Clinical, Neuroimaging, and Genetic Features of the Patients with L-2-Hydroxyglutaric Aciduria.
L-2-Hydroxyglutaric aciduria (L2HGA) is a very rare inherited metabolic disease with autosomal recessive inheritance [Online Mendelian Inheritance in Man (OMIM) #236792]. Since its first description in 1980 by Duran et al., (1) many additional cases of various ethnical backgrounds have been reported. Affected patients have slowly progressive deterioration with cerebellar ataxia, mild or moderate mental retardation, and extrapyramidal and pyramidal symptoms, and seizures and variable macrocephaly (2). L2HGA is characterized by elevated levels of L-2-hydroxyglutaric acid (L2HG) in urine, cerebrospinal fluid (CSF), and, to a lesser extent, plasma. Increased levels of L2HG are pathognomic for L2HGA (1,3). Neuroimaging findings generally show subcortical leukoencephalopathy, cerebellar atrophy and changes in dentate nuclei and putamen (4). L-2-hydroxyglutarate (Figure 1) in nature suggests that it is endogenously produced in humans. This result is due to the findings that the excretion of L-2-hydroxyglutarate in patients with L2HGA is little affected by the diet and that L-2-hydroxyglutarate accumulates in cultured cells deficient in L-2-hydroxyglutarate dehydrogenase (L2HGDH) (5). L2HGDH belongs to a large family of flavin adenine dinucleotide (FAD)-linked dehydrogenases and oxidases. L-2-hydroxyglutarate is formed from alpha-ketoglutarate (metabolite in the tricarboxylic acid cycle) by the side activity of the mitochondrial L-malate dehydrogenase. L-2-hydroxyglutarate accumulation is toxic to the human brain, causing a leukoencephalopathy and increasing the sensibility to develop tumours (6). Episodes of acute metabolic decompensation do not occur, and brain damage is not related to acidosis in L2HGA patients. It's a difference from other forms of organic acidurias (7). The disease-causing gene, L2HGDH gene (L2HGDH), and its first pathogenic mutations were identified in 2004 (8,9). Treatment of L2HGA is under investigation; case reports have described positive effects of FAD sodium in combination with levocarnitine chloride in one patient (10) and riboflavin, a precursor of FAD, in another patient (11). The present study describes the clinical presentation and mutation analysis and follow up findings of our patients with L2HGA at Ege University Pediatric Metabolism and Nutrition Unit.
Materials and Methods
Eight patients who were diagnosed with L2HGA between the years of 2004-2016 were included in this study. Patients' demographical features; age, sex and age at diagnosis, consanguinity; clinical findings (such as; psychomotor retardation, loss of skills, extrapyramidal symptoms, seizures, behavioural problems) and head circumference (the presence of macrocephaly) were recorded. Urine 2-hydroxy (2-OH) glutaric acid levels at the diagnosis and L2HGDH gene analysis were analysed retrospectively. Radiological features were retrospectively included to the analysis.
Median age of the patients was 17 (9.5-37) years and median age at diagnosis was 8 years (2-25 years). Female/male ratio of the patients was 5/3. Patient 1, 2 and Patient 6,7 were sibling. The main symptoms of the patients were psychomotor retardation (8/8), cerebellar ataxia (5/8), extrapyramidal symptoms (7/8), and seizures (4/8). All patients have behavioural problems. Five parents had consanguinity marriage. Five patients' head circumferences were known and none of them had macrocephaly. Clinical and demographical findings of the patients were detailed in Table I. Patient 6 diagnosed at the age of 25 years. Speech difficulties developed at the earlier ages, walking difficulties and seizures developed at the age of 25 years. Her sister with the same diagnosis (follow up at different clinic) had speech delay at the early childhood and learning difficulties at school age and tremor at the age of 15 years. All patients could walk without support before they lost of walking ability. Three patients' unsupported walking ages were not applicable. Patient 3 had psychomotor retardation and behavioural problems. He had milder clinic symptoms. Elevated urinary 2-OH glutaric acid was detected and median level of the urine 2-OH glutaric acid at the diagnosis was 146 (60-1460 nmol/mol creat). Two patients have homozygous R335X, two homozygous R282Q, two homozygous R302L, and one compound heterozygous P302L/A64T mutation in L2HGDH gene. One of the patient's L2HGDH gene analysis was not applicable. Detail diagnostic laboratory findings of the patients were given in Table II. Characteristic magnetic resonance imaging (MRI) findings including subcortical cerebral white matter (WM) abnormalities with T2 hyperintensities of the dentate nucleus, globus pallidus, putamen was detected. WM hyperintensities were detected in all patients. Dentate nucleus hyperintensities were detected in 3 patients, basal ganglion hyperintensities were detected in 5 patients and cystic encephalomalasia in one patient. Cranial MRI findings of the patient were detailed in Table III. In patient 2 cranial MRI shows WM involvement, cerebral atrophy and spongiform changes (Figure 2). In patient 3, cranial MRI reveals bilateral globus pallidus and caudate nucleus involvements (Figure 3).
L2HGA is a very rare inherited metabolic disease with autosomal recessive inheritance (OMIM #236792). Affected individuals only have neurological manifestations, including mild to moderate psychomotor retardation, cerebellar ataxia, variable macrocephaly, and epilepsy (7,12-14). In our study similar to the literature the main symptoms of the patients were psychomotor retardation, cerebellar ataxia, extrapyramidal symptoms, and seizures. In the literature large studies demonstrated that during the disease course the main clinical findings were developmental delay (93%), cerebellar ataxia (82%), epilepsy (72%), and macrocephaly (48%) (2). It is interesting that in our study the available head circumferences were all normal. We couldn't get an information about the head circumferences of the 3 patients. In the earlier stages of the disease hypotonia was most prevalent and spasticity in the latter stages of disease in their cohort. Neurological decompensation (e.g., loss of skills and the development of speech deficits) was also present in a quarter of the patients (15). In our study loss of the skills were detected in 5 patients and all of them developed speech deficits. Also, all patients had behavioural problems. The clinical symptoms usually recognise during infancy or childhood. The cases in the literature reported as adult onset were diagnosed as adult onset but, in retrospect, the patients had symptoms during childhood (2). Patient 6 diagnosed at the age of 25 years. Speech difficulties developed at the earlier ages, walking difficulties and seizures developed at the age of 25 years. Her sister with the same diagnosis had speech delay at the early childhood and learning difficulties at school age and tremor at the age of 15 years. Mild symptoms may explain the late diagnosis ages. Seizures manifest in most of the patients (7). In our study 4 of the patients had the history of seizures. Patient 1 had the history of febrile seizures between the age of 3-4 years.
The diagnosis is supported by increased levels of L-2-hydroxyglutarate acid in urine, plasma, and cerebro-spinal fluid (1). Some patients show increased levels of L-lysine and pipecolate in CSF suggesting a defect in alternative degradation pathway of lysine (16). We had not performed CSF analysis in our patients and plasma lysine levels were normal. We detected high 2-OH glutaric acid levels in all patients. Determination of L-2-OH isoform could not have performed. The diagnosis of the disease confirmed by L2HGDH gene analysis in 6 patients. L2HGDH gene analysis of the patient 7 was not applicable but she has high urine 2-OH glutaric acid levels and also she has the sibling with genetically diagnosed L2HGA (patient 6). Cranial MRI findings generally show subcortical leukoencephalopathy, cerebellar atrophy and changes in basal ganglion, in dentate nucleus (17). Steenweg et al. (17) investigated 56 patients with L2HGA and they found that with increasing disease duration, WM abnormalities and basal ganglia signal intensity abnormalities become more diffuse and cerebral WM atrophy arises. The few descriptions of histologic brain findings in L2HGA reported WM spongiosis, demyelination, and cystic degeneration, mostly in the subcortical regions (17). In our study all patients had WM changes on cranial MR. Three patients had bilateral dentate nucleus hyperintensities. Cranial MR investigation of patient 6 revealed cystic encephalomalasia. Isikay (18) reported the case with L2HGA who had macrocephaly and cerebral multicystic lesions. Few data on proton MR spectroscopic (MR-S) changes are available. Anghileri et al. (19) detected 2 hydroxy glutarate peak in the WM of the three L2HGA patients. In our study decreased N-acetyl aspartate and choline peaks were detected on MR-S. Successful therapeutic trials have been reported in patients L2HGA. The patient described by Yilmaz (11) a 16 years old boy, had been treated with riboflavin for nearly 2 years and during treatment at 100 mg/day partial improvement in his cognitive and motor performances was observed and urinary secretion was decreased. Samuraki et al. (10) described 43 years old woman with L2HGA who was treated with FAD (30 mg/day) and carnitine. Significant improvement in her tremor and dystonia was detected and decreased urinary excretion of L2 hydroxy glutarate was detected (10). In our study half of the patients treated with riboflavin and due to the irregular follow up its difficult to give a comment on the treatment response. But we observed clinical stability. Two of our patients (siblings) have homozygous R335X (nonsense mutation) and 2 patients had homozygous p.P302L mutations. These mutations were reported in Turkish patients by Topcu et al. (8). Two patients had homozygous R282Q mutations which was previously reported by Samuraki et al. (10) Patient 3 had the p.P302L (c905 C>T)/p.A64T (c.1906G>A) compound heterozygote mutation. According to our knowledge p.A64T (c.1906G>A) had not been reported. Most patients reach adulthood. Increased incidence of brain tumours has been reported (20-22). A major difference between L2HGA and other dicarboxylic acidurias is that it is associated with a significant increase in the incidence of brain tumours. Six cases who developed brain tumour have been reported for a total of 100 known patients (6).
The symptoms of L2HGA are usually progressive. Some patients with milder clinical findings start having problems late in life. Early diagnosis of the patients may be useful because riboflavin treatment increases the activity of proteins in some patients. Regular follow up is also important because of the increased incidence of brain tumours.
Informed Consent: Consent form was filled out by all participants.
Peer-review: External and internal peer-reviewed.
Surgical and Medical Practices: E.C., M.K., H.Y., E.E. Concept: E.C., M.C., S.K.U., Design: E.C., M.C., Data Collection or Processing: E.C., S.K.U., C.E., S.H., Analysis or Interpretation: E.K., H.O., F.O., Literature Search: E.C., S.K.U., Writing: E.C., M.C., S.K.U.
Conflict of Interest: No conflict of interest was declared by the authors.
Financial Disclosure: The authors declared that this study received no financial support.
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[iD] Ebru Canda (1), [iD] Melis Kose (1), [iD] Havva Yazici (1), [iD] Esra Er (1), [iD] Cenk Eraslan (2), [iD] Sema Kalkan Ucar (1), [iD] Sara Habif (3), [iD] Emin Karaca (4), [iD] Huseyin Onay (4), [iD] Ferda Ozkinay (4), [iD] Mahmut Coker (4)
(1) Ege University Faculty of Medicine, Department of Pediatrics, Division of Pediatric Metabolism and Nutrition, Izmir, Turkey
(2) Ege University Faculty of Medicine, Department of Radiology, Izmir, Turkey
(3) Ege University Faculty of Medicine, Department of Biochemistry, Izmir, Turkey
(4) Ege University Faculty of Medicine, Department of Genetics, Izmir, Turkey
Address for Correspondence
Ebru Canda MD, Ege University Faculty of Medicine, Department of Pediatrics, Division of Pediatric Metabolism and Nutrition, Izmir, Turkey Phone: +90 505 525 29 16 E-mail: email@example.com ORCID ID: orcid.org/0000-0002-9175-1998
Received: 06.11.2017 Accepted: 25.12.2017
Table I. Demographical and clinical findings of the patients with L-2-hydroxyglutaric aciduria Patient no 1 (a) 2 (a) 3 4 5 Age (year) 19 11 9.5 14 32 Age at diagnosis (year) 6 6 7 2 16 Gender Female Female Male Female Female Consanguinity + + + - + Head circumferences 55.5 cm 52.5 cm 52 cm 55 cm NA (50-98p) (50-98p) (50-98p) (50-98p) Psychomotor retardation - - + + + Unsupported walking age 13 17 24 36 NA (months) Loss of skills + + - + - Behavioural problems + + + + + Seizures + - - - - Cerebellar ataxia + + - + + Extrapyramidal symptoms + + - + + Patient no 6 (b) 7 (b) 8 Age (year) 37 25 13 Age at diagnosis (year) 25 12 9 Gender Male Female Male Consanguinity + + + Head circumferences NA NA 55 cm (50-98p) Psychomotor retardation + + + Unsupported walking age NA 18 12 (months) Loss of skills + + - Behavioural problems + + + Seizures + + + Cerebellar ataxia + - - Extrapyramidal symptoms + + + NA: Not applicable, (a) sibling, (b) sibling Table II. Diagnostic laboratory findings of the patients with L-2-hydroxyglutaric aciduria Patient no 1 2 Urine 2-OH glutaric 150 250 acid (mmol/mol/creat) L2HGDH gene mutations R335X (CGA>TGA) R335X (CGA>TGA) homozygous homozygous Patient no 3 4 5 Urine 2-OH glutaric 308 143 78 acid (mmol/mol/creat) L2HGDH gene mutations p.P302L (c905C>T) p.P302L R282Q /p.A64T (c.1906G>A) (c905 C>T) c.1003C>T compound heterozygote homozygous homozygous Patient no 6 7 8 Urine 2-OH glutaric 76 1460 135 acid (mmol/mol/creat) L2HGDH gene NA mutations R282Q p.P302L homozygous (c905 C>T) homozygous NA: Not applicable, L2HGDH: L-2-hydroxyglutarate dehydrogenase, 2-OH: 2-hydroxy Table III. Cranial magnetic resonance imaging findings of the patients with L-2-hydroxyglutaric aciduria Patient no Cranial MRI findings 1 Bilateral cerebral atrophy, white matter T2 hyperintensities MR-S decreased NAA and choline peak 2 Bilateral cerebral atrophy, white matter T2 hyperintensities Bilateral dentate nucleus and capsula externa diffusion restriction Substantia nigra T2 hyperintensities MR-S decreased NAA and choline peak 3 Bilateral subcortical white matter hyperintensities MR-S decreased NAA and choline peak 4 Bilateral cerebral white matter T2 hyperintensities and diffusion restriction Bilateral putamen, bilateral caudate nucleus T2 hyperintensities and diffusion restriction Bilateral internal and external capsula hyperintensities 5 Bilateral cerebral white matter T2 hyperintensities 6 Bilateral cerebral hemisphere at basal ganglion levels cystic encephalomalasia 7 Bilateral subcortical white matter T2 hyperintensities Dentate nucleus T2 hyperintensities 8 Bilateral white matter T2 hyperintensities Basal ganglion T2 hyperintensities Bilateral nucleus dentate hyperintensities MR-S: N-acetyl aspartate, MRI: Magnetic resonance imaging, NAA: N-acetyl-aspartate
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|Title Annotation:||Original Article|
|Author:||Canda, Ebru; Kose, Melis; Yazici, Havva; Er, Esra; Eraslan, Cenk; Ucar, Sema Kalkan; Habif, Sara; Ka|
|Publication:||The Journal of Pediatric Research|
|Date:||Mar 1, 2018|
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