J Inherit Metab Dis DOI 10.1007/s10545-015-9872-2

SSIEM 2014

Ketogenic diets in patients with inherited metabolic disorders S. Scholl-Bürgi 1 & A. Höller 1 & K. Pichler 1 & M. Michel 1 & E. Haberlandt 2 & D. Karall 1

Received: 15 January 2015 / Revised: 5 June 2015 / Accepted: 5 June 2015 # SSIEM 2015

Abstract Ketogenic diets (KDs) are diets that bring on a metabolic condition comparable to fasting, usually without catabolism. Since the mid-1990s such diets have been widely used in patients with seizures/epilepsies, mostly children. This review focuses on the use of KDs in patients with various inherited metabolic disorders (IMD). In glucose transporter type 1 deficiency syndrome (GLUT1-DS) and pyruvate dehydrogenase complex (PDHc) deficiency, KDs are deemed the therapy of choice and directly target the underlying metabolic disorder. Moreover, in other IMD, mainly of intermediary metabolism such as glycogen storage diseases and disorders of mitochondrial energy supply, KDs may ameliorate clinical symptoms and laboratory parameters. KDs have also been used successfully to treat symptoms such as seizures/ epilepsy in IMD, e.g. in urea cycle disorders and non-ketotic hyperglycinemia. As a note of caution, catabolism may cause the condition of patients with IMD to deteriorate and should thus be avoided during KDs. For this reason, careful monitoring (clinical, laboratory and apparatus-supported) is warranted. In some IMDs specific macronutrient supply is critical. Therefore, in cases of PDHc deficiency the carbohydrate intake tolerated without lactate increase and in urea cycle

Communicated by: Shamima Rahman Presented at the Annual Symposium of the Society for the Study of Inborn Errors of Metabolism, Innsbruck, Austria, September 2-5, 2014 * S. Scholl-Bürgi [email protected] 1

Department of Pediatrics I, Inherited Metabolic Disorders, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria

2

Department of Pediatrics I, Neuropediatrics, Medical University of Innsbruck, Innsbruck, Austria

disorders the protein tolerance should be determined. Considering this, it is particularly important in patients with IMD that the use of KDs be individualized and well documented. Abbreviations ADSL Adenylosuccinate lyase AEDs Antiepileptic drugs ASL Argininosuccinate lyase ATP Adenosine triphosphate CoA Coenzyme A CSF Cerebrospinal fluid CKD Classical ketogenic diet COX Cytochrome c oxidase DNA Deoxyribonucleic acid e.g For example FADH2 Flavin adenine dinucleotide GABA Gamma amino butyric acid GLUT1-DS Glucose transporter type 1 deficiency syndrome GSD/GSDs Glycogen storage disease/glycogen storage diseases KD/KDs Ketogenic diet/ketogenic diets IMD/IMDs Inherited metabolic disorder/inherited metabolic disorders LGIT Low glycemic index treatment MAD Modified Atkins diet MCT Medium chain triglycerides MELAS Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes MtDNA Mitochondrial DNA N Number NADH + H+ Nicotinamide dinucleotide NKH Non-ketotic hyperglycinemia OXPHOS Oxidative phosphorylation PDHc Pyruvate dehydrogenase complex

J Inherit Metab Dis

POLG SSADH TCA

Polymerase gamma Succinic semialdehyde dehydrogenase Tricarboxylic acid

Ketogenic diets — introduction Ketogenic diets (KDs) are diets that bring on a metabolic condition comparable to fasting, but usually without catabolism. They have a low carbohydrate and high fat content and, depending on the form of ketogenic diet (KD), a defined or variable protein content. The aim of this review is to give an overview of the use of KDs in IMDs (Figs. 1 and 2) and to describe the process flow of KDs in these disorders (Fig. 3). KDs can be used in IMDs in two different ways: firstly, to target the underlying metabolic condition by bypassing the metabolic fault, and secondly, to treat the clinical symptoms of the inherited metabolic disorder such as seizures/epilepsy. As some IMDs may worsen with catabolism, ketosis should be achieved and maintained without catabolism.

Ketogenic diets targeting underlying metabolic disorder

have been reported since it was first described in 1991 (De Vivo et al 1991). Seizures/epilepsy, a movement disorder and cognitive impairment or combinations of these symptoms are the clinical hallmarks of this IMD (Klepper and Leiendecker 2007). KDs (mostly in the form of classical ketogenic diets (cKDs)) are the treatment of choice, because the ketones bypass the deficiency of the blood-brain glucose transporter. Beside cKDs, a modified Atkins diet (MAD) was reported to be effective in more than 20 patients of all age groups with GLUT1-DS (Ito et al 2008 (n=1); Slaughter et al 2009 (n=1); Kitamura et al 2012 (n=1); Ito et al 2011 (n=6); Haberlandt et al 2014 (n=1); Leen et al 2013 (n=4); Ohshiro-Sasaki et al 2014 (n=1); Ramm-Pettersen et al 2014 (n=6)). Not all patients with GLUT1-DS treated with various forms of KD experience complete resolution of symptoms. Therefore, treatment with triheptanoin as an anaplerotic substance was administered in 14 children and adults not on the KD. This caused an improvement in the seizure rate (and spike-wave activity), and most patients also experienced an improvement in neuropsychological performance and cerebral metabolic rate (Pascual et al 2014). A combination of both KD and triheptanoin supplementation was not reported in GLUT1-DS patients. Glycogen storage diseases (GSDs)

Glucose transporter type 1 deficiency syndrome (GLUT1-DS) Patients with GLUT1-DS (OMIM #606777) show a broad clinical spectrum. More than 300 patients with GLUT1-DS

In GSDs storage of glycogen in various organs (with the exception of GSD 0, where the formation of glycogen is impaired) induces long-term impairment of organ function, causing mainly cardiomyopathy, myopathy or hepatopathy. The glycogen

Fig. 1 KDs used in IMD to target the underlying metabolic disorder (mostly disorders of intermediary metabolism); (modified after Scholl-Bürgi and Klepper 2013; in red: main metabolic pathways of KDs)

GSD IIIa GSD V

fatty acids GLUT1-DS

glucose

glucose

PFK deficiency

ketone bodies

PDHc deficiency

acetyl-CoA

pyruvate

FADH2 TCA cycle

NADH+H+

respiratory chain (RC)

ATP

J Inherit Metab Dis Fig. 2 KDs in mitochondrial disorders (modified after Rahman 2012; 1Joshi et al 2009 (n=1); Cardenas and Amato 2010 (n=1); Spiegler et al 2011 (n=2); Martikainen et al 2012 (n=1) and Khan et al 2012 (n=1); 2Steriade et al 2014 (n=1); 3Kang et al 2006 (n=1); Kang et al 2007 (n=9); Laugel et al 2007 (n=1); Seo et al 2010 (n=1); Yoon et al 2014 (n=1); 4Kang et al 2007 (n=1); 5 Kang et al 2007 (n=3); 6Kang et al 2007 (n=1))

mitochondrion

outer membran

inner membran POLG1 mutation (Alpers-Huttenlocher syndrome) (n=6)1

mtDNA replication

transcription

MT-TL1 (MELAS syndrome) ( n=1)2

solute import

translation protein import

assembly of mitochondrial respiratory chain MRS complexes

II I

III

V

IV

Q Q (n=13) 3

(n=1)4

(n=3)5

(n=1)6 (combined CI/CIV)

enzyme deficiency leads to short-term metabolic consequences such as inability to supply glucose in fasting periods with subsequent hypoglycemia. For most GSDs, the treatment of choice is to continuously supply carbohydrates and avoid fasting periods. Glycogen storage disease type III (GSD III; Forbes or Cori disease; debranching enzyme deficiency) (n=5) GSD III (OMIM #232400) is caused by a deficiency of the debranching enzyme (amylo-1,6-glucosidase). Two different clinical types of GSD III can be distinguished. GSD IIIa involves liver and muscle (skeletal and heart muscle), whereas GSD IIIb involves only liver (Dagli et al 2010). To avoid hypoglycemia a high-protein diet and/or frequent feeds are used (Dagli et al 2010). Valayannopoulos et al (2011) reported on successful treatment of severe cardiomyopathy in a GSD IIIa patient with synthetic ketone bodies (D,L-3hydroxybutyrate), 2:1 ketogenic and high-protein diet. The

authors speculated that chronic ketosis leads to lower insulin levels and subsequently to decreased glycogen disposition in the various organs. Additionally, gluconeogenesis may be increased due to high protein supply ((n=1); Valayannopoulos et al 2011). Ketogenic diets (cKD or MAD) without supplementation of synthetic ketone bodies were successfully used in four additional patients with GSD IIIa, causing marked improvement of cardiomyopathy (Brambilla et al 2014 (n= 2, cKD); Mayorandan et al 2014 (n=2, MAD)). Glycogen storage disease type V (GSD V; McArdle's disease; muscle glycogen phosphorylase deficiency) (n=1) In GSD V (OMIM #232600) the deficiency of muscle glycogen phosphorylase causes exercise intolerance with muscular pain and myoglobinuria. Busch et al treated a 55-year-old man with GSD V with a KD and achieved a marked improvement in exercise tolerance (n=1; Busch et al 2005; Vorgerd and Zange 2007).

yes

no alternatives

termination

no

indication

preexamination

KD KD suitable ?

yes planing

implementation (form KD)

KD KD success full?

maintenance

monitoring

no

Fig. 3 Process flow for KDs in IMD

yes

withdrawl?

J Inherit Metab Dis

Phosphofructokinase (PFK) deficiency As PFK is the rate-limiting step in glycolysis, PFK deficiency causes a disturbance in ATP production from glucose through anaerobic and aerobic glycolysis. In a 2-year-old boy with i n f a n t i l e P F K d e f i c i e n c y, s e v e r e m y o p a t h y a n d arthrogryposis, KD was commenced at the age of 4 months and produced clinical improvement. Despite this initial improvement, the patient died of pneumonia at the age of 35 months (n=1; Swoboda et al 1997). Disorders of mitochondrial energy supply (Bmitochondrial disorders^) Disorders of mitochondrial energy supply can manifest at any time with any symptom in any organ (Munnich et al 1996). Tissues with a high energy requirement such as the brain are especially affected. The metabolic derangement results from disturbance of mitochondrial energy supply at different levels (Fig. 2). The main biochemical change effected by KDs is a deprivation of carbohydrates that produces a fatty acid-based energy supply for the body. This results in Ba myriad of metabolic changes^ (Huffman and Kossoff 2006) with ketosis (βhydroxybutyrate, acetoacetate, acetone), but usually without catabolism. KDs may cause changes not only in intermediary metabolism, but also more specific changes in mitochondrial metabolism or function, namely: & &

& &

they reduce the proportion of mutated mtDNA and improve respiratory chain function in cultured cells with mutated mtDNA heteroplasmy (Santra et al 2004), they decrease cytochrome c oxidase (COX)-negative muscle fibers and induce mitochondrial biogenesis in an animal model for late-onset mitochondrial myopathy (AholaErkkilä et al 2010), they increase mitochondrial uncoupling protein activity in the hippocampus and decrease the production of reactive oxygen species in rats fed a KD (Sullivan et al 2004), they increase the citrate synthase along with complex I and catalase activity caused by medium-chain triglyceride-derived decanoic acid (C10) in a neuronal cell line (Hughes et al 2014).

Pyruvate dehydrogenase complex (PDHc) deficiency PDHc is a multienzyme complex catalyzing the irreversible conversion of pyruvate to acetyl-CoA. Thus, PDHc deficiency involves a disturbed aerobic energy supply from glucose. Because of this biochemical phenotype KDs are likely to be the therapy of choice in PDHc deficiency, as acetyl-CoA

bypasses PDHc reaction, and have been used in many patients (e.g. by Falk et al 1976; Wijburg et al 1992; Wexler et al 1997; Prasad et al 2011). In such patients ketosis improves both the patient's clinical condition and lactate and pyruvate levels (Falk et al 1976). However, despite bypassing the deficient enzyme complex Bmanagement is still far from ideal although early institution of a KD may be helpful in some cases^ (Prasad et al 2011). Unfortunately, data to support the use of KDs in PDHc deficiency Bare based on a few uncontrolled case reports, in which dietary composition varied widely^ (Weber et al 2001). Mitochondrial DNA depletion syndromes (MDS) (n=6) Mitochondrial DNA depletion syndromes are characterized by a severe, tissue-specific decrease in mtDNA copy number with resulting organ failure. Mitochondrial DNA (mtDNA) polymerase gamma (POLG) is one of the enzymes catalyzing mtDNA replication. BPOLG-related disorders show a continuum of broad and overlapping phenotypes presenting from early childhood to late adulthood^ (El-Hattab and Scaglia 2013). Patients with mutations in the POLG gene may develop intractable epilepsy with variable associated clinical symptoms. Additionally, mutations in the POLG gene can be associated with Alpers-Huttenlocher syndrome (OMIM #203700), a progressive neuronal degeneration of childhood with liver disease. Treatment options are limited and consist of a symptomatic treatment with antiepileptic drugs (and avoidance of valproic acid). Joshi et al 2009 reported on a 55-month-old girl with heterozygous mutation in the POLG gene, who remained seizurefree for seven months after initiation of KD (4:1). Additionally, her EEG improved dramatically. The patient died at the age of 66 months following an infection and reduced compliance with the diet due to respiratory failure (n= 1; Joshi et al 2009). Cardenas and Amato (2010) described a 14-month-old girl with compound heterozygosity for three POLG gene mutations, who developed epilepsia partialis continua and subsequently generalized status epilepticus. Treatment with antiepileptic drugs and the KD successfully terminated her seizures, but she remained severely encephalopathic. At the age of 19 months she developed liver failure and died (n=1; Cardenas and Amato 2010). Of two additional patients with Alpers-Huttenlocher syndrome treated with KD one became more alert and seizure activity ceased for a few weeks, whereas the other did not respond to the KD (n=2; Spiegler et al 2011). Additionally, Martikainen et al reported on a 26-year-old woman with homozygous mutation in the POLG gene and non-convulsive-status epilepticus. After initiation of low glycemic index treatment, a form of KD, as addon therapy to phenytoin, oxcarbazepine and levetiracetam symptoms resolved (n=1; Martikainen et al 2012). In a 13month-old boy diagnosed at the age of 9 months with Alpers-

J Inherit Metab Dis

Huttenlocher syndrome due to heterozygous mutations in the POLG gene KD was well tolerated and seizures substantially decreased, but the boy died one month later (n=1; Khan et al 2012). In conclusion, KD used in six patients with POLG gene mutation brought a substantial initial reduction in seizure activity in 5/6 patients. Despite this initial improvement outcome is poor once symptoms manifest themselves. In other mitochondrial DNA depletion syndromes (e.g. TK2, DGOUK, SUCLA2, SUCLG1, RRM2B, TYMP, C10orf2) KD has not been used as a therapeutic option.

symptoms (n=1; Laugel et al 2007). In a 5-month-old girl with Ohtahara syndrome associated with complex I deficiency Bseizures were completely controlled and suppression-burst patterns disappeared three months after starting^ KD (2:1) and mitochondrial cocktail supplementation (n=1; Seo et al 2010). Recently, Yoon et al reported on a B7-year-old boy with Lennox-Gastaut syndrome combined with mitochondrial respiratory chain complex I deficiency, whose medically intractable seizures were successfully brought under control with a PUFA-enriched MAD without any significant adverse events^ (n=1; Yoon et al 2014).

Disorders of mitochondrial transcription and translation (n=1)

Isolated complex II (n=1) and IV deficiency (n=3) and complex I/IV deficiency (n=1) In addition to the nine patients with isolated complex I deficiency, Kang et al reported the successful use of KD in patients with isolated complex II (n=1), complex IV (n=3) and complex I/IV (n=1) deficiency (Kang et al 2007). In all patients seizure frequency was reduced, and in three patients KD eliminated seizures. Thus, the effect of KDs seems not to be linked to specific types of MRC deficiencies (Kang et al 2007).

Mitochondrial encephalopathy with lactic acidosis and strokelike episodes syndrome (MELAS; OMIM #540000) is caused mostly by the common mutation m.3243A>G in the MT-TL1 gene. Steriade et al (2014) reported on the use of KD and magnesium citrate as add-on therapy to AED in a 22-yearold patient with MELAS and a disease-causing mutation in the MT-TL1 gene (m.3260A>G), after which the patient was free of seizures (n=1; Steriade et al 2014). Disorders of the mitochondrial respiratory chain (MRC) In 24 patients with mitochondrial respiratory chain defects and intractable epilepsy Lee et al (2008) reported that treatment with a 4:1 KD eliminated seizures in 12 patients. Additionally, two patients experienced a >90 % decrease in seizure frequency and four patients a 50–90 % decrease (n=24; Lee et al 2008). Data on which MRC responded best to KD treatment are not available. Isolated complex I deficiency (NADH ubiquinone oxidoreductase deficiency) (n=13) Compared to carbohydrate oxidation, beta-oxidation of fatty acids provides more FADH2, thereby bypassing complex I of the mitochondrial respiratory chain. Thus, it was speculated that especially complex I deficiencies may respond to KDs (Roef et al 2002; Rahman 2012). Of nine patients with isolated complex I deficiency, five showed a marked (>90 %) reduction in seizure frequency, whereas an additional three patients showed a reduction of more than 50 % (n=9; Kang et al 2007). In an additional patient with Landau-Kleffner syndrome and complex I deficiency KD normalized cognitive function (n=1; Kang et al 2006). Laugel et al (2007) reported on a 7-year-old boy with progressive ophthalmoplegia presenting at 7 months of age and later developing cerebellar ataxia, spasticity and dystonia. Complex I deficiency in muscle and missense mutations in the NDUFV1 gene were detected. KD 3:1 and sodium citrate commenced at the age of 10 months improved the ophthalmoplegia, but were unable to correct other neurologic

Ketogenic diet targeting symptoms (mainly seizures/epilepsy) in inherited metabolic disorders Non ketotic hyperglycinemia (NKH) NKH (OMIM #605899) is an inherited disorder of glycine metabolism causing seizures, myoclonic jerks, characteristic Bhiccups^ and encephalopathy in the first days of life (neonatal form). Cusmai et al (2012) reported on three patients with the neonatal form of NKH treated not only with sodium benzoate, dextromethorphan and antiepileptic drugs (AEDs), but also with cKD (4:1) after initial fasting for 24 hours. Seizure frequency and glycine concentrations in cerebrospinal fluid and plasma decreased, but glycine CSF/plasma ratio increased. Despite the more than 50 % reduction in seizure frequency and the improved quality of life, all three patients presented with severe psychomotor delay and spastic tetraparesis (n=3; Cusmai et al 2012). Argininosuccinate lyase (ASL) deficiency ASL deficiency (OMIM #207900), an inherited disorder of the urea cycle, leads to hyperammonemia and arginine deficiency. Long-term outcome is complicated due to frequently observed epilepsy. Peuscher et al reported on two patients with ASL deficiency, in whom KD was used for treatment of epilepsy. As patients with urea cycle disorders are prone to develop hyperammonemia, especially in catabolic situations, KD was gradually implemented with ongoing protein restriction. One patient showed a reduction in seizure frequency of

J Inherit Metab Dis Table 1 Recommended preliminary investigations to exclude contraindications (as far as possible)

Succinic semialdehyde dehydrogenase (SSADH) deficiency

Laboratory investigations blood

SSADH deficiency (4-hydroxybutyric aciduria; OMIM #271980) is an inherited disorder of GABA degradation manifesting in a broad clinical spectrum including psychomotor retardation, ataxia and epilepsy (Gibson et al 1997). It was shown that in Aldh5a1(-/-) mice KD restores hippocampal ATP levels (Nylen et al 2009) and significantly improves clinical phenotype (Nylen et al 2008). However, there are no reports of KD treatment of patients with SSADH deficiency.

blood cell count, liver and kidney parameters, CRP, creatine kinase, electrolytes, glucose, cholesterol, triglycerides, uric acid, blood gas analysis, lactate, ammonia, amino acids, acylcarnitine profile, ketone bodies, levels of medication,

urine calcium, creatinine, phosphate, organic acids Apparatus-supported investigations electrocardiogramm, echocardiography, abdominal ultrasound, electroencephalogramm, (magnetic resonance imaging), others Premedication type, levels, formulation (carbohydrate content)

Ketogenic diets in inherited metabolic disorders — practical issues more than 50 %, whereas no effect was noted in the other patient (n=2; Peuscher et al 2011).

To exclude additional contraindications and stage preexisting disorders such as kidney, liver or heart disease in patients with known IMD laboratory and apparatus-supported investigations should be performed (Table 1 and Fig. 3). Several types of KD are used to treat pharmacoresistant childhood epilepsy and IMD. Dietary composition differs mainly in fat-to-non-fat ratio and fatty acid composition. Most common is the cKD. Its fat-to-non-fat ratio can vary from 4:1 to 2:1. depending on age, side-effects and acceptance (Kossoff et al 2009a, b). Novel KDs (low glycemic index treatment (LGIT), modified Atkins diet (MAD)) are gaining in popularity as they tend to be more practicable and palatable than cKD, and therefore encourage compliance. All types bring on ketosis although ketone body levels vary according to the dietary regimen (Klepper and Leiendecker 2013). cKD is the most restrictive type of KD. Nevertheless, the amount of carbohydrate intake can be lower in MAD than in cKDs (Fig. 4). In MAD daily carbohydrate intake is reduced to 10 g per day at initiation of the diet and fat supply is increased to up to 65 % of energy (Kossoff and Dorward

Adenylosuccinate lyase (ADSL) deficiency ADSL deficiency (OMIM #103050) is an inherited disorder of purine metabolism that causes an accumulation of succinylnucleosides. Approximately 50 % of such patients present with epilepsy, which is often intractable (Jurecka et al 2015). Therapy is symptomatic and aims to treat the seizures (Jurecka et al 2015). Jurecka et al reported on a patient with ADSL deficiency, who was treated with KD for two years. After initiation of KD the patient remained seizure-free. KD was discontinued when the patient developed metabolic hyperchloremic acidosis with Fanconi syndrome. The Fanconi syndrome resolved one month after cessation of KD and seizures returned at a frequency of several times a day (n=1; Jurecka et al 2012). In another patient with ADSL (type II) KD improved seizure control (n=1; Jurecka et al 2014).

100 Percentage ofEnergy (Total: 1000kcal)

Fig. 4 Composition of different KDs in a patient receiving 1000 kcal (modified after Kossoff and Wang 2013; Note: MAD can have a lower carbohydrate content than cKDs, and in MAD and LGIT the protein supply may be relatively high; *Values are approximate, may vary in literature)

90 80 70 cKD 4:1 60 cKD 3:1 50

cKD 2:1

40

MAD*

30

LGIT*

20 10 0 Fat

Protein

Carbohydrate

J Inherit Metab Dis

2008). A modified version of cKD is the medium-chain triglycerides- (MCT) enriched KD. It allows a less strict dietary regimen because of the MCT's higher ketogenic potential (Kossoff et al 2009a, b). Using the LGIT, about 10 % of energy comes from carbohydrates, whereas 20–30 % comes from protein and 60–70 % from fat (Pfeifer and Thiele 2005). Therefore, carbohydrate intake may vary between 40 and 60 g/day. Foods with a glycemic index of less than 50 should be chosen (Kossoff et al 2009a, b). Initialization of KD can be done in an inpatient as well as an outpatient setting (Kossoff et al 2009a, b). Especially in patients with IMD, initiation of KD as an inpatient should be considered because each patient adapts in his own manner and acute complications may be anticipated during the initial phase (Kang et al 2007). It is well known that at initiation neither liquid restriction nor fasting is required for ketosis (Bergqvist et al 2005). As fasting brings on catabolism in patients with IMD, it should be avoided at any price. For this reason, the dietary fat ratio was gradually increased over several weeks or months and ketosis was achieved without fasting (Swoboda et al 1997; Peuscher et al 2011; Valayannopoulos et al 2011), or calorie intake was gradually increased (Kang et al 2007). Moreover, patients with IMD who refuse food intake during KD can provoke catabolism and subsequently metabolic derangement. In one patient with PDHc deficiency acute and chronic catabolism led to elevated cholesterol and triglyceride levels that resolved after increased calorie intake, feeding a less restrictive KD and supplementation of ω-3 fatty acids (Di Pisa et al 2012). Hypoglycemia was not observed in the patients with GSD IIIa or GSD V, but was observed in two patients with complex I deficiency that caused KD to be terminated in one patient and low-dose prednisolone to be administered in the other (Kang et al 2007). In patients with PDHc deficiency the tolerated glucose intake should be monitored by measuring lactate levels (Stenlid et al 2014). As protein supply in MAD is high and poorly defined, this form of KD should not be used in patients with urea cycle disorders because of the risk of hyperammonemia. In contrast, in patients with GLUT1-DS and GSD IIIa modified Atkins diet was used as an alternative to cKD.

Conclusion KDs are the therapy of choice in GLUT1-DS and PDHc deficiency, but are also increasingly reported for other IMDs. KDs can target the underlying pathophysiology or clinical symptoms (mainly seizures/epilepsy). Practical recommendations for patients with IMD who are treated with KDs include

avoiding fasting and catabolism and ensuring close clinical and biochemical monitoring. Conflicts of Interest None.

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Ketogenic diets in patients with inherited metabolic disorders.

Ketogenic diets (KDs) are diets that bring on a metabolic condition comparable to fasting, usually without catabolism. Since the mid-1990s such diets ...
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