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Glucose transporter type 1 deficiency: Ketogenic diet in three patients with atypical phenotype
Brain & Development 32 (2010) 404–408 www.elsevier.com/locate/braindev
Original article
Glucose transporter type 1 deficiency: Ketogenic diet in three patients with atypical phenotype Pierangelo Veggiotti a,*, Federica Teutonico a, Enrico Alfei a, Nardo Nardocci b, Giovanna Zorzi b, Anna Tagliabue c, Valentina De Giorgis a, Umberto Balottin a a
Department of Child Neurology and Psychiatry, Fondazione IRCCS Istituto Neurologico ‘‘C.Mondino”, Via Mondino, 2, 27100 Pavia, Italy b Department of Child Neurology, Fondazione IRCCS Istituto Neurologico ‘‘Carlo Besta,” Milan, Italy c Study and Research Center on Human Nutrition and Eating Disorders, University of Pavia, Pavia, Italy Received 30 October 2008; received in revised form 14 April 2009; accepted 24 April 2009
Abstract Glucose transporter type I deficiency syndrome (GLUT-1 DS) is an inborn error of glucose transport characterized by seizures, developmental delay, spasticity, acquired microcephaly and ataxia. Diagnosis is based on the finding of low cerebrospinal fluid glucose, in the absence of hypoglycemia, and identification of GLUT-1 gene mutation on chromosome 1. The classic phenotype is a severe form of early onset epileptic encephalopathy, but patient with different clinical presentation have been reported expanding the clinical spectrum. In particular, many patients show a prominent movement disorder other than epilepsy. It is known that this disease represents a treatable condition and ketogenic diet (KD) is the elective treatment in GLUT-1 DS patients. We report on KD in three unrelated Italian GLUT-1 DS female patients, diagnosed in early adulthood, all presenting with an atypical phenotype. Preliminary results seem to demonstrate efficacy of KD on paroxysmal movement disorder while positive effect on cognitive impairment result less evident. Ó 2009 Elsevier B.V. All rights reserved. Keywords: Ketogenic diet; GLUT-1; GLUT-1 DS; Paroxysmal movement disorder; EEG and Seizures
1. Introduction Glucose transporter type I deficiency syndrome (GLUT-1 DS OMIM No. 606777) is an inborn error of glucose transport characterized by seizures, developmental delay, spasticity, acquired microcephaly and ataxia [1]. It was first described by De Vivo and colleagues in 1991 [2] and substantial progress in the idenAbbreviations: GLUT-1 DS, glucose transporter type I deficiency syndrome; GLUT-1, glucose transporter type I; KD, ketogenic diet; CSF, cerebrospinal fluid; PED, paroxysmal exercise-induced dyskinesias; PNKD, paroxysmal non-kinesigenic dyskinesias. * Corresponding author. Tel.: +39 0382 380280; fax: +39 0382 380206. E-mail address: [email protected] (P. Veggiotti). 0387-7604/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.braindev.2009.04.013
tification and understanding of the disease have been brought in recent years. Clinical symptoms are caused by a defect in glucose transport across the blood–brain barrier as demonstrated by the finding of low cerebrospinal fluid (CSF) glucose in the absence of hypoglycemia. The gene encoding the GLUT-1 protein is located on the short arm of chromosome 1. The ‘‘classic” clinical phenotype is a form of early onset epileptic encephalopathy characterized by seizures, developmental delay, spasticity, acquired microcephaly and ataxia [1]. Nevertheless, several variants of GLUT-1 DS have been recognized recently [3–5] and, in particular, many patients show a prominent movement disorder other than epilepsy [6,7].
P. Veggiotti et al. / Brain & Development 32 (2010) 404–408
Treatment is based on the possibility to provide an alternative fuel for the brain or to increase the GLUT1 activity [2,8]. Ketogenic diet (KD) is now considered the treatment of choice for the disease. In fact, the diet-derived ketone bodies cross the blood–brain barrier and can provide an alternative, non-glucose, fuel source for brain metabolism. There is good clinical evidence that KD effectively controls seizures [9], but limited results are available regarding its efficacy on clinical symptoms other than epilepsy [7]. We report on preliminary results of KD treatment in three patients with GLUT-1 DS, all presenting with prominent paroxysmal movement disorder.
2. Methods Patients have been evaluated at Department of Child Neurology and Psychiatry, Fondazione IRCCS Istituto Neurologico ‘‘C.Mondino” in Pavia, from January 2007 to February 2008. All patients and their relatives had given informed consent for the clinical study including video documentation. All patients were treated with the classic 3:1 (fat:[protein + carbohydrate]) KD with the only modification being the initial fast was replaced by a gradual increase in calories [10]. The daily caloric content was calculated for maintenance of an individual’s ideal weight and increased by thirds every day until a full-calorie goal was reached. The diet was supplemented with vitamins and minerals as needed. Patients were evaluated at T0 (baseline) and at T1 (1 month after achieving the 3:1 ratio), T2 (3 months after achieving the 3:1 ratio) and T3 (6 months after achieving the 3:1 ratio) during the follow up. At each time they underwent to a specific protocol including: neurological examination, metabolic screening (including urine and blood ketone levels), video-EEG monitoring during wakefulness and NREM-sleep and cognitive evaluation (WAIS-R: Wechsler Adult Intelligence Scale) [11]. In particular, neurological examination include some time locked physical resistance tasks: (1) maintaining a postural position of Mingazzini I and II; (2) sitting and standing from a chair (number of times); (3) climbing and descending a series of 10 steps (number of times) and (4) deambulation. Strength level was evaluated on different muscular groups (deltoid, triceps, quadriceps, ileopsoas) and assessed based on the M.R.C. (Medical Research Council) classification with five categories (0, no contraction; 1, flicker or trace of contraction; 2, active movement with gravity eliminated; 3, active movement against gravity; 4, active movement against gravity and resistance, 5, normal power).
405
The protocol was always performed at the same time during the day (in the morning before lunch time). A video documentation of the neurological exam and time locked tasks were obtained from each patient. 3. Results Our illustrative cases were all females age ranged 19–20 years old. There was no positive familial history. All patients had a global developmental delay as first symptom. Two patients had seizures starting within the first 6 months, characterized by myoclonic absences (patients 2 and 3) and complex partial seizures (patient 3). Seizures persisted over time, but were quite satisfactory controlled by antiepileptic drugs (valproate, carbamazepine). EEG revealed theta slow waves over the central regions in all cases and interictal epileptiform discharges consistent with generalized irregular spike and wave bursts at 3.5 Hz, only in patient 3. Patient 1 had never had seizures. Neurological examination showed a variable combination of ataxia, spasticity, dystonia, microcephaly and mental retardation. All patients had paroxysmal movement disorder as the most relevant and disabling symptom. Based upon precipitating factors, duration, semeiology and distribution the episodes were consistent with paroxysmal non-kinesigenic dyskinesias (PNKD) (patient 1) and with paroxysmal exercise-induced dyskinesias (PED) (patients 2 and 3). The phenomenology of paroxysmal events will be described in details. 3.1. Patient 1 At age 3 months she started to present daily brief attacks of eye incoordination, that progressively decreased in frequency and disappeared by age 3 years. At 1 year she experienced several cyanotic tonic spells during fever. Since age 4 years she had daily episodes of irregular and asynchronous hyperkinesias, involving head and shoulders, associated with arms dystonic posturing and movements. The paroxysms lasted from 10 min up to 1 h and showed no clear relation with food intake or exercise; during the longer ones, the patient complained discomfort and refused to stand and walk. 3.2. Patient 2 Since age 7 years she manifested episodes of rigidity of legs, hyperextension of trunk, abnormal movement of arms, always occurring after exercise (walking for at least 20 min or running). Duration of episodes was 5– 30 min and they disappeared by stopping the motor activity and resting.
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P. Veggiotti et al. / Brain & Development 32 (2010) 404–408
3.3. Patient 3 Since age 10 years, she experienced attacks of dystonic postures of one leg, sometimes involving the contralateral and the upper limbs, accompanied by painful muscle contracture. These episodes constantly occurred after 10–30 min walking, resolved with rest and were more rapidly stopped by sugar intake. The clinical features, including a video documentation of the paroxysmal dyskinesias, have been previously described in details [12]. Genetic analysis disclosed de novo heterozygous mutations in the GLUT-1 gene: two nonsense mutations (W48X in patient 1 and Q238X in patient 2) and a missense mutation (R126C in patient 3) [13]. In all patients ketogenic diet was well tolerated. No significant adverse events or metabolic complications were observed, except for a mild elevation of blood uric acid detected in patient 1 and completely corrected with a higher fluid intake. Follow up data are summarized in Table 1. Within 2 weeks after initiation of KD there was a rapid and complete disappearance of paroxysmal dyskinesias (both PNKD and PED). In particular, in patient 3 the voluntary interruption of KD during the first month of treatment, because of a mild concomitant infection (Epstein–Barr virus), brought to an immediate reappearance of characteristic paroxysmal phenomena
reported in her history. After recovery and resumption of the dietetic regime, the paroxysmal events disappeared again after few days. Within 1 month of starting the diet, an increase in global resistance to physical effort was reported by parents and patients and demonstrated by neurological examination (Table 1). These results had a great impact on patient quality of life since every physical activity had to be stopped after only few minutes because of the onset of paroxysmal dyskinesias and a concomitant significant reduction in strength level. Complex motor disorder consistent with spastic, ataxic and dystonic elements resulted moderately improved with variable degree in the three patients. Patients 2 and 3 showed a clear improvement in dysarthric speech, writing (Fig. 1) and some fine motor skills. EEG showed a significant and rapid improvement in background activity and organization in all cases with no evidence of the central slow activity demonstrated at T0. Further, epileptic discharges disappeared completely in patient 3, thus allowing to discontinue antiepileptic medication. There was no clear improvement in cognitive impairment in all cases. The blood BOHB level increased during the first days of diet not being as high as 2.1 mM and were maintained between 1.7 and 3 mM during follow up period.
Table 1 Follow up of GLUT-1 patients on ketogenic diet. Patient 1
Epileptic seizures Paroxysmal dyskinesias Dysarthria Ataxia Spasticity Dystonia Strength level (MCR classification)
Patient 3
T0
T1
T2
T3
T0
T1
T2
T3
T0
T1
T2
PNKD + ++ ++ + 4
+ + ++ + 5
+ + ++ + 5
+ + ++ + 5
PED + + + + 4
+ + + 5
+ + + 5
+ + + 5
PED + + 4
+ 5
+ 5
6000 4 5 11500 N
6500 8 6 13000 N
7000 10 7 14000 N
2000 7 5 9500 Theta activity
6000 10 8 12000 N
7000 10 8 13000 N
9000 15 10 >15000 N
700 14 8 13000 N
9000 24 8 >15000 N
<45 (<45;<45)
/
/
<45 (47; <45)
50 (60; 45)
/
/
45 (50; 45)
5000 6 6 10000 Theta activity, irregular spike and wave 50 (59; 54)
/
/
0.32
2.10
2.2
2.80
0.26
1.86
2.8
3
0.15
1.71
2.4
Resistance to prolonged physical effort 4300 Task 1* Task 2** 3 3 Task 3*** 9000 Task 4**** EEG Theta activity
Cognitive impairment TIQ (VIQ; PIQ) BOHB level (mM)
Patient 2
+: Present; : absent; PNKD: paroxysmal non-kinesigenic dyskinesias; PED: paroxysmal exercise-induced dyskinesias; Task 1: maintaining a postural position of Mingazzini I and II; Task 2 sitting and standing from a chair (number of times); Task 3: climbing and descending a series of 10 steps (number of times); Task 4: deambulationß BOHB: beta-hydroxybutyrate.
P. Veggiotti et al. / Brain & Development 32 (2010) 404–408
Fig. 1. Writing before and after ketogenic diet in patient 2. After KD treatment writing improved in the following features: (1) amplitude resulted reduced with an increased ability to write inside the margins of the lines (2) graphic trace resulted firmer and linear because of absence of paroxysmal movements interfering with the activity of writing.
4. Discussion Ketogenic diet might represent the first choice of treatment in GLUT-1 patients. It has been demonstrated to be effective in the control of epileptic disorders [9,13,14] whereas its efficacy on non-epileptic symptoms remains limited [7]. One of the major problematic issue in the treatment of our patients concerned the appropriate fat/other nutrient ratio to use in order to achieve a good efficacy and to prolong as long as possible the diet. In literature, there are data referring to the early onset form [‘‘classic form”] in which the GLUT-1 transporter deficit was complete and a ratio of 4:1 was indicated to supply the most quantity of energy [1]. Our patients were quite different, since they were young adults affected by a GLUT-1 deficit who had to radically change their dietary habits and to carry out the ketogenic diet for as long as possible. Thus, we had to find a right balance between the need to provide a valid energetic alternative source and a diet which could have a satisfying taste to support their compliance as much as possible. Starting from this considerations, we decided for a 3:1 (fat:non-fat) ketogenic meal plan. The decision was suggested by an other work [9] and, also, by our experi-
407
ence with ketogenic diet in Lafora’s disease patients, who were young adults and had to follow a long-term treatment too. In these patients the diet resulted well-tolerated and without long-term significant side effects [14]. In our GLUT-1 patients, follow up confirmed these data consistent with a positive compliance, no significant adverse effects or metabolic abnormality. The most striking result of the diet in our illustrative cases was the disappearance of paroxysmal events demonstrated in all cases. It was complete and quite immediate, within only few days, after the beginning of treatment. This result determined a radical improvement in the quality of life of our subjects who became able to move and walk without restraint and not disturbed by the onset of paroxysmal sudden movements that made their autonomy very limited. Another interesting result was an important improvement in terms of resistance to physical effort associated with the ability to walk long distances recorded by both patients and parents. The interpretation of this result remains controversial. It could be influenced by the absence of paroxysmal movements interfering with gross motor functions as walking. In fact, if not disturbed by paroxysmal movements, patients could walk and have not to resume after the onset of dyskinesias. Nevertheless, the strength level increase demonstrated in all patients during the neurological exam and in some specific physical resistance tasks at both T1 and T2 compared to T0, might indicate that the radical improvement in walking could be explained either by the disappearance of the paroxysmal disorders and by an effective positive change in muscular strength. Another major improvement was demonstrated similarly in EEG picture of all patients that progressively normalized, thus allowing to discontinue the anticonvulsivant medication [15]. The neurological picture consisting of a combination of spastic, ataxic and dystonic elements resulted moderately improved with variable degree in our three patients (evident only in patients 2 and 3). In our cases undergoing a 3:1 ketogenic diet, blood beta-hydroxybutyrate (BOHB) levels resulted lower when compared to classic 4:1 diet as expected. It is noteworthy that movement improvement was induced with blood levels of BOHB as low as 1.7–3 mM according to previous report [16], thus suggesting that movement disorders in GLUT-1 patients might improve more easily by the diet compared to other symptoms (i.e., seizures). This result might suggest that a blood BOHB should not be so high to allow fuel availability for brain metabolism in atypical phenotype in which a residual function of GLUT-1 might be preserved [1]. As suggested in previous literature [1], there was no evidence of a significant cognitive improvement in our patients. Since mental retardation represents an element
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of the syndrome, we might suggest that a late therapeutic intervention might have no effect on this complex function. A future challenge might be to include, in the next studies, a precise and extensive neuropsychological assessment to investigate specific functions that could be positively influenced by treatment. Finally, a main point to take into account might be the importance of an early diagnosis [8] that could allow to increase the possibility of a specific treatment, as KD, to affect in a meaningful way the complex group of symptoms in GLUT-1 patients [8].
Acknowledgments The authors thank EEG technicians Papalia Grazia, Fasce Marco, and nurses Lunghi Simona and Nisandic Pavica, for their support. References [1] Wang D, Pascual JM, Yang H, Engelstad K, Jhung S, Sun RP, et al. Glut-1 deficiency syndrome: clinical, genetic and therapeutic aspects. Ann Neurol 2005;57:111–8. [2] De Vivo DC, Trifiletti RR, Jacobson RI, Ronen GM, Behmand RA, Harik SI. Defective glucose transport across the blood–brain barrier as a cause of persistent hypoglycorrhachia, seizures and developmental delay. N Engl J Med 1991;325:703–9. [3] Klepper J, Leiendocker B. GLUT1 deficiency syndrome – 2007 update. Dev Med Child Neurol 2007;49:707–16. [4] Klepper J, De Vivo DC, Webb DW, Klinge L, Voit T. Reversible infantile hypoglicorrachia: possible transient disturbance in glucose transport? Pediatr Neurol 2003;29:321–5. [5] Klepper J. Impaired glucose transport into the brain: the expanding spectrum of glucose transporter type 1 deficiency syndrome. Curr Opin Neurol 2004;17:193–6.
[6] Overweg-Plandsoen WC, Groener JEM, Wang D, Onkenhout W, Brouwer OF, Bakker HD, et al. GLUT1 deficiency without epilepsy – an exceptional case. J Inherit Metab Dis 2003;26:559–63. [7] Friedman JR, Thiele EA, Wang D, Levine KB, Cloherty EK, Pfeifer HH, et al. Atypical GLUT1 deficiency with prominent movement disorder responsive to ketogenic diet. Mov Disord 2006;21:241–5. [8] Klepper J, Voit T. Facilitated glucose transporter protein type 1 (GLUT1) deficiency syndrome: impaired glucose transport into brain – a review. Eur J Pediatr 2002;161:295–304. [9] Klepper J, Diefenbach S, Kohlschutter A, Voit T. Effects of the ketogenic diet in the glucose transporter 1 deficiency syndrome. Prostaglandins Leukot Essent Fatty Acids 2004;70:321–7. [10] Kossoff EH, Zupec-Kania BA, Amark PE, Ballaban-Gil KR, Bergqvist AG, Blackford R, et al. Optimal clinical management of children receiving the ketogenic diet: Recommendations of the International Ketogenic Diet Study Group. The Charlie Foundation, and the Practice Committee of the Child Neurology Society. Epilepsia 2009;50:304–17. [11] Wechsler D. WAIS-R: Wechsler Adult Intelligence Scale (Italian Version). Florence, Italy: Organizzazioni Speciali; 1997. [12] Zorzi G, Castellotti B, Zibordi F, Gellera C, Nardocci N. Paroxysmal movement disorders in GLUT1 deficiency syndrome. Neurology 2008;71:311–7. [13] Ito Y, Oguni H, Nakayama T, Matsuo M, Funatsuka M, Voit T, et al. Clinical presentation, EEG studies, and novel mutations in two cases of GLUT1 deficiency syndrome in Japan. Brain Dev 2005;27:311–7. [14] Cardinali S, Canafoglia L, Bertoli S, Franceschetti S, Lanzi G, Tagliabue A, et al. A pilot study of a ketogenic diet in patients with Lafora body disease. Epilepsy Res 2006;69:129–34. [15] Von Moers A, Brockman K, Wang D, Korenke CG, Huppke P, De Vivo DC, et al. EEG features of GLUT-1 deficiency syndrome. Epilepsia 2002;43:941–5. [16] Fujii T, Ho YY, Wang D, De Vivo DC, Miyajima T, Wong HY, et al. Three Japanese patients with glucose transporter type 1 deficiency syndrome. Brain Dev 2007;29:92–7.
Original article
Glucose transporter type 1 deficiency: Ketogenic diet in three patients with atypical phenotype Pierangelo Veggiotti a,*, Federica Teutonico a, Enrico Alfei a, Nardo Nardocci b, Giovanna Zorzi b, Anna Tagliabue c, Valentina De Giorgis a, Umberto Balottin a a
Department of Child Neurology and Psychiatry, Fondazione IRCCS Istituto Neurologico ‘‘C.Mondino”, Via Mondino, 2, 27100 Pavia, Italy b Department of Child Neurology, Fondazione IRCCS Istituto Neurologico ‘‘Carlo Besta,” Milan, Italy c Study and Research Center on Human Nutrition and Eating Disorders, University of Pavia, Pavia, Italy Received 30 October 2008; received in revised form 14 April 2009; accepted 24 April 2009
Abstract Glucose transporter type I deficiency syndrome (GLUT-1 DS) is an inborn error of glucose transport characterized by seizures, developmental delay, spasticity, acquired microcephaly and ataxia. Diagnosis is based on the finding of low cerebrospinal fluid glucose, in the absence of hypoglycemia, and identification of GLUT-1 gene mutation on chromosome 1. The classic phenotype is a severe form of early onset epileptic encephalopathy, but patient with different clinical presentation have been reported expanding the clinical spectrum. In particular, many patients show a prominent movement disorder other than epilepsy. It is known that this disease represents a treatable condition and ketogenic diet (KD) is the elective treatment in GLUT-1 DS patients. We report on KD in three unrelated Italian GLUT-1 DS female patients, diagnosed in early adulthood, all presenting with an atypical phenotype. Preliminary results seem to demonstrate efficacy of KD on paroxysmal movement disorder while positive effect on cognitive impairment result less evident. Ó 2009 Elsevier B.V. All rights reserved. Keywords: Ketogenic diet; GLUT-1; GLUT-1 DS; Paroxysmal movement disorder; EEG and Seizures
1. Introduction Glucose transporter type I deficiency syndrome (GLUT-1 DS OMIM No. 606777) is an inborn error of glucose transport characterized by seizures, developmental delay, spasticity, acquired microcephaly and ataxia [1]. It was first described by De Vivo and colleagues in 1991 [2] and substantial progress in the idenAbbreviations: GLUT-1 DS, glucose transporter type I deficiency syndrome; GLUT-1, glucose transporter type I; KD, ketogenic diet; CSF, cerebrospinal fluid; PED, paroxysmal exercise-induced dyskinesias; PNKD, paroxysmal non-kinesigenic dyskinesias. * Corresponding author. Tel.: +39 0382 380280; fax: +39 0382 380206. E-mail address: [email protected] (P. Veggiotti). 0387-7604/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.braindev.2009.04.013
tification and understanding of the disease have been brought in recent years. Clinical symptoms are caused by a defect in glucose transport across the blood–brain barrier as demonstrated by the finding of low cerebrospinal fluid (CSF) glucose in the absence of hypoglycemia. The gene encoding the GLUT-1 protein is located on the short arm of chromosome 1. The ‘‘classic” clinical phenotype is a form of early onset epileptic encephalopathy characterized by seizures, developmental delay, spasticity, acquired microcephaly and ataxia [1]. Nevertheless, several variants of GLUT-1 DS have been recognized recently [3–5] and, in particular, many patients show a prominent movement disorder other than epilepsy [6,7].
P. Veggiotti et al. / Brain & Development 32 (2010) 404–408
Treatment is based on the possibility to provide an alternative fuel for the brain or to increase the GLUT1 activity [2,8]. Ketogenic diet (KD) is now considered the treatment of choice for the disease. In fact, the diet-derived ketone bodies cross the blood–brain barrier and can provide an alternative, non-glucose, fuel source for brain metabolism. There is good clinical evidence that KD effectively controls seizures [9], but limited results are available regarding its efficacy on clinical symptoms other than epilepsy [7]. We report on preliminary results of KD treatment in three patients with GLUT-1 DS, all presenting with prominent paroxysmal movement disorder.
2. Methods Patients have been evaluated at Department of Child Neurology and Psychiatry, Fondazione IRCCS Istituto Neurologico ‘‘C.Mondino” in Pavia, from January 2007 to February 2008. All patients and their relatives had given informed consent for the clinical study including video documentation. All patients were treated with the classic 3:1 (fat:[protein + carbohydrate]) KD with the only modification being the initial fast was replaced by a gradual increase in calories [10]. The daily caloric content was calculated for maintenance of an individual’s ideal weight and increased by thirds every day until a full-calorie goal was reached. The diet was supplemented with vitamins and minerals as needed. Patients were evaluated at T0 (baseline) and at T1 (1 month after achieving the 3:1 ratio), T2 (3 months after achieving the 3:1 ratio) and T3 (6 months after achieving the 3:1 ratio) during the follow up. At each time they underwent to a specific protocol including: neurological examination, metabolic screening (including urine and blood ketone levels), video-EEG monitoring during wakefulness and NREM-sleep and cognitive evaluation (WAIS-R: Wechsler Adult Intelligence Scale) [11]. In particular, neurological examination include some time locked physical resistance tasks: (1) maintaining a postural position of Mingazzini I and II; (2) sitting and standing from a chair (number of times); (3) climbing and descending a series of 10 steps (number of times) and (4) deambulation. Strength level was evaluated on different muscular groups (deltoid, triceps, quadriceps, ileopsoas) and assessed based on the M.R.C. (Medical Research Council) classification with five categories (0, no contraction; 1, flicker or trace of contraction; 2, active movement with gravity eliminated; 3, active movement against gravity; 4, active movement against gravity and resistance, 5, normal power).
405
The protocol was always performed at the same time during the day (in the morning before lunch time). A video documentation of the neurological exam and time locked tasks were obtained from each patient. 3. Results Our illustrative cases were all females age ranged 19–20 years old. There was no positive familial history. All patients had a global developmental delay as first symptom. Two patients had seizures starting within the first 6 months, characterized by myoclonic absences (patients 2 and 3) and complex partial seizures (patient 3). Seizures persisted over time, but were quite satisfactory controlled by antiepileptic drugs (valproate, carbamazepine). EEG revealed theta slow waves over the central regions in all cases and interictal epileptiform discharges consistent with generalized irregular spike and wave bursts at 3.5 Hz, only in patient 3. Patient 1 had never had seizures. Neurological examination showed a variable combination of ataxia, spasticity, dystonia, microcephaly and mental retardation. All patients had paroxysmal movement disorder as the most relevant and disabling symptom. Based upon precipitating factors, duration, semeiology and distribution the episodes were consistent with paroxysmal non-kinesigenic dyskinesias (PNKD) (patient 1) and with paroxysmal exercise-induced dyskinesias (PED) (patients 2 and 3). The phenomenology of paroxysmal events will be described in details. 3.1. Patient 1 At age 3 months she started to present daily brief attacks of eye incoordination, that progressively decreased in frequency and disappeared by age 3 years. At 1 year she experienced several cyanotic tonic spells during fever. Since age 4 years she had daily episodes of irregular and asynchronous hyperkinesias, involving head and shoulders, associated with arms dystonic posturing and movements. The paroxysms lasted from 10 min up to 1 h and showed no clear relation with food intake or exercise; during the longer ones, the patient complained discomfort and refused to stand and walk. 3.2. Patient 2 Since age 7 years she manifested episodes of rigidity of legs, hyperextension of trunk, abnormal movement of arms, always occurring after exercise (walking for at least 20 min or running). Duration of episodes was 5– 30 min and they disappeared by stopping the motor activity and resting.
406
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3.3. Patient 3 Since age 10 years, she experienced attacks of dystonic postures of one leg, sometimes involving the contralateral and the upper limbs, accompanied by painful muscle contracture. These episodes constantly occurred after 10–30 min walking, resolved with rest and were more rapidly stopped by sugar intake. The clinical features, including a video documentation of the paroxysmal dyskinesias, have been previously described in details [12]. Genetic analysis disclosed de novo heterozygous mutations in the GLUT-1 gene: two nonsense mutations (W48X in patient 1 and Q238X in patient 2) and a missense mutation (R126C in patient 3) [13]. In all patients ketogenic diet was well tolerated. No significant adverse events or metabolic complications were observed, except for a mild elevation of blood uric acid detected in patient 1 and completely corrected with a higher fluid intake. Follow up data are summarized in Table 1. Within 2 weeks after initiation of KD there was a rapid and complete disappearance of paroxysmal dyskinesias (both PNKD and PED). In particular, in patient 3 the voluntary interruption of KD during the first month of treatment, because of a mild concomitant infection (Epstein–Barr virus), brought to an immediate reappearance of characteristic paroxysmal phenomena
reported in her history. After recovery and resumption of the dietetic regime, the paroxysmal events disappeared again after few days. Within 1 month of starting the diet, an increase in global resistance to physical effort was reported by parents and patients and demonstrated by neurological examination (Table 1). These results had a great impact on patient quality of life since every physical activity had to be stopped after only few minutes because of the onset of paroxysmal dyskinesias and a concomitant significant reduction in strength level. Complex motor disorder consistent with spastic, ataxic and dystonic elements resulted moderately improved with variable degree in the three patients. Patients 2 and 3 showed a clear improvement in dysarthric speech, writing (Fig. 1) and some fine motor skills. EEG showed a significant and rapid improvement in background activity and organization in all cases with no evidence of the central slow activity demonstrated at T0. Further, epileptic discharges disappeared completely in patient 3, thus allowing to discontinue antiepileptic medication. There was no clear improvement in cognitive impairment in all cases. The blood BOHB level increased during the first days of diet not being as high as 2.1 mM and were maintained between 1.7 and 3 mM during follow up period.
Table 1 Follow up of GLUT-1 patients on ketogenic diet. Patient 1
Epileptic seizures Paroxysmal dyskinesias Dysarthria Ataxia Spasticity Dystonia Strength level (MCR classification)
Patient 3
T0
T1
T2
T3
T0
T1
T2
T3
T0
T1
T2
PNKD + ++ ++ + 4
+ + ++ + 5
+ + ++ + 5
+ + ++ + 5
PED + + + + 4
+ + + 5
+ + + 5
+ + + 5
PED + + 4
+ 5
+ 5
6000 4 5 11500 N
6500 8 6 13000 N
7000 10 7 14000 N
2000 7 5 9500 Theta activity
6000 10 8 12000 N
7000 10 8 13000 N
9000 15 10 >15000 N
700 14 8 13000 N
9000 24 8 >15000 N
<45 (<45;<45)
/
/
<45 (47; <45)
50 (60; 45)
/
/
45 (50; 45)
5000 6 6 10000 Theta activity, irregular spike and wave 50 (59; 54)
/
/
0.32
2.10
2.2
2.80
0.26
1.86
2.8
3
0.15
1.71
2.4
Resistance to prolonged physical effort 4300 Task 1* Task 2** 3 3 Task 3*** 9000 Task 4**** EEG Theta activity
Cognitive impairment TIQ (VIQ; PIQ) BOHB level (mM)
Patient 2
+: Present; : absent; PNKD: paroxysmal non-kinesigenic dyskinesias; PED: paroxysmal exercise-induced dyskinesias; Task 1: maintaining a postural position of Mingazzini I and II; Task 2 sitting and standing from a chair (number of times); Task 3: climbing and descending a series of 10 steps (number of times); Task 4: deambulationß BOHB: beta-hydroxybutyrate.
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Fig. 1. Writing before and after ketogenic diet in patient 2. After KD treatment writing improved in the following features: (1) amplitude resulted reduced with an increased ability to write inside the margins of the lines (2) graphic trace resulted firmer and linear because of absence of paroxysmal movements interfering with the activity of writing.
4. Discussion Ketogenic diet might represent the first choice of treatment in GLUT-1 patients. It has been demonstrated to be effective in the control of epileptic disorders [9,13,14] whereas its efficacy on non-epileptic symptoms remains limited [7]. One of the major problematic issue in the treatment of our patients concerned the appropriate fat/other nutrient ratio to use in order to achieve a good efficacy and to prolong as long as possible the diet. In literature, there are data referring to the early onset form [‘‘classic form”] in which the GLUT-1 transporter deficit was complete and a ratio of 4:1 was indicated to supply the most quantity of energy [1]. Our patients were quite different, since they were young adults affected by a GLUT-1 deficit who had to radically change their dietary habits and to carry out the ketogenic diet for as long as possible. Thus, we had to find a right balance between the need to provide a valid energetic alternative source and a diet which could have a satisfying taste to support their compliance as much as possible. Starting from this considerations, we decided for a 3:1 (fat:non-fat) ketogenic meal plan. The decision was suggested by an other work [9] and, also, by our experi-
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ence with ketogenic diet in Lafora’s disease patients, who were young adults and had to follow a long-term treatment too. In these patients the diet resulted well-tolerated and without long-term significant side effects [14]. In our GLUT-1 patients, follow up confirmed these data consistent with a positive compliance, no significant adverse effects or metabolic abnormality. The most striking result of the diet in our illustrative cases was the disappearance of paroxysmal events demonstrated in all cases. It was complete and quite immediate, within only few days, after the beginning of treatment. This result determined a radical improvement in the quality of life of our subjects who became able to move and walk without restraint and not disturbed by the onset of paroxysmal sudden movements that made their autonomy very limited. Another interesting result was an important improvement in terms of resistance to physical effort associated with the ability to walk long distances recorded by both patients and parents. The interpretation of this result remains controversial. It could be influenced by the absence of paroxysmal movements interfering with gross motor functions as walking. In fact, if not disturbed by paroxysmal movements, patients could walk and have not to resume after the onset of dyskinesias. Nevertheless, the strength level increase demonstrated in all patients during the neurological exam and in some specific physical resistance tasks at both T1 and T2 compared to T0, might indicate that the radical improvement in walking could be explained either by the disappearance of the paroxysmal disorders and by an effective positive change in muscular strength. Another major improvement was demonstrated similarly in EEG picture of all patients that progressively normalized, thus allowing to discontinue the anticonvulsivant medication [15]. The neurological picture consisting of a combination of spastic, ataxic and dystonic elements resulted moderately improved with variable degree in our three patients (evident only in patients 2 and 3). In our cases undergoing a 3:1 ketogenic diet, blood beta-hydroxybutyrate (BOHB) levels resulted lower when compared to classic 4:1 diet as expected. It is noteworthy that movement improvement was induced with blood levels of BOHB as low as 1.7–3 mM according to previous report [16], thus suggesting that movement disorders in GLUT-1 patients might improve more easily by the diet compared to other symptoms (i.e., seizures). This result might suggest that a blood BOHB should not be so high to allow fuel availability for brain metabolism in atypical phenotype in which a residual function of GLUT-1 might be preserved [1]. As suggested in previous literature [1], there was no evidence of a significant cognitive improvement in our patients. Since mental retardation represents an element
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of the syndrome, we might suggest that a late therapeutic intervention might have no effect on this complex function. A future challenge might be to include, in the next studies, a precise and extensive neuropsychological assessment to investigate specific functions that could be positively influenced by treatment. Finally, a main point to take into account might be the importance of an early diagnosis [8] that could allow to increase the possibility of a specific treatment, as KD, to affect in a meaningful way the complex group of symptoms in GLUT-1 patients [8].
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