l-2-hydroxyglutaric aciduria

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L-2-hydroxyglutaric aciduria is a rare organic aciduria but has characteristic MRI findings especially in the early stages . This can allow for early diagnosis, often prior to biochemical investigations.

Epidemiology

As it is inherited in an autosomal recessive fashion, consanguineous marriages are a risk factor for this disease.

Clinical presentation

Affected children are often initially normal, which can lead to a delay in diagnosis . The disease has an insidious onset with slow progress, and diagnosis is commonly in late childhood to early adolescence. Initial clinical features are developmental delay and learning difficulties, and in later years cerebellar signs become the dominant clinical manifestation . Seizures also occur in the majority of patients, especially in the setting of pyrexia.

Pathology

Due to the relative rarity of L-2-Hydroxyglutaric aciduria, few histological reports of this disease exist. White matter spongiosis, demyelination and cystic degeneration have been described, most pronounced in the subcortical regions .

Markers

Definitive diagnosis relies on the identification of L-2-Hydroxyglutaric aciduria in urine, where it is usually massive raised; plasma and CSF levels are also elevated. This needs to be performed in a center equipped for metabolic investigations as chiral differentiation (i.e. L vs D-isomer) needs to be performed with chromatography for correct diagnosis . However, MRI is also useful in this respect as the imaging findings of the two isomers are widely different . Prenatal diagnosis is possible by examination of amniotic fluid .

Lysine levels in urine, plasma and CSF are also usually elevated.

Genetics

L-2-Hydroxyglutaric aciduria is inherited in an autosomal recessive fashion. The disease gene L2HGDH was first identified in 2004, and numerous mutations of the gene have since been described .

Radiographic features

MRI

L-2-Hydroxyglutaric aciduria is a leukoencephalopathy with a consistent and characteristic MRI pattern that should strongly suggest the diagnosis . The MRI changes seen are bilateral and symmetrical, as would be expected from a neurometabolic disorder. There is a centripetal pattern of involvement, with the white matter abnormalities affecting the subcortical U-fibers first, and then progressing to a deeper confluent pattern. Even in the advanced stages, the deep white matter of the periventricular region, corpus callosum and internal capsule remain preserved. An anterior-posterior gradient can also be observed, with the confluency of the white matter in the frontoparietal region first before affecting the rest of the white matter.

Some mild broadening of the gyri is seen, which relates to the spongiform changes seen pathologically.

In addition to the white matter changes, grey matter signal changes are seen in the basal ganglia structures, and hence L-2-Hydroxyglutaric aciduria is not strictly a ‘leukoencephalopathy’. Basal ganglia involvement appears to be a consistent feature of the disease , but this is less prominent than in other organic acidopathies (e.g. glutaric aciduria Type 1, propionic acidemia, methylmalonic acidemia).

In the posterior fossa, the dentate nuclei are affected, but the brainstem and cerebellar white matter are spared. A further finding in the posterior fossa is that the vermis becomes highly atrophic. In the supratentorial brain, atrophic changes progress at a slower pace.

Signal characteristics

T1: low signal
T2/FLAIR: high signal
GE/SWI: no susceptibility artefact
DWI: increased diffusivity (consistent with spongiform change)
T1 + C+ (Gd): no enhancement
MR spectroscopy: decreased NAA and Cho peaks; increase mI; no lactate

Treatment and prognosis

No specific treatment exists for L-2-Hydroxyglutaric aciduria ; management is mainly supportive as is the case in most leukoencephalopathies. Patients often survive into adulthood.

A number of small case series have suggested that affected patients are at increased risk of CNS tumors . However, it is difficult to ascertain this due to the small numbers involved.

History and etymology

L-2-Hydroxyglutaric aciduria was first reported in 1980 , and there has since been about 295 cases described in the literature .

Differential diagnosis

The centripetal pattern of white matter involvement limits the differential diagnosis. The absence of brainstem involvement in L-2-Hydroxyglutaric aciduria is an important differentiating feature.

Canavan disease: The brainstem is affected. The putamen and caudate nuclei are usually spared, as are the dentate nuclei. No antero-posterior gradient is seen. Markedly elevated NAA on MR spectroscopy.

Kearns-Sayre syndrome: The brainstem and thalami are affected in most patients. The globus pallidus and caudate nuclei are mineralized on CT.