Neuroimaging Spectrum of Inherited Neurotransmitter Disorders

Abstract

Inherited neurotransmitter disorders are rare neurometabolic conditions which encompass genetic disorders of neurotransmitter metabolism or transport. The clinical manifestations of these rare disorders are often nonspecific, ranging from encephalopathies and seizures to movement disorders. As a consequence, neurotransmitter disorders are underrecognized and often misdiagnosed. Accurate and timely diagnosis is, however, of utmost importance, given the availability of therapeutic strategies. A high index of clinical suspicion and familiarity with the neuroimaging phenotypes is therefore crucial. While the imaging features of various neurotransmitter disorders often overlap and are nonspecific, imaging can be helpful in providing useful clues to guide the diagnostic algorithm for uncommon conditions in a neonate presenting with nonspecific neurological symptoms. In this review paper, we aim to bring together current knowledge of neuroimaging phenotypes associated with inherited (primary) disorders of neurotransmitter biosynthesis. Magnetic resonance imaging phenotypes of disorders of monoamine biosynthesis, primary cerebral folate deficiency, disorders of pyridoxine metabolism, disorders of gamma-aminobutyric acid metabolism, nonketotic hyperglycinemia (glycine encephalopathy), disorders of serine biosynthesis, and cerebral creatine deficiency syndrome will be discussed and illustrated with case examples.

Novel Protein Biomarkers of Monoamine Metabolism Defects Correlate with Disease Severity

“…Those changes are more common in severe patients than in mild patients (63% vs. 19%, respectively). 3,32 OMGP is a glycosylphosphatidylinositolanchored protein expressed mainly by central nervous system neurons and oligodendrocytes. 33 During development, OMGP expression parallels myelination, increasing from birth to early adulthood until it decreases and reaches a stable expression level in the adult.…”

“…Brain magnetic resonance imaging, which is usually normal, may show white matter abnormalities in T2-weighted images in PTPS deficiency, whereas basal ganglia calcifications have been reported in DHPR deficiency. 32 Our proteomic study has detected some relevant proteins associated to BH4 disorders regardless the specific defect (Table 2). Among them, decreased expression of the COL6A3 protein was found in posttreatment samples.…”

Inherited paediatric neurometabolic disorders, can brain magnetic resonance imaging predict?

“…Neurometabolic disorders can be classified by various methods based on clinical and biochemical characteristics, area of brain involvement, or cellular organelle. 4 Imaging based classification includes leukodystrophy )primary involvement of white matter due to genetic abnormality(, leukoencephalopathy )secondary involvement of white matter either due to genetic or acquired systemic disorder(, poliodystrophy )predominant involvement of grey matter(, and pandydystrophy )mixed involvement of both white and grey matter(. 5 Central nervous system white matter is usually affected, 6 and can result from various pathologic process like delayed myelination )myelin maturation delayed for expected age(, hypomyelination )scarcity of myelin or arrest in myelination process(, dysmyelination )deposition of abnormally composed fragile myelin(, demyelination )secondary loss of myelin that may have been previously normal( and myelinopathy )vacuolating due to deranged brain iron and water hemostasis(.…”

“…7 Analyzing pattern recognition in MR imaging and clinical clues help to narrow the differential, tailor subsequent laboratory )targeted metabolomics( or genetic investigations )either requiring single gene testing or broad-spectrum genetic testing i.e., whole exome sequencing/ WES(. 4 The MRI can be helpful in diagnostic workup of various diseases and may be decisive for early management even before arrival of costly and time-consuming biochemical or genetic testing results. 8 We therefore sought to highlight ability of MRI in predicting diagnoses of inherited neurometabolic disorders in neonates and young children considering certain MRI findings.…”

“…Timing of any therapeutic intervention is of strategic importance considering limited regenerative capacity of the brain. 4 By adopting our selected imaging criteria, we were able to suggest metabolic diseases like glutaric aciduria, MSUD (Figure 1), adrenoleukodystrophies, urea cycle defects, MLD ) Figure 2(, and NCL ) Figure 3(. Although MR spectroscopic imaging was not available in every case, however, when available and characteristic ) Figure 4&5(, such information also helped in suggesting such disorder.…”