VLCAD deficiency: Follow-up and outcome of patients diagnosed through newborn screening in Victoria.

Very long chain acyl-CoA dehydrogenase (VLCAD) deficiency is an inherited metabolic disorder of fatty acid oxidation. Treatment practices of the disorder have changed over the past 10-15years since this disorder was included in newborn screening programs and patients were diagnosed pre-symptomatically. A genotype-phenotype correlation has been suggested but the discovery of novel mutations make this knowledge limited. Herein, we describe our experience in treating patients (n=22) diagnosed through newborn screening and mutational confirmation and followed up over a median period of 104months. We report five novel mutations. In 2013 we formalised our treatment protocol, which essentially follows a European consensus paper from 2009 and our own experience. The prescribed low natural fat diet is relaxed for patients who are asymptomatic when reaching age 5years but medium-chain triglyceride oil is recommended before and after physical activity regardless of age. Metabolic stability, growth, development and cardiac function are satisfactory in all patients. There were no episodes of encephalopathy or hypoglycaemia but three patients had episodes of muscle pain with our without rhabdomyolysis. Body composition studies showed a negative association between dietary protein intake and percent body fat. Larger patient cohort and longer follow up time are required for further elucidation of genotype-phenotype correlations and for establishing the role of dietary protein in metabolic stability and long-term healthier body composition in patients with VLCAD deficiency.

Early clinical manifestations and eating patterns in patients with urea cycle disorders.

OBJECTIVES: To characterize dietary habits and eating patterns in patients with a urea cycle disorder (UCD), and to identify dietary habits that may serve as clues to lead to earlier diagnosis of these disorders. STUDY DESIGN: This was a retrospective study of clinical and dietary data from hospital records of all patients with UCD (n = 90) attending the Royal Children's Hospital in Melbourne between 1972 and 2010. RESULTS: Protein aversion, food refusal, frequent vomiting, poor appetite, and adverse reaction to high-protein-containing foods were documented in the majority of patients with available detailed dietary protein intake data. Fourteen of the 90 admissions for metabolic deterioration in which information regarding the precipitating factor(s) were available were directly related to protein intake (5 higher and 9 lower than prescribed). CONCLUSION: Protein aversion is a common feature of UCD and may serve as a diagnostic clue in patients presenting with food refusal, recurrent vomiting, behavioral problems, mental retardation, and "unexplained" episodes of altered consciousness. Dietary history should be included in the investigation of these symptoms, which might lead to earlier diagnosis. Metabolic decompensation is more frequently related to low energy/protein intake than to high protein intake in these patients. Special attention should be given to protein aversion, which often leads to eating patterns that make it difficult for a patient to achieve the prescribed daily protein requirement.

Efficacy of the ketogenic diet: which epilepsies respond?

We report the efficacy of the ketogenic diet in refractory epilepsies focusing on outcomes with regard to epilepsy syndromes and etiology in children and adults with refractory epilepsy. Sixty-four consecutive children and four adults were prospectively enrolled from 2002 to 2009; seven were excluded from analysis. The classical ketogenic diet was initiated on an inpatient basis with dietary ratios ranging from 2:1 to 4:1 fat to carbohydrate and protein. Patients were classified according to syndrome and etiology using the 1989 and more recent 2010 International League Against Epilepsy (ILAE) classification systems. Responders were defined as >50% reduction in seizure frequency compared to baseline. Syndromes included symptomatic generalized (52), genetic (idiopathic) generalized (7), and focal epilepsies (2) and etiologies included structural (24), genetic (18), and unknown (19). Twenty-nine (48%) of 61 patients were responders at 3 months. Two children became seizure-free: one with focal epilepsy of unknown etiology and another with refractory childhood absence epilepsy. Responsive syndromes included migrating partial epilepsy of infancy, childhood absence epilepsy, focal epilepsy, epilepsy with myoclonic-atonic seizures, and Dravet syndrome. Children with lissencephaly and hypoxic ischemic encephalopathy had surprisingly good responses. The ketogenic diet is an effective treatment for children and adults with refractory epilepsy. The response is predicted by type of epilepsy syndrome. Accurate characterization of the electroclinical syndrome is an important factor in decisions about timing of initiation of the ketogenic diet.

Modified low ratio ketogenic therapy in the treatment of adults with super-refractory status epilepticus.

BACKGROUND: Induction of ketosis by manipulation of nutrition intake has been proposed as an adjunctive treatment for super-refractory status epilepticus (SRSE). However, the classical 4:1 ketogenic ratio may not meet the nutrition needs, specifically protein for critically ill adults. The aim of this study was to analyze the outcomes of adults with SRSE who received a lower ketogenic ratio of 2:1 grams of fat to non-fat grams, including 20%-30% of energy from medium chain triglycerides. METHODS: We reviewed patients aged ≥18 years with SRSE treated with ketogenic therapy between July 2015 and December 2020 at two quaternary teaching hospitals in Melbourne, Australia. Data collected from medical records included patient demographics, nutrition prescription, clinical outcomes, and ketogenic therapy-related complications. The primary outcome of the study was to assess tolerability of ketogenic therapy. RESULTS: Twelve patients (female = 7) were treated with ketogenic therapy for SRSE. Patients received between 4 and 8 antiseizure medications and 1-5 anesthetic agents prior to commencement of ketogenic therapy. Blood beta-hydroxybutyrate concentrations were variable (median = 0.5 mmol/L, range: 0.0-6.1 mmol/L). SRSE resolved in 10 cases (83%) after a median of 9 days (range: 2-21 days) following commencement of ketogenic therapy. Ketogenic therapy-associated complications were reported in five patients, leading to cessation in two patients. CONCLUSION: Despite the challenge in maintaining ketosis during critical illness, low ratio 2:1 ketogenic therapy incorporating medium chain triglycerides is tolerable for adults with SRSE. Further studies are required to determine the optimal timing, nutrition prescription and duration of ketogenic therapy for SRSE treatment.

Effect of tetrahydrobiopterin on Phe/Tyr ratios and variation in Phe levels in tetrahydrobiopterin responsive PKU patients.

BACKGROUND: Whilst a reduction in blood phenylalanine (Phe) levels is essential in patients with PKU, a decrease in Phe/Tyrosine (Tyr) ratio and fluctuations in blood Phe levels over time have been recently associated with improved neuropsychological outcome. The aim of this study was to identify if Tetrahydrobiopterin (BH(4)) offers additional benefit based on the assumption that these 2 factors are beneficial. METHOD: Since 2002, 9 patients identified through NBS as BH(4) responsive (BH(4) group) and 25 non-responsive patients (non-BH(4) group) produced a total of 1384 and 4415 samples, respectively, for analysis. Statistical analysis was performed to compare mean and median Phe levels, Tyr levels and Phe/Tyr ratios in BH(4) and non BH(4) responsive patients. RESULTS: Variations in blood Phe levels were greater in the non-BH(4) group (BH(4): median 338 µmol/L, 95% Confidence Interval (CI) 329-346, mean: 358 µmol/L, CI 350-366; non-BH(4): median 338 µmol/L CI 332-344, mean: 370 µmol/L CI 364-376). Variations in blood Tyr levels were slightly greater in the non-BH(4) group: (BH(4): median 59 µmol/L CI 58-61, mean 67 CI 66-69; non-BH(4): median 62 µmol/L CI 61-63, mean 70 CI 69-71). The variation in Phe/Tyr ratios was greater in the non-BH(4) group (mean 6.12, CI 5.9-6.3) than in the BH(4) group (Mean 5.44, CI 5.3-5.6), particularly at blood Phe levels >600 µmol/L. CONCLUSION: BH(4) responsive patients have smaller variations in blood Phe levels and tighter Phe/Tyr ratios than non-BH(4) responsive patients, particularly at high blood Phe levels. If decreased fluctuations in Phe levels and a decreased Phe/Tyr ratio are indeed neuro-protective, then BH(4) responsiveness is advantageous over diet alone in PKU. Neuropsychological testing in patients who have been treated with BH(4) long term may be able to ascertain the clinical benefit of these biochemical findings.

Practical Considerations for Ketogenic Diet in Adults With Super-Refractory Status Epilepticus.

PURPOSE OF REVIEW: Ketogenic diet therapy can be used as an adjuvant treatment of super-refractory status epilepticus (SRSE). However, the drug and metabolic interactions with concomitant treatments present a challenge for clinicians. In this review, we focus on the practical considerations of implementing ketogenic dietary therapy in the acute setting, including the dietary composition, potential drug-diet interactions, and monitoring during ketogenic treatment. RECENT FINDINGS: This report describes the ketogenic diet therapy protocol implemented for the treatment of SRSE and a review of the current evidence to support clinical practice. SUMMARY: The control of SRSE is critical in reducing morbidity and mortality. There is emerging evidence that ketogenic diet may be a safe and effective treatment option for these patients.

Optimal clinical management of children receiving the ketogenic diet: recommendations of the International Ketogenic Diet Study Group.

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 December 2006, The Charlie Foundation commissioned a panel comprised of 26 pediatric epileptologists and dietitians from nine countries with particular expertise using the KD. This group was created in order to create a consensus statement regarding the clinical management of the KD. Subsequently endorsed by the Practice Committee of the Child Neurology Society, this resultant manuscript addresses issues such as patient selection, pre-KD counseling and evaluation, specific dietary therapy selection, implementation, supplementation, follow-up management, adverse event monitoring, and eventual KD discontinuation. This paper highlights recommendations based on best evidence, including areas of agreement and controversy, unanswered questions, and future research.

The effect of the ketogenic diet on the developing skeleton.

The ketogenic diet (KD) is a medically supervised, high fat, low carbohydrate and restricted protein diet which has been used successfully in patients with refractory epilepsy. Only one published report has explored its effect on the skeleton. We postulated that the KD impairs skeletal health parameters in patients on the KD. Patients commenced on the KD were enrolled in a prospective, longitudinal study, with monitoring of Dual-energy X-ray absorptiometry (DXA) derived bone parameters including bone mineral content and density (BMD). Areal BMD was converted to bone mineral apparent density (BMAD) where possible. Biochemical parameters, including Vitamin D, and bone turnover markers, including osteocalcin, were assessed. Patients were stratified for level of mobility using the gross motor functional classification system (GMFCS). 29 patients were on the KD for a minimum of 6 months (range 0.5-6.5 years, mean 2.1 years). There was a trend towards a reduction in lumbar spine (LS) BMD Z score of 0.1562 (p=0.071) per year and 20 patients (68%) had a lower BMD Z score at the end of treatment. While less mobile patients had lower baseline Z scores, the rate of bone loss on the diet was greater in the more mobile patients (0.28 SD loss per year, p=0.026). Height adjustment of DXA data was possible for 13 patients, with a mean reduction in BMAD Z score of 0.19 SD. Only two patients sustained fractures. Mean urinary calcium-creatinine ratios were elevated (0.77), but only 1 patient developed renal calculi. Children on the KD exhibited differences in skeletal development that may be related to the diet. The changes were independent of height but appear to be exaggerated in patients who are ambulant. Clinicians should be aware of potential skeletal side effects and monitor bone health during KD treatment. Longer term follow up is required to determine adult/peak bone mass and fracture risk throughout life.

Linear growth of children on a ketogenic diet: does the protein-to-energy ratio matter?

Ketogenic diet is a structured effective treatment for children with intractable epilepsy. Several reports have indicated poor linear growth in children on the diet but the mechanism of poor growth has not been elucidated. We aimed to explore whether the protein to energy ratio plays a role in linear growth of children on ketogenic diet. Data regarding growth and nutrition were, retrospectively, collected from the clinical histories of 35 children who were treated with ketogenic diet for at least 6 months between 2002 and 2010. Patients were stratified into groups according to periods of satisfactory or poor linear growth. Poor linear growth was associated with protein or caloric intake of <80% recommended daily intake, and with a protein-to-energy ratio consistently ≤1.4 g protein/100 kcal even when protein and caloric intakes were adequate. We recommend a protein-to-energy ratio of 1.5 g protein/100 kcal be prescribed to prevent growth retardation.

The ketogenic diet in refractory childhood epilepsy.

OBJECTIVE: To report the efficacy and tolerability of the ketogenic diet (KD) in refractory paediatric epilepsy. METHODS: Twenty-six consecutive children were treated with the classical KD from 1996 to 2001. The epilepsy syndromes included symptomatic generalized epilepsy (15), idiopathic generalized epilepsy (4), symptomatic partial epilepsy (1) and unclassified epilepsy (6). One child was lost to follow up. RESULTS: Median age at initiation of the KD was 6.1 years. Median duration of the treatment was 9 months. Twelve children (48%) were treated for >12 months; one still remains on the KD. Four children (16%) became seizure-free. Five children (20%) had 50-99% reduction in seizures, seven (28%) had <50% reduction in seizures and eight (36%) had no improvement. Age, seizure-type and aetiology did not predict response. The medications were decreased in 33% of the children. The KD was discontinued in 64% of the children because of poor efficacy and in 12% because of side-effects. Problems during initiation of the KD included asymptomatic hypoglycaemia (24%) and vomiting (12%). Later complications included poor growth (20%), hyperlipidaemia (16%), hypercalcuria (8%), hypocarnitaemia (8%), constipation (8%), pancreatitis (4%) and decreased bone density (4%). There were no deaths. A 3-month trial of the KD costs A3879 dollars. The first 12 months cost A7275 dollars with a cost of A4528 dollars each year, thereafter. CONCLUSIONS: The KD is an effective treatment for some children with refractory epilepsy, being generally well tolerated and rarely associated with side-effects. Response is not necessarily predicted by age, syndrome or aetiology. A prospective study of the KD is presently underway.