N-acetyl aspartate (NAA) is a commonly evaluated neuronal metabolite in 1H-Magnetic Resonance Spectroscopy (1H-MRS). The resonance at a specific chemical shift, although typically attributed to NAA, may reflect contributions from other N-acetyl-containing compounds. This study sought to identify the neuroimaging substrates with a greater-than-expected prominence of the singlet peak at 2.02 ppm in 1H-MRS across various conditions and to explore their biochemical basis. The operational definition was a conspicuously tall singlet at 2.02 ppm whose amplitude exceeded the expected NAA peak relative height of choline and creatine peaks for that anatomical region and acquisition TE (time to echo). A retrospective descriptive analysis was performed on the institutional imaging database. The search terms for identifying entities included "elevated NAA", "prominent NAA", and "elevated peak at 2.02 ppm". The clinical and imaging features were recorded for eight cases that fulfilled the search criteria. Eight entities fulfilled the search criteria in retrospective analysis. The conditions were Canavan's disease, Pelizaeus-Merzbacher disease, Pelizaeus-Merzbacher-like disease, Salla's disease, colloid cyst, neurenteric cyst, tumoral cyst, and mucinous adenocarcinoma metastasis. A higher-than-expected/elevated peak at 2.02 ppm chemical shift at the predicted location of NAA in 1H-MRS was noted in these cases, all of which had an N-acetylated molecule in the pathological milieu. An accentuated 2.02 ppm peak on ¹H-MRS should not be interpreted as NAA-specific without contextual correlation. The chemical shift of 2.02 ppm is a metabolite signature of the methyl protons of the N-acetyl group and provides no further information about attached moieties. The signal may arise from a wide gamut of compounds with N-acetyl groups arising from diverse biochemical substrates in metabolic, cystic, and neoplastic lesions, as elucidated. Awareness of these mimics improves diagnostic accuracy and prevents misinterpretation of spectroscopy findings.

GJC2 encodes connexin 47 (Cx47), a gap junction protein expressed by oligodendrocytes that forms gap junction channels (GJCs) between adjacent oligodendrocytes (or astrocytes, via heterotypic Cx47-Cx43 GJCs). Autosomal recessive mutations of GJC2 lead to at least three central nervous system phenotypes: Pelizaeus-Merzbacher-like disease 1 (PMLD1), spastic paraparesis 44 (SPG44), and a minimal leukodystrophy. Here, we describe the clinical, functional, and molecular effects of two mutations in GJC2, p.G40S, and p.R244P, identified in two different families with GJC2-related disorders. Expressed exogenously, p.G40S forms GJC plaques like WT but does not functionally couple with WT nor with Cx43. p.R244P also fails to demonstrate functional coupling. Moreover, plaque formation is absent, concomitant with intracellular connexin accumulation. When the two mutants are co-expressed in a compound heterozygous state, plaques form, but no GJC coupling is detected in any configuration. MD simulations demonstrate that p.G40S modifies secondary structure of the pore-lining α-helix, disrupting supersecondary interactions with the N-terminal helix and predicting channel closure. p.R244P simulations are characterized by partial loss of the extracellular β-sheet domains and a marked reduction of electrostatic interactions between the connexin and lipid headgroups of the plasma membrane, suggesting pathways by which p.R244P mutation impairs GJC formation. This combination of in vitro assays and molecular simulations provides mechanistic insight into the pathogenesis of GJC2-related disease.

Hypomyelinating leukodystrophies are a subset of genetic white matter diseases characterized by insufficient myelin deposition during development. MRI patterns are used to identify hypomyelinating disorders, and genetic testing is used to determine the causal genes implicated in individual disease forms. Clinical course can range from severe, with patients manifesting neurologic symptoms in infancy or early childhood, to mild, with onset in adolescence or adulthood. This chapter discusses the most common hypomyelinating leukodystrophies, including X-linked Pelizaeus-Merzbacher disease and other PLP1-related disorders, autosomal recessive Pelizaeus-Merzbacher-like disease, and POLR3-related leukodystrophy. PLP1-related disorders are caused by hemizygous pathogenic variants in the proteolipid protein 1 (PLP1) gene, and encompass classic Pelizaeus-Merzbacher disease, the severe connatal form, PLP1-null syndrome, spastic paraplegia type 2, and hypomyelination of early myelinating structures. Pelizaeus-Merzbacher-like disease presents a similar clinical picture to Pelizaeus-Merzbacher disease, however, it is caused by biallelic pathogenic variants in the GJC2 gene, which encodes for the gap junction protein Connexin-47. POLR3-related leukodystrophy, or 4H leukodystrophy (hypomyelination, hypodontia, and hypogonadotropic hypogonadism), is caused by biallelic pathogenic variants in genes encoding specific subunits of the transcription enzyme RNA polymerase III. In this chapter, the clinical features, disease pathophysiology and genetics, imaging patterns, as well as supportive and future therapies are discussed for each disorder.