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BRIEF COMMUNICATIONS: O. Bähr, I. Mader, J. Zschocke, J. Dichgans, and J.B. Schulz Adult onset glutaric aciduria type I presenting with a leukoencephalopathy Neurology 2002; 59: 1802-1804 [Abstract] [Full text] [PDF]

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Reply to Letter to the Editor

J B Schulz, O Bahr   (22 January 2003)

Adult onset glutaric aciduria type I presenting with a leukoencephalopathy

S Kolker, G F Hoffman   (22 January 2003)

Reply to Letter to the Editor 22 January 2003
J B Schulz University of Tubingen Germany, O Bahr Send Correspondence to journal: Re: Reply to Letter to the Editor joerg.b.schulz{at}uni-tuebingen.de J B Schulz, et al.	We thank Drs. Kölker and Hoffmann for their comments. Especially their speculation about two possible entities of glutaric aciduria type I (GA I), one early-onset and one adult-onset course, confirms the importance of regular screening of newborns for metabolic dysfunctions. If adult-onset GA I is an own entity, more patients should be identified not showing the classical illness in childhood, but remaining asymptomatic to adulthood. Interesting information should arise during the follow-up of these patients, that would help to understand the long-term course of GA I. We do not know, for instance, whether current therapies are sufficient for these patients or if they need any therapy at all. Without her headaches, our patient might have never been identified as a GA I, as they are not surely related to the GA I and her neurologic symptoms were only mild. The natural course of adult-onset GA I is unknown. Without progression she may have stayed unrecognized for her whole life, without any therapy. Regarding the neuroradiologic findings, we admit that white matter changes are not rare in GA I, but they are not pathognomonic and do not give a clear hint towards GA I. We emphasized the point of view from the perspective of adult neurology. A 19-year-old woman with the main finding of a severe leukoencephalopathy in CT and MRI scans would simply not raise the question: “Is she suffering a glutaric aciduria? ” One single case does not answer the question, whether there is an own entity of adult-onset GA I or not, but it adds GA I to the possible diagnoses of leukencephalopathies in adulthood. Possibly, a few unsolved cases of leukencephalopathy in adults now will be identified as glutaric acidurias and increase the number of adult-onset cases to help defining the entity of adult-onset GA I.
Adult onset glutaric aciduria type I presenting with a leukoencephalopathy 22 January 2003
S Kolker University Children's Hospital, G F Hoffman Send Correspondence to journal: Re: Adult onset glutaric aciduria type I presenting with a leukoencephalopathy Stefan_Koelker{at}med.uni-heidelberg.de S Kolker, et al.	In their study Bähr et al. [1] describe adult onset of glutaric aciduria type I (GA-I) as a leukoencephalopathy. This case report is remarkable since in this organic acid disorder adult-onset of neurologic disease has not been reported before. However, the authors did not mention that white matter changes are frequent in children with GA-I and are prominent features of other so-called “cerebral” organic acid disorders, such as D-2- and L-2-hydroxyglutaric acidurias, and Canavan disease reviewed by Kölker et al. [2] Although acute striatal destruction is the most impressive and clinically relevant manifestation of GA-I, in most children the white matter is also affected, characterized by delayed myelination and T2 prolongation of periventricular white matter. White matter changes may not be seen early in course of the disease but may precede striatal degeneration. [3] A recent meta-analysis on 115 patients with GA-I documented white matter abnormalities in 56% of patients. [4] In addition, post mortem analysis demonstrated spongiform leukoencephalopathy of cortical white matter in GA-I patients who died during acute encephalopathic crises. [5] Notably, a recently published mouse model for GA-I also revealed a focal, spongiform myelinopathy in all Gcdh-deficient mice, maximal in frontal cortex and increasing with age, resembling white matter abnormalities in affected patients. [6] The main question arising from the case report of Bähr et al. [1] is whether leukoencephalopathy may become a common manifestation for those adult patients with GA-I, who survived infancy and childhood unharmed although never treated. The relative number of patients who escape neurological manifestations in early childhood and remain asymptomatic is low [3], but is likely to increase following a greater awareness of the disorder and an increasing institution of population screening by tandem mass spectrometry. Previous reports demonstrated that white matter abnormalities in GA-I develop over time. Thus, white matter abnormalities might be subtle or moderate in childhood but could become prominent in adults. It can be speculated that early-onset GA-I, revealing acute striatal destruction during acute crises, and adult-onset GA-I, revealing leukoencephalopathy as characteristic feature, represent two age-specific manifestations of this disease. If leukoencephalopathy would be also detected in other adults with GA-I, it should be considered whether this might be prevented by life -long dietary treatment. References: 1.Bähr O, Mader I, Zschocke J, Dichgans J, Schulze JB. Adult onset glutaric aciduria type 1 presenting with a leukoencephalopathy. Neurology 2002;59:1802-1804. 2.Kölker S. Mayatepek E, Hoffman GF. White matter disease in cerebral organic acid disroders: clinical implications and suggested pathomechanism. Neuropediatrics, in press. 3.Hoffmann GF, Athanassopoulos S, Burlina AB, et al. Clinical course, early diagnosis, treatment, and prevention of disease in glutaryl-CoA dehydrogenase deficiency. Neuropediatrics 1996; 27: 115-123. 4.Bjugstad KB, Goodman SI, Freed CR. Age at symptom onset predicts severity of motor impairment and clinical outcome of glutaric aciduria type I. J Pediatr 2000; 137: 681-686. 5.Chow CW, Haan EA, Goodman SI, et al. Neuropathology of glutaryl-CoA dehydrogenase deficiency. Acta Neuropathol 76: 590-594. 6.Koeller DM, Woontner M, Crnic LS, et al. Biochemical, pathologic and behavioral analysis of a mouse model of glutaric acidemia type I. Hum Mol Genet 2002; 11: 347-357.