Long-term clinical outcome, therapy and mild mitochondrial dysfunction in hyperprolinemia.

Although hyperprolinemia type-II has a discriminative metabolic phenotype and is frequently associated with neurological system involvement, the casual relation between the metabolic abnormalities and the clinical features, except for those of the secondary B6 deficiency, has been frequently debated. In order to evaluate disease frequency and the neuro-metabolic outcome we searched our laboratory database between 1992 and 2010, including 20,991 urinary organic acid profiles. From these individuals 16,720 parallel blood samples were available, and were investigated by serum amino acid analysis. We also evaluated the clinical, neurological, psychological features, laboratory data and vitamin levels and therapeutic effect in metabolically confirmed hyperprolinemia. Due to the mitochondrial localization of both ALDH4A1 and PRODH mitochondrial enzyme complex activity was evaluated and oxygen consumption was measured to assess ATP production in patient-fibroblasts. The Mitochondrial Disease Score was used to evaluate clinical mitochondrial dysfunction. The child behavior checklist was used to screen for psychopathology. We found four patients with increased urinary P5C diagnosed with hyperprolinemia type II, and only one patient had hyperprolinemia type I. All children with hyperprolinemia type II had low normal B6 concentration, and three of the patients had biochemical markers suggesting mitochondrial dysfunction. Mitochondrial dysfunction was confirmed in a muscle biopsy in one case. Intellectual disability was found in two adolescent patients. All patients showed seizures and significant behavioral problems, including anxiety and hallucinations. The clinical course was non-progressive and independent from the B6 concentration and B6 therapy. Hyperprolinemia is a rare inborn error. Individuals with hyperprolinemia should be monitored closely due to their frequent behavioral problems.

Wrinkled skin and fat pads in patients with ALG8-CDG: revisiting skin manifestations in congenital disorders of glycosylation.

Glycosylation is the posttranslational coupling of sugar chains to proteins or lipids. Proper glycosylation is essential for normal protein structure, function, and trafficking. Mutations in the glycosylation pathway lead to a phenotypically heterogeneous group of metabolic disorders, the congenital disorders of glycosylation (CDG). Some of these conditions, including PMM2-CDG, frequently present with recognizable skin abnormalities such as abnormal fat distribution, skin wrinkling, or peau d'orange, whereas others, such as COG7-CDG and ATP6V0A2-CDG, have been described in association with cutis laxa: wrinkled, inelastic, and sagging skin. Ichthyosis is also common in several types of CDG. ALG8-CDG is a severe disorder characterized by dysmorphic features, failure to thrive, protein-losing enteropathy, neurologic and ophthalmologic problems, and developmental delay. We reviewed the clinical features in all nine previously reported patients diagnosed with ALG8-CDG with a special focus on their skin signs. Three of the nine patients had abnormal fat distribution and skin wrinkling. As the spectrum of CDG presenting with skin signs expands further, we suggest screening for CDG in all patients presenting with any type of central nervous involvement and wrinkled skin, cutis laxa, severe ichthyosis, or abnormal fat distribution.

Perinatal and early infantile symptoms in congenital disorders of glycosylation.

Congenital disorders of glycosylation (CDG) are a rapidly growing family of inborn errors. Screening for CDG in suspected cases is usually performed in the first year of life by serum transferrin isoelectric focusing or mass spectrometry. Based on the transferrin analysis patients can be biochemically diagnosed with a type 1 or type 2 transferrin pattern, and labeled as CDG-I, or CDG-II. The diagnosis of CDG is frequently delayed due to the highly variable phenotype, some cases showing single organ involvement and others mimicking syndromes, like skeletal dysplasia, cutis laxa syndrome, or congenital muscle dystrophy. The aim of our study was to evaluate perinatal abnormalities and early discriminative symptoms in 58 patients consecutively diagnosed with diverse CDG-subtypes. Neonatal findings and clinical features in the first months of life were studied in 36 children with CDG-I and 22 with CDG-II. Maternal complications were found in five, small for gestational age in nine patients. Five children had abnormal neonatal screening results for hypothyroidism. Congenital microcephaly and neonatal seizures were common in CDG-II. Inverted nipples were uncommon with 5 out of 58 children. Dysmorphic features were mostly nonspecific, except for cutis laxa. Early complications included feeding problems, cardiomyopathy, thrombosis, and bleeding. Cases presenting in the neonatal period had the highest mortality rate. Survival in CDG patients is highly dependent on early intervention therapy. We recommend low threshold screening for glycosylation disorders in infants with neurologic symptoms, even in the absence of abnormal fat distribution. Growth retardation and neonatal bleeding increase suspicion for CDG.

Thyroid function in PMM2-CDG: diagnostic approach and proposed management.

Glycoproteins are essential in the production, transport, storage and regulation of thyroid hormones. Altered glycosylation has a potential impact on thyroid function. Abnormal thyroid function tests have been described in patients with congenital disorders of glycosylation. We evaluated the reliability of biochemical markers and investigated thyroid function in 18 PMM2-CDG patients. We propose an expectative therapeutic approach for neonates with thyroid abnormalities in CDG.

Changes in body size and body composition in survivors of childhood cancer: seven years follow-up of a prospective cohort study.

BACKGROUND & AIMS: Cancer treatment is known to have impact on nutritional status, and both underweight and overweight have been reported in several studies in survivors. A limitation of most studies is that they relied on retrospective data or were limited to a subgroup of patients. The current study aims to describe changes in body size and body composition prospectively seven years after diagnosis in a heterogeneous sample of childhood cancer survivors and to evaluate associated factors. METHODS: The study population consisted of children diagnosed with hematological, solid and brain malignancies aged 0-18 years at diagnosis. Data of body size, body composition, and associated factors were collected at diagnosis, one year and seven years after diagnosis. RESULTS: In the total cohort mean BMI z-score increased during treatment. In children with hematological and brain malignancies BMI z-score continued to increase after end of treatment leading to quadrupling of the prevalence of obesity seven years after diagnosis. BMI at diagnosis (ß = -0.34, P = 0.007) and maternal BMI (ß = 0.25, P = 0.046) were associated with the increase in BMI z-score. Mean fat mass (FM) z-score, already high at diagnosis, increased during treatment in children with hematological and brain malignancies and evened out during follow-up. Changes in FM z-score were predicted by type of malignancy (hematologic malignancy versus solid tumor ß = 0.48, P = 0.008; brain tumor versus solid tumor ß = 0.45, P = 0.012). Mean fat free mass (FFM) z-scores started low at diagnosis, particularly in patients with brain tumors, increased during treatment in patients with solid and brain malignancies, though decreased in children with hematological malignancies. At 7 years follow-up a clear increase to normal was seen. Age at diagnosis (ß = 0.43, P = 0.004) and initial FFM (ß = -0.49, P = 0.001) were found to be significant predictors for changes in FFM z-scores. CONCLUSIONS: The finding that the once obtained extra weight and FM during treatment persisted after termination of treatment in children with hematological and brain malignancies, stresses the importance to create awareness about the risk of developing overweight in children during cancer treatment.

Metabolic cutis laxa syndromes.

Cutis laxa is a rare skin disorder characterized by wrinkled, redundant, inelastic and sagging skin due to defective synthesis of elastic fibers and other proteins of the extracellular matrix. Wrinkled, inelastic skin occurs in many cases as an acquired condition. Syndromic forms of cutis laxa, however, are caused by diverse genetic defects, mostly coding for structural extracellular matrix proteins. Surprisingly a number of metabolic disorders have been also found to be associated with inherited cutis laxa. Menkes disease was the first metabolic disease reported with old-looking, wrinkled skin. Cutis laxa has recently been found in patients with abnormal glycosylation. The discovery of the COG7 defect in patients with wrinkled, inelastic skin was the first genetic link with the Congenital Disorders of Glycosylation (CDG). Since then several inborn errors of metabolism with cutis laxa have been described with variable severity. These include P5CS, ATP6V0A2-CDG and PYCR1 defects. In spite of the evolving number of cutis laxa-related diseases a large part of the cases remain genetically unsolved. In metabolic cutis laxa syndromes the clinical and laboratory features might partially overlap, however there are some distinct, discriminative features. In this review on metabolic diseases causing cutis laxa we offer a practical approach for the differential diagnosis of metabolic cutis laxa syndromes.

Nijmegen paediatric CDG rating scale: a novel tool to assess disease progression.

Congenital disorders of glycosylation (CDG) are a group of clinically heterogeneous inborn errors of metabolism. At present, treatment is available for only one CDG, but potential treatments for the other CDG are on the horizon. It will be vitally important in clinical trials of such agents to have a clear understanding of both the natural history of CDG and the corresponding burden of disability suffered by patients. To date, no multicentre studies have attempted to document the natural history of CDG. This is in part due to the lack of a reliable assessment tool to score CDG's diverse clinical spectrum. Based on our earlier experience evaluating disease progression in disorders of oxidative phosphorylation, we developed a practical and semi-quantitative rating scale for children with CDG. The Nijmegen Paediatric CDG Rating Scale (NPCRS) has been validated in 12 children, offering a tool to objectively monitor disease progression. We undertook a successful trial of the NPCRS with a collaboration of nine experienced physicians, using video records of physical and neurological examination of patients. The use of NPCRS can facilitate both longitudinal and natural history studies that will be essential for future interventions.