Oral ribose supplementation in dystroglycanopathy: A single case study.

Three forms of muscular dystrophy-dystroglycanopathies are linked to the ribitol pathway. These include mutations in the isoprenoid synthase domain-containing protein (ISPD), fukutin-related protein (FKRP), and fukutin (FKTN) genes. The aforementioned enzymes are required for generation of the ribitol phosphate linkage in the O-glycan of alpha-dystroglycan. Mild cases of dystroglycanopathy present with slowly progressive muscle weakness, while in severe cases the eyes and brain are also involved. Previous research showed that ribose increased the intracellular concentrations of cytidine diphosphate-ribitol (CDP-ribitol) and had a therapeutic effect. Here, we report the safety and effects of oral ribose supplementation during 6 months in a patient with limb girdle muscular dystrophy type 2I (LGMD2I) due to a homozygous FKRP mutation. Ribose was well tolerated in doses of 9 g or 18 g/day. Supplementation with 18 g of ribose resulted in a decrease of creatine kinase levels of 70%. Moreover, metabolomics showed a significant increase in CDP-ribitol levels with 18 g of ribose supplementation (p < 0.001). Although objective improvement in clinical and patient-reported outcome measures was not observed, the patient reported subjective improvement of muscle strength, fatigue, and pain. This case study indicates that ribose supplementation in patients with dystroglycanopathy is safe and highlights the importance for future studies regarding its potential effects.

International practices in the dietary management of fructose 1-6 biphosphatase deficiency.

BACKGROUND: In fructose 1,6 bisphosphatase (FBPase) deficiency, management aims to prevent hypoglycaemia and lactic acidosis by avoiding prolonged fasting, particularly during febrile illness. Although the need for an emergency regimen to avoid metabolic decompensation is well established at times of illness, there is uncertainty about the need for other dietary management strategies such as sucrose or fructose restriction. We assessed international differences in the dietary management of FBPase deficiency. METHODS: A cross-sectional questionnaire (13 questions) was emailed to all members of the Society for the Study of Inborn Errors of Metabolism (SSIEM) and a wide database of inherited metabolic disorder dietitians. RESULTS: Thirty-six centres reported the dietary prescriptions of 126 patients with FBPase deficiency. Patients' age at questionnaire completion was: 1-10y, 46% (n = 58), 11-16y, 21% (n = 27), and >16y, 33% (n = 41). Diagnostic age was: <1y, 36% (n = 46); 1-10y, 59% (n = 74); 11-16y, 3% (n = 4); and >16y, 2% (n = 2). Seventy-five per cent of centres advocated dietary restrictions. This included restriction of: high sucrose foods only (n = 7 centres, 19%); fruit and sugary foods (n = 4, 11%); fruit, vegetables and sugary foods (n = 13, 36%). Twenty-five per cent of centres (n = 9), advised no dietary restrictions when patients were well. A higher percentage of patients aged >16y rather than ≤16y were prescribed dietary restrictions: patients aged 1-10y, 67% (n = 39/58), 11-16y, 63% (n = 17/27) and >16y, 85% (n = 35/41). Patients classified as having a normal fasting tolerance increased with age from 30% in 1-10y, to 36% in 11-16y, and 58% in >16y, but it was unclear if fasting tolerance was biochemically proven. Twenty centres (56%) routinely prescribed uncooked cornstarch (UCCS) to limit overnight fasting in 47 patients regardless of their actual fasting tolerance (37%). All centres advocated an emergency regimen mainly based on glucose polymer for illness management. CONCLUSIONS: Although all patients were prescribed an emergency regimen for illness, use of sucrose and fructose restricted diets with UCCS supplementation varied widely. Restrictions did not relax with age. International guidelines are necessary to help direct future dietary management of FBPase deficiency.

Dysphagia, malnutrition and gastrointestinal problems in patients with mitochondrial disease caused by the m3243A>G mutation.

BACKGROUND: Previous research has shown that dysphagia and gastrointestinal problems occur frequently in carriers of the m.3243A>G mutation; however, the exact frequency and severity have not been determined. We hypothesise that adult carriers have an increased risk for malnutrition. METHODS: In this observational study we evaluated the presence of gastrointestinal problems and dysphagia in 92 carriers of the m.3243A>G mutation. The severity of the general disease involvement was classified using the Newcastle Mitochondrial Disease Adult Scale (NMDAS). Gastrointestinal involvement, dysphagia and the risk for malnutrition were scored using the Gastrointestinal Symptoms Questionnaire and the Malnutrition Universal Screening Tool. Gastrointestinal symptoms and anthropometrics were compared with healthy controls. RESULTS: Our results show that the height, weight and body mass index (BMI) of these carriers were lower than the national average (p < 0.05). Seventy-nine carriers (86%) suffered from at least one gastrointestinal symptom, mainly flatulence or hard stools. Both frequency and severity of symptoms were significantly increased compared with reference data of healthy Dutch adults. Of the carriers, 45% reported (mostly mild) dysphagia. Solid foods cause more problems than liquids. A negative correlation between BMI and heteroplasmy levels in urinary epithelial cells (UEC) was present (Spearman correlation coefficient = - 0.319, p = 0.003). CONCLUSION: Dysphagia and gastrointestinal problems, especially constipation, are common symptoms in the total m.3243A>G carriers cohort and are not related to heteroplasmy levels in UEC or disease severity. The severity of gastrointestinal problems as well as overall disease severity is associated with an increased risk for malnutrition.

Dietary practices in pyridoxine non-responsive homocystinuria: a European survey.

BACKGROUND: Within Europe, the management of pyridoxine (B6) non-responsive homocystinuria (HCU) may vary but there is limited knowledge about treatment practice. AIM: A comparison of dietetic management practices of patients with B6 non-responsive HCU in European centres. METHODS: A cross-sectional audit by questionnaire was completed by 29 inherited metabolic disorder (IMD) centres: (14 UK, 5 Germany, 3 Netherlands, 2 Switzerland, 2 Portugal, 1 France, 1 Norway, 1 Belgium). RESULTS: 181 patients (73% >16 years of age) with HCU were identified. The majority (66%; n=119) were on dietary treatment (1-10 years, 90%; 11-16 years, 82%; and >16 years, 58%) with or without betaine and 34% (n=62) were on betaine alone. The median natural protein intake (g/day) on diet only was, by age: 1-10 years, 12 g; 11-16 years, 11 g; and >16 years, 45 g. With diet and betaine, median natural protein intake (g/day) by age was: 1-10 years, 13 g; 11-16 years, 20 g; and >16 years, 38 g. Fifty-two percent (n=15) of centres allocated natural protein by calculating methionine rather than a protein exchange system. A methionine-free l-amino acid supplement was prescribed for 86% of diet treated patients. Fifty-two percent of centres recommended cystine supplements for low plasma concentrations. Target treatment concentrations for homocystine/homocysteine (free/total) and frequency of biochemical monitoring varied. CONCLUSION: In B6 non-responsive HCU the prescription of dietary restriction by IMD centres declined with age, potentially associated with poor adherence in older patients. Inconsistencies in biochemical monitoring and treatment indicate the need for international consensus guidelines.

Successful weight loss in two adult patients diagnosed with late-onset long-chain Fatty Acid oxidation defect.

UNLABELLED: Patients with long-chain fatty acid oxidation defect (LCFAOD) cannot tolerate fasting and are restricted in their physical activity, hence their increased risk of obesity. Experts therefore advise avoidance of catabolic situations and discourage weight reduction in these patients.Two patients with late-diagnosed LCFAOD undergoing treatment at two academic centers successfully lost weight under supervision of a metabolic dietitian. Patient 1 (male, 47 years) diagnosed with CPT 2 deficiency lost 10 kg body weight in a 3-month period with the help of an energy and LCT-restricted, MCT- and carbohydrate-rich diet in combination with an exercise program. CK levels, C16, C18, and C18:1 levels of his acylcarnitine profile and his blood pressure decreased during the period of weight reduction. Patient 2 (male, 39 years) has a VLCAD deficiency. Dietary advice was energy and LCT restriction, MCT and carbohydrate-enriched food with raw cornstarch added during the night. Patient 2 lost almost 40 kg body weight to 87.6 kg (BMI 25.1) in 2 years. CK, insulin, TG, and ALAT blood levels decreased. CONCLUSION: Weight reduction without loss of metabolic control seems possible in late-onset LCFAOD patients. No metabolic crisis occurred in these two patients, while the positive effects of weight reduction were clear. The residual enzyme function in late-onset LCFAOD may be one of the reasons that metabolic decompensation was prevented. In addition, dietary adjustments to prevent excessive fatty acid oxidation likely contributed as well. Therefore, expert supervision by a dietician specialized in metabolic diseases is recommended. Concise SentenceContrary to the current literature, weight loss in patients with late-diagnosed LCFAOD can be successful. A description of two FOAD patients who lost weight without encountering negative side effects at two academic centers is given.

A survey of natural protein intake in Dutch phenylketonuria patients: insight into estimation or measurement of dietary intake.

This study investigated which methods patients and parents used to determine phenylalanine (Phe) intake and the relationship between the methods applied, age, and blood Phe concentration, as this practice had not been studied before in relation to metabolic control. A questionnaire was sent to 327 Dutch phenylketonuria patients (age 0-29 years) to investigate the method used to determine Phe intake (either by estimation, exact measurement, or a combination of both). Mean blood Phe concentration of each individual patient was related to the method reported to be used. Three different age groups (<10 years, > or =10-15 years, and > or =16 years) were distinguished. The response rate for the questionnaires was 73%. In these 188 patients, data for both Phe concentrations and questionnaires could be used. Of these, 75 used exact measurement, 75 used estimation, and 38 used both methods. The number of patients that estimated Phe intake clearly increased with age. Whatever method was used, an increase in Phe concentrations was seen with age. During childhood, exact measurement was used more frequently, and from adolescence on estimation was used more frequently. The method (exact measurement and/or estimation) did not result in statistically different Phe concentrations in any of the three age groups, although blood Phe concentration tended to be lower in adolescence using exact measurement. Data suggest that estimation and exact measurement of Phe intake are both reliable methods. Therefore, in addition to exact measurement, patients should be instructed in both methods at an early age, so that both methods can be used adequately.

Oral desmopressin as a new treatment modality for primary nocturnal enuresis in adolescents and adults: a double-blind, randomized, multicenter study. Dutch Enuresis Study Group.

PURPOSE: We evaluated the efficacy and safety of 2 oral doses of desmopressin compared to 20 micrograms. nasal spray and baseline values in the treatment of primary nocturnal enuresis. MATERIALS AND METHODS: A multicenter study was done comparing oral dosages (200 and 400 micrograms.) of desmopressin (4-week, randomized, double-blind phase followed by 12 weeks of open label treatment with 400 micrograms.) to 20 micrograms. nasal spray in 66 adults and adolescents 12 to 45 years old with primary nocturnal enuresis. RESULTS: No significant differences were found between the 2 doses of desmopressin tablets or between the tablets and 20 micrograms. nasal spray during the double-blind phase. However, patients who initially received 200 micrograms. desmopressin tablets experienced fewer wet nights after they completed 12 weeks of open label treatment when the dose was escalated to 400 micrograms. tablets. Those who received 400 micrograms. tablets initially maintained response during this phase. Desmopressin tablets were well tolerated at both dose levels: 96% of patients and 94% of physicians rated the tolerability as excellent. CONCLUSIONS: Desmopressin tablets are an effective and safe alternative for treatment of nocturnal enuresis.

Cytogenetic analysis of epithelial renal-cell tumors: relationship with a new histopathological classification.

Renal-cell carcinomas (RCC) are clinically, histologically and cytogenetically very heterogeneous. The present histological WHO classification shows no clear correlation between histologic subtypes and specific chromosomal abnormalities. In 1986, a new classification was proposed by Thoenes and Störkel based on the cell type from which the tumor arises. They distinguish 5 cell types: clear-cell, chromophilic, chromophobic, ductus Bellini and oncocytic. Results of 105 primary tumors show that, in this new classification, there is a correlation between different subtypes of renal-cell tumor and specific chromosomal abnormalities at a microscopic and/or molecular level. The clear-cell compact type shows structural aberrations of chromosomes I, 3, 4, 5q, 6, 10q, 11q and 12q, together with polysomy of chromosomes X, 4, 5, 7, 10, 12, 15, 16, 19, 20, 21 and 22, monosomy of chromosomes 3, 8, 9, 13, 14, and loss of Y. The main characteristics of the chromophilic tubulo-papillary type are trisomies 7 and 17, and loss of the Y-chromosome. Chromophobic carcinoma seems to be correlated with, inter alia, polysomy 7, trisomies 12, 16, 18, 19, structural abnormalities of 11q, and telomeric associations. Oncocytomas do not reveal any specific chromosomal anomaly, except for trisomy 7. Loss of heterozygosity on 3p is only found in the clear-cell compact type. Some specific chromosomal abnormalities correlate with a particular grade of the tumor. These correlations support the hypothesis that specific chromosomal abnormalities play a role in the histogenesis and oncogenesis of RCC. They may be important for tumor diagnosis and clinical prognosis.

Iliac artery-ureteral fistula associated with an indwelling ureteral stent.

We report on a patient with an ureteroiliac artery fistula, which developed after double J stenting. The stent was introduced because of unilateral hydronephrosis 2 months after a Wertheim-Meigs operation preceded by cesium application. The presenting symptom of gross hematuria was initially misjudged to originate from the kidney. The diagnostic difficulties in this case are discussed.