Joerg Klepper

Children's Hospital Aschaffenburg-Alzenau, Germany · Paediatrics and Paediatric Neurology

Unlabelled: The aim of this research was to characterize cognitive abilities in patients with Glut1-Deficiency syndrome (Glut1DS) following ketogenic diet therapy (KDT). Methods: The cognitive profiles of eight children were assessed using the Wechsler Intelligence Scale (WISC-IV). The effect of ketogenic diet therapy (KDT) on individual subarea...

Objectives: The manuscript serves as an update on the current management practices for infantile spasm syndrome (ISS). It includes a detailed summary of the level of current evidence of different treatment options for ISS and gives recommendations for the treatment and care of patients with ISS. Methods: A literature search was performed using t...

To date, five congenital defects of glucose transporters are known. The clinical picture depends on tissue-specific expression and substrate specificity of the affected transporter. SGLT1 deficiency causes intestinal glucose-galactose malabsorption, a condition that presents with severe osmotic diarrhoea and dehydration soon after birth. In renal g...

Ketogenic diets have been treating epilepsy for over 100 years, and in recent decades the awareness and applications of ketogenic therapies have expanded dramatically. The second edition of Ketogenic Diets and Metabolic Therapies: Expanded Roles in Health and Disease honors the major milestone of entering the second century of metabolic therapies....

Febrile seizures (FS) are usually self-limiting and cause no morbidity. Nevertheless they represent very traumatic events for families. There is a need to identify key messages that reassure carers and help to prevent inappropriate, anxiety-driven behaviors associated with “fever phobia.” No recommendations have been proposed to date regarding the...

Glut1 Deficiency Syndrome (Glut1DS) is a brain energy failure syndrome caused by impaired glucose transport across brain tissue barriers. Glucose diffusion across tissue barriers is facilitated by a family of proteins including glucose transporter type 1 (Glut1). Patients are treated effectively with ketogenic diet therapies (KDT) that provide a su...

Henoch-Schönlein Purpura (HSP) or IgA vasculitis is the most common systemic vasculitis of childhood and may affect skin, joints, gastrointestinal tract, and kidneys. Skin manifestations of HSP are characteristic and include a non-thrombocytopenic palpable purpura of the lower extremities and buttocks. Rarely, HSP may initially present as or evolve...

Mutations in the SACS gene have been initially reported in a rare autosomal recessive cerebellar ataxia syndrome featuring prominent cerebellar atrophy, spasticity and peripheral neuropathy as well as retinal abnormalities in some cases (autosomal recessive spastic ataxia of Charlevoix–Saguenay, ARSACS). In the past few years, the phenotypic spectr...

Ketogenic dietary therapies (KDT) are established, effective nonpharmacologic treatments for intractable childhood epilepsy. For many years KDT were implemented differently throughout the world due to lack of consistent protocols. In 2009, an expert consensus guideline for the management of children on KDT was published, focusing on topics of patie...

Purpose: BECTS (benign childhood epilepsy with centrotemporal spikes) is associated with characteristic EEG findings. This study examines the influence of anti-convulsive treatment on the EEG. Methods: In a randomized controlled trial including 43 children with BECTS, EEGs were performed prior to treatment with either Sulthiame or Levetiracetam...

Multiple sulfatase deficiency (MSD) is an ultra-rare neurodegenerative disorder that results in defective sulfatase post-translational modification. Sulfatases in the body are activated by a unique protein, formylglycine-generating enzyme (FGE) that is encoded by SUMF1. When FGE is absent or insufficient, all 17 known human sulfatases are affected,...

Background and aims: Glut1 Deficiency (Glut1D) is caused by impaired glucose transport into brain. The resulting epileptic encephalopathy and movement disorders can be treated effectively by high-fat carbohydrate-restricted ketogenic diet therapies (KDT) mimicking fasting and providing ketones as an alternative cerebral fuel. Recently 6-24 months...

Background: Although a larger number of antiepileptic drugs became available in the last decades, epilepsy remains drug-resistant in approximately a third of patients. Ketogenic diet (KD), first proposed at the beginning of the last century, is complex and has anticonvulsant effects, yet not completely understood. Over the last decades, different...

Glucose transporter type 1 deficiency syndrome (GLUT1DS) is a neurometabolic disorder with a complex phenotypic spectrum but simple biomarkers in cerebrospinal fluid. The disorder is caused by impaired glucose transport into the brain resulting from variants in SCL2A1. In 10% of GLUT1DS patients, a genetic diagnosis can not be made. Using whole-gen...

Mutations in SCN2A, a gene encoding the voltage-gated sodium channel Nav1.2, have been associated with a spectrum of epilepsies and neurodevelopmental disorders. Here, we report the phenotypes of 71 patients and review 130 previously reported patients. We found that (i) encephalopathies with infantile/childhood onset epilepsies (≥3 months of age) o...

Ketogenic diets have been used to treat epilepsy for nearly a century. Alongside enduring clinical success with a ketogenic diet, metabolism’s critical role in health and in diseases in the central nervous system and throughout the body is increasingly appreciated. Furthermore, metabolism-based strategies have been proven equal or even superior to...

View Supplementary Video Movement disorders are a major feature of Glut1 deficiency. As recently identified in adults with paroxysmal exercise‐induced dystonia, similar events were reported in pediatric Glut1 deficiency. In a case series, parent videos of regular motor state and paroxysmal events were requested from children with Glut1 deficiency o...

Background: The ketogenic diet (KD) is an established, effective non-pharmacologic treatment for drug resistant childhood epilepsy. For a long time, the KD was not recommended for use in infancy (under the age of 2 years) because this is such a crucial period in development and the perceived high risk of nutritional inadequacies. Indeed, infants a...

Background/Purpose: Opsoclonus-Myoclonus Syndrome (OMS) is a rare neurological disorder characterized by jerking conjugated bulbar movements, ataxia with myoclonus, and psychiatric symptoms. OMS results from various etiologies, including paraneoplastic, parainfectious, toxic-metabolic, and idiopathic causes. OMS can appear at any age, the average a...

Background: Acute necrotizing encephalopathy of childhood (ANEC) is a rare, febrile encephalopathy due to neurotropic viral infection causing rapid alteration of consciousness and seizures. In cranial magnetic resonance imaging (cMRI), symmetrical involvement of the thalami is characteristic, as is absence of pleocytosis and increased protein level...

Background/Aim: Glut1 Deficiency (Glut1D) represents a rare metabolic encephalopathy with many faces. A defect in the facilitated glucose transporter GLUT1at the blood-brain barrier and in brain cells impairs cerebral glucose transport. Patients present with epilepsy, developmental delay, movement abnormalities or a complex combination of these fea...

Objectives This report aims to define treatment goals, to summarize the evidence level (EL) of different treatment options for infantile spasms (IS), both in terms of efficacy and adverse effect, and to give recommendations for the management of IS. Methods The Cochrane and Medline (1966-July 2014) databases were searched. Literature known to the g...

High-fat ketogenic diets are the only treatment available for Glut1 deficiency (Glut1D). Here, we describe an 8-year-old girl with classical Glut1D responsive to a 3:1 ketogenic diet and ethosuximide. After 3 years on the diet a gradual increase of blood lipids was followed by rapid, severe asymptomatic hypertriglyceridemia (1,910 mg/dL). Serum lip...

Objective: To give a comprehensive overview of the phenotypic and genetic spectrum of STXBP1 encephalopathy (STXBP1-E) by systematically reviewing newly diagnosed and previously reported patients. Methods: We recruited newly diagnosed patients with STXBP1 mutations through an international network of clinicians and geneticists. Furthermore, we p...

D-Glucose and other monosaccharides are hydrophilic substances that cannot easily cross the lipophilic bilayer of the cell membrane. Since these carbohydrates are most important for the energy supply of essentially all cell types, specific transport mechanisms have had to evolve: proteins embedded in the cell membrane function as hydrophilic pores...

Table S1. Analysis of means of diagnosis vs. sex, presence of PEs, and Glut1D phenotype.

Video 2. Part A: normal gait of a 13‐year‐old girl with Glut1D. Part B: choreatiform PEs—the patient was unable to rest in the hotel lobby after a walk through town on a winter day. She was clearly distressed, but unable to stop the PEs while hugging her mother for support. Ketosis at the time of PEs was not determined.

Data S1. Supplemental Questionnaire 1

Video 3. Part A: mildly impaired gait of a 13‐year‐old girl with Glut1D. KD was discontinued 1 year before the occurrence of PEs. Part B: dyskinesic‐dystonic PEs. The patient was on her way back from school. Episodes were painful, triggered by exercise, and required a period of rest for symptoms to resolve.

Video 1. Part A: normal gait of a 6‐year‐old boy with Glut1D while on a KD. Part B: ataxic‐dystonic PEs at the age of 3 years occurring daily before the diagnosis of Glut1D was made and a KD initiated.

Background Isolated optic neuritis (ON) in childhood may remain a single episode or mark the clinical beginning of multiple sclerosis (MS). Higher age and pathological cranial MRI (cMRI) at presentation were previously demonstrated as independent risk factors of conversion to MS. Objective To further evaluate potential MS risk factors, including c...

This commentary is on the the original article by Schoeler et al. on pages 969–976 of this issue.

We retrospectively evaluated predictors of conversion to multiple sclerosis (MS) in 357 children with isolated optic neuritis (ON) as a first demyelinating event who had a median follow-up of 4.0 years. Multiple Cox proportional-hazards regressions revealed abnormal cranial magnet resonance imaging (cMRI; HR 5.94; 95% CI: 3.39-10.39; p<0.001), pres...

A 4-year-old Turkish girl of consanguineous parents was hospitalized for the evaluation of headaches and recurrent febrile episodes of unknown origin. Her medical history was unremarkable except for a few episodes of uncomplicated oral thrush. Meningitis was diagnosed and Candida albicans was the only pathogen identified by PCR and culture. Despite...

Aims: Isolated optic neuritis (ON) in childhood may remain a singular event or indicate the beginning of multiple sclerosis (MS). Higher age and pathological cranial MRI at presentation were previously demonstrated as independent risk factors of conversion to MS. To further evaluate potential risk factors for MS, including cerebrospinal fluid (CSF)...

PurposeA prospective, epidemiologic study was conducted to assess whether the 2009 pandemic influenza A(H1N1) vaccination in Germany almost exclusively using an AS03-adjuvanted vaccine (Pandemrix) impacts the risk of Guillain–Barré syndrome (GBS) and its variant Fisher syndrome (FS).Methods Potential cases of GBS/FS were reported by 351 participati...

Epilepsy is a phenotypically and genetically highly heterogeneous disorder with >200 genes linked to inherited forms of the disease. To identify the underlying genetic cause in a patient with intractable seizures, optic atrophy, severe intellectual disability (ID), brain abnormalities, and muscular hypotonia, we performed exome sequencing in a 5-ye...

Carbohydrates are one of the most important sources of energy in the human organism. Within the body, glucose is the most abundant monosaccharide which can be stored as glycogen, a branched polymer, in liver and muscle. Inborn errors of metabolism may affect the uptake, distribution and reabsorption of monosaccharides in different organs, a process...

Analysis of CSF is daily routine in patients with acute neurologic disorders like CNS infections. In those patients, the finding of a low CSF glucose may influence further diagnostic workup and therapeutic choices. The interpretation of a low CSF glucose in patients with a chronic neurologic disorder, however, is a less common practice. We present...

Calcifications in the basal ganglia are a common incidental finding and are sometimes inherited as an autosomal dominant trait (idiopathic basal ganglia calcification (IBGC)). Recently, mutations in the PDGFRB gene coding for the platelet-derived growth factor receptor β (PDGF-Rβ) were linked to IBGC. Here we identify six families of different ance...

The classical ketogenic diet has been used for refractory childhood epilepsy for decades. It is also the treatment of choice for disorders of brain energy metabolism, such as Glut1 deficiency syndrome. Novel ketogenic diets such as the modified Atkins diet and the low glycemic index treatment have significantly improved the therapeutic options for...

Glucide metabolism comprises pathways for transport, intermediate metabolism, utilization, and storage of carbohydrates. Defects affect multiple organs and present as systemic diseases. Neurological symptoms result from hypoglycemia, lactic acidosis, or inadequate storage of complex glucide molecules in neurological tissues. In glycogen storage dis...

The Ketogenic Diet in GLUT1 Deficiency Syndrome The Ketogenic Diet in Pyruvate Dehydrogenase Deficiency The Ketogenic Diet in Other Neurometabolic Conditions References

Increasingly, the absence of SLC2A1 mutations causes pediatricians to abandon the diagnosis of Glut1 deficiency. For several reasons this is not justified. Potential disease mechanisms in SLC2A1-negative Glut1 deficiency are discussed.

This commentary is on the original article by Ramm‐Pettersen et al on pages 440–447 of this issue.

Familial idiopathic basal ganglia calcification (IBGC) or Fahr's disease is a rare neurodegenerative disorder characterized by calcium deposits in the basal ganglia and other brain regions, which is associated with neuropsychiatric and motor symptoms. Familial IBGC is genetically heterogeneous and typically transmitted in an autosomal dominant fash...

Glucose transporter 1 (GLUT1) deficiency syndrome (DS) results from impaired glucose transport into brain. We describe the case of an 8-year-old girl with early-onset myoclonic epilepsy unresponsive to eight anticonvulsants. Oral steroid treatment achieved dramatic seizure control at the expense of Cushing syndrome and progressive fatty liver disea...

To date, five congenital defects of monosaccharide transporters are known (◘ Fig. 11.1). Their clinical picture depends on tissue-specific expression and substrate specificity of the affected transporter.

Glucose transporter type 1 deficiency syndrome (GLUT1-DS) is caused by a defect in glucose transport across the blood-brain barrier. The main symptoms are epilepsy, developmental delay, movement disorders, and deceleration of head circumference. A ketogenic diet has been shown to be effective in controlling epilepsy in GLUT1-DS. We report a female...

About 10% of epilepsies in childhood are refractory to anticonvulsants. Here the ketogenic diet has been re-established as an effective treatment option worldwide. Restriction of carbohydrates and a high lipid diet can result in seizure control similar to anticonvulsants. A pediatric/dietary team, supplements, and close support are required to esta...

GLUT-1 deficiency syndrome (GLUT-1 DS) is a disorder of cerebral glucose transport associated with early infantile epilepsy and microcephaly. We report two boys who presented with refractory absence epilepsy associated with hypoglycorrhachia, both of whom have genetically confirmed GLUT-1 DS. We propose that these children serve to expand the pheno...

GLUT1 deficiency syndrome (GLUT1DS) is caused by impaired glucose transport into brain and is effectively treated by means of a ketogenic diet. In clinical practice the diagnosis of GLUT1DS often is challenging due to the increasing complexity of symptoms, diagnostic cut-offs for hypoglycorrhachia and genetic heterogeneity. In terms of treatment al...

Glucose transporter type 1 deficiency syndrome (GLUT1DS) is increasingly recognized as a cause of various neurological disorders but a high index of suspicion is important to make the diagnosis. We report two Chinese patients with GLUT1DS, one of which had a novel mutation in the SLC2A1 gene.

Glucose transporter-1 deficiency syndrome is caused by mutations in the SLC2A1 gene in the majority of patients and results in impaired glucose transport into the brain. From 2004-2008, 132 requests for mutational analysis of the SLC2A1 gene were studied by automated Sanger sequencing and multiplex ligation-dependent probe amplification. Mutations...

GLUT1DS is a treatable encephalopathy and should be suspected In children with unexplained neurological disorders often but not always associated with epilepsy and/or developmental delay. In every patient with unexplained lowCSF glucose in the setting of normal blood glucose and low-to normal CSF lactate.

Multiple Sulfatase Deficiency (MSD) is a rare inherited autosomal recessive disorder of metabolism. MSD is caused by mutations in the sulfatase- modifying- factor 1 (sumf1) -gene, encoding the formylglycine-generating enzyme (FGE). FGE posttranslationally modifies newly synthesized sulfatases and an impaired FGE function results in the release of l...

GLUT1 deficiency syndrome (GLUT1DS) is understood as a monogenetic disease caused by heterozygous SLC2A1 gene mutations with autosomaldominant and sporadic transmission. We report on a six-year-old girl from an inbred Arab family with moderate global developmental delay, epilepsy, ataxia, hypotonia, and hypoglycorrhachia (CSF glucose 36 mg/dL; CSF...

Pyridox(am)ine-5'-phosphate oxidase converts pyridoxine phosphate and pyridoxamine phosphate to pyridoxal phosphate, a cofactor in many metabolic reactions, including neurotransmitter synthesis. A family with a mutation in the pyridox(am)ine-5'-phosphate oxidase gene presenting with neonatal seizures unresponsive to pyridoxine and anticonvulsant tr...

In this study we clinically and genetically characterize a consanguineous family with a homozygous novel missense mutation in the delta-sarcoglycan gene and a second delta-sarcoglycan mutation that has previously been reported to cause severe autosomal-dominant dilated cardiomyopathy. We identified a novel missense mutation in exon 6 (p.A131P) of t...

The effects of a long-term ketogenic diet in children with Glut1 deficiency syndrome on metabolism are unknown. Our results indicate a characteristic effect of a long-term ketogenic diet on glucose and lipid homeostasis in Glut1 deficiency syndrome. Although serum lipids and apolipoproteins reflect a proatherogenic lipoprotein profile, adipocytokin...

Glucose transporter type 1 (GLUT1) deficiency syndrome (GLUT1DS, OMIM 606777) is caused by impaired glucose transport into brain mediated by GLUT1, the glucose transporter at the blood-brain barrier. The condition is diagnosed by hypoglycorrhachia, impaired glucose uptake into erythrocytes, and heterozygous mutations in the SLC2A1 gene (OMIM 138140...

The ketogenic diet (KD) is an established, effective nonpharmacologic treatment for intractable childhood epilepsy. The KD is provided differently throughout the world, with occasionally significant variations in its administration. There exists a need for more standardized protocols and management recommendations for clinical and research use. In...

Pyridox(am)ine-5'-phosphate oxidase converts pyridoxine phosphate and pyridoxamine phosphate to pyridoxal phosphate, a cofactor in many metabolic reactions, including neurotransmitter synthesis. A family with a mutation in the pyridox(am)ine-5'-phosphate oxidase gene presenting with neonatal seizures unresponsive to pyridoxine and anticonvulsant tr...