L‐2‐Hydroxyglutaric Aciduria Complicated by Cerebral Neoplasm

L‐2‐Hydroxyglutaric aciduria (L2HGA) is an autosomal recessive metabolic disorder caused by pathogenic variants in the L‐2‐hydroxyglutarate dehydrogenase (L2HGDH) gene, which is located at chromosome 14q.22.1. ¹ Clinical manifestations of L2HGA include delayed developmental milestones, epilepsy (both febrile and afebrile seizures), ataxia, progressive encephalopathy, psychomotor and cognitive decline, signs of pyramidal and extrapyramidal dysfunction, and macrocephaly. ² , ³ , ⁴ Patients with L2HGA face a heightened risk (5%–40%) of developing cerebral neoplasms. ⁵ The literature documents several neoplasms, such as astrocytoma, oligodendroglioma, ependymoma, medulloblastoma, and embryonal tumors, in patients with L2HGA. ⁵ , ⁶ , ⁷ In this report, we present a young man with genetically confirmed L2GHA who developed new‐onset focal deficits and a decline in clinical status due to a mass lesion in the brain, underscoring the association between L2HGA with cerebral neoplasms.

Case Report

A 20‐year‐old man presented with abnormal movements and posturing of the body since the age of 12. The symptoms began with involuntary blinking of the eyes, followed a few months later by abnormal neck posturing. Over the next few months, he developed posturing of the right upper and lower limbs and bending of the trunk to the right side. Two years into the illness, he experienced jerky movements in his neck and limbs, gait imbalance, and a gradual decline in cognitive abilities. At 15, he was evaluated by a physician and underwent a brain magnetic resonance imaging (MRI) (Data S1). He was referred for further evaluation but did not pursue it. For the next 3 years, he continued symptomatic therapy with levodopa, clonazepam, trihexyphenidyl, and baclofen without significant benefits. He presented to our outpatient clinic at the age of 20 with complaints of worsening motor and cognitive symptoms, notably over the past 2 years and a new onset of weakness in the right side of the body.

His birth and developmental history were significant for delayed crying, delayed motor and language milestones, and intellectual disability. There was no history of seizures. His family history is shown in Figure 1.

FIG. 1.

Pedigree chart of the patient.

Examination showed impaired cognitive functions with poor attention, compromised executive functions, reduced verbal fluency, difficulty with complex comprehension, deficits in visual and verbal memory, and poor performance in visuospatial and constructional abilities. He had slow, slurred, and effortful speech; slow and hypometric saccades; a flattened nasolabial fold on the right side; spasticity in the limbs (right > left); mild right hemiparesis; and generalized hyperreflexia with ankle clonus and bilateral extensor plantar responses. He exhibited generalized jerky dystonia affecting the craniofacial and cervical regions, trunk, and limbs, with axial and appendicular ataxia (Video 1). The clinical details of the affected younger brother are provided in Data S2 and Video 2.

Video 1.

Examination of the patient at age 20 revealed generalized jerky dystonia affecting the craniofacial and cervical regions, trunk, and limbs. He had axial (trunk and gait) and appendicular (left > right) ataxia. He had facial asymmetry with a flattened nasolabial fold on the right. There was no significant parkinsonism.

Video 2.

Video of the affected brother at the age of 18 showing generalized dystonia, appendicular ataxia (left > right), and spastic‐ataxic‐dystonic gait. There were no signs of parkinsonism. Examination also revealed cognitive impairment, spastic dysarthria, slow and hypometric saccades, spasticity of limbs, and hyperreflexia (not shown in video).

The patient's MRI brain (Fig. 2) showed widespread hyperintensities and volume loss in the subcortical white matter, whereas the brainstem, thalami, corpus callosum, and cerebellar white matter remained unaffected. A new mass lesion involving the caudate and genu of the internal capsule was located in the left frontal white matter, which was not seen in the previous neuroimaging. A gas chromatography–mass spectrometry analysis of both brothers showed increased excretion of 2‐hydroxyglutaric acid. The diagnosis was further confirmed by whole‐exome sequencing (Data S1) of the index case, revealing a homozygous likely pathogenic variant in the L2HGDH gene (c.1072delA p.Ile358fs*25, Exon 9, AR). Genetic testing for the affected brother or parents was not performed due to financial constraints. The patient was referred to the Neurosurgery Department but did not attend his appointment and subsequently succumbed to his illness.

FIG. 2.

Brain MRI (magnetic resonance imaging) of the index patient at the age of 20 years; Brain MRI showing ill‐defined (A) FLAIR (fluid‐attenuated inversion recovery) and (B) T2WI (T2‐weighted imaging) hyperintensity in the juxtacortical > periventricular white matter in a fronto‐parietal–temporal‐occipital distribution, along with external capsules. Consequent matter volume loss is observed, causing sulcal and bilateral lateral ventricle dilation. Altered signal intensity is observed in bilateral caudate and putamen, with volume loss. The cerebellum shows a slightly altered signal in the dentate nuclei, with subcortical hyperintensity in the bilateral cerebellar hemispheres. Relative sparing of the corpus callosum, internal capsules, and thalami is observed. (C) The brainstem is normal in morphology and signal intensity without any atrophy. (D) A heterogeneously hyperintense lesion, with focal mass effects, is observed within the left inferior frontal white matter, left caudate, genu of the internal capsule, and left anterior thalamus with minimal foci of contrast enhancement.

Discussion

Patients with L2HGA have an increased risk of cerebral neoplasms. However, the mechanisms of L2HGA‐associated neoplasms are unclear. One theory suggests that dysfunction of L2HGDH, an enzyme involved in metabolic repair, results in L2‐hydroxyglutarate (L2‐HG) buildup, reaching carcinogenic levels in the brain. Prolonged excess L2‐HG exposure, an oncometabolite, may drive neoplastic transformations. A similar increase in 2‐hydroxyglutarate has been reported in high‐grade gliomas with IDH1 mutations. ⁵ , ⁶ Although IDH1 mutations and L2HGA may share 2‐HG‐driven oncogenesis, they differ in many aspects: etiology (somatic vs. germline), metabolic context (D2‐HG vs. L2‐HG), and effect in the brain (local vs. diffuse). Most cases of cerebral neoplasms related to L2HGA lack information on IDH1 mutation data. ⁷

The comparable levels of urine hydroxyglutaric acid in patients with or without malignant brain tumors suggest that the only L2‐hydroxyglutaric acid level is not responsible for tumorigenesis. ⁶ However, the levels of this metabolite in body fluids might not truly reflect the metabolic conditions present in brain tissue.

Considering the variety of tumor types observed in patients with L2HGA, it is also unlikely that the genetic abnormality linked to L2HGA directly causes the genetic alterations associated with brain tumor development. ⁸ The mitogenic growth factors that emerge during demyelination and remyelination processes in disease progression also do not seem to contribute to tumor formation, as similar malignant tumors have not been observed in other white matter disorders. ⁶ A recent hypothesis suggests the oncogenesis in L2HGA likely follows a 2‐step process: the initial event involves the buildup of L‐2‐hydroxyglutaric acid. The oncogenesis in L2HGA probably relies on a secondary genetic hit (eg, mutations of different tumor suppressor genes) or other contributing factors, such as epigenetic dysregulation or oxidative stress resulting from a pro‐tumorigenic environment caused by persistent metabolic disruptions. ⁷ However, further research is needed to understand the relationship between L2HGA and brain tumors fully.

There have been occasional reports of brain tumors occurring in one of the siblings affected by L2HGA, particularly in pediatric populations. ⁹ Rarely, multiple family members with L2HGA may develop cerebral neoplasms, as illustrated in a case series involving an Arab kindred, where 3 of 4 adult siblings, all carrying the same genetic variant L2HGA, developed brain neoplasms. ¹⁰ In most patients with L2HGA, symptoms related to tumors typically emerge as the disease progresses rather than as the initial presenting feature. ⁵ Rapid deterioration of L2‐HGA is uncommon and warrants caution, as it could indicate the development of a cerebral neoplasm. Patients with L2HGA should have regular clinical follow‐up and imaging (once every 1–2 years) to identify tumor development. ⁵ Any sudden or unexpected worsening of symptoms or the new onset of focal deficits, as seen in our case, should raise suspicion and prompt neuroimaging.

Author Roles

(1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical analysis: A. Design, B. Execution, C. Review and critique; (3) Manuscript preparation: A. Writing of the first draft, B. Review and critique.

D.M.R.: 1A, 1B, 1C, 3A

R.K.: 1B, 1C

B.P.: 1B, 1C

R.R.: 1B, 3B

D.G.: 1C, 3B

A.A.: 1C, 3B

A.K.P.: 1C, 3B

A.K.S.: 3B

Disclosures

Ethical Compliance Statement: The authors confirm that an institutional review board's approval was not required for this work. Appropriate written informed consent was obtained from the patient's parent to publish clinical information and videos. We confirm that we have read the journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Sources and Conflicts of Interest: This study was supported by the Intramural Research Grant (A‐817), AIIMS Delhi. The authors have no conflict of interest.

Financial Disclosures for the Previous 12 Months: The authors declare that there are no additional disclosures to report.

Supporting information

Data S1. Investigations of index patient. MRI (magnetic resonance imaging) brain of the index patient at the age of 15 years. Genetic report of the index patient.

Data S2. Summary and neuroimaging of the affected younger sibling.