Phenotype Presentation and Molecular Diagnostic Yield in Non-5q Spinal Muscular Atrophy

Abstract

Background and objectives: Spinal muscular atrophy (SMA) is mainly caused by homozygous SMN1 gene deletions on 5q13. Non-5q SMA patients' series are lacking, and the diagnostic yield of next-generation sequencing (NGS) is largely unknown. The aim of this study was to describe the clinical and genetic landscape of non-5q SMA and evaluate the performance of neuropathy gene panels in these disorders.

Methods: Description of patients with non-5q SMA followed in the different neuromuscular reference centers in France as well as in London, United Kingdom. Patients without a genetic diagnosis had undergone at least a neuropathy or large neuromuscular gene panel.

Results: Seventy-one patients from 65 different families were included, mostly sporadic cases (60.6%). At presentation, 21 patients (29.6%) showed exclusive proximal weakness (P-SMA), 35 (49.3%) showed associated distal weakness (PD-SMA), and 15 (21.1%) a scapuloperoneal phenotype (SP-SMA). Thirty-two patients (45.1%) had a genetic diagnosis: BICD2 (n = 9), DYNC1H1 (n = 7), TRPV4 (n = 4), VCP, HSBP1, AR (n = 2), VRK1, DNAJB2, MORC2, ASAH1, HEXB, and unexpectedly, COL6A3 (n = 1). The genetic diagnostic yield was lowest in P-SMA (6/21, 28.6%) compared with PD-SMA (16/35, 45.7%) and SP-SMA (10/15, 66.7%). An earlier disease onset and a family history of the disease or consanguinity were independent predictors of a positive genetic diagnosis. Neuropathy gene panels were performed in 59 patients with a 32.2% diagnostic yield (19/59). In 13 additional patients, a genetic diagnosis was achieved through individual gene sequencing or an alternative neuromuscular NGS.

Discussion: Non-5q SMA is genetically heterogeneous, and neuropathy gene panels achieve a molecular diagnosis in one-third of the patients. The diagnostic yield can be increased by sequencing of other neuromuscular and neurometabolic genes. Nevertheless, there is an unmet need to cluster these patients to aid in the identification of new genes.

Figure 1. Distribution of Patients With a Positive Genetic Diagnosis According to the Spinal Muscular Atrophy (SMA) Subtype

Thirty-two patients with a genetic diagnosis achieved through neuropathy gene panel (n = 19: DYNC1H1 x6, BICD2 x4, TRPV4 x4, HSPB1, VCP, VRK1, DNAJB2, MORC2), individual gene sequencing (n = 8: BICD2 x3, AR x2, HSPB1, HEXB, and COL6A3), and other neuromuscular NGS (n = 5: BICD2 x2, DYNC1H1, VCP, and ASAH1). Neg: negative; NGS: next-generation sequencing; P-SMA: proximal SMA; PD-SMA; proximo-distal SMA; SP-SMA: scapuloperoneal SMA.

Figure 2. Differing MRI Muscle Involvement in Non-5q Spinal Muscular Atrophy (SMA) Patients

T1-weighted MRI sequences of 5 patients with variants in the 3 most frequent non-5q SMA genes (DYNC1H1, BICD2, and TRPV4) as well as in Sandhoff disease (HEXB) and COL6A3. Muscles with yellow arrows had marked fat replacement; muscles with white arrows were completely or partially spared. (A) Quadriceps, semitendinosus, and adductor magnus muscle degeneration in a patient with Sandhoff disease presenting as P-SMA. (B) The previously described quadriceps muscle degeneration with adductor longus and semitendinosus sparing in a patient with DYNC1H1 PD-SMA. In this case, sartorius and gracillis muscle fat replacement is also observed. (C) Quadriceps and sartorious muscle degeneration with more important lower limb involvement in a patient with BICD2 PD-SMA. Notice some degree of paraspinal muscle atrophy and important scoliosis. (D) Tibialis anterior and gastrocnemius medialis involvement with sparing of muscles of the thigh and paraspinal and deltoid muscle degeneration in a patient with TRPV4 SP-SMA. (E) Finally, the characteristic muscle fat replacement in a “sandwich patter” of soleus and quadriceps muscles (yellow arrowheads) in a patient with COL6A3 mutations and a pure SMA phenotype. AL = adductor longus; AM = adductor magnus; De = deltoid; GM = gastrocnemius medialis; Gr = gracillis; PS = paraspinal; Quad = quadriceps; Sa = sartorious; ST = semitendinosus; TA = tibialis anterior.

Figure 3. Flow Diagram With the Recommended Diagnostic Approach in Non-5q Spinal Muscular Atrophy (SMA) Patients

All 3 different sections (genetic, clinical, and ancillary findings) are critical for a correct final diagnosis. Findings in each section should be confronted to findings in the other 2 sections before establishing a definitive diagnosis. Genes underscored show an autosomal dominant (AD) transmission while the rest show an autosomal recessive (AR) transmission, with the exception of the COL6 genes (COL6A1, COL6A2, COL6A3), which may be both AD and AR. The Figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license. CK = creatine kinase; NCS = nerve conduction studies; NGS = next-generation sequencing; SNAP = sensory nerve action potential.