We report on a preterm neonate of 30 weeks gestational age who presented with marked muscular hypotonia and severe respiratory failure at birth and was diagnosed with congenital myotonic dystrophy. Neuroimaging at 36 gestational weeks demonstrated diffuse T2-hyperintense signal of the supratentorial white matter and a simplified gyration and sulcation pattern. Follow-up imaging showed progressive myelination, brain maturation and decrease in T2-signal of the white matter. We discuss possible pathomechanisms for white matter signal abnormalities in this neonate.
Congenital myotonic dystrophy (CMD) is an autosomal-dominant inherited disease resulting from an unstable CTG expansion within the DMPK gene on chromosome 19q13.1, 2 Prenatal polyhydramnios followed by a neonatal presentation of respiratory failure, severe hypotonia (‘floppy baby’), muscle weakness, poor feeding and skeletal deformities is typically seen in CMD.3, 4, 5 Myotonia has never been observed even by electromyography in affected neonates. CMD is inherited from the mother because triplet expansion during meiosis occurs in the maternal line. In newborns with suspected CMD, careful clinical examination of the mother may reveal subtle myotonia and weakness. The diagnosis may be confirmed by identification of the abnormal CTG expansion in the DMPK gene.6
Neuroimaging has an important role in the work-up of ‘floppy babies’.7 Magnetic resonance imaging (MRI) may identify structural brain abnormalities and signal abnormalities of the gray or white matter and guide the clinicians to targeted genetic analysis. To our knowledge, neuroimaging findings have been reported only in three neonates with CMD.6, 8 We report on serial neuroimaging findings in a preterm with CMD and discuss possible pathomechanisms for white matter (WM) signal abnormalities.
A baby-girl was born at 30 4/7 gestational weeks by emergency Caesarean section. The family history was positive for a half sibling with autism and early cataract and exercise intolerance of the maternal grandmother. At delivery, there was no spontaneous respiratory effort with an Apgar score of 1, 3 and 6 at 1, 5 and 10 min. She was intubated and received one dose of surfactant. The initial cord blood gas revealed a pH of 7.22 and a base deficit of −5. The birth weight was 1062 g (11th percentile) and head circumference of 27 cm (31st percentile). The neonatal intensive care course was complicated by respiratory failure requiring intubation and ventilation for 134 days. After extubation, she needed noninvasive pressure support until she was weaned to nasal cannula for the last month of her admission.
The initial brain MRI study at 46 days of life (corrected age of 36 gestational weeks) revealed diffuse T2-hyperintensity of the supratentorial WM, mild ventricular dilatation and a simplified gyration and sulcation pattern. The follow-up brain MRI, 18 weeks later, showed progressive myelination with relative decrease and normalization of the T2-weighted WM signal, mild ventricular dilatation and prominence of the interhemispheric spaces. The gyration and sulcation pattern appeared more complex and age appropriate (Figure 1).
On examination at 38 weeks of gestation, she had a symmetric, narrow shaped head and face and marked generalized hypotonia. Given the clinical picture of marked neonatal hypotonia, respiratory failure requiring intensive support, significant feeding issues and a significant family history of neurodevelopmental disabilities, a metabolic and genetic work up was carried out. This included an elevated creatine phosphokinase (296 U l−1, normal 24 to 170) and ammonia (68 μmol l−1, normal 0 to 32). Glucose, pyruvate, lactate, bicarbonate, transaminases, fT4, TSH, creatinine and urinalysis were normal. Acylcarnitine profile showed abnormalities consistent with medication-induced changes. Abnormalities in urine organic acids were consistent with inotrope use and an immature liver. Plasma amino acids were consistent with malnourishment. Very-long-chain fatty acids level and succinyl-CoA-synthetase activity were normal. No mutations were found within the DGUOK and POLG genes. A karyotype reveals 46, XX. A microarray and Prader–Willi methylation test were normal. Because of the differential diagnosis of CMD1, the mother also underwent a neurological examination. Unfortunately, this was not possible until the patient was about 38 weeks corrected gestation. Examination of the mother revealed myotonic facies, mild bilateral ptosis, exercise intolerance and percussion myotonia of the thenar muscles. Electromyography showed myotonic discharges. These findings in the mother initiated a genetic analysis in our patient that revealed an abnormal expansion of 943 CTG repeats in the DMPK gene confirming the diagnosis of CMD.
The neonatal diagnosis of CMD can be straightforward based on reduced fetal movements, polyhydramnios, marked muscular hypotonia and weakness, respiratory failure, feeding difficulties and percussion myotonia of the maternal muscles.3, 4 The clinical suspicion typically leads to targeted genetic analysis and neuroimaging is not required. In our patient, the presence of multiple complications of prematurity and the lack of a neurological examination of the mother in the early postnatal days made the diagnosis of CMD more challenging and other differential diagnoses were initially considered.7 As part of the work-up of a ‘floppy baby’, a brain MRI was performed.
In our patient, the most striking finding of the brain MRI at the corrected age of 36 gestational weeks was a diffuse T2-hyperintense WM signal. We are aware of only two previous case reports on neonatal neuroimaging findings in CMD.8, 9 In these three neonates, neuroimaging findings were similar to those of our patient. The pathomechanism of WM changes in CMD and, particularly, in our patient is arguable. Three possible explanations may be considered: primary WM involvement in CMD, changes due to secondary, for example, hypoxic CMD complications and WM signal hyperintensity on T2-weighted MRI related to prematurity.
Multifocal, often asymmetrical lesions within the subcortical and/or deep WM with a predilection for the anterior temporal lobes are well-known in children and adults with myotonic dystrophy type 1.10, 11 Similar WM changes have also been demonstrated in children, but not in neonates with CMD.11 Age of onset of these lesions is not known. Diffusion tensor imaging studies reveal that (1) WM abnormalities in CMD and myotonic dystrophy type 1 may be not limited to myelin, but also involve axons, and (2) significant microstructural changes may occur over time leading to progressive myelin destruction.11, 12 In our patient, signal abnormalities involved all the supratentorial WM and improved over time.
In neonates with CMD, respiratory failure is typically present and may cause hypoxic brain injuries. Tanabe et al. reported on signal abnormalities and volume reduction of the periventricular WM in seven children with CMD and showed a significant correlation between Apgar scores and severity of neuroimaging findings.13 Similar findings were shown in children with neonatal hypoxic injuries, but without CMD. In our patient, Apgar scores were low, but cord blood gas was normal, she did not have known persistent hypoxia and WM changes were diffuse and improved on follow-up.
Until 36 weeks of gestation, neuroimaging physiologically does not show the presence of myelin within the supratentorial WM. Because of the minimal myelin and high water content, WM appears hyperintense on T2-weighted images. In addition, the gyration and sulcation pattern are rather simple with branched sulci only in the parieto-occipital areas. Neuroimaging findings in our patient are compatible with the corrected gestational age.
In conclusion, we report on T2-hyperintense WM signal in a preterm neonate with CMD at 36 gestational weeks. The improvement at follow-up and neuroimaging findings compatible with the gestational age argues for a dominant role of prematurity in explaining the WM signal in our patient. This case suggests that WM signal changes in CMD are not neonatal in onset even in a highly symptomatic newborn.
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We are grateful to Professor Ronald D Cohn, Division of Clinical and Metabolic Genetics, the Hospital for Sick Children, University of Toronto, Canada, and Professor Jaap Valk, Department of Radiology, VU University Medical Center, Amsterdam, the Netherlands, for interesting and helpful discussions about this patient.
The authors declare no conflict of interest.
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Bosemani, T., Jasien, J., Johnston, M. et al. Neonatal neuroimaging findings in congenital myotonic dystrophy. J Perinatol 34, 159–160 (2014). https://doi.org/10.1038/jp.2013.142
- congenital myotonic dystrophy
- magnetic resonance imaging
- white matter
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