these treatments and for combination therapies that may enhance efficacy (source: Unmet Needs in the Treatment of Spinal Muscular Atrophy).
Early Diagnosis and Screening: Improved newborn screening and early diagnosis are essential to initiate treatment before significant motor neuron degeneration occurs. Current screening practices may not identify all cases of SMA3 early enough to optimize treatment outcomes (source: Unmet Needs and the Future of Treatment in SMA).

4. Current Treatment Options:

Current treatment options for SMA3 include:

SMN Upregulation Therapies: Treatments such as Nusinersen (Spinraza) and Risdiplam (Evrysdi) aim to increase the levels of survival motor neuron (SMN) protein, which is deficient in SMA patients. These therapies have shown efficacy in improving motor function and slowing disease progression (source: PMID 38461122).
Gene Therapy: Onasemnogene Abeparvovec (Zolgensma) is a gene replacement therapy that provides a copy of the SMN1 gene to halt disease progression. However, it is primarily indicated for younger patients and may not be suitable for all SMA3 patients (source: PMID 37776479).
Supportive Care: This includes physical therapy, respiratory support, and nutritional management. While these interventions can improve quality of life, they do not address the underlying genetic cause of the disease.

Limitations: Current treatments do not reverse existing damage to motor neurons, and their effectiveness may vary based on the age of initiation and the severity of the disease. Additionally, access to these therapies can be limited by cost and availability, particularly in underserved populations.

5. Current Clinical Trials:

Numerous clinical trials are ongoing to explore new treatment options and combinations for SMA3. For instance, the SUNFISH trial is investigating the efficacy of Risdiplam in patients with type 2 and type 3 SMA. Other trials are focusing on combination therapies that may enhance treatment outcomes (source: Unmet Needs in the Treatment of Spinal Muscular Atrophy).

6. Additional Context:

The landscape of SMA treatment is rapidly evolving, with ongoing research aimed at addressing the unmet needs identified. Advocacy groups like Cure SMA are actively working to raise awareness and push for policy changes that improve access to care and treatment for SMA patients. The integration of patient and caregiver perspectives into research and treatment planning is crucial for developing effective strategies to meet the diverse needs of individuals living with SMA3.