Ogino, S. & Wilson, R. B. Genetic testing and risk assessment for spinal muscular atrophy (SMA). Hum. Genet. 111, 477-500

Harvard University, Cambridge, Massachusetts, United States
Human Genetics (Impact Factor: 4.82). 01/2003; 111(6):477-500. DOI: 10.1007/s00439-002-0828-x
Source: PubMed


Spinal muscular atrophy (SMA) is one of the most common autosomal recessive diseases, affecting approximately 1 in 10,000 live births, and with a carrier frequency of approximately 1 in 50. Because of gene deletion or conversion, SMN1 exon 7 is homozygously absent in approximately 94% of patients with clinically typical SMA. Approximately 30 small intragenic SMN1 mutations have also been described. These mutations are present in many of the approximately 6% of SMA patients who do not lack both copies of SMN1, whereas SMA of other patients without a homozygous absence of SMN1 is unrelated to SMN1. A commonly used polymerase chain reaction/restriction fragment length polymorphism (PCR-RFLP) assay can be used to detect a homozygous absence of SMN1 exon 7. SMN gene dosage analyses, which can determine the copy numbers of SMN1 and SMN2 (an SMN1 homolog and a modifier for SMA), have been developed for SMA carrier testing and to confirm that SMN1 is heterozygously absent in symptomatic individuals who do not lack both copies of SMN1. In conjunction with SMN gene dosage analysis, linkage analysis remains an important component of SMA genetic testing in certain circumstances. Genetic risk assessment is an essential and integral component of SMA genetic testing and impacts genetic counseling both before and after genetic testing is performed. Comprehensive SMA genetic testing, comprising PCR-RFLP assay, SMN gene dosage analysis, and linkage analysis, combined with appropriate genetic risk assessment and genetic counseling, offers the most complete evaluation of SMA patients and their families at this time. New technologies, such as haploid analysis techniques, may be widely available in the future.

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    • "Deletion analysis consists of the detection of the complete absence of exon 7 in the SMN1 gene. The detection rate of this diagnostic testing for an affected individual is 94–95 % (Lefebvre et al. 1998; Ogino and Wilson 2002; Wang et al. 2007) with almost 100 % specificity (Rodrigues et al. 1995; Wang et al. 2007). With deletion analysis, the polymerase chain reaction-RFLP assay utilizes restriction enzymes to cut only the SMN2 exon 7 polymerase chain reaction products. "
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    ABSTRACT: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular condition with degeneration of the anterior horn cells in the spinal column. Five SMA subtypes exist with classification dependent upon the motor milestones achieved. Study of the SMN1 (survival motor neuron) and SMN2 genes as well as the concepts of the "2 + 0" carriers, gene conversion, de novo mutations and intragenic mutations allow for a better understanding of SMA. Detailing the carrier and diagnostic testing options further deepens the genetic counselor's knowledge of SMA. A review of care guidelines and research options is included as this information gives a patient a well-rounded view of SMA. Although SMA is most commonly associated with the SMN1 gene, a number of spinal muscular atrophies not caused by genetic changes in this gene may be included as differential diagnoses until confirmatory testing can be completed. SMA is a complex condition requiring a detailed knowledge on the genetic counselor's part in order to explain the disorder to the patient with clarity thus facilitating increased communication and decision making guidance with the patient.
    Full-text · Article · Aug 2015 · Journal of Genetic Counseling
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    • "Approximately 2–5% of patients are compound heterozygotes for a deletion of at least SMN1 exon 7 and an intragenic inactivating mutation of SMN1[1,3]. Nearly 2% of parents of an affected child are not carriers of a SMN1 gene mutation, and in these SMA cases the other altered allele is hit by a " de novo " mutation[3,4]. Changes in expression of the centromeric copy of SMN (SMN2) are known to modify the phenotype567. "
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    ABSTRACT: We report a 3-year-old female with type I spinal muscular atrophy (SMA) born to a young and non-consanguineous couple. The child presented at two months of life with intense muscle weakness affecting predominantly proximal portions of the limbs, especially the legs, muscle hypotonia, fasciculation of the tongue, and severe respiratory muscle involvement. She remained in an intensive care unit with an assisted ventilation system from the fourth month of life. She died at 3years of age from pulmonary infection. Molecular analysis confirmed the diagnosis of SMA but revealed that only the father was an asymptomatic carrier. Because SMN1 is mapped in a complex region containing repetitive elements due to an inverted duplication of approximately 500kb, we carry out an SNP array and detected a 1.3Mb deletion including the SMN1 and SMN2 genes that explain the disease.
    Full-text · Article · Feb 2013 · Neuromuscular Disorders
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    • "Two survival motor neuron (SMN) genes on chromosome 5q13 have been correlated with SMA: telomeric SMN1 and centromeric SMN2. SMA is caused by deletions or loss-of-function mutations in SMN1 with the retention of SMN2 [5-8], resulting in production of insufficient full-length SMN transcripts. SMN2 primarily transcribes exon 7-excluded mRNA because of a C-to-T transition at position 6 in exon 7 [9,10] and produces an unstable C-terminally truncated SMN protein. "
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    ABSTRACT: Background Proximal spinal muscular atrophy (SMA), a neurodegenerative disorder that causes infant mortality, has no effective treatment. Sodium vanadate has shown potential for the treatment of SMA; however, vanadate-induced toxicity in vivo remains an obstacle for its clinical application. We evaluated the therapeutic potential of sodium vanadate combined with a vanadium detoxification agent, L-ascorbic acid, in a SMA mouse model. Methods Sodium vanadate (200 μM), L-ascorbic acid (400 μM), or sodium vanadate combined with L-ascorbic acid (combined treatment) were applied to motor neuron-like NSC34 cells and fibroblasts derived from a healthy donor and a type II SMA patient to evaluate the cellular viability and the efficacy of each treatment in vitro. For the in vivo studies, sodium vanadate (20 mg/kg once daily) and L-ascorbic acid (40 mg/kg once daily) alone or in combination were orally administered daily on postnatal days 1 to 30. Motor performance, pathological studies, and the effects of each treatment (vehicle, L-ascorbic acid, sodium vanadate, and combined treatment) were assessed and compared on postnatal days (PNDs) 30 and 90. The Kaplan-Meier method was used to evaluate the survival rate, with P < 0.05 indicating significance. For other studies, one-way analysis of variance (ANOVA) and Student's t test for paired variables were used to measure significant differences (P < 0.05) between values. Results Combined treatment protected cells against vanadate-induced cell death with decreasing B cell lymphoma 2-associated X protein (Bax) levels. A month of combined treatment in mice with late-onset SMA beginning on postnatal day 1 delayed disease progression, improved motor performance in adulthood, enhanced survival motor neuron (SMN) levels and motor neuron numbers, reduced muscle atrophy, and decreased Bax levels in the spinal cord. Most importantly, combined treatment preserved hepatic and renal function and substantially decreased vanadium accumulation in these organs. Conclusions Combined treatment beginning at birth and continuing for 1 month conferred protection against neuromuscular damage in mice with milder types of SMA. Further, these mice exhibited enhanced motor performance in adulthood. Therefore, combined treatment could present a feasible treatment option for patients with late-onset SMA.
    Full-text · Article · Feb 2013 · BMC Medicine
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