A 1-day-old boy is evaluated in the neonatal intensive care unit due to severe hypotonia, poor feeding, and respiratory distress. The patient was born to a 30-year-old woman via vaginal delivery; the pregnancy was complicated by polyhydramnios. The neonate's mother has a history of recurrent muscle cramps, mostly in her hands; her face is long and narrow and lacks expression. She is otherwise healthy. The patient's length, weight, and head circumference are at the 30th percentile. Examination shows profound hypotonia, truncal and appendicular weakness, and marked hyporeflexia. Flexion deformities and clubfoot are present bilaterally. Assuming that the patient and his mother have the same inheritable condition, which of the following mechanisms best explains their different phenotypic presentations?
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Compared to his mother, this neonate has profound symptoms of muscle weakness. These findings suggest genetic anticipation, in which an inherited condition presents earlier and with more severe disease in successive generations.
The most likely diagnosis in this case is myotonic dystrophy (DM), an autosomal dominant disorder caused by a trinucleotide repeat expansion:
With increasing repeat expansion length, DM can cause worsening symptoms in successive generations, as seen in this infant.
(Choice B) Genetic heterogeneity describes different genetic mutations causing the same disease (eg, tuberous sclerosis). This mechanism is inconsistent with this patient's symptoms because affected members of the same family would have the same mutation. Moreover, this mother and child have markedly different disease manifestations.
(Choice C) Germline mosaicism occurs when an unaffected parent has gametes with a mutated allele that is passed to offspring; it is typically suspected when multiple siblings have an autosomal dominant disorder with phenotypically normal parents.
(Choice D) Prader-Willi syndrome often occurs due to maternal imprinting, in which a loss-of-function mutation in the paternal allele is inherited while the maternally inherited allele is silenced. Infants can have profound disease (eg, hypotonia, feeding difficulties), but the mother would not be affected.
(Choice E) Single nucleotide polymorphism (SNP) refers to a variation at a single base pair within a DNA sequence. SNPs occur frequently throughout the genome and contribute to genetic variation within the population. If located near or within a gene, they may be markers of certain genetic diseases but would not cause the increasingly severe manifestations seen in this family's successive generations.
Educational objective:
Anticipation describes an inherited condition that presents earlier and with more severe disease in successive generations. In myotonic dystrophy, increasing length of the pathogenic trinucleotide repeat expansion accounts for severe hypotonia in a neonate (congenital) and mild symptoms (eg, myotonia, facial weakness) in a parent (classic [adult]).