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SMA SPINAL MUSCULAR ATROPHY. Dr Pupak Derakhshandeh, PhD Ass Prof of Medical Science of Tehran University. DELETION OF SMN AND NAIP GENES IN IRANIAN PATIENTS WITH SPINAL MUSCULAR ATROPHY. SMA. Gene: SMN (Survival Motor Neuron) Motor Neuron; Anterior Horn; Spinal Cord

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Dr Pupak Derakhshandeh, PhD Ass Prof of Medical Science of Tehran University

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SMA SPINAL MUSCULAR ATROPHY

Dr PupakDerakhshandeh, PhD

Ass Prof of Medical Science of Tehran University


DELETION OF SMN AND NAIP GENES IN IRANIAN PATIENTS WITH SPINAL MUSCULAR ATROPHY


SMA

  • Gene: SMN (Survival Motor Neuron)

  • Motor Neuron; Anterior Horn; Spinal Cord

  • Second most common fatal autosomal recessive disorder after CF

  • Second most common pediatric neuromuscular disorder after DMD

  • Incidence : 1 in 6000-10000 live births

  • Carrier frequency : 1 in 40-60


CLASSIFICATION

  • SMA TYPE I (Werdnig-Hoffmann)

  • SMA TYPE II (Classic)

  • SMA TYPE III (Kugelberg-Welander)


SMA TYPE I

  • Severe form of SMA

  • Onset : first 6 months

  • Death : < 2 year

  • Never raising the head or sitting


SMA TYPE II

  • Less sever

  • Clinical appearing : < 18 months

  • Able to sit unaid

  • Death : about 9 years


SMA TYPE III

  • Mildest form of SMA

  • Onset : > 18 months

  • Walking without aid


OTHER CLASSIFICATION


DIAGNOSIS

  • EMG

  • Muscle Biopsy

  • Genetic Testing/PND


GENETICS

  • 1990: The three types of SMA were mapped to 5q13

  • The SMA locus contain two inverted copies of a 500kb element

  • The two copies named telomeric and centromeric


GENETIC MAP

  • Three candidate genes named SMN (Survival Motor Neuron), NAIP (Neuronal Apoptosis Inhibitory Protein) and P44 were identified in this locus

  • Up to 95% of SMA patients (SMNI-III) are homozygously deleted for two exons (7&8) of both telomeric copy of SMN gene (SMNt)


Deletions

  • Up to 5% of SMA patients have frameshift mutations, gene conversions and point mutation

  • Exons 5 and 6 of NAIPt gene are deleted in approximately 50% of type I SMA and 18% of types II and III SMA

  • P44t is lacked or intrrupted in 73% of SMA type I patients and 7% in types II and III


The summery of normal alleles (N) , mutant alleles (M) and deletion types (D) of SMN


MOLECULAR DIAGNOSIS & PND

  • PCR-SSCP or PCR-RFLP of SMN gene enables confirmation of a suspected clinical diagnosis of SMA or prenatal diagnosis

  • These two techniques based on nucleotide differences of both exon 7 and exon 8 of telomeric and centromeric copy of SMN


Deletion Analysis of SMN gene

  • Exones 7 and 8 of SMN gene were amplified and cut by Dra I and Dde I , respectively. (only centromeric copy is cutted)

  • Absence of SMNt exone(s) 7 (and 8) confirm diagnosis ofSMA


Exon 7, DraI

Exon 8, DdeI

188 bp

164bp

188 bp

123 bp

65 bp


SMN Deletion Analysis

  • SMNt Exon 7 is deleted in affected child

Derakhshandeh-Peykar, et al. Annal Acad Med, 2007(Depart Med Gen & NRCGEB)


NAIP Gene Deletion Analysis

  • Exones 5 & 6 of NAIP gene were amplified with exon 13 which was the internal control

  • Absence of exon

    5 and exon 6 ( which

    only exist within the

    telomeric functional

    copy of NAIP) was

    detected in ~50% of

    type I SMA and 18%

    of types II and III SMA


NAIP Deletion analysis

Derakhshandeh-Peykar, et al. Annal Acad Med, 2007(Depart Med Gen & NRCGEB)


  • The objective of this study was to genetically characterize the childhood onset spinal muscular atrophy in Iran.


  • Various deletion haplotypes were constructed by using genotypes of SMN and NAIP genes.

  • Haplotype A, which has the deletions of all two involved genes, were deleted in approximately 83% of type I and II SMA but not in type III and was found predominantly in the severe group with an early onset at less than 6 month of age.

  • we report Thirty four our experiences for prenatal diagnosis


  • These studies suggested that the frequency of gene deletions of SMN1 and NAIP gene is a few higher than previous reports. It is may be due to high rate of consanguine marriage by Iranian Muslims (96 % in this families). Thus, the conformation of SMA related gene deletion will also be a useful tool for the pre and postnatal diagnostic. In addition to common PCR methods for SMN exon 7 and 8 and NAIP exons 4 and 5, we also conducted multiplex PCR of exon 5, 6 and 13 of the NAIP telomere in one reaction.


Molecular Genetics Group

Derakhshandeh

Esmaiili

Rahmani

Babrzadeh

Taeb

Attaran

Sajedifar

Farhud


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