L-2-hydroxyglutaric aciduria – review of literature and case series

Annals of Medicine and Surgery · 8 authors, 4 centres

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TL;DR

This paper presents two sisters with L-2-hydroxyglutaric aciduria (L2HGA) diagnosed via clinical presentation, specific MRI findings, and genetic testing. It also reviews the literature, noting characteristic neurological symptoms and the potential for improvement with riboflavin and L-carnitine treatment.

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The report describes two Pakistani sisters, born to consanguineous parents, presenting with psychomotor delay, seizures, ataxia, intentional tremors, and dysarthria. Diagnosis of L2HGA was confirmed by urinary analysis of 2-hydroxyglutaric acid, characteristic brain MRI showing centripetal subcortical white matter changes, and identification of a homozygous pathogenic L2HGDH gene variant (c.829C>T, p.Arg227*). No definitive treatment exists, but the authors report clinical improvement in these sisters and other cases following riboflavin and L-carnitine supplementation.

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case_report

SPECIALTY

neurology

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ORIGINAL PAPER

PMC10129278

L-2-hydroxyglutaric aciduria – review of literature and case series

Annals of Medicine and Surgery

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ABSTRACT

Background: L-2-hydroxyglutaric aciduria (L2HGA) is an autosomal recessive, slowly progressive neurodegenerative disease characterized by psychomotor delay and cerebellar dysfunction. The biochemical hallmark is increased concentrations of L2HG in body fluids. Brain MRI exhibits characteristic centripetal extension of the white matter involvement that differentiates it from other leukodystrophies. The authors report two sisters from Pakistan with L2HGA with 4 years of follow-up. The authors have also compared the clinical outcome of our patients with 45 previously reported patients with L2HGA for whom treatment and clinical outcome was reported. Case presentation: The authors report two sisters with L2HGA from Pakistan born to consanguineous parents. The 15- and 17-year-old girls presented with psychomotor delay, seizures, ataxia, intentional tremors, and dysarthria. Both had normal anthropometric measurements for age. Exaggerated tendon reflexes and bilateral sustained ankle clonus were observed in addition to cerebellar signs. Urine organic acids analysis showed marked excretion of 2-hydroxyglutaric acid, chiral differentiation of 2-hydroxyglutaric acid showed it to be L2HGA. Brain MRI of the 15-year-old showed diffuse subcortical white matter changes evident by T2/FLAIR hyperintense signals bilaterally, particularly in the frontal region in the centripetal distribution with some diffusion restriction along involvement of globus pallidus. The characteristic MRI pattern raised the suspicion of L2HGA. Targeted L2HGDH sequencing identified a homozygous pathogenic variant, c.829C>T (p.Arg227*) in L2HGDH gene in both girls. Both parents were heterozygous carriers of the familial variant. Conclusion: Neuroradiological features of centripetal subcortical leukoencephalopathy with basal ganglia and dentate nuclei involvement are rather specific to L2HGA and should lead to further biochemical investigations to look for L2HGA and L2HGDH gene sequencing.

CITATION EXPORT

Sibtain Ahmed, Ayra Siddiqui, Ralph J. DeBerardinis et al.. L-2-hydroxyglutaric aciduria – review of literature and case series. Annals of Medicine and Surgery. (2023). https://doi.org/10.1097/MS9.0000000000000326

AUTHORS

8 · 4 CENTRES

Sibtain Ahmed, Ayra Siddiqui, Ralph J. DeBerardinis, Min Ni, Wen Gu Lai, Feng Cai, Hieu S. Vu, Bushra Afroze

aSection of Clinical Chemistry, Department of Pathology and Laboratory Medicine
bMedical College
cDepartment of Paediatrics and Child Health, the Aga Khan University (AKU) Hospital, Karachi Pakistan
dChildren’s Medical Center Research Institute at UT Southwestern, Howard Hughes Medical Institute, UT Southwestern Medical Center, Dallas, Texas, USA