Clinical Phenotype of Pediatric and Adult Patients With Spinal Muscular Atrophy With Four SMN2 Copies: Are They Really All Stable?

Abstract

ObjectiveThe aim of this study was to provide an overview of the clinical phenotypes associated with 4 SMN2 copies.MethodsClinical phenotypes were analyzed in all the patients with 4 SMN2 copies as part of a nationwide effort including all the Italian pediatric and adult reference centers for spinal muscular atrophy (SMA).ResultsThe cohort includes 169 patients (102 men and 67 women) with confirmed 4 SMN2 copies (mean age at last follow‐up = 36.9 ± 19 years). Six of the 169 patients were presymptomatic, 8 were classified as type II, 145 as type III (38 type IIIA and 107 type IIIB), and 8 as type IV. The remaining 2 patients were asymptomatic adults identified because of a familial case. The cross‐sectional functional data showed a reduction of scores with increasing age. Over 35% of the type III and 25% of the type IV lost ambulation (mean age = 26.8 years ± 16.3 SD). The risk of loss of ambulation was significantly associated with SMA type (p < 0.0001), with patients with IIIB and IV less likely to lose ambulation compared to type IIIA. There was an overall gender effect with a smaller number of women and a lower risk for women to lose ambulation. This was significant in the adult (p = 0.009) but not in the pediatric cohort (p = 0.43).InterpretationOur results expand the existing literature on natural history of 4 SMN2 copies confirming the variability of phenotypes in untreated patients, ranging from type II to type IV and an overall reduction of functional scores with increasing age. ANN NEUROL 2023

5qSMA: standardised retrospective natural history assessment in 268 patients with four copies of SMN2

“…Looking at the age at which this loss of ambulation occurred, there was, as expected, a wide age range with a distribution that is relatively uniform. This observation largely confirms the findings documented in the comprehensive review by Wirth et al in 2021 [ 27 ] and the recent study by Ricci et al, who found an overall risk of walking loss of 35% in their cohort of SMA types 3 and 4 [ 16 ]. The time between "age at symptom onset" and "loss of ambulation" also showed a large variation.…”

“…There is a potential bias in the determination of the SMN2 copy number, as we know that especially the older determinations of the SMN2 copy number can be very inaccurate. It is therefore possible that not all patients have the correct copy number and that some patients with three copies may have been included, which was shown in the recent work by Ricci et al to be 10% in their 4 SMN2 copy cohort [ 16 ]. However, the observation that only 6.3% are ventilator dependent suggests that the substantial subset of patients with early motor symptoms from infancy have not been inadvertently included due to an incorrect copy number.…”

“…Existing studies have reported significant variability in the clinical presentation and disease progression of SMA in individuals with 4 SMN2 copies (16, 17). A recent study published in 2022, which originally focused on gender differences, reported a median age of onset for their 4-copy SMA cohort of 4.75 years (13), and another very recent study from Italy, which focused on disease progression and subgroup classification, revealed that 22% of their patients developed the disease before the age of 3 years [ 16 ]. In a recent study from the German SMA Newborn Screening Model Projects, we were able to demonstrate that a notable proportion of SMA patients with 4 SMN2 copies (5 of 7 patients, all subjects investigated under the age of 5) developed the disease between 1.5 and 4 years, with the majority experiencing very subtle symptoms [ 17 ], but some individuals suffering from significant and irreversible motor regression.…”

Consensus from the Brazilian Academy of Neurology for the diagnosis, genetic counseling, and use of disease-modifying therapies in 5q spinal muscular atrophy

“… 149 In addition, recent work confirmed the variability of phenotypes in untreated patients with four copies of SMN2 , ranging from type 2 to type 4, and an overall reduction of functional scores with increasing age. 150 These findings indicate the importance of treating these patients earlier.…”