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

Undiagnosed Phenylketonuria Can Exist Everywhere: Results From an International Survey

peer reviewedMany countries do not have a newborn screening (NBS) program, and immigrants from such countries are at risk for late diagnosis of phenylketonuria (PKU). In this international survey, 52 of 259 patients (20%) with late diagnosed PKU were immigrants, and 145 of the 259 (55%) were born before NBS or in a location without NBS. © 2021 The Author

Cobblestone-like brain dysgenesis and altered glycosylation in congenital cutis laxa. Debre type

Objective: To delineate a new syndrome of brain dysgenesis and cutis laxa based on the description of 11 patients belonging to nine unrelated families recruited through an international collaboration effort. Methods: Careful clinical assessment of patients from birth to the age of 23 years with follow-up studies ranging from 3 to 20 years. Biochemical studies of serum proteins glycosylation by isoelectric focusing and capillary zone electrophoresis were performed in 10 patients. Brain MRI studies using conventional methods were analyzed in eight patients. Results: An expanded clinical spectrum of a syndrome comprising facial dysmorphia (enlarged anterior fontanelles, downward slant of palpebral fissures, prominent root of the nose), a connective tissue disorder (inguinal hernia, hip dislocation, high myopia), and neurologic impairment was defined. Early developmental delay was followed by onset of generalized seizures by the end of the first decade and a subsequent neurodegenerative course. A defect of N- or N- plus O-glycosylation of serum transferrins and ApoCIII was observed in 10 patients. An unusual cobblestone-like cortical malformation over the frontal and parietal regions was seen in eight patients and cerebellar abnormalities, including two patients with Dandy-Walker malformation, were observed in three patients. Conclusions: Our results suggest that autosomal recessive cutis laxa, Debré type, initially considered a dermatologic syndrome, is a multisystemic disorder with cobblestone-like brain dysgenesis manifesting as developmental delay and an epileptic neurodegenerative syndrome. It might represent a metabolic cause of Dandy-Walker malformation. It is associated with a deficient N- and-O glycosylation of proteins and shares many similarities with muscle-eye-brain syndromes

De Barsy syndrome and ATP6V0A2-CDG

Comment on: Eur J Hum Genet. 2009 Sep;17(9):1099-11

Undiagnosed Phenylketonuria Can Exist Everywhere: Results From an International Survey

Many countries do not have a newborn screening (NBS) program, and immigrants from such countries are at risk for late diagnosis of phenylketonuria (PKU). In this international survey, 52 of 259 patients (20%) with late diagnosed PKU were immigrants, and 145 of the 259 (55%) were born before NBS or in a location without NBS

Newborn screening for homocystinurias: Recent recommendations versus current practice

Purpose: To assess how the current practice of newborn screening (NBS) for homocystinurias compares with published recommendations. Methods: Twenty-two of 32 NBS programmes from 18 countries screened for at least one form of homocystinuria. Centres provided pseudonymised NBS data from patients with cystathionine beta-synthase deficiency (CBSD, n = 19), methionine adenosyltransferase I/III deficiency (MATI/IIID, n = 28), combined remethylation disorder (cRMD, n = 56) and isolated remethylation disorder (iRMD), including methylenetetrahydrofolate reductase deficiency (MTHFRD) (n = 8). Markers and decision limits were converted to multiples of the median (MoM) to allow comparison between centres. Results: NBS programmes, algorithms and decision limits varied considerably. Only nine centres used the recommended second-tier marker total homocysteine (tHcy). The median decision limits of all centres were ≥ 2.35 for high and ≤ 0.44 MoM for low methionine, ≥ 1.95 for high and ≤ 0.47 MoM for low methionine/phenylalanine, ≥ 2.54 for high propionylcarnitine and ≥ 2.78 MoM for propionylcarnitine/acetylcarnitine. These decision limits alone had a 100%, 100%, 86% and 84% sensitivity for the detection of CBSD, MATI/IIID, iRMD and cRMD, respectively, but failed to detect six individuals with cRMD. To enhance sensitivity and decrease second-tier testing costs, we further adapted these decision limits using the data of 15 000 healthy newborns. Conclusions: Due to the favorable outcome of early treated patients, NBS for homocystinurias is recommended. To improve NBS, decision limits should be revised considering the population median. Relevant markers should be combined; use of the postanalytical tools offered by the CLIR project (Collaborative Laboratory Integrated Reports, which considers, for example, birth weight and gestational age) is recommended. tHcy and methylmalonic acid should be implemented as second-tier markers

Cutis laxa

Contains fulltext : 127730.pdf (publisher's version ) (Closed access)Cutis laxa is an inherited or acquired disease characterized by redundant, sagging and inelastic skin. In inherited cutis laxa an abnormal synthesis of extracellular matrix proteins occurs due to genetic defects coding for diverse extracellular matrix components. Recently, different inborn errors of metabolism have been found to be associated with cutis laxa as well. In some of these metabolic conditions the pathomechanism of cutis laxa remains unknown. Cutis laxa can be inherited in an autosomal dominant, autosomal recessive and X-linked recessive inheritance pattern. Besides the skin abnormalities, in most inherited forms multiple organ systems are involved, leading to a severe, in some forms even lethal, multisystem disorder. To date no effective treatment is available for cutis laxa. This chapter focuses on inherited forms of cutis laxa, offering a practical guideline for clinicians, biochemist and geneticist to diagnose and differentiate between the different forms of cutis laxa, and providing a concise theoretical reference

Decreased plasma L-arginine levels in organic acidurias (MMA and PA) and decreased plasma branched-chain amino acid levels in urea cycle disorders as a potential cause of growth retardation: Options for treatment

Background and aim: Patients with methylmalonic acidemia (MMA) and propionic acidemia (PA) and urea cycle disorders (UCD), treated with a protein restricted diet, are prone to growth failure. To obtain optimal growth and thereby efficacious protein incorporation, a diet containing the essential and functional amino acids for growth is necessary. Optimal growth will result in improved protein tolerance and possibly a decrease in the number of decompensations. It thus needs to be determined if amino acid deficiencies are associated with the growth retardation in these patient groups. We studied the correlations between plasma L-arginine levels, plasma branched chain amino acids (BCAA: L-isoleucine, L-leucine and L-valine) levels (amino acids known to influence growth), and height in MMA/PA and UCD patients. Methods: We analyzed data from longitudinal visits made in stable metabolic periods by patients registered at the European Registry and Network for Intoxication Type Metabolic Diseases (E-IMD, Chafea no. 2010 12 01). Results: In total, 263 MMA/PA and 311 UCD patients were included, all aged below 18 years of age. In patients with MMA and PA, height z-score was positively associated with patients' natural-protein-to-energy prescription ratio and their plasma L-valine and L-arginine levels, while negatively associated with the amount of synthetic protein prescription and their age at visit. In all UCDs combined, height z-score was positively associated with the natural-protein-to-energy prescription ratio. In those with carbamylphosphate synthetase 1 deficiency (CPS1-D), those with male ornithine transcarbamylase deficiency (OTC-D), and those in the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome subgroup, height z-score was positively associated with patients' plasma L-leucine levels. In those with argininosuccinate synthetase deficiency (ASS-D) and argininosuccinate lyase deficiency (ASL-D), height was positively associated with patients' plasma L-valine levels. Conclusion: Plasma L-arginine and L-valine levels in MMA/PA patients and plasma L-leucine and L-valine levels in UCD patients, as well as the protein-to-energy prescription ratio in both groups were positively associated with height. Optimization of these plasma amino acid levels is essential to support normal growth and increase protein tolerance in these disorders. Consequently this could improve the protein-to-energy intake ratio

Evaluation of dietary treatment and amino acid supplementation in organic acidurias and urea-cycle disorders

Collaborators :Hörster F, Matzkuhn H, Mütze U, Kowoll ME, Dressel M, Jelsig AM, de Lonlay P, Wijburg FA, Bosch A, Freisinger P, Jeltsch K, Posset R, Boy N, Mengler K, Augoustides-Savvopoulou P, Avram P, Deleanu C, Baumgartner MR, Häberle J, Blasco-Alonso J, Burlina AB, Rubert L, Cazorla AG, Saladelafont ECI, Dionisi-Vici C, Martinelli D, Dobbelaere D, Mention K, Grünewald S, Chakrapani A, Hwu WL, Chien YH, Lee NC, Karall D, Scholl-Bürgi S, Lachmann R, De Laet C, Matsumoto S, de Meirleir L, Mühlhausen C, Schiff M, Peña-Quintana L, Djordjevic M, Sarajlija A, Sykut-Cegielska J, Wisniewska A, Leao-Teles E, Alves S, Vara R, Vives-Pinera I, Ortega DG, Morris A, Zeman J, Honzik T, Chabrol B, Arnaudo F, Cano A, Thompson N, Eyskens F, Lindner M, Lüsebrink N, Jalan A, Sokal E, Legros V, Nassogne MC. INTRODUCTION: Organic acidurias (OAD) and urea-cycle disorders (UCD) are rare inherited disorders affecting amino acid and protein metabolism. As dietary practice varies widely, we assessed their long-term prescribed dietary treatment against published guideline and studied plasma amino acids levels. METHOD: We analyzed data from the first visit recorded in the European registry and network for intoxication type metabolic diseases (E-IMD, Chafea no. 2010 12 01). RESULTS: In total, 271 methylmalonic aciduria (MMA) and propionic aciduria (PA) and 361 UCD patients were included. Median natural protein prescription was consistent with the recommended daily allowance (RDA), plasma L-valine (57%) and L-isoleucine (55%) levels in MMA and PA lay below reference ranges. Plasma levels were particularly low in patients who received amino acid mixtures (AAMs-OAD) and L-isoleucine: L-leucine: L-valine (BCAA) ratio was 1.0:3.0:3.2. In UCD patients, plasma L-valine, L-isoleucine and L-leucine levels lay below reference ranges in 18%, 30% and 31%, respectively. In symptomatic UCD patients who received AAM-UCD, the median natural protein prescription lay below RDA, while their L-valine and L-isoleucine levels and plasma BCAA ratios were comparable to those in patients who did not receive AAM-UCD. Notably, in patients with ornithine transcarbamylase syndrome (OTC-D), carbamylphosphate synthetase 1 syndrome (CPS1-D) and hyperammonemia-hyperornithinemia-homocitrullinemia (HHH) syndrome selective L-citrulline supplementation resulted in higher plasma L-arginine levels than selective L-arginine supplementation. CONCLUSION: While MMA and PA patients who received AAMs-OAD had very low BCAA levels and disturbed plasma BCAA ratios, AAMs-UCD seemed to help UCD patients obtain normal BCAA levels. In patients with OTC-D, CPS1-D and HHH syndrome, selective L-citrulline seemed preferable to selective L-arginine supplementation. This article is protected by copyright. All rights reserved