Phenotype variability in patients with infantile spinal muscular atrophy: Distal muscle weakness and peripheral neuropathy in compound heterozygotes with SMN1 gene deletions

Abstract

Objective: To present atypical phenotype with distal muscle weakness and neurographic signs of distal axonal degeneration in compound heterozygous patients with infantile spinal muscular atrophy (iSMA). Methods: Electromyography and neurography, molecular genetics DNA and RNA studies. Results: We present 4 patients with iSMA (1–18 years): 2 boys (onset age 2 and 3 monhtsmonths) and 2 girls (onset age 13 and 24 months, now wheelchair bound) with pronounced distal muscles weakness. Electromyoneurography revealed neurogenic pattern with severe axonal lesion in all patients. Both male patients died at the age 2 and 4 years. In two sibs (brother and sister) heterozygous paternal deletion of exon 7 and 8 was detected by MLPA, associated with maternal intragenic SMN1 gene missense mutation c689C>T p.S230L in exon 5. Prenatal diagnosis in the third pregnancy revealed only intragenic SMN1 gene mutation c689C>T p.S230L in exon 5, and healthy child was born. Next generation sequencing for hereditary neuropathies (clinical exome) revealed heterozygous paternal mutation c.505T>C; p.Y169H in the SH3TC2 gene in both sibs, confirmed by Sanger sequencing. In two other unrelated patients, compound heterozygosity of exons 7 and 8 deletion in SMN1 gene and intragenic missense mutation c821C>T(pT274I) in exon 6 was detected. Nerve biopsy confirmed loss of myelinated axons and axonal degeration in one of the female patients presented. Only one SMN2 gene copy was detected in all patients reported. Conclusion: Significant distal muscle weakness in patients with atypical iSMA might be result of distal axonal degeneration caused by intragenic SMN1 gene mutations probably aggravated by heterozygous missense mutation in SH3TC2 gene in two sibs and only one SMN2 copy in all patients. The functional consequences of point mutations are milder than of SMN1 deletions, since iSMA patients with one SMN2 copy generally have a congenitally lethal disease course, not seen in our patients.