Benefits and drawbacks of guanidinoacetic acid as a possible treatment to replenish cerebral creatine in AGAT deficiency.

Arginine-glycine amidinotransferase (AGAT) deficiency is a rare inherited metabolic disorder that severely affects brain bioenergetics. Characterized by mental retardation, language impairment, and behavioral disorders, AGAT deficiency is a treatable condition, where long-term creatine supplementation usually restores brain creatine levels and improves its clinical features. In some cases of AGAT deficiency, creatine treatment might be somewhat limited due to possible shortcomings in performance and transport of creatine to the brain. Guanidinoacetic acid (GAA), a direct metabolic precursor of creatine, has recently been suggested as a possible alternative to creatine to tackle brain creatine levels in experimental medicine. AGAT patients might benefit from oral GAA due to upgraded bioavailability and convenient utilization of the compound, while possible drawbacks (e.g. brain methylation issues, neurotoxicity, and hyperhomocysteinemia) should be accounted as well.

Changes in Energy Intake and Diet Quality during an 18-Month Weight-Management Randomized Controlled Trial in Adults with Intellectual and Developmental Disabilities.

BACKGROUND: Previous research indicates that individuals with intellectual and developmental disabilities (IDDs) are at risk for poor diet quality. OBJECTIVE: The purpose of this secondary analysis was to determine whether two different weight-loss diets affect energy intake, macronutrient intake, and diet quality as measured by the Healthy Eating Index-2010 (HEI-2010) during a 6-month weight-loss period and 12-month weight-management period, and to examine differences in energy intake, macronutrient intake, and HEI-2010 between groups. DESIGN: Overweight/obese adults with IDDs took part in an 18-month randomized controlled trial and were assigned to either an enhanced Stop Light Diet utilizing portion-controlled meals or a conventional diet consisting of reducing energy intake and following the 2010 Dietary Guidelines for Americans. Proxy-assisted 3-day food records were collected at baseline, 6 months, and 18 months, and were analyzed using Nutrition Data System for Research software. HEI-2010 was calculated using the data from Nutrition Data System for Research. PARTICIPANTS/SETTING: The study took place from June 2011 through May 2014 in the greater Kansas City metropolitan area. MAIN OUTCOME MEASURES: This was a secondary analysis of a weight-management intervention for adults with IDDs randomized to an enhanced Stop Light Diet or conventional diet, to examine differences in energy intake, macronutrient intake, and HEI-2010 across time and between groups. STATISTICAL ANALYSES PERFORMED: Independent- and paired-samples t tests and general mixed modeling for repeated measures were performed to examine group differences and changes at baseline, 6 months, and 18 months between the enhanced Stop Light Diet and conventional diet groups. RESULTS: One hundred and forty six participants (57% female, mean±standard deviation age=36.2±12.0 years) were randomized to either the enhanced Stop Light Diet or conventional diet group (77 enhanced Stop Light Diet, 69 conventional diet) and provided data for analysis at baseline, 124 completed the 6-month weight-loss period, and 101 completed the 18-month study. Participants on the enhanced Stop Light Diet diet significantly reduced energy intake at 6 and 18 months (both P<0.001), but those on the conventional diet did not (both P=0.13). However, when accounting for age, sex, race, education level, and support level (mild vs moderate IDD), there was a significant decrease during the 18-month intervention in energy intake for the enhanced Stop Light Diet and conventional diet groups combined (P<0.01 for time effect), but no significant group difference in this change (P=0.39 for group-by-time interaction). There was no significant change in total HEI-2010 score at 6 and 18 months (P=0.05 and P=0.38 for the enhanced Stop Light Diet group; P=0.22 and P=0.17 for the conventional diet group), and no significant group difference at 6 and 18 months (P=0.08 and P=0.42). However, when participants' age, sex, race, education level, and support level were accounted for, mixed modeling indicated a significant increase in total HEI-2010 scores for the enhanced Stop Light Diet and conventional diet groups combined during the 18-month intervention (P=0.01 for time effect). CONCLUSIONS: The results of this study found that after controlling for demographic factors, individuals with IDDs can decrease their energy intake and increase their diet quality, with no significant differences between the enhanced Stop Light Diet and conventional diet groups.

Different concentrations of docosahexanoic acid supplement during lactation result in different outcomes in preterm Sprague-Dawley rats.

PROPOSE: In this study, we evaluated the effects of different concentrations of docosahexanoic acid (DHA) supplement on preterm Sprague-Dawley rat pups, and in parallel, measured the phosphorylation activity of the mTOR pathway in the hippocampal CA1 area. METHODS: Preterm Sprague-Dawley rat pups were randomly assigned to experimental groups which included; a sufficient DHA group (100 mg/kg/day); an enriched DHA group (300 mg/kg/day); an excess DHA group (800 mg/kg/day); and a deficient DHA group (normal saline gavage 0.1 ml/10 g). Body weight (g) was measured at days 1/7/14/21/28/42, respectively. Spatial learning and memory were also tested using the Morris water maze at week 6 (day 42). Finally, activation of the mTOR signaling pathway in hippocampal CA1 area were evaluated by western blotting. RESULTS: Postnatal sufficient/enriched docosahexanoic acid supplement ameliorated body weight restriction, spatial learning and memory restriction, and decreased phosphorylation of AKT, mTOR, P70S6K1, and 4EBP1 in hippocampal CA1 area. Furthermore, excess docosahexanoic acid supplement impeded weight gain and spatial learning and memory, perturbed serum unsaturated fatty acid, and downregulated phosphorylation of AKT, mTOR, P70S6K1, and 4EBP1 in hippocampal CA1 area. CONCLUSION: Postnatal sufficient/enriched DHA supplement ameliorated growth and spatial learning and memory impairment and upregulated the mTOR pathway in preterm pups, although excessive DHA supplement did not have any beneficial effects.

[Prospective study of ketogenic diet in treatment of children with global developmental delay].

OBJECTIVE: To study the effect of ketogenic diet (KD) on neurobehavioral development, emotional and social behaviors, and life ability in children with global developmental delay (GDD). METHODS: A prospective case-control study was performed for hospitalized children with GDD, who were randomly divided into KD treatment group (n=40) and conventional treatment group (n=37). The children in both groups were given comprehensive rehabilitation training, and those in the KD treatment group were given modified Atkins diet in addition to the comprehensive rehabilitation training. The children in both groups were assessed with the Gesell Developmental Scale, Chinese version of Urban Infant-Toddler Social and Emotional Assessment (CITSEA)/Achenbach Child Behavior Checklist (CBCL), and Infants-Junior High School Students' Social Life Abilities Scale (S-M scale) before treatment and after 3, 6, and 9 months of treatment. The two groups were compared in terms of the improvements in neurobehavioral development, emotional and social behaviors, and social life ability. RESULTS: After 3, 6, and 9 months of treatment, the KD treatment group had significantly greater improvements in the scores of the adaptive, fine motor, and language quotients of the Gesell Developmental Scale compared with the conventional treatment group (P<0.05); the KD treatment group had significantly greater improvements in CITSEA/CBCL scores than the conventional treatment group (P<0.05). The KD treatment group had a greater improvement in the score of the S-M scale after 9 months of treatment (P<0.05). During the KD treatment, 6 children experienced diarrhea and 1 experienced mild urinary stones. CONCLUSIONS: KD can improve the neurobehavioral development and behavioral and emotional behaviors in children with GDD, and it has few adverse effects.

Position of the Academy of Nutrition and Dietetics: nutrition services for individuals with intellectual and developmental disabilities and special health care needs.

It is the position of the Academy of Nutrition and Dietetics that nutrition services provided by registered dietitian nutritionists (RDNs) and nutrition and dietetics technicians, registered (NDTRs), who work under RDN supervision, are essential components of comprehensive care for adults with intellectual and developmental disabilities (IDD) and children and youth with special health care needs (CYSHCN). Nutrition services should be provided throughout life in a manner that is interdisciplinary, family-centered, community based, and culturally competent. Individuals with IDD and CYSHCN have many risk factors requiring nutrition interventions, including growth alterations (eg, failure to thrive, obesity, or growth retardation), metabolic disorders, poor feeding skills, drug-nutrient interactions, and sometimes partial or total dependence on enteral or parenteral nutrition. Furthermore, these individuals are also more likely to develop comorbid conditions, such as obesity or endocrine disorders that require nutrition interventions. Poor nutrition-related health habits, limited access to services, and long-term use of multiple medications are considered health risk factors. Timely and cost-effective nutrition interventions can promote health maintenance and reduce risk and cost of comorbidities and complications. Public policy for individuals with IDD and CYSHCN has evolved, resulting in a transition from institutional facilities and programs to community and independent living. The expansion of public access to technology and health information on the Internet challenges RDNs and NDTRs to provide accurate scientific information to this rapidly growing and evolving population. RDNs and NDTRs with expertise in this area are best prepared to provide appropriate nutrition information to promote wellness and improve quality of life.

Sporadic and familial glut1ds Italian patients: A wide clinical variability.

PURPOSE: GLUT1 deficiency syndrome is a treatable neurological disorder characterized by developmental delay, movement disorders and epilepsy. It is caused by mutations in the SLC2A1 gene inherited as an autosomal dominant trait with complete penetrance, even if most detected SCL2A1 mutations are de novo. Our aim is to present a wide series of Italian patients to highlight the differences among subjects with de novo mutations and those with familial transmission. METHODS: We present clinical and genetic features in a series of 22 GLUT1DS Italian patients. Our patients were classified in two different groups: familial cases including GLUT1DS patients with genetically confirmed affected relatives and sporadic cases with detection of SLC2A1 de novo mutation. RESULTS: We found remarkable differences in the severity of the clinical picture regarding the type of genetic inheritance (sporadic versus familial): sporadic patients were characterized by an earlier epilepsy-onset and higher degree of intellectual disability. No significant differences were found in terms of type of movement disorder, whilst Paroxysmal Exertion-induced Dyskinesia (PED) is confirmed to be the most characteristic movement disorder type in GLUT1DS. In familial cases the clinical manifestation of the disease was particularly variable and heterogeneous, also including asymptomatic patients or those with minimal-symptoms. CONCLUSION: The finding of a "mild" phenotype in familial GLUT1DS gives rise to several questions: the real incidence of the disease, treatment option with ketogenic diet in adult patients and genetic counseling.

Cognitive impairment associated with low ferritin responsive to iron supplementation.

BACKGROUND: Iron deficiency is the most common nutritional deficiency in children. It affects 9% of children ages 1-3 years. Iron is essential for effective mitochondrial electron transport and neurotransmitter synthesis. Iron deficiency has been correlated with impaired psychomotor development, pica, attention deficit disorder, periodic limb movements of sleep, and breath-holding spells. Ferritin is the storage form of iron. PATIENT SERIES: We assessed three children referred for developmental concerns. Extensive testing and neuroimaging were all unremarkable except for low iron stores. Dietary histories revealed excessive milk consumption in two of the children. After dietary adjustments and iron supplementation, iron stores normalized. CONCLUSIONS: This cohort demonstrated a dramatic improvement in cognition once iron stores were repleted, suggesting iron studies should be considered as part of initial investigations of patients with cognitive concerns.

Zinc deficiency and toxicity in pediatric practice.

PURPOSE OF REVIEW: Zinc is a commonly overlooked deficiency in developed countries, occurring in infants, children, and adolescents during critical growth periods. The purpose of this review is to present the evidence of zinc deficiencies and toxicities as well as treatment in pediatrics. RECENT FINDINGS: During the last decade, the significance of zinc deficiency in childhood growth, morbidity, and mortality has been recognized by a number of large-scale supplementation trials in underdeveloped countries. Recognition of the recent nationwide shortage of injectable zinc available for total parenteral nutrition supplementation over the last 2 years focused attention on the possibility of zinc deficiency in the United States. SUMMARY: Although primarily thought of as a problem reserved for underdeveloped countries, zinc deficiency has increasing pediatric prevalence in the USA. Zinc is an essential trace element in the body that is responsible for numerous structural, catalytic, and biochemical functions. Deficiencies can occur because of poor dietary intake, long-term parenteral nutrition without supplementation, and enteral causes such as malabsorption. Zinc deficiency is closely associated with stunting, respiratory infections, diarrhea, and dermatitis. Deficiency is hard to define solely by the serum levels. Clinicians should utilize a combination of serum zinc levels, presenting signs and symptoms, and nutritional intake via oral, enteral, and parenteral routes to accurately assess the deficiency risk and diagnosis.

One-carbon metabolism in neurodevelopmental disorders: using broad-based nutraceutics to treat cognitive deficits in complex spectrum disorders.

Folate and choline, two nutrients involved in the one-carbon metabolic cycle, are intimately involved in regulating DNA integrity, synthesis, biogenic amine synthesis, and methylation. In this review, we discuss evidence that folate and choline play an important role in normal cognitive development, and that altered levels of these nutrients during periods of high neuronal proliferation and synaptogenesis can result in diminished cognitive function. We also discuss the use of these nutrients as therapeutic agents in a spectrum of developmental disorders in which intellectual disability is a prominent feature, such as in Fragile-X, Rett syndrome, Down syndrome, and Autism spectrum disorders. A survey of recent literature suggests that nutritional supplements have mild, but generally consistent, effects on improving cognition. Intervening with supplements earlier rather than later during development is more effective in improving cognitive outcomes. Given the mild improvements seen after treatments using nutrients alone, and the importance of the genetic profile of parents and offspring, we suggest that using nutraceutics early in development and in combination with other therapeutics are likely to have positive impacts on cognitive outcomes in a broad spectrum of complex neurodevelopmental disorders.

Two novel mutations in the BCKDK (branched-chain keto-acid dehydrogenase kinase) gene are responsible for a neurobehavioral deficit in two pediatric unrelated patients.

Inactivating mutations in the BCKDK gene, which codes for the kinase responsible for the negative regulation of the branched-chain α-keto acid dehydrogenase complex (BCKD), have recently been associated with a form of autism in three families. In this work, two novel exonic BCKDK mutations, c.520C>G/p.R174G and c.1166T>C/p.L389P, were identified at the homozygous state in two unrelated children with persistently reduced body fluid levels of branched-chain amino acids (BCAAs), developmental delay, microcephaly, and neurobehavioral abnormalities. Functional analysis of the mutations confirmed the missense character of the c.1166T>C change and showed a splicing defect r.[520c>g;521_543del]/p.R174Gfs1*, for c.520C>G due to the presence of a new donor splice site. Mutation p.L389P showed total loss of kinase activity. Moreover, patient-derived fibroblasts showed undetectable (p.R174Gfs1*) or barely detectable (p.L389P) levels of BCKDK protein and its phosphorylated substrate (phospho-E1α), resulting in increased BCKD activity and the very rapid BCAA catabolism manifested by the patients' clinical phenotype. Based on these results, a protein-rich diet plus oral BCAA supplementation was implemented in the patient homozygous for p.R174Gfs1*. This treatment normalized plasma BCAA levels and improved growth, developmental and behavioral variables. Our results demonstrate that BCKDK mutations can result in neurobehavioral deficits in humans and support the rationale for dietary intervention.

Proposed remedies for some developmental disorders.

Developmental disorders (DDs) are important leading cause of disability in developed countries and also in the United States. DDs are a group of individual conditions that result from abnormal nervous system development and cause altered function. They can begin at any time from prenatal to 22 years of age and the disability usually presents itself throughout a person's life time. Down syndrome, autism, neural tube defects, schizophrenia, cretinism, and attention-deficit hyperactivity disorder are among the most common DDs that currently plague numerous countries and have varying incidence rates. Their occurrence may be partially attributable to the lack of certain dietary nutrients. Notably, essential vitamins, minerals, and ω-3 fatty acids are often deficient in the general population of America and developed countries and are exceptionally deficient in patients suffering from mental disorders. Typically, most of these disorders are treated with prescription drugs, but many of these drugs cause unwanted side effects. Therefore, psychiatrists recommend alternative or complementary nutritional remedies to overcome the adverse effects of those drugs. Studies have shown that daily supplements of vital nutrients, such as that contain amino acids, often effectively reduce symptoms of the patients, because they are converted into neurotransmitters that alleviate depression and other mental disorders. The aim of this article is to discuss the role of dietary imbalances in the incidence of DD and to emphasize which dietary supplements can aid in the treatment of the above-mentioned DD.

Disturbed energy metabolism and muscular dystrophy caused by pure creatine deficiency are reversible by creatine intake.

Creatine (Cr) plays an important role in muscle energy homeostasis by its participation in the ATP-phosphocreatine phosphoryl exchange reaction mediated by creatine kinase. Given that the consequences of Cr depletion are incompletely understood, we assessed the morphological, metabolic and functional consequences of systemic depletion on skeletal muscle in a mouse model with deficiency of l-arginine:glycine amidinotransferase (AGAT(-/-)), which catalyses the first step of Cr biosynthesis. In vivo magnetic resonance spectroscopy showed a near-complete absence of Cr and phosphocreatine in resting hindlimb muscle of AGAT(-/-) mice. Compared with wild-type, the inorganic phosphate/ß-ATP ratio was increased fourfold, while ATP levels were reduced by nearly half. Activities of proton-pumping respiratory chain enzymes were reduced, whereas F(1)F(0)-ATPase activity and overall mitochondrial content were increased. The Cr-deficient AGAT(-/-) mice had a reduced grip strength and suffered from severe muscle atrophy. Electron microscopy revealed increased amounts of intramyocellular lipid droplets and crystal formation within mitochondria of AGAT(-/-) muscle fibres. Ischaemia resulted in exacerbation of the decrease of pH and increased glycolytic ATP synthesis. Oral Cr administration led to rapid accumulation in skeletal muscle (faster than in brain) and reversed all the muscle abnormalities, revealing that the condition of the AGAT(-/-) mice can be switched between Cr deficient and normal simply by dietary manipulation. Systemic creatine depletion results in mitochondrial dysfunction and intracellular energy deficiency, as well as structural and physiological abnormalities. The consequences of AGAT deficiency are more pronounced than those of muscle-specific creatine kinase deficiency, which suggests a multifaceted involvement of creatine in muscle energy homeostasis in addition to its role in the phosphocreatine-creatine kinase system.

Developmental progress and creatine restoration upon long-term creatine supplementation of a patient with arginine:glycine amidinotransferase deficiency.

BACKGROUND: Arginine:glycineamidinotransferase (AGAT/GATM) deficiency has been described in 9 patients across 4 families. Here we describe the clinical outcome and response to creatine supplementation in a patient of the second family affected with AGAT deficiency-a 9-year-old girl. PATIENT AND METHODS: Delayed motor milestones were noticed from 4 months of age and at 14 months moderate hypotonia, developmental delay and failure to thrive. Laboratory studies revealed low plasma creatine as well as extremely low levels of guanidinoacetic acid in urine and plasma. Proton magnetic resonance spectroscopy (MRS) of the brain showed absence of creatine. DNA sequence analysis revealed a homozygous mutation (c.484+1G>T) in the AGAT/GATM gene. AGAT activity was not detectable in lymphoblasts and RNA analysis revealed a truncated mRNA (r.289_484del196) that is degraded via Nonsense Mediated Decay. At 16 months, Bayley's Infant Development Scale (BIDS) showed functioning at 43% of chronologic age. Oral creatine supplementation (up to 800 mg/kg/day) was begun. RESULTS: At age 9 years she demonstrated advanced academic performance. Partial recovery of cerebral creatine levels was demonstrated on MRS at 25 months of age. Brain MRS at 40 months of age revealed a creatine/NAA ratio of about 80% of that in age-matched controls. CONCLUSIONS: 8 years post initiation of oral creatine supplementation, patient demonstrates superior nonverbal and academic abilities, with average verbal skills. We emphasize that early diagnosis combined with early treatment onset of AGAT deficiency may lead to improvement of developmental outcome.

Factores de riesgo de retraso en el crecimiento linear en niños de 12 a 120 meses de edad en Arandas, Jalisco-México / Risk factors associated to growth retardation in children 12 to 120 months of age in Arandas, Jalisco-México

El propósito fue identificar los factores asociados a retraso en el crecimiento en niños de una región semi-rural en Arandas, Jalisco, México. En estudio transversal analítico se incluyeron 432 niños de 12 a 120 meses. Se analizaron variables sociales, demográficas, económicas, dietéticas y patológicas. Se utilizó la puntuación Z del índice talla/edad (< -1 DE y < - 2 DE) para evaluar el déficit de crecimiento. Con la prueba de chi cuadrada y la razón de momios (IC 95 por ciento) se estimaron los factores de riesgo y protección. Los factores de riesgo fueron: > tres niños en la familia [RM 1.71 (1.01, 2.87)], consumo de sodas azucaradas > 4 veces por semana [RM 2.36 (1.19-4.73), ingreso familiar mensual < 200 USA dólares [RM 3.5 (1.28, 9.76)] y gasto per cápita en alimentación < 10 por ciento de un salario mínimo (100 USA dólares al mes) [RM 1.81 (1.06, 3.09)]; edad < 24 meses [RM 2.02 (1.09, 3.75)], adición de azúcar al biberón [RM 8.56 (1.84, 54.9)], modificación de la dieta durante la diarrea [RM 2.40 (1.02, 5.77)] ingestión de leche < 4 veces a la semana [RM 2.71 (1.55, 4.73)] y casi significativo: consumo de frijoles [RM 1.75 (0.98, 3.13)]. Factores de protección: familia nuclear [RM 0.28 (0.09, 0.85)] y dilución adecuada de la fórmula de alimentación [RM 0.71 (0.60, 0.85)]. En el modelo de regresión los factores de riesgo fueron: consumo de sodas, frijoles y adición de azúcar u otros edulcorantes al biberón.

The purpose was to identify risk factors associated to deficit on linear growth in children from a semi-rural population in Arandas, Jalisco, Mexico. In a cross sectional study 432 children, 12 to 120 months old were included. Social, demographic, economical, dietetic and pathological characteristics and deficit in the height /age index (< - 1 and - 2 z score) were considered. A chi square test and Odds Ratio (CI 95 percent) to identify the risk and protection factors were also obtained. Risk factors for height/age deficit were: > 3 children in the family [OR 1.71 (1.01, 2.87)], soft drinks consumption > 4 times a week [OR 2.36 (1.19-4.73)], family’s monthly income < 200 USA dollars [OR 3.5 (1.28, 9.76)] and per capita food expenses < 10 percent of a minimum salary (100 USA dollars a month) [OR 1.81 (1.06, 3.09)]; age < 24 months [OR 2.02 (1.09, 3.75)], adding sweeteners to the bottle [OR 8.56 (1.84, 54.9)], diet modification during diarrhea [OR 2.40 (1.02, 5.77)], milk intake < 4 times a week [OR 2.71 (1.55, 4.73)] and nearly significant, bean consumption [1.75 (0.98, 3.13). Protection factors: nuclear family [OR 0.28 (0.09, 0.85)] and an adequate infant formula dilution [OR 0.71 (0.60, 0.85)]. In multivariate models associated factors to deficit of height were higher consumption of soft drinks, beans and the addition of sweeteners to the bottle. In addition to socioeconomic variables, lower consumption of high quality food and proteins and higher intake of legumes were important risk factors for mild and moderate deficit height/age.

Supplementation with antioxidants and folinic acid for children with Down's syndrome: randomised controlled trial.

OBJECTIVES: To assess whether supplementation with antioxidants, folinic acid, or both improves the psychomotor and language development of children with Down's syndrome. DESIGN: Randomised controlled trial with two by two factorial design. SETTING: Children living in the Midlands, Greater London, and the south west of England. PARTICIPANTS: 156 infants aged under 7 months with trisomy 21. INTERVENTION: Daily oral supplementation with antioxidants (selenium 10 mug, zinc 5 mg, vitamin A 0.9 mg, vitamin E 100 mg, and vitamin C 50 mg), folinic acid (0.1 mg), antioxidants and folinic acid combined, or placebo. MAIN OUTCOME MEASURES: Griffiths developmental quotient and an adapted MacArthur communicative development inventory 18 months after starting supplementation; biochemical markers in blood and urine at age 12 months. RESULTS: Children randomised to antioxidant supplements attained similar developmental outcomes to those without antioxidants (mean Griffiths developmental quotient 57.3 v 56.1; adjusted mean difference 1.2 points, 95% confidence interval -2.2 to 4.6). Comparison of children randomised to folinic acid supplements or no folinic acid also showed no significant differences in Griffiths developmental quotient (mean 57.6 v 55.9; adjusted mean difference 1.7, -1.7 to 5.1). No between group differences were seen in the mean numbers of words said or signed: for antioxidants versus none the ratio of means was 0.85 (95% confidence interval 0.6 to 1.2), and for folinic acid versus none it was 1.24 (0.87 to 1.77). No significant differences were found between any of the groups in the biochemical outcomes measured. Adjustment for potential confounders did not appreciably change the results. CONCLUSIONS: This study provides no evidence to support the use of antioxidant or folinic acid supplements in children with Down's syndrome. TRIAL REGISTRATION: Clinical trials NCT00378456.

GLUT1 deficiency with delayed myelination responding to ketogenic diet.

Monitoring effects of a ketogenic diet in GLUT1 deficiency syndrome without seizures is difficult. Neuroimaging is considered uninformative. We report the case of a boy with neurodevelopmental delay, severe ataxia, an E54X-mutation in the SLC2A1 gene (previously GLUT1), and neuroimaging abnormalities indicative of delayed myelination. Six months on a ketogenic diet resulted in an improved high subcortical white matter signal on T2-weighted images and a reduced N-acetylaspartate/creatine ratio. We conclude that delayed subcortical myelination may occur in GLUT1 deficiency syndrome as a nonspecific finding reflecting developmental delay. In patients without seizures, cranial magnetic resonance imaging and magnetic resonance spectroscopy may prove useful tools to monitor the response to a ketogenic diet.

Fat intolerance in developmentally impaired children with severe feeding intolerance.

Children with a variety of genetic, metabolic, and neurologic disorders can suffer from severe feeding intolerance that is unresponsive to medical, surgical, and nutritional therapy. Developmentally disabled tube-fed children with severe upper gastrointestinal symptoms that persisted after fundoplication who were unresponsive to all medical, surgical, and nutritional interventions underwent a thorough gastrointestinal evaluation, including gastroscopy, pH-metry, upper gastrointestinal barium series, and gastric emptying studies. They were placed on a low-fat diet, and the symptoms before and after the diet were compared. The patients were then rechallenged with incremental increases in fat until the symptoms recurred or the patients reached their former fat concentration. Six children meeting the study criteria were evaluated. Four of these patients had a significant improvement in symptoms, oral intake and feeding tolerance with a decrease in fat intake, and relapse of symptoms when fat calories were increased. Improvement occurred in children who had been intolerant to duodenal feeding. We were subsequently able to wean two children from tube feeding. Dietary fat can provoke upper gastrointestinal symptoms in children with gastric and intestinal dysmotility. Short-term manipulation of dietary fat intake can improve tolerance to feeding.

Atypical GLUT1 deficiency with prominent movement disorder responsive to ketogenic diet.

Glucose transport protein deficiency due to mutation in the GLUT1 gene is characterized by infantile onset and chronic seizure disorder, microcephaly, global developmental delays, and hypoglycorrhachia. We describe a 10-year-old normocephalic male with prominent ataxia, dystonia, choreoathetosis, and GLUT1 deficiency whose motor abnormalities improved with a ketogenic diet. We illustrate the motor abnormalities, at baseline and after ketogenic diet, that characterize this unusual case. This case broadens the phenotype of GLUT1 deficiency and illustrates the importance of cerebrospinal fluid (CSF) evaluation in detecting potentially treatable conditions in children with undiagnosed movement disorders.