Objective: To highlight the evolution of movement disorder phenotype and diagnostic challenges in a child with L-2-hydroxyglutaric aciduria (L2HGA).

Background: L2HGA is a rare autosomal-recessive neurometabolic disorder characterized by progressive leukoencephalopathy with cerebellar and extrapyramidal manifestations. Movement disorders are common but may evolve gradually, and diagnosis can be challenging when metabolic and genetic investigations are initially inconclusive.

Method: We describe the longitudinal clinical, radiological, biochemical, and genetic findings of a child with progressive neurological symptoms suggestive of a neurometabolic disorder.

Results: A 7-year-old boy presented with delayed motor milestones, recurrent falls, and a generalized tonic–clonic seizure. Brain MRI demonstrated diffuse bilateral white-matter hyperintensities involving subcortical U-fibers, basal ganglia, and dentate nuclei, suggestive of L-2-hydroxyglutaric aciduria. Initial metabolic screening and targeted sequencing of the L2HGDH gene were non-diagnostic. Over the following years, the patient developed progressive cognitive decline and a movement disorder characterized by upper limb action tremor, resting tremor, head nodding, dysarthria, and spastic-ataxic gait. At 15 years, examination revealed cerebellar signs including dysdiadochokinesia, past-pointing, and impaired tandem gait. Repeat urinary gas chromatography–mass spectrometry demonstrated elevated 2-hydroxyglutarate, confirming the metabolic abnormality. Whole-exome sequencing with copy-number variation analysis identified a homozygous exon 9 deletion in the L2HGDH gene, establishing the diagnosis. The patient remained ambulant with assistance but had progressive functional decline.

Conclusion: L-2-hydroxyglutaric aciduria may present with a slowly progressive movement disorder dominated by cerebellar ataxia and tremor. Intermittent metabolic abnormalities and limitations of standard sequencing may delay diagnosis. Integration of clinical phenotype, characteristic neuroimaging, and advanced genomic approaches including CNV analysis is critical for resolving the diagnostic odyssey in rare neurometabolic movement disorders.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/diagnostic-odyssey-in-l-2-hydroxyglutaric-aciduria-a-case-with-progressive-cerebellar-and-extrapyramidal-movement-disorder/