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Gropman et al. J Transl Genet Genom 2020;4:429-45 I http://dx.doi.org/10.20517/jtgg.2020.09 Page 433

demonstrated abnormalities with microstructural disorganization that has shown some association with
[44]
the degree of NPC1 severity .

KRABBE DISEASE
Studies using DTI have shown that radial diffusivity and fractional anisotropy are sensitive in vivo as
biomarkers of white matter microstructural damage in this condition. Using DTI, early white matter injury
has been detected in asymptomatic neonates with Krabbe. The DTI metrics have shown to correlate with
motor and cognitive functions after hematopoietic stem cell transplantation (HSCT), and as a marker of
[45]
white matter development .
ORNITHINE TRANSCARBAMYLASE DEFICIENCY
MR imaging in patients with ornithine transcarbamylase deficiency (OTCD) is often normal in late-
[46]
onset disease, heterozygotes, or in those not in hyperammonemic crisis. Gropman et al. used DTI to
study adults with OTCD. In all cases, DTI proved more sensitive than T2-weighted imaging for detecting
abnormalities in normal-appearing white matter. The extent of abnormality in white matter in turn
correlated with cognitive deficits. The location of the deficits in the frontal white matter correlated with
pathways that subserve executive function, attention, and working memory which are impaired in this
patient population .
[46]

Given that the goal of therapy in IEMs is to decrease morbidity to the brain and other organs,
understanding the impact of these disorders on brain injury and remodeling can help frame treatment and
monitoring in patients. Differential neural networks underlying a cognitive process may arise due to injury
to the native pathway, and/or development of an accessory pathway over time. Since T1 and T2 weighted
changes in white matter tracts are only sensitive to significant, macroscopic damage, quantitative, early
microscopic features of myelination and axonal integrity can be gleaned by using DWI and DTI which are
[46]
used to study microstructural variance in white matter fiber tracts .

MAGNETIC RESONANCE SPECTROSCOPY
Magnetic resonance spectroscopy (MRS) is an imaging technique used to measure brain metabolism . It
[47]
is popular in IEMs for monitoring of disease progression and therapeutic response.

MRS is noninvasive. Its use allows one to gain information relevant to tissue biochemistry and
[48]
metabolism . MRS is performed with the same hardware used for anatomical imaging. Instead of an
image, a spectrum is produced. The area under the peaks is proportionall to the concentration of the
relevant metabolite. MRS studies of humans and genetically altered animals are feasible as are studies
[49]
of cultured cells, histological tissue samples, and chemical extracts of tissues . A benefit of MRS is
the lack of ionizing radiation. Therefore repeated scanning of patients including infants and children is
feasible and acceptable. However, MRS is very sensitive to movement and the peaks can become wide and
uninterpretable which makes it a difficult imaging modality to perform in unsedated children.

MRS allows measurement of chemicals in the brain. It is based on the principles of nuclear magnetic
resonance. Magnetic resonance reveals the interaction between a molecule and an external magnetic field.

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The nuclei most relevant to complex human conditions are H, P, C, Li, and F. Those most studied
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include hydrogen ( H) (also referred to as proton MRS) and phosphorus ( P). ( C) imaging is cumbersome
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but can be useful to study flux through the citric acid cycle which is relevant for many of the inborn errors
of metabolism.