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in this article. These imaging modalities will be discussed in the context of several inborn errors of metabolism
including Galactosemia, Phenylketonruia, Maple syrup urine disease, Methylmalonic acidemia, Niemann-Pick
Disease, type C1, Krabbe Disease, Ornithine transcarbamylase deficiency, Sjogren Larsson syndrome, Pelizeaus-
Merzbacher disease, Pyruvate dehydrogenase deficiency, Nonketotic Hyperglycinemia and Fabry disease. Space
constraints do not allow mention of all the disorders in which one of these modalities has been investigated, or
where it would add value to diagnosis or disease progression.

Keywords: Genetics, inborn error of metabolism, MRI, Magnetic Resonance Spectroscopy, functional near infrared
spectroscopy, functional MRI, diffusion tensor imaging, neuroimaging

INTRODUCTION
Many inborn errors of metabolism (IEMs) are associated with an acute onset of progressive symptoms
[1-5]
and irreversible brain injury . Research from preclinical models is delving into the etiologies of how
a metabolite intoxication accounts for the specific cognitive and neurologic findings observed in IEM
[6,7]
patients related to the time of injury or many years later . IEM-associated brain injury patterns may be
region specific and primarily cause gray matter or white matter damage, but typically is more complicated
and may include damage to neurons and the supporting glia at the same time or later in the course. In
children, this occurs on the backdrop of development of some of the very systems that are impacted later,
[8]
such as executive function .

It is not clear why a global insult such as IEM may cause more selective damage to particular sets of
cells. This could involve deep gray matter neurons, white matter, the putamen (and to a lesser degree, the
[10]
[9]
globus pallidi) as seen in glutaric aciduria type 1 , putamen in certain mitochondrial cytopathies , or
[11]
the globus pallidus in methylmalonic acidemia . There may be damage to regions that share a particular
neurotransmitter system. This remains poorly understood and often requires preclinical investigations.
Neuroimaging has already shown great potential for the investigation and management of IEM and other
genetic conditions. Given its non invasive nature, it allows for longitudinal assessments and follow-up. Each
modality may contribute something unique about the timing or pathology, and can be used as a biomarker
to study the disease course or therapeutic intervention. One criticism has been that the findings on routine
T1 and T2-weighted imaging are nonspecific and may not allow differentiation between disorders. In
those cases, additional magnetic resonance images (MRI) sequences and/or modalities enables a higher
diagnostic specificity. Beyond establishing a diagnosis, MRI may be used to understand pathology, disease
progression and long term impact of the disease on higher cognitive function with the use of functional
MRI (fMRI) and functional near infrared spectroscopy (fNIRS). The latter techniques are important as
therapy may lead to a decrease in a blood metabolite, yet there may be an elevation of a toxic compound
in the CNS and the impact of damage on cognition and function may not be fully understood. These
advanced modalities are not available in every hospital. However, the purpose of this review is not to
mandate use of certain imaging modalities, but rather to highlight when certain imaging sequences may be
useful to further understand the pathogenesis of a metabolic disorder. In addition, due to space constraints,
it will not be possible to list every condition and its imaging characteristics. Rather, specific disorders
will be highlighted in which recent literature has suggested the value of MRI in these conditions. Lastly,
research into practice will use examples as to how multimodal imaging is applied in the clinical setting,
leading to improved clinical management.

The term “neuroimaging” describes sequences beyond T1 and T2 weighted imaging. Most clinical routine
images at major medical centers include a fluid attenuation inversion recovery (FLAIR). Some centers