L2-Hydroxyglutaric Aciduria: Clinical and Biochemical Evaluation of 33 Patients from a Single Center



  • Publication Type: Conference Paper / Full Text
  • City: İstanbul
  • Country: Turkey
  • Page Numbers: pp.1-547
  • Istanbul University Affiliated: Yes


Abstract: L2-hydroxyglutaric aciduria (L2HGA; OMIM #236792) is a rare, chronic

progressive, autosomal recessively inherited metabolic disease. It affects exclusively the

central nervous system and produces a variety of clinical neurological deficits. We report33

patients with L2HGA from 26 families; 18 (%54.5) are females and 15 (%45.4) are males.

Consanguineous marriages were reported in twenty families (%76.9). The main clinical

findings were neurodevelopmental delay and seizures in early childhood. Additional findings

were cerebellar ataxia, intentional tremor and macrocephaly. Diagnosis was confirmed by

increased levels of L2-hydroxyglutaric acid in urine and specific findings in brain magnetic

resonance imaging (MRI). A bimodal distribution in the age of onset was observed. Twentytwo

patients were diagnosed between 5 months to 1.5 years of age, possibly due to early

seizures. Eleven were diagnosed between 5 to 9 years of age with mild ataxia, unexplained

psychomotor delay and mild to moderate mental retardation. In urine organic acid analysis,

2-hydroxyglutaric acid levels were 2 to 50 times higher than the reference range. There was

no correlation between the amount of urinary excretion and the severity of disease. MRI

revealed subcortical white matter abnormalities in cerebral hemispheres in all patients,

changes in basal ganglia and dentate nuclei involvement nearly in all patients. The mean

follow-up period was 20 years, slow progression of symptoms was observed and there was

no mortality due to the disease. Five patients were treated with riboflavin, which resulted in

clinical improvement.


L2-hydroxyglutaric aciduria (L2HGA) is a rare, autosomal recessively inherited

neurodegenerative organic aciduria. It affects exclusively the central nervous system with

slow progression and without episodes of acute metabolic decompensation. In the first years

of life patients present with developmental delay, seizures or macrocephaly; followed by

cerebellar ataxia, intentional tremor, mild to severe mental retardation. Most patients reach

adulthood. Diagnosis is confirmed by increased levels of L2-hydroxygluaric acid in urine

and specific findings in brain magnetic resonance imaging (MRI). There is no correlation

between the severity of the disease and the amount of L2HGA in urine. However, the disease

duration rather than clinical presentation is presumed to correlate with the severity of MR

findings (x1). The purpose of this study is to clarify the disease pattern and share our


Case series

This study included 33 patients (18 females and 15 males) from 26 families with L2HGA

followed by Istanbul Medical Faculty, Department of Pediatric Nutrition and Metabolism.

Twenty families had consanguineous marriages (%76.9). The mean age of onset of symptoms

was bimodally distributed. Twenty-two patients were diagnosed between 5 months to 1.5

years of age; 13 had seizures, 5 neurodevelopmental delay, 2 ataxia and other 2 siblings with

L2HGA at referral. Those two with siblings were noticed to have growth retardation around

1.5 years of age. Eleven patients were diagnosed between 5 to 9 years of age; 7 of them had

learning disabilities and developmental delay, 2 had seizures and 2 had ataxia at referral.

Diagnosis was based on clinical, biochemical and neuroradiological findings. The main

clinical findings were mental retardation, cerebellar ataxia and neurodevelopmental delay.

Organic acid analysis in urine showed, 2-hydroxyglutaric acid levels that were 2 to 50 times

higher than the reference range and with no other specific excretion. There was no correlation

between the amount of urinary excretion of L2HGA and the severity of disease. MRI showed

specific findings. Subcortical white matter abnormalities were present and bilaterally

symmetrical in all cases. Dentat nucleus was affected in 31 patients. The globus pallidus,

nucleus caudatus, putamen, external and internal capsules were variably affected. None of

our patients had solid or cystic lesions on MRI. Twenty-two patients had seizures. None of

them had resistant seizures and only 5 needed to use two anticonvulsants. The mean followup

period was 20 years. We noticed that the progression of the disease slowed after puberty

and no mortality due to the disease was observed. The patients generally had chronic nonprogressive

encephalopathy with no acute deteriorations. None of them became wheelchair


L2HGDH gene mutational analysis was performed in two of our patients, which revealed

homozygous missense mutations in both. To date, five patients received riboflavin treatment.

A few months after the initiation of treatment, we found significant improvement in motor


The oldest patient was a 42-year-old woman with a healthy 16-year-old child with good

school success. After treatment with protein restricted diet, riboflavin, coenzyme-Q

supplementations, and a program for body weight control significant improvement in selfcare

skills was observed.


The clinical, laboratory and imaging characteristics of our patients indicate that, they had

similar characteristics with patients reported previously (2). This is compatible with L2HGA

being a relatively limited disease with its specific findings.

The role of L2-hydroxyglutaric acid in human metabolism and the underlying metabolic

defect remains unknown. Mutations in the gene encoding L2-hydroxyglutaric acid

dehydrogenase is known to cause disease (3) and the symptoms are thought to be due to the

toxic effect of accumulation of L2-hydroxyglutaric acid in central nervous system (4). In

recent studies, it is stated that, antioxidant therapy and protein restricted diet may be effective

in preventing oxidative stress and brain damage (5). Although there is no standard treatment

recommendation riboflavin, coenzyme-Q and -if deficient- carnitine supplements are

recommended. The fact that riboflavin improves clinical findings, raises the question whether

the initiation of treatment before neurological symptoms fully established, will contribute to

the course of the disease.

Malignant brain tumor development has been previously reported in cases with L2HGA (6).

When a new neurological symptom occurs, this should be considered in the evaluation.

Further studies including genetic investigations will contribute to prediction of the course of

the disease and various clinical types.