44.1 Clinical Features
and Laboratory Investigations
D
-2-Hydroxyglutaric aciduria is a rare neurometabol- ic disorder with autosomal recessive inheritance. Two different variants are distinguished: a severe variant and a mild variant. The two variants have never been observed within the same family.
Severe
D-2-hydroxyglutaric aciduria results in neo- natal- or early-infantile-onset encephalopathy with serious epilepsy, hypotonia, visual failure, and no or little development. The infants are often irritable and lethargic. Episodic vomiting may be present. Inspira- tory stridor, dyspnea, and apnea may occur. Further signs may be spasticity, chorea, or dystonia. Both macrocephaly and microcephaly may occur. Many patients have signs of cardiomyopathy. Hepatomegaly is of rare occurrence. Signs of mild facial dysmor- phism consisting of a flat face with a broad nasal bridge and external ear anomalies are frequent. Early death may occur, but the patients may also survive with severe developmental delay and epilepsy.
Mild
D-2-hydroxyglutaric aciduria is clinically much more variable. Hypotonia, developmental delay of variable severity, and epilepsy are the most frequent signs of the disease. Macrocephaly may be present. Multiple cerebral infarctions associated with acute-onset neurological signs have been report- ed in one patient with
D-2-hydroxyglutaric aciduria and no identifiable known vascular risk factors (van der Knaap et al. 1999b). Cardiomyopathy has been observed in few patients. However, some pa- tients have no clinical problems that can be related to the
D-2-hydroxyglutaric aciduria. These patients are detected in the course of screening for
D-2-hydroxy- glutaric aciduria in a family with a symptomatic child.
Laboratory investigations reveal elevated urinary excretion of
D-2-hydroxyglutaric acid; plasma and CSF levels are also increased. The urinary organic acid profile often shows elevated excretion of 2-keto- glutarate, sometimes accompanied by elevated excre- tion of other citric acid cycle intermediates and lac- tate. Nonketotic dicarboxylic aciduria is observed in some patients. Prenatal diagnosis is possible by as- sessment of
D-2-hydroxyglutaric acid concentration in amniotic fluid. A few patients with the severe phe- notype have combined
D- and
L-2-hydroxyglutaric aciduria. It has been suggested that these patients rep-
resent a separate third variant. Prenatal diagnosis may not be reliable in this latter disorder.
44.2 Pathology
There is a detailed histopathological description of only one patient with a severe phenotype (Eeg-Olofs- son et al. 2000). The boy had severe psychomotor re- tardation and epilepsy and died at the age of 14 years.
The middle cerebral arteries showed multiple saccu- lar aneurysms. There was diffuse atrophy of the cere- bral white matter with marked dilation of the lateral ventricles. Microscopy showed loss of myelinated fibers and some astrogliosis within the cerebral white matter. The cerebral cortex was intact. The basal gan- glia and cerebellum showed slight atrophy. Micro- scopically, there was some loss of Purkinje cells and a reduction of cerebellar white matter. The brain stem was intact.
44.3 Pathogenetic Considerations
D
-2-hydroxyglutaric aciduria is caused by a deficien- cy of the mitochondrial enzyme
D-2-hydroxyglu- tarate dehydrogenase, which converts
D-2-hydroxy- glutarate into 2-ketoglutarate. The enzyme is encoded by a gene with the code name MGC25181, located on chromosme 2p25.3. It is not yet known whether defi- ciency of this enzyme underlies the disease in all pa- tients.
D
-2-hydroxyglutaric acid is a metabolic intermedi- ate in a variety of pathways. It is striking that the uri- nary organic acid profile often shows elevated excre- tion of 2-ketoglutarate. Sometimes the increased uri- nary excretion of 2-ketoglutarate is accompanied by elevated excretion of other citric acid cycle interme- diates. The latter abnormalities probably reflect a sec- ondary disturbance of the citric acid cycle and mito- chondrial respiratory chain. It has been shown that el- evated levels of
D-2-hydroxyglutaric acid in brain tis- sue lead to strong inhibition of cytochrome-c oxidase activity (complex IV) in a dose-dependent manner in vitro (da Silva et al. 2002). Secondary respiratory chain dysfunction may be important in the patho- physiology of the clinical symptomatology in
D-2-hy- droxyglutaric aciduria. The nonketotic dicarboxylic aciduria observed in some patients may reflect a sec-
D -2-Hydroxyglutaric Aciduria
Chapter 44
044_Valk_d_2_Hydroxyglutaric 08.04.2005 16:01 Uhr Seite 338
ondary disturbance of the mitochondrial fatty acid b-oxidation.
44.4 Therapy
Treatment is entirely symptomatic.
44.5 Magnetic Resonance Imaging
In the early-onset severe variant of
D-2-hydroxyglu- taric aciduria, MRI performed in the first few months of life shows signs of delayed cerebral maturation, in- cluding delayed myelination and gyration (Fig. 44.1).
Gyri are insufficiently branched, and in some patients focal agyria is found, particularly in the occipital re- gion. The sylvian fissure is wide open due to insuffi- cient formation of the frontal and temporal opercula (Fig. 44.1). The lateral ventricles are usually mildly
enlarged, mainly in the posterior part. The ventricu- lar enlargement is often combined with mildly en- larged frontal subarachnoid spaces and frontal sub- dural effusions (Figs. 44.1 and 44.2). Secondary sub- dural hematomas may occur. Within the first few months of life, subependymal germinolytic cysts are almost invariably present over the head and corpus of the caudate nucleus (Fig. 44.1). They disappear with time and are rarely seen after 6 months. Follow-up MRI in the second year of life shows more advanced gyration, but myelination remains delayed and in some patients patchy white matter abnormalities are seen (Fig. 44.2). The lateral ventricles may become highly enlarged due to white matter atrophy. In one patient, multiple aneurysms of the large cerebral ar- teries were found (Eeg-Olofsson et al. 2000; Fig. 44.3).
In the mild variant of
D-2-hydroxyglutaric aciduria, subependymal cysts and delayed myelination may be seen on early MRI. The lateral ventricles and the subarachnoid spaces may be mildly dilated. Subdural
44.5 Magnetic Resonance Imaging 339
Fig. 44.1. T
1-weighted (first row) and T
2-weighted (second row) images in a 4-month-old patient with the severe variant of
D-2-hydroxyglutaric aciduria. The lateral ventricles are enlarged, most pronouncedly in the posterior region.The sub- arachnoid spaces are also mildly enlarged. Myelination and
gyration are delayed. The opercula are insufficiently devel-
oped and the gyri are too coarse for the age of the infant.There
are large subependymal cysts over the body of the caudate
nucleus. From van der Knaap et al. (1999a), with permission
044_Valk_d_2_Hydroxyglutaric 08.04.2005 16:01 Uhr Seite 339
effusions may be seen. On follow-up, MRI may be normal, or it may show deficient myelination or bilat- eral multifocal, patchy abnormalities in the cerebral white matter or a combination of the two. The ventri- cles are often mildly dilated (Fig. 44.4). In one patient, multiple infarctions developed in the territories of
the major cerebral arteries (van der Knaap et al.
1999b).
The imaging findings in patients with combined
D
