Journal of Genetic Disorders & Genetic Reports ISSN: 2327-5790

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Case Report, J Genet Disor Genet Rep Vol: 5 Issue: 3

Homozygous Point Mutation in a Patient with Spinal Muscular Atrophy Type 1

Isa Abdi Rad1*, Ali Vahabi1 and Ahad Ghazavi2
1Department of Medical Genetics, Motahrai Hospital, Urmia University of Medical Sciences, Iran
2Department of Pediatrics, Motahrai Hospital, Urmia University of Medical Sciences, Iran
Corresponding author : Isa Abdi Rad
Professor of Neurogenetics, Medical Genetic Department, Motahari Hospital, Urmia University of Medical Sciences, Iran,
Tel: 0098 +44 32240166
E-mail: [email protected], [email protected]
Received: May 11, 2016 Accepted: June 16, 2016 Published: June 20, 2016
Citation: Rad IA, Vahabi A, Ghazavi A (2016) Homozygous Point Mutation in a Patient with Spinal Muscular Atrophy Type 1. J Genet Disor Genet Rep 5:3. doi:10.4172/2327-5790.1000137

Abstract

Spinal muscular atrophy (SMA) is an autosomal recessive disease with progressive hypotonia and muscle atrophy resulting from degeneration of the anterior horn cells in the spinal cord and the brain stem nuclei. The molecular diagnosis of SMA is based on the determination of SMN1 (survival motor neuron 1) gene copy number which shows homozygous deletion in approximately 96% of the patients. Approximately 4% of patients with SMA has no homozygous deletion and retain at least one copy of the SMN1 gene with pathogenic insertions, deletions, or point mutations. And also, very rarely, both alleles are affected with point mutations. We report SMA type 1 patient with homozygous point mutation [c.549 del C (p.Lys184ser fs 29)] resulting in frame-shift in SMN1 gene. The patient was the second offspring of a consanguineous family whose first child also died due to SMA1. To the best of our knowledge, this homozygous point mutation on the SMN1 gene has not been reported yet

Keywords: Spinal muscular atrophy; SMN1 gene; Homozygous point mutation

Keywords

Spinal muscular atrophy; SMN1 gene; Homozygous point mutation

Introduction

Spinal muscular atrophy (SMA) is an autosomal recessive disease with progressive loss of anterior horn cells in the spinal cord and the brain stem nuclei resulting in proximal weakness and atrophy symmetrically [1].
The clinical classification of SMA is based on age of onset and maximum function attained. Type I (Werdnig-Hoffman disease) presents less than six months of age; type II (Dubowitz disease) onsets between 6-18 months of age; type III (Kugelberg-Welander disease), presents after 18 months of age; and type IV (adult type) is an adult onset form. A prenatal onset type (SMA 0) also has been proposed, with arthrogryposis, facial weakness, and respiratory failure. The incidence of SMAs is 1/6000–1/10,000 live births [2,3]. SMN1 (survival motor neuron 1) gene subjects to homozygous deletions in exon 7 in more than 95% of SMAs patients where severity often attenuated by the presence of more than two copies of SMN2 gene [4-6].
The remaining 3-5% of SMA patients has at least one copy of SMN1 gene associated with other allele with subtle mutations [7-10].
These subtle mutations include base substitutions, and small insertions or deletions resulting in frame-shift [4,11-13]. So, DNA sequencing is indicated in patients with clinical diagnosis of SMA who don’t reveal homozygote exon-7 deletion on the SMN1 gene.
Although, more than 60 subtle mutations of SMN1 gene have been reported worldwide [10], homozygous point mutation, that is, both allele affected by a point mutation, is a very rare event on the SMN1 gene. Mutations are distributed along the entire coding sequence of the SMN1 gene where approximately half of them are located in exons 3 and 6.
Here, we report homozygous point mutation on exon 5 of SMN1 gene in a Werdnig-Hoffmann disease, which, to the best of our knowledge, has not been reported yet.

Case Profile

A two-month-old girl referred to the neurogenetic department due to hypotonia presented at birth. Her neurologic examination revealed profound hypotonia, proximal muscle weakness, absent deep tendon reflexes, respiratory insufficiency, and tongue fasciculation. Based on the clinical findings, she was diagnosed as SMA type I. Electro diagnostic study was also compatible with SMA type I. She had a brother who expired at the age of three months with the same clinical features as seen in her. The parents are consanguineous with F=1/16 (first cousin).
Molecular genetic test for deletions of exons 7 and 8 was negative. However, considering the high clinical and electro diagnostic support of SMA1, the patients sample has been sent for DNA sequencing which revealed homozygous point mutation c.549 del C at exon 5 which confirmed by Sanger sequencing. This mutation results in frame-shift in SMN1 gene [c.549 del C (p.Lys184ser fs 29)] (Figure 1).
Figure 1: c.549 del C (p.Lys184ser fs 29) detected at the exon 5 of SMN1 gene by sequencing.

Discussion

All types of SMA disease are typically diagnosed by determination of SMN1 gene copy number via detection of homozygous deletions in exon 7 which are seen in more than 95% of SMAs patients. DNA sequencing is indicated in the remaining 3-5% of patients which have only one copy of SMN1 gene and expected to have other allele with subtle mutations [7-10]. Homozygous point mutation on the SMN1 gene, that is both allele affected by point mutations, is a very rare event in SMA patients.
In our patient, there was no heterozygote or homozygote deletion in exons 7 and 8 of SMN1 gene, however, according to the clinical and electro diagnostic findings, the diagnosis of SMA1 was highly suspected. So, the patient’s peripheral blood sample has been sent for DNA sequencing which revealed homozygous point mutation c.549 del C at exon 5 which confirmed by Sanger sequencing. This mutation results in frame-shift in SMN1 gene [c.549 del C (p.Lys184ser fs 29)]. Although to the best of our knowledge, this point mutation has not been reported yet, considering the frame-shift nature of the mutation at the coding region of the gene, it could be considered as pathologic finding. So, this pathologic mutation is a molecular confirmation for the clinical diagnosis of the SMA type 1 in our patient.
Although, DNA sequencing is routinely carried out on SMA patient with only one copy of SMN1 gene, we recommend that DNA sequencing should be carried out in all patients with clinical diagnosis of SMA who shows even two copies of SMN1 gene.

Acknowledgment

We thank the patient’s family and Molecular Diagnostics Laboratory colleagues.

References

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