Unusual Magnetic Resonance Imaging Findings in 3-Hydroxy-3-Methylglutaryl-Coenzyme A Lyase Deficiency

A 3-year-old child, born to nonconsanguineous parents, presented with neuroregression following an episode of acute febrile illness with hypoglycemia, transaminitis, and metabolic acidosis at 2 years of age. He had seizures and developmental delay in the past 8 months following a trivial fall. On examination, normocephaly, bipyramidal signs, and dystonia were observed. Blood lactate was 3.6 mmol/L (0.5–2 mmol/L) and urine Gas Chromatography-Mass Spectrometry showed increased excretion of 3-hydroxy isovaleric, methylglutaric acid, and 3-hydroxy-3-methylglutaric acid. Imaging revealed progressive cavitating leukodystrophy (PCL; [Figs. 1] and [2]). Differentials of vanishing white Matter (VWM), organic aciduria, and mitochondrial PCL were suspected. Whole exome sequencing revealed likely pathogenic compound heterozygous variants of HMGCL gene ([Table 1]). Our patient has been managed with dietary plan, carnitine supplementation, and optimization of antiepileptic medications.

Fig. 1 Axial CT images show mild patchy hypodensity in the peripheral posterior frontoparietal white matter (A, B) bilaterally at 8 months. On follow-up at 13 months, these evolved to confluent hypodensity in the frontoparietal white matter (arrows, C, D). CT, computed tomography.

Fig. 2 Axial (A, B) and sagittal (C) T2, axial T1 postcontrast (D), FLAIR (E), DWI (F, G) and (H) images at 3 years of age show marked hyperintensity of the frontoparietal white matter bilaterally (asterisk, A) with evidence of rarefaction (asterisk, D, E). Linear stripes (arrows, E), involvement of the middle blade of CC sparing the inner and outer rims (arrows, B, C) with diffusion restriction of the involved white matter (F–H) are noted as well. Short single voxel MRS (I) at centrum semiovale shows double peaks at 1.3 and 2.4 ppm (arrows). DWI, diffusion weighted imaging; FLAIR, fluid-attenuated inversion recovery; MRS, magnetic resonance spectroscopy. ADC, apparent diffusion coefficient; TE, echo time.

Table 1 Comparative MRI characteristics of leukodystrophies with progressive cavitation (VWM and mitochondrial PCL), HMG-CoA lyase deficiency, and our patient[a]

Genes and suggestive MRI features	Early childhood VWM disease[4]	Mitochondrial related PCL	HMG CoA lyase deficiency
			Established features	Current case
Associated genes	EIF2B1–5	Multiple complex I–IV related genes Genes related to iron-sulfur clusters biogenesis and MMDS:NFU1 (MMDS 1), BOLA3 (MMDS 2), IBA57 (MMDS 3) Elongation factor related genes: EFTu, EFG1 (see section Additional Reading for references)	HMGCL	HMGCL Novel mutations: exon4: c.286del (p.Gln96ArgfsTer11)—pathogenic Exon3: c.228T > A (p.Phe76Leu)—variant of uncertain significance
Extent of white matter involvement	Symmetrical and diffuse (involving almost all lobes)	Frontoparietal (can have gradients of involvement) Can spare parts of few lobes, especially temporal, occipital	Frontoparietal multifocal, patchy (early) to confluent (late)	Frontoparietal Few patchy areas Temporal, occipital lobes spared
Subcortical white matter including U-fibers	Spared, can be involved later in the course	Tends to periventricular predominant, subcortical mostly spared (can be involved in few areas but not the main feature)	Present but variable, spares U-fibers	Involved, U-fibers involved in few areas but mostly spared
Linear stripes on FLAIR	Linear stripes present due to rarefaction	Generally lacks linear stripes or are milder (except NDUFA2)[5]. Instead shows multifocal small to large cystic cavities	Nil	Linear stripes present
Diffusion restriction	Involves the apparently normal white matter along the peripheral aspects of the rarefied regions/cavities	Mostly peripheral aspects of the cavities/rarefied regions, can be diffuse	Mild diffusion restriction can be present	Diffusely present (peripheral as well as central aspect of the rarefied white matter)
CC—pattern of involvement, extent	Diffuse inner rim involvement, outer rim spared Genu and splenium initially, to diffuse especially later on	Middle blade involvement, spares the inner and outer rims (can involve all) More remarkable swelling, diffusion restriction	Spared	Partial involvement of the middle blade of the genu, outer and inner rim spared. Rest of the CC not involved
Cerebellum, pons	Present, especially later on	Variable	Spared	Spared
Suggestive MRS findings	Diffuse decrease in all metabolites. eventual lactate and glucose signal (similar to CSF)	Lactate peak at 1.3 ppm Simultaneous lactate peak at 1.3 ppm and succinate peak at 2.4 ppm in complex-II deficiency	Peaks at 1.3 and 2.4 ppm (similar to complex II), related to multiple complex organic acids[3]	Peaks at 1.3 and 2.4 ppm

Abbreviations: BOLA3, bolA family member 3; CC, corpus callosum; CSF, cerebrospinal fluid; EIF2B1, Eukaryotic Translation Initiation Factor 2B Subunit Alpha; FLAIR, fluid-attenuated inversion recovery; HMG-CoA, hydroxy-methylglutaryl-coenzyme A; HMGCL, hydroxy-methylglutaryl-coenzyme A lyase; IBA57, iron-sulfur cluster assembly homolog; MMDS, Multiple mitochondrial dysfunctions syndrome; MRI, magnetic resonance imaging; NDUFA2, NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 2; NFU1, NFU1 iron-sulfur cluster scaffold homolog; PCL, progressive cavitating leukodystrophy; VWM, vanishing white matter.

^a Based on the most common or dominant features.

PCL in hydroxy-methylglutaryl-coenzyme A (HMG-CoA) lyase (HMGCL) deficiency has been described on computed tomography (CT) previously, however, not on MRI.[1] While some overlapping features with VWM (rarefaction and linear fluid-attenuated inversion recovery [FLAIR] stripes) and mitochondrial PCL (diffusion restriction, middle blade of corpus callosum, and magnetic resonance spectroscopy [MRS] peaks) were noted, many features were unusual for both ([Table 1]). Simultaneous MRS peaks at 1.3 and 2.4 ppm in HMGCL deficiency are also seen with complex-II mitochondrial leukodystrophy where they represent lactate and succinate, respectively.[2] [3] This report outlines an unusual PCL phenotype in HMGCL deficiency.

Publication History

Received: 06 December 2021

Accepted: 17 February 2022

Accepted Manuscript online:
22 February 2022

Article published online:
28 August 2022

• References

• 1 Gibson KM, Breuer J, Nyhan WL. 3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: review of 18 reported patients. Eur J Pediatr 1988; 148 (03) 180-186
• 2 Morató L, Bertini E, Verrigni D. et al. Mitochondrial dysfunction in central nervous system white matter disorders. Glia 2014; 62 (11) 1878-1894
• 3 Roland D, Jissendi-Tchofo P, Briand G. et al. Coupled brain and urine spectroscopy - in vivo metabolomic characterization of HMG-CoA lyase deficiency in 5 patients. Mol Genet Metab 2017; 121 (02) 111-118
• 4 van der Lei HD, Steenweg ME, Barkhof F. et al. Characteristics of early MRI in children and adolescents with vanishing white matter. Neuropediatrics 2012; 43 (01) 22-26
• 5 Alagia M, Cappuccio G, Torella A. et al; TUDP. Cavitating and tigroid-like leukoencephalopathy in a case of NDUFA2-related disorder. JIMD Rep 2020; 52 (01) 11-16

• Additional Reading (for Mitochondrial Related Progressive Cavitating Leukodystrophy)

• 1 Hartman TG, Yosovich K, Michaeli HG. et al. Expanding the genotype-phenotype spectrum of ISCA2-related multiple mitochondrial dysfunction syndrome-cavitating leukoencephalopathy and prolonged survival. Neurogenetics 2020; 21 (04) 243-249
• 2 Zhang J, Liu M, Zhang Z. et al. Genotypic spectrum and natural history of cavitating leukoencephalopathies in childhood. Pediatr Neurol 2019; 94: 38-47
• 3 Ishiyama A, Sakai C, Matsushima Y. et al. IBA57 mutations abrogate iron-sulfur cluster assembly leading to cavitating leukoencephalopathy. Neurol Genet 2017; 3 (05) e184
• 4 Morató L, Bertini E, Verrigni D. et al. Mitochondrial dysfunction in central nervous system white matter disorders. Glia 2014; 62 (11) 1878-1894