Congenital Hypotonia Panel: Spinal Muscular Atrophy Deletions, Prader-Willi/Angelman Syndrome Methylation, Myotonic Dystrophy, and Uniparental Disomy 14

Condition Description

The Congenital Hypotonia Panel consists of tests for five genetic conditions most often associated with isolated congenital hypotonia in newborns: spinal muscular atrophy, myotonic dystrophy (type 1), Prader-Willi syndrome, Angelman syndrome, and maternal UPD 14.

Spinal muscular atrophy (SMA) is the second most common lethal, autosomal recessive disorder in Caucasians. SMA is characterized by anterior horn cell degeneration which causes a symmetrical muscle weakness and wasting.  Approximately 95%-98% of patients will have loss of both copies of the SMN1 gene. Approximately 2%-5% of patients are compound heterozygotes for an SMN1 deletion and an SMN1 intragenic mutation.

Myotonic dystrophy, type I (DM), is the most common adult form of muscular dystrophy, ranging from congenital to adult onset. The congenital form typically presents with hypotonia, muscle weakness, or respiratory distress, and may progress to include mental retardation or early death. Myotonic dystrophy type I is an autosomal dominant disorder, associated with an expansion of an unstable triplet (CTG) repeat in the DMPK gene. The size of the repeat expansion correlates with the severity of the phenotype.

Prader-Willi syndrome (PWS) is characterized by neonatal onset of severe hypotonia, feeding difficulty and failure to thrive, which may be preceded by decreased fetal movement in utero. An insatiable appetite may develop in later infancy or early childhood and can lead to obesity, if not controlled. Many children with PWS have short stature, hypogonadism, small hands and feet, and mild to moderate mental retardation. Many individuals with PWS may have recognizable patterns of behavior marked by stubbornness and temper tantrums. However, in the neonatal period, PWS may manifest only as isolated hypotonia, usually accompanied by feeding problems, with no obvious dysmorphic features.

Prader-Willi syndrome is caused by absence of the paternally derived 15q11.2-q13 region by one of several genetic mechanisms. Approximately 70% of individuals have a deletion in the paternal 15q11.2-q13 region. Approximately 25%-35% of individuals have maternal uniparental disomy, receiving two copies of chromosome 15 from the mother and no chromosome 15 from the father. Approximately 2% of individuals have other imprinting mutations which repress expression of the genes critical to the Prader-Willi region.

Angelman syndrome (AS) is caused by loss of expression of the maternally inherited UBE3A gene and is characterized by severe developmental delay, severe speech impairment, gait ataxia and/or tremulousness of the limbs, and a unique behavior with an inappropriate happy demeanor that includes frequent laughing, smiling, and excitability. During infancy individuals with AS typically have a normal phenotype. However, some affected individuals may have feeding problems and hypotonia.

Maternal UPD 14 is characterized by neonatal hypotonia, prenatal and postnatal growth retardation, small hands and feet, feeding difficulties and precocious puberty.  Many of these characteristics are similar to those found in Prader-Willi syndrome and studies have indicated that a significant number of patients with maternal UPD 14 are suspected to have Prader-Willi syndrome in infancy.  Distinctive features of maternal UPD 14 include constant prenatal growth failure, less-specific facial characteristics, and better intellectual development.  In addition to patients reported with complete maternal UPD 14, patients with epimutations and patients with a microdeletion of the 14q32.3 imprinted region have been reported with a upd(14)mat-like phenotype.  Hosoki et al. enrolled 78 patients with infant hypotonia who tested negative for Prader-Willi syndrome into their study.  Abnormal hypomethylation of the MEG3 promoter was identified in 5 of the 78 patients.  Three of these patients had complete maternal UPD 14, one had an epimutation, and one was mosaic for maternal UPD 14.  The patients reported with epimutations have clinical features that are indistinguishable from patients with complete maternal UPD 14.  Their patient with mosaic maternal UPD 14 had clinical features typical of complete maternal UPD 14 as well.   

Genes (4)

Indications

This test is indicated for newborns with isolated, congenital hypotonia.

Methodology

This hypotonia panel includes four assays:
  • Testing for spinal muscular atrophy consists of PCR amplification of exons 7 and 8 of the SMN1 gene. Homozygous deletions of either or both exons can be detected using restriction enzyme fragment size analysis.
  • Testing for myotonic dystrophy consists of PCR amplification and fragment size analysis to detect smaller alleles, combined with Southern analysis to detect large expansions.
  • Testing for PWS and AS consists of methylation sensitive PCR analysis of the SNRPN gene.
  • Testing for maternal UPD 14 consists of methylation sensitive PCR analysis of the MEG3 gene.

    Detection and Reference Range

    Detection
    Reference Range

    Specimen Requirements

    Type: Whole Blood

    Specimen Requirements:

    In EDTA (purple top) or ACD (yellow top) tube:
    Infants (<2 years): 3 ml
    Children (>2 years): 3-5 ml
    Older Children & Adults: 5-10 ml

    Specimen Collection and Shipping: Refrigerate until time of shipment. Ship sample within 5 days of collection at room temperature with overnight delivery.

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