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We thank Drs. Agripnidis and Hak for their thoughtful critique of our recent publication and for highlighting the importance of age-specific interpretation of diffusion-weighted imaging (DWI) of the cerebellum in infants.
Their observations raise important points regarding normal cerebellar maturation, which we agree must inform interpretation of diagnostic brain MRIs in early infancy. However, we believe that the cerebellar abnormalities presented in our Norrie Disease (ND) cases reflect a pathologic process beyond expected developmental change.
Importantly, we would like to provide additional clinical and imaging information that was not included in our original manuscript for reasons of brevity. In both patients, cerebellar signal abnormality on T2-weighted images was present at presentation (Figs 1, 4, and 5), along with reduced ADC values, and cerebellar enhancement. In Case 1 (the 5-week-old), a follow-up MRI at 3 years and 6 months demonstrated chronic evolved cerebellar injury (Fig 2 and 3).
Additionally, the cerebellar ADC abnormalities in both infants were first detected through subjective visual inspection and subsequently confirmed by quantitative analysis. This diagnostic approach reflects standard clinical practice and emphasizes the contribution of visually recognizing apparent, regionally specific signal abnormalities, particularly in genetically confirmed neurovascular conditions.
Quantitative ADC measurements from the initial studies were:
These values fall near or below the 2 SD lower bounds published by Özkan et al. for cerebellar cortex in infants under 6 months (1). While values in this range may reflect normal variation, the coexistence of cerebellar enhancement and T2 signal abnormalities at presentation—along with chronic changes on follow-up—suggests that the findings reflected true cerebellar pathology.
We note that while ADC values decrease in early infancy (1), the absolute ADC measurement alone does not distinguish normal from abnormal, especially when diffusion changes are accompanied by enhancement and/or T2 signal abnormalities, which were present in both of our cases. Additionally, while early postnatal ADC reductions can reflect physiological maturation, this process is typically symmetric, homogeneous, and not associated with signal abnormalities or long-term structural injury (2) distinguishing our findings (Fig 6) from expected maturation.
The imaging abnormalities we describe align with the known pathophysiology of Norrie Disease. NDP mutations disrupt Wnt/β-catenin signaling, which is essential for cerebrovascular development and blood-brain barrier integrity. Animal models show cerebellar vascular dysgenesis and increased permeability, providing biological support for our findings of cerebellar enhancement, reduced diffusion, and injury (3, 4,5).
In conclusion, while we agree that cerebellar ADC values can be low in normal infancy, in our cases, this finding occurred alongside cerebellar enhancement, T2 signal changes, and structural injury on follow-up MRI, in a disease with a known vascular mechanism. Together, these features strongly support pathological interpretation.
We appreciate the opportunity for this dialogue and to clarify these points and to expand upon our original findings.
Respectfully, Kevin Ferenchak, MD; Julie B. Guerin, MD; Asra Nayab, MBBS; Gesina F. Keating, MD; Madeline Q. Lopour, MS; Lauren A. Dalvin, MD; Lisa A. Schimmenti, MD; Brittni A. Scruggs, MD, PhD; V. Michelle Silvera, MD.
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