Isolated exon 8 deletion in type 1 spinal muscular atrophy with bilateral optic atrophy: Unusual genetic mutation leading to unusual manifestation?D Maiti, M Bhattacharya, S Yadav
Department of Pediatrics, Maulana Azad Medical College and Lok Nayak Hospital, New Delhi, India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0022-3859.105451
Source of Support: None, Conflict of Interest: None
Proximal spinal muscular atrophy (SMA) or type 1 SMA is a fatal autosomal recessive disorder usually caused by homozygous deletion of exons 7 and 8 in the survivor motor neuron (SMN) gene. Additional deletion of the neuronal apotosis inhibitory protein (NAIP) gene exacerbates the clinical severity. Isolated exon 8 deletion has been reported in a single case series of SMA types 2 and 3 and never with SMA type 1. While extraocular muscles are typically spared, there are a few case reports documenting associated external ophthalmoplegia. Optic atrophy is a hitherto unreported association of SMA. We report a 10-month-old male infant with SMA type 1 with optic atrophy due to isolated deletion of exon 8 of the SMN gene with intact exon 7 and NAIP gene.
Keywords: Exon 7, exon 8, optic atrophy, survivor motor neuron gene, spinal muscular atrophy
Spinal muscular atrophy (SMA) is a clinically and genetically heterogenous group of disorders caused by homozygous deletion of exons 7 and 8 in the SMN1 gene.  Isolated exon 8 deletion has been reported in only one case series till date.  Similar proteins such as the axonal SMN (a-SMN) are also being studied in the pathogenesis of SMA. 
Clinically, SMA is characterized by progressive flaccid muscular weakness with three disease subtypes depending on age of onset and clinical severity. While extraocular muscles are typically spared, there are a few case reports reporting associated external ophthalmoplegia. ,,, To the best of our knowledge, optic atrophy has not been reported in association with SMA.
We report a 10-month-old male infant with SMA type 1 with optic atrophy (previously unreported) due to isolated deletion of exon 8 of the SMN gene.
A 10-month-old male infant presented with delayed motor milestones and excessive floppiness since birth. He was a product of nonconsanguinous marriage and was born at 38 weeks of gestation by vaginal delivery. Antenatal history was uneventful with no history of decreased fetal movements as perceived by mother. Antenatal ultrasounds were normal with no evidence of polyhydramnios.
Soon after birth, mother noticed generalized floppiness and paucity of spontaneous movements in the baby. The baby also had a poor suck at the breast and a weak cry. He had not achieved complete head holding at the time of presentation. He kept his hands mostly open, did not reach out for objects but could grasp objects placed in his hands. He started cooing around 3 months of age and could speak monosyllables from 9 months of age. The child responded to his name from 9 months of age. He did not focus on his mother's face or follow moving objects.
On examination, there was no facial dysmorphism. There was generalized hypotonia. Power was up to grade 3/5 in all four limbs. Deep tendon reflexes were not elicitable. Plantar reflexes were downgoing. Fundus examination showed bilateral primary optic atrophy. Thyroid function test, total CPK levels, and MRI head were normal.
Restriction enzyme analyses of the PCR amplified SMN exons 7 and 8 demonstrated the presence of both centromeric and telomeric copies of exon 7 and absence of telomeric exon 8. To exclude a sequence conversion of telomeric exon 8, the region surrounding exons 7 and 8 were amplified. Analysis of this resulting fragment failed to show any product of telomeric exon 7. NAIP gene was found to be intact.
Based on clinical manifestations and genetic studies, diagnosis of SMA type 1 was made.
Melki et al., in 1990, mapped the gene for types 1-3 SMA by linkage studies to chromosome 5q13.  Among the candidate genes located in this region, the survivor motor neuron (SMN) gene and the neuronal apoptosis inhibitory protein (NAIP) gene were suggested to play an important role. While loss of SMN1 gene is essential for pathogenesis of SMA, disruption of SMN2 and NAIP contributes to disease severity. 
Homozygous deletion of exons 7 and 8 in the telomeric copy of SMN1 are detected in more than 95% of SMA patients. In approximately 5% of cases of SMA of all types, the telomeric version of exon 7 is absent while the telomeric exon 8 is present.  Isolated exon 8 deletion, as seen in our patient, has been rarely reported.  NAIP is disrupted in 45% of patients with type 1 disease and in 18% of SMA 2 and 3 individuals.  In an Indian study, Dastur et al. reported homozygous deletion of exons 7 and 8 of SMN1 and NAIP (exon 5) in 73% of SMA 1 patients, while the rest had deletion of exons 7 and 8 of SMN1 only. Isolated exon 8 deletion was not reported. 
The SMN gene encodes the ubiquitous SMN protein and the selective vulnerability of the anterior horn cells to low levels of SMN protein remains unexplained. The axonal SMN protein (a-SMN) is a truncated form of SMN and has specific axogenic properties. Although the role of a-SMN is not known in the pathogenesis of SMA at present, in vitro studies have indicated significant morphologic abnormalities in anterior horn cells with mutated a-SMN protein.  Thus, the a-SMN protein could be an additional factor in the pathogenesis of SMA especially when associated with hitherto unreported clinical associations.
The disorder is characterized by degeneration of anterior horn cells of the spinal cord, resulting in progressive flaccid muscular weakness. The condition is clinically heterogeneous and has been divided into three subtypes (types 1-3) according to the age of onset and clinical severity. The hallmark of SMA type 1 is severe, progressive muscle weakness and hypotonia. Patients present by 6 months of age, with 95% of patients having signs and symptoms by 3 months. Bulbar dysfunction includes poor suck, reduced swallowing, and respiratory failure.  While extraocular muscles are typically spared, a few clinical case reports have reported associated external ophthalmoplegia. ,,, However, these reports do not give a genotypic correlation. Optic atrophy is an unreported association of SMA.
In the case series by Gambardella et al.,  both patients had exon 8 deletion with intact exon 7 and one of them also had a concommitant deletion in the NAIP gene. Clinically, both had typical features of SMA types 2 and 3. Hence, the authors concluded that exon 8 deletion resulted in milder variants of SMA. Additional deletions in NAIP gene exacerbated severity, as seen in the patient with SMA type 2. This is unlike our patient who had features characteristic of type 1 SMA, the severest variety of SMA, with isolated deletion of exon 8 and intact exon 7 and NAIP gene. Moreover, he also had associated optic atrophy, while the previous case series did not report any ocular manifestations.
In conclusion, isolated exon 8 deletion of the SMN gene is an unusual and rarely reported mutation of SMA. Optic atrophy is an as yet unreported association. Our patient had SMA type 1 with optic atrophy with isolated exon 8 deletion and intact exon 7 and NAIP gene, making this case worth reporting. There is also a possibility of mutation involving other proteins (e.g. the a-SMA) giving rise to this unusual phenotype.