An interesting case of metabolic dystonia: L-2 hydroxyglutaric aciduria.

L-2-hydroxyglutaric aciduria (L-2-HGA), a neurometabolic disorder caused by mutations in the L-2 hydroxyglutarate dehydrogenase (L-2-HGDH) gene, presents with psychomotor retardation, cerebellar ataxia, extrapyramidal symptoms, macrocephaly and seizures. Characteristic magnetic resonance imaging findings include subcortical cerebral white matter abnormalities with T2 hyperintensities of the dentate nucleus, globus pallidus, putamen and caudate nucleus. The diagnosis can be confirmed by elevated urinary L-2 hydroxyglutaric acid and mutational analysis of the L-2-HGDH gene. We report two siblings with dystonia diagnosed by classical neuroimaging findings with elevated urinary 2 hydroxyglutaric acid. Riboflavin therapy has shown promising results in a subset of cases, thus highlighting the importance of making the diagnosis in these patients.

Introduction

L-2-hydroxyglutaricaciduria (L-2_HGA), is a rare neurometabolic disorder with around 300 cases reported so far in literature. We report 2 siblings with L-2-HGA presenting with dystonia as the predominant symptom along with classical neuroimaging findings and elevated urinary 2-hydroxyglutaric acid (2-HGA).

L-2-HGA, is known to be the first disease of “metabolite repair.” It is caused by mutations in the L-2-hydroxyglutarate dehydrogenase (L-2-HGDH) gene present on chromosome 14q22.1, which encodes L-2-HGDH. L-2-hydroxyglutarate is formed from alpha-ketoglutarate (α-ketoglutarate) (metabolite in the tricarboxylic acid cycle) by the side activity of the mitochondrial L-malate dehydrogenase. L-2-hydroxyglutarate has no known physiological function and its accumulation is toxic to the human brain, causing a leukoencephalopathy and increasing the susceptibility to develop tumours.[1] L-2-HGDH, a flavin adenine dinucleotide (FAD)-linked mitochondrial enzyme then catalyses the irreversible conversion of L-2-hydroxyglutarate to α-ketoglutarate preventing the accumulation of. L-2-hydroxyglutarate. Hence it is known as a metabolite repair enzyme [Figure 1].

Figure 1

L-2 hydroxyglutaric acid metabolic pathway. NADH: Nicotinamide adenine dinucleotide, FAD: Flavin adenine dinucleotide

Clinically it manifests with neurological symptoms (psychomotor retardation, cerebellar ataxia, extrapyramidal symptoms, macrocephaly and epilepsy). The diagnosis of L-2-HGA can be made based on magnetic resonance imaging (MRI), biochemical analysis and mutational analysis of L-2-HGDH gene.[2] Gregerson et al. (1977) first identified D- and L-2-hydroxyglutaricacids (D-2HG and L-2HG) in human urine.[3] Chalmers et al. and Duran et al. (1980) first described patients with D-2-hydroxyglutaric aciduria (D-2-HGA) and L-2-HGA respectively.[45] Muntau et al. (2000) described a case of combined L-2-HGA and D-2-HGA.[6] Riboflavin therapy has shown promising results in a subset of cases, thus highlighting the importance of making the diagnosis in these patients.[7]

Case Report

A 13 year, developmentally normal male, born to 2nd degree consanguineous parentage, with an uneventful perinatal period, presented to us with an abnormal gait and abnormal body postures from the age of 10 years. There had been a gradual worsening of these symptoms over the last 3 years. He is one of three sibs with one early sib death and had poor scholastic performance since early on. On examination, he had marked dystonic posturing of head, trunk and upper limbs with head turned predominantly to the right side. He had an explosive speech with normal cranial nerves and exaggerated deep tendon reflexes. Head circumference was 55 cm. Ophthalmological examination did not show Kayser Fleischer ring. Blood counts, renal parameters with electrolytes, liver enzymes, serum ceruloplasmin and urinary copper were normal. MRI brain revealed diffuse T2/FLAIR hyperintensity involving bilateral subcortical white matter of both cerebral hemispheres, caudate and lentiform nucleus, deep cerebellar white matter with sparing of the periventricular white matter [Figures 2–4]. No ventriculomegaly, cysts or white matter rarefaction were seen. MR spectroscopy showed decreased N-acetyl aspartate peak. In view of classical neuroimaging findings, L-2-HGA was suspected. Urinary organic acids was done using gas chromatography/mass spectrometry (GC-MS), which showed elevated 2-OH glutaric acid levels (37.37 fold elevation) with normal levels of glutaric acid, ethyl malonic acid and isovaleryl-glycine.

Figure 2

Axial T2 W magnetic resonance brain showing hyperintensities in the dentate nucleus of cerebellum

Figure 4

T2 hyperintensities involving subcortical white matter sparing the periventricular regions

Axial T2 W magnetic resonance showing hyperintensities in subcortical white matter, the caudate nucleus and lentiform nucleus

A 16-year-old female child, elder sibling of the previous patient asymptomatic until 10 years of age, presented with difficulty in walking in the form of dragging of the left foot with progressive worsening over the last 6 years. She also had slurring of speech and tremors of both upper limbs causing inability to feed self with no diurnal variations. On examination, her head circumference was 54 cm, alert, responding to commands with an explosive speech. She had dystonic posturing of the distal part of both lower and upper limbs with exaggeration during activity. Other systems were normal. Her investigations revealed normal blood counts, serum electrolytes, liver enzymes and renal parameters. Her neuroimaging findings revealed subcortical white matter and deep cerebellar T2 weighted hyperintense lesions. Urinary organic acid profile revealed 26.7 fold elevation of 2 hydroxyglutaric acid.

The clinical presentation, classical MRI and metabolic findings confirm the diagnosis of L-2-HGA in the siblings. Both of them have been started on vitamin B2 and L-dopa and have shown improvement in the dystonia.

Discussion

Both our patients had symptom onset at around 10 years of age with extrapyramidal symptoms-dystonia being the predominant symptom. The younger sib had predominant dystonia of the trunk while the elder had predominant limb dystonia. Age at symptom onset of L-2-HGA described in literature varies from infancy to 35 years.[78] Clinical symptoms include developmental delay, epilepsy, macrocephaly, cerebellar ataxia and extrapyramidal symptoms with a slow progression of symptoms.[7] Characteristic MRI findings in L-2-HGA includes predominant subcortical cerebral white matter abnormalities and hyperintense T2 signal abnormalities of the dentate nucleus, globus pallidus, putamen and caudate nucleus.[7910] Provisional diagnosis of the disorder is suggested by abnormal brain MRI findings.[7]

The MRI brain of our patients showed diffuse subcortical white matter with deep cerebellar involvement suggesting the diagnosis and urinary organic acid screening with GC-MS revealed increased 2-hydroxyglutarate (2-HG). The chiral configuration differentiates the L and D forms as 2-HG can be elevated in L-2 OH, D-2 OH and L-2-HGA, D-2-HGA. The clinical presentation of D-2-HGA and L-2-HGA varies. Furthermore, plasma and cerebrospinal fluid amino acid analysis may show elevated lysine in L-2-HGA. Genetic characterization can confirm L-2-HGA and aid in genetic counseling and future prenatal diagnosis.[7] However, to the best of our knowledge chiral differentiation is presently being done in very few centers around the world. Hence, the differentiation is mainly guided by clinical and neuroimaging findings.

The clinical phenotype of D-2-OH includes developmental delay, hypotonia and epilepsy, as the primary features with age of onset for type I D-2-OH being within the first 6 years and type II D-2-OH being within 2 years. The course of the type II disease is mainly described as progressive, though a static disease, or even improvement have been reported in some.[7] The neuroradiological findings of D-2-OH include enlargement of the lateral ventricles, enlarged frontal subarachnoid spaces, subdural effusions, subependymal pseudocysts, signs of delayed cerebral maturation and multifocal cerebral white-matter abnormalities.[7] The later age at onset, predominant extrapyramidal symptoms with the classical MRI findings suggest the diagnosis of L-2-HGA in our patients.

Treatment strategies described in the literature include FAD, vitamin B2 and levocarnitine. FAD, a co-substrate for L-2-HGDH, helps restore L-2-HGDH enzyme activity and decreases L-2-HGA excretion. However, FAD supplementation has shown to be effective only in the milder missense mutations in L-2-HGDH, whereas truncated enzymes are not responsive. Riboflavin an FAD precursor has also shown to halt the progression of leucodystrophy and improvement in symptoms.[7] Our patients have been started on Riboflavin and levodopa and at 6 months follow-up have shown improvement in the dystonia.

Conclusions

L-2-HGA should be considered as in the differential diagnosis of dystonia and extrapyramidal symptoms in late childhood and MRI pattern recognition aids in the diagnosis. Therapy with vitamin B2 has been shown to be successful in few patients.