Page 144 - Read Online

Page 434 Gropman et al. J Transl Genet Genom 2020;4:429-45 I http://dx.doi.org/10.20517/jtgg.2020.09

In order for MRS to effectively measure the key metabolites, the molecules must be relatively mobile within
the tissue. Large macromolecules (i.e., molecular weights greater than 20,000 Daltons) do not show enough
free movement and cannot be detectedd. There must also be a large enough concentration of atomic nuclei
of a specific type to generate a recognizable signal/noise ratio in the millimolar range concentration.

The peak areas correspond to the number of nuclei and are extrapolated to concentration. Proton MRS is
[49]
the most widely used spectroscopy technique for the brain . The most common chemicals studied are
N-acetyl-L-aspartate (NAA), total creatine (tCr) which is a sum of creatine (Cr) and phosphocreatine (PCr),
choline (Cho), myo-inositol (mI), lactate (Lac), glutamate (Glu), and glutamine (Gln), known on low field
MRI as “Glx”. In addition, amino acids, lipid, and gamma-aminobutyric acid (GABA) may be detected;
but require editing. The number of metabolites seen will depend upon the chosen echo time (TE) and field
strength with more metabolites seen on short TE. Long TE MRS is sufficient to evaluate lactate (if present),
NAA, creatine, and choline Glu. Gln and mI are not detectable at long TE due to short relaxation times.
These common chemicals can provide information about disease states: NAA: mitochondrial oxidative
metabolism and marker for neuronal viability. It is also the source of acetyl groups for lipid synthesis; Cr
and phosphocreatine (PCr): markers of creatine to phosphocreatine energy conversion; Cho: precursor for
the neurotransmitter acetylcholine and membrane phospholipids, phosphatidylcholine, and sphingomyelin;
mI: neuronal signaling molecule of the phosphoinositide pathway and osmoregulation; Lac: marker of
anaerobic metabolism and Glu and Gln: neurotransmitters in the CNS. A number of MRS studies have
been conducted in IEMs and are shown in the table [Table 1]. Figure 1A shows a normal MRS, and
Figure 1B and C show spectra with missing or extra peaks. A few disorders are highlighted below.

GLUTARIC ACIDURIA TYPE I
Acute striatal necrosis is a devastating consequence of the encephalopathic crisis seen in patients with glutaric
aciduria type I (GA-I). Insidious-onset patients have been shown to have a latency phase of 3.5 months
[51]
to 6.5 years between detection and clinical manifestation of dorsolateral putaminal lesions . MR
spectroscopy showed a decreased N-acetyl-aspartate (NAA) peak and NAA/creatinine (Cr) ratio at
the basal ganglia in three encephalopathic patients. The values of NAA/Cr ratios in these patients were
below that of controls (range: 0.97-1.12 vs. 1.61-1.97). In patients with motor symptoms, MRI showed
abnormalities in FLAIR and T2-weighted sequences. There was bilateral and symmetrical hyperintensity in
the putamen, caudate, globus pallidus and cerebral peduncles.

MAPLE SYRUP URINE DISEASE
MRS has also been used in maple syrup urine disease (MSUD). The most specific biomarker is elevation
of leucine, isoleucine and valine and corresponding 2-oxo acids. This corresponds to a peak at 0.9 ppm on
[52]
MRS. Heindel et al. reported a nine-year-old patient who suffered acute metabolic decompensation. The
elevated peak at 0.9 ppm was seen in the early phase of disease, during decompensation and normalized
after recovery .
[53]

PELIZEAUS-MERZBACHER DISEASE
Pelizeaus-Merzbacher disease (PMD) is a hypomyelination disorder due to a primary defect in myelin
[54]
[55]
[56]
formation . Delayed and low myelin is appreciated on MRI . Pizzini et al. have observed reduction in
[57]
NAA and mild increase in choline levels in the affected white matter. Sener noted a reduction in Cho/Cr .
METHYLMALONIC ACIDEMIA
Methylmalonic academia (MMA) , an autosomal recessive disorder of amino acid metabolism occurs
[58]
due to inability to convert methylmalonic acid to succinic acid. MMA results from mutation of the
methylmalonyl-CoA mutase apoenzyme, or its coenzyme adenosyl cobalamin . MMA typically presents
[58]