At what age should children of a parent with Myotonic Dystrophy type 1 (DM1) be tested for DM1?

Testing Children of a Parent with Myotonic Dystrophy Type 1

Children of a parent with DM1 should undergo genetic testing based on clinical presentation rather than a predetermined age, with testing indicated immediately if symptoms are present at any age, including neonatal period for congenital DM1, and offered as predictive testing for asymptomatic at-risk children after appropriate genetic counseling. 1

Clinical Context for Testing Decisions

The timing and approach to testing depends critically on whether the child is symptomatic versus asymptomatic, and which parent carries the mutation:

Symptomatic Children - Test Immediately

Any child showing signs of DM1 should be tested immediately regardless of age. 1 Key clinical presentations include:

• Congenital DM1 (neonatal period): Generalized hypotonia, respiratory distress, feeding difficulties, and developmental delay 2
• Childhood-onset: Delayed motor milestones (not walking by 16-18 months), cognitive deficits, facial weakness, myotonia, or gastrointestinal disturbances 3, 4
• Equivocal presentations: Unexplained cardiac conduction abnormalities, early cataracts, or progressive muscle weakness 1

Asymptomatic At-Risk Children - Predictive Testing

Predictive testing of asymptomatic at-risk family members should be performed after identification of a fully-variable allele in an affected relative. 1 However, this requires careful consideration:

• Genetic counseling is mandatory before testing asymptomatic children 2, 1
• The decision involves balancing early detection benefits against psychosocial implications
• Testing allows for early surveillance of cardiac complications, which are life-threatening and present in approximately 80% of DM1 patients 2

Critical Maternal vs. Paternal Inheritance Distinction

The parent's sex profoundly impacts offspring risk and should guide testing urgency:

• Maternal transmission: Almost exclusively responsible for congenital DM1 with the largest repeat expansions (1000-6000 repeats) 2
• Paternal transmission: Can transmit the mutation but rarely results in congenital forms 2
• Prenatal testing should be strongly considered when the mother is affected, particularly if fetal ultrasound shows hypotonia, positional abnormalities, or hydramnios 1

Genetic Anticipation and Disease Severity

A significant increase in allele size in a child compared with the parent confers a high likelihood of earlier onset and more severe phenotype. 2 This anticipation phenomenon means:

• Children typically present earlier and more severely than their affected parent 2
• CTG repeat length correlates with severity: 50-100 repeats (mild), 100-1000 repeats (classic), 1000-6000 repeats (congenital) 2, 1
• However, repeat size does not perfectly predict severity due to somatic mosaicism 2, 4

Testing Methodology

Direct DNA testing using PCR combined with Southern blot analysis is the gold standard for DM1 diagnosis. 1 Key technical points:

• PCR detects smaller expansions (<100 repeats) rapidly and cost-effectively 1
• Southern blot is necessary for larger expansions (>100 repeats) which appear as diffuse smears due to somatic mosaicism 1
• Do not rely solely on PCR, as larger expansions may not amplify reliably and will be missed 1
• Next-generation sequencing should not be used as a standalone method due to technological limitations 1

Clinical Implications of Early Detection

Early diagnosis allows timely initiation of surveillance and management that impacts morbidity and mortality:

• Cardiac monitoring is critical, as cardiac arrhythmias and respiratory complications are the most frequent primary causes of death in DM1 2
• Risk of cardiac disease is higher in younger patients (2-30 years old) 2
• Progressive atrioventricular or intraventricular conduction defects and tachyarrhythmias are life-threatening complications 2
• Multidisciplinary surveillance incorporating neurology, cardiology, pulmonology, and ophthalmology improves outcomes 3

Important Caveats

Approximately 3-8% of DM1 patients have CCG or other interruptions within their CTG expansions, which can result in milder phenotypes and later onset despite similar repeat lengths. 1, 5 This can complicate genotype-phenotype predictions.

Variable alleles (35-49 repeats) may be identified in asymptomatic individuals, requiring careful genetic counseling. 1 These individuals are not affected but their children are at risk for expansion to disease-causing ranges.

Rare spontaneous contractions to normal repeat ranges have been reported, explaining some cases of apparent nonpenetrance. 2