Page 98 - BH-2-3

Brain & Heart L2-hydroxyglutaric aciduria

The three major types of 2HGA are D-2- prime feature in the biochemical results for L2HGA is,
hydroxyglutaric aciduria (D2HGA), L-2-hydroxyglutaric other than the elevated 2-hydroxyglutaric (2-OHG) level,
aciduria (L2HGA), and D, L-2-hydroxyglutaric aciduria the L form accounts for >90% of the isoforms. Absolute
(DL2HGA). L2HGA is caused by variants in L-2- configuration of D and L forms of 2HG was performed
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hydroxyglutarate dehydrogenase gene (L2HGDH, through capillary gas-liquid chromatography as described
OMIM : 609584) gene located on chromosome 14q21.3. by Duran et al. In addition, magnetic resonance
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It encodes the L2HGDH enzyme, which is a flavin adenine spectroscopy shows reduced levels of N-acetyl aspartate
dinucleotide (FAD)-linked mitochondrial enzyme known and elevated choline and myoinositol peaks in the case
as a metabolite repair enzyme. 1 of L2HGA. Characteristic MRI findings of the L2HGA
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Alpha-ketoglutarate (αKG), a metabolite of the are bilaterally symmetrical, centripetal, subcortical white
tricarboxylic acid cycle, is converted to L-2-hydroxyglutaric matter T2 hyperintensities of the dentate nucleus, globus
acid (L2HG) by the action of mitochondrial enzyme malate pallidus, putamen, and caudate nucleus. The deep white
dehydrogenase. L2HG is then irreversibly converted back matter of the periventricular region, corpus callosum,
into αKG by the L2HGDH to prevent the accumulation of internal capsule, and brain stem are preserved. 9
L2HG (Figure 1). 1 The mainstay of management for L2HGA is through
Thus, the deficiency of L2HGDH causes the supportive and symptomatic measures such as L-carnitine
accumulation of L2HG, which is toxic to myelin, causing supplementation and rehabilitation, which is best
leukodystrophy in subcortical white matter and basal achieved through a multidisciplinary team approach.
ganglia. Elevated L2HG level also has a carcinogenic Genetic counseling and prenatal diagnosis through the
effect resulting in brain tumors such as medulloblastoma, measurement of L2HG levels in amniotic fluid are also
oligodendrocytoma, and gliomas, probably due to the employed to detect the risk of giving birth to infants with
demyelinating and remyelinating process leading to L2HGA, a significant part of the overall management
overproduction of mitogenic growth factors. Several of this disorder. It has been demonstrated that treating
case reports in the published literature describe the cases patients with riboflavin, which acts as a FAD precursor, is
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of patients diagnosed with L2HGA developing brain therapeutically effective in a subset of cases. Since they
tumors. 5,6 are at increased risk of developing brain tumors, patients
with L2HGA may need follow-up sessions, with periodic
L2HGA usually presents with psychomotor retardation,
macrocephaly, cerebellar ataxia, seizures, pyramidal and MRI brain examination. In addition, the disease condition
is monitored annually using urine L2HG testing, as the
extrapyramidal signs. In addition, seizures and growth disease activity is consistent with the L2HG level.
stunting may occur. The age of onset of the disease varies
from 3 to 35 years. Short attention span and hyperactivity 2. Case presentation
have been reported in children aged <10 years of age.
Cerebellar involvement usually becomes prominent A 12-year-old boy born from a third-degree consanguineous
around 12 years of age. The disease course of L2HGA marriage presented with a learning disability, bilateral
resembles that of static encephalopathy. According to cerebellar signs, and tonic extensor spasms in his limbs. He
the literature, acute encephalopathy is rarely reported in also had difficulty in buttoning and unbuttoning his shirt
children affected by L2HGA. Although autism does not and in writing. Based on historical records, the patient had
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typically fall within the phenotypic spectrum of the disease, an uncomplicated perinatal and postnatal period with a
a case featuring severe autistic features in a 3-year-old child birth weight of 3.4 kg. He underwent normal development
has been reported. D2HGA presents early with delayed up to the age of 4 years, but he had been complained of his
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development, seizures, hypotonia, cerebral abnormalities, poor school performance and attention deficits by teachers
and cardiomyopathy. DL2HGA presents with severe at preschool.
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neurodevelopmental dysfunction in early infancy and On examination, the patient had relative macrocephaly
intractable seizures associated with respiratory distress. 4 with an occipito-frontal circumference of 55 cm, which is
th
th
Diagnosis of L2HGA is made based on clinical and between 75 and 85 percentile for the age and sex; tonic
biochemical findings, as well as characteristic findings extensor spasms in all four limbs; and positive cerebellar
in MRI. The main biochemical finding contributing to signs bilaterally. The scale for the assessment and rating of
L2HGA diagnosis is the elevated 2HGA levels in urine, ataxia (SARA) score was 13.5. He clearly had an abnormal
cerebrospinal fluid, and, to a lesser extent, plasma, gait and was unable to perform tandem walking for
which are detected through organic acid analysis by gas more than 10 steps. Based on the results from the Test
chromatography/mass spectrometry (GC/MS). Another of Nonverbal Intelligence, Third Edition (TONI–3), we

Volume 2 Issue 3 (2024) 2 doi: 10.36922/bh.2145