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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

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