Case study
Riboflavin treatment in a case with l-2-hydroxyglutaric aciduria

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Abstract

L-2-hydroxyglutaric aciduria (LHGuria) is a rare neurometabolic disorder, which has characteristic clinical and laboratory features. The recent findings imply that LHG dehydrogenase is responsible for the disease and is FAD-dependent. Therefore, it might be expected that riboflavin could enhance any residual activity. We present our observations from nearly 2-year-long riboflavin treatment in a 16-year-old boy with LHGuria. During riboflavin treatment of 100 mg/d, partial improvement in his cognitive and motor performances was observed. Urinary LHG excretion decreased from 5990 mmol/mol creatinine to 1490 mmol/mol creatinine. Moreover, when riboflavin treatment was interrupted, significant disturbances in both symptoms and urinary LHG excretion (6360 mmol/mol creatinine) occurred in the patient. After the resettlement of riboflavine treatment, the patient resumed to his previous clinical status in a week. The improvement went further minimally under the dose of 200 mg/d, but no further improvement happened with 300 mg/d. The present case suggests that riboflavin could be considered as a potential therapeutic approach in LHGuria until the optimal treatment of LHGuria is established.

Introduction

L-2-hydroxyglutaric aciduria (LHGuria) (OMIM:236792) is one of the chronic progressive neurodegenerative disorders in the group of organic acidurias. The disorder has a remarkably consistent clinical, biochemical and neuroradiological pattern.1 Clinically, the disease is characterized by psychomotor delay followed by cerebellar ataxia, dysarthria, moderate-to-severe mental deterioration and macrocephaly. Extrapyramidal (dystonia, choreic movements), pyramidal (spastic paresis) and pseudobulbar signs and seizures may also occur. It is usually diagnosed in infancy and childhood, and has a slowly progressive course extending well into adolescence and adulthood. However, it might be diagnosed in the neonatal period or in the adulthood as well. Different from other organic acidurias, LHGuria is potentially associated with central nervous system tumors. Magnetic resonance imaging (MRI) characteristically shows leukodystrophic abnormalities, and abnormal signals in dentate nuclei and basal ganglia. The diagnosis of LHGuria depends on detecting increased levels of LHG in urine by means of gas chromatography–mass spectrometry.

Although LHGuria is a rare neurometabolic disease, many significant findings have been reported recently.2, 3, 4, 5 The mutated gene has been localized on chromosome 14q22, and many different mutations have been detected.2 Rzem et al.3 demonstrated that LHG was metabolized in rat tissues by a membrane-bound mitochondrial dehydrogenase, which catalyzes specifically the oxidation of L-2-hydroxyglutarate to alpha-ketoglutarate (Fig. 1). The gene that had been linked to LHGuria has been detected to encode a mitochondrial membrane-bounded enzyme, LHG dehydrogenase (EC 1.1.99.2). Furthermore, this enzyme in rat liver was stimulated by flavin-adenine dinucleotide (FAD), which suggests that FAD serves as a cofactor. It has also shown that the enzyme produced in human embryonic kidney cells transfected with a cDNA encoding the product of the human gene had similar biochemical characteristics as the rat liver enzyme.4 LHG dehydrogenase activity in those transfected cells was modestly stimulated by FAD. Given the latest finding, riboflavin deserves to be evaluated as a potential treatment modality in LHGuria. In this report, we present a case with LHGuria and changes occurring in the clinical and laboratory findings during nearly 2 years of riboflavin treatment.

Section snippets

Case report

The patient was referred to our department because of gait disturbance, speech difficulty and mental retardation when he was a 16-year-old. He was born from Turkish nonconsanguineous parents. The parents described developmental delay in his motor, social and language skills since his infancy, but they thought that his developmental delaying had been secondary to his low birth weight. He was not able to walk independently until 3 years of age. Besides walking difficulties, impaired language

Discussion

Riboflavin is the cofactor of FMN and FAD, which acts as electron carriers in redox reactions in human metabolism. It is involved in many metabolic disorders and has been considered in the treatment of several inborn errors of metabolism such as Glutaric aciduria I, mild variants of electron transfer flavoprotein dehydrogenase, short chain acyl CoA dehydrogenase and congenital lactic acidosis, complex I deficiency.6 Moreover, riboflavin has been noted increasingly in various disorders such as

Acknowledgements

The author thanks for Prof. Turgay Coşkun and Prof. Meral Topçu for their great contribution to our evaluation of this case.

References (11)

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