Spinal muscular atrophy (SMA) is the second most common lethal autosomal recessive disorder of childhood, affecting approximately 1 in 6,000-10,000 births, with a carrier frequency of 1 in 40-60. There is no effective cure or treatment for this disease. Thus, the availability of prenatal testing is important. The aim of this study was to establish an efficient and rapid method for prenatal diagnosis of SMA and genetic counseling in families with risk for having a child with SMA. In this paper we present the results from prenatal diagnosis in Macedonian SMA families using direct analysis of fetal DNA. The probands of these families were previously found to be homozygous for a deletion of exons 7 and 8 of SMN1 gene. DNA obtained from chorionic villas samples and amniocytes was analyzed for deletions in SMN gene. SMN exon 7 and 8 deletion analysis was performed by polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP). Of the 12 prenatal diagnoses, DNA analysis showed normal results in eight fetuses. Four of the fetuses were homozygote for a deletion of exons 7 and 8 of SMN1. After genetic counseling, the parents of the eight normal fetuses decided to continue the pregnancy, while in the four families with affected fetuses, the pregnancy was terminated. The results were confirmed after birth.
Friedreich's ataxia (FRDA) is rare a progressive neuro degenerative disorder of autosomal recessive inheritance, which is associated with an unstable expansion of a GAA trinucleotide repeat in the first intron of the frataxin gene on chromosome 9q13. We have performed molecular analyses of the frataxin gene of 40 patients with spino cerebellar ataxia from the Republic of Macedonia. Fifteen had early onset of progressive ataxia (before the age of 25), while the remainder were over 25 years old at the time of diagnosis. Only 14 patients had a mutation in the frat axin gene and all of these had early onset ataxia. The number of GAA repeats was in the normal range in 50 healthy individuals.
Spinal muscular atrophy (SMA) is classified according to the age of onset and severity of the clinical manifesta tions into: acute (Werding-Hoffman disease or type I), intermediate (type II) and juvenile (Kugelberg-Wilander disease or type III) forms. All three SMAs have been linked to markers at 5q11.2-q13.3. Two candidate genes deleted in SMA patients are the survival motor neuron (SMN) gene and the neuronal apoptosis inhibitory protein (NAIP) gene. We have performed molecular analyses of these genes in 30 unrelated Macedonian families (17 with type I, eight with type II and five with type III forms of the disease). Deletions of exons 7 and 8 of the SMN gene were found in 76.6% (23/30) of patients (94.1% in type I, 87.5% in type II). Among these 23 families, 19 had both exons deleted, while four had deletions only of exon 7. Deletions of exon 5 of the NAIP gene were found in 41.2% (7/17) patients with type I SMA and in 12.5% (1/8) of patients with type II SMA. No deletions of the SMN gene were found in 30 parents and 30 normal controls. We found 2/30 (6.7%) parents to be homozygous for the dele tion of exon 5. Our data support the hypothesis that the telomeric SMN gene plays a major role in determining the clinical course of the disease, while the defects in the NAIP gene have only a modifying effect on the phenotype.
Duchenne muscular dystrophy (DMD) is an Xlinked recessive disorder caused by mutations in the dystrophin gene at Xp21.2. Mutations include gross deletions (60%), duplications (10%), and point mutations (30%). Duchenne muscular dystrophy is a serious and disabling disease. Progressive muscle wasting, which leads to severe disability and early death, make DMD highly distressing disorders to both patient and family. Since no effective treatment is as yet available, prenatal diagnosis is important for prevention of the disease. In this paper, we present our results from prenatal diagnoses in Macedonian DMD families. For prenatal diagnosis of 15 pregnancies at risk of having a DMD child, we used multiplex polymerase chain reaction (mPCR), multiplex ligation-dependent probe amplification analysis (MLPA) and DNA linkage analysis, using highly polymorphic intragenic short tandem repeat [STR-(CA) n] markers. DNA material was extracted from chorionic villus and amniotic fluid samples. Eight of the fetuses were male, three of whom had deletions in the dystrophin gene and five were normal. Two of the female fetuses were carriers of deletions in the dystrophin gene.
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