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Background: Maternal phenylketonuria (mPKU) is a pathologic condition occurring in the fetus of a mother with PKU that is caused by prolonged elevated intrauterine blood phenylalanine (Phe) levels, which can lead to congenital abnormalities and mental retardation of newborns. Management of PKU during pregnancy can be challenging as protein substitutes may exacerbate nausea, vomiting, and gastrointestinal symptoms. Aim: To report the successful management of four PKU pregnant women. Methods: The patients were administered with prolonged-release amino acid supplementation and were recommended to follow a strict diet. Blood Phe concentration, adherence to diet, and occurrence of adverse events were monitored. Results: All patients achieved safe levels of blood Phe concentration (120-360 µmol/L) since preconception and during pregnancy (mean Phe concentration values of 143.34 ± 137.59, 226.48 ± 194.57, 186.68 ± 133.67, and 187.47 ± 42.59 µmol/L). During the first trimester of pregnancy, all patients manifested gastrointestinal symptoms such as nausea, gastrointestinal reflux, and abdominal bloating, which were managed by either changing protein substitute or extending the time window between different meals and amino acid mixtures administration. The four women continued their pregnancies without experiencing further complications and delivered neonates with normal growth parameters and no malformations. Conclusion: Findings of this case series suggest that the intake of a prolonged-release amino acid mixture in granules is well tolerated by pregnant PKU patients, eventually leading to good metabolic control and fetal growth within normal ranges., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Fabry Disease (FD) (OMIM 301500) is a metabolic X-linked inherited lysosomal storage disorder that results from the deficient activity of Alpha-Galactosidase A (Alpha-Gal), a lysosomal hydrolase that cleaves neutral glycosphingolipids with terminal N-linked galactosyl moieties, mainly globotriaosylceramides (Gb3). The enzyme, encoded by a 12-kb gene mapping on the long arm (Xq22.1 region) of the X chromosome, is constituted by a glycosylated subunit of approximately 55 kD, synthesized as an inactive precursor that undergoes maturation in endoplasmic reticulum (ER) and Golgi apparatus before being delivered to the lysosome to form a functional dimer. The gene is comprised of seven exons and, so far, >1000 different mutations have been described as associated to FD (www.dbfgp.org/dbFgp/fabry/FabryGP.htm). Clinical phenotypes are divided in two main classes, classic or non-classic, based on clinical and biochemical findings. Non-classic FD, usually recognized as late-onset forms with oligosymptomatic phenotype, presents with symptoms restricted solely to cardiocytes, kidneys or brain associated to missense misfolding mutations. In the group of the non-classic FD, special attention should be given to patients carrying the c.376A > G (p.Ser126Gly) mutation. The lack of clear experimental evidences on its pathogenetic role, despite the clinical pictures of the patients with severe ischaemic lesions, renal involvement and acroparesthesias, led many authors to classify this mutation as inconsistent, non-pathogenetic, and consequently not eligible to the current pharmacological treatments for FD. To shed light on the cellular processes affected by this mutation and to assess if the biochemical pathways involved with, could really have a significant pathogenetic impact, we studied the mutation in silico and in COS-7 and HEK 293 cell models. We found p.Ser126Gly, even retaining both high degree of synthesis and residual activity, is mostly stacked into the ER inducing unfolded protein response (UPR) with reduced trafficking to the lysosome. These data strongly suggest that p.Ser126Gly could trigger a pathogenetic mechanism different from the classic and well assessed increased turnover with loss of biological activity described for other missense mutations. This mechanism seems mainly related to a negative gain of function, with ER retention and UPR activation and could lead, via inflammation and/or apoptosis, to irreversible cell damage., Competing Interests: Declaration of Competing Interest This work was supported by a grant from Amicus Therapeutics, United States (to Prof Daniela Concolino). The funding source had no involvement in the research here presented at any stage., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Mucolipidosis II and III are lysosomal storage diseases caused by pathogenetic mutations in GNPTAB and GNPTG genes which cause an impaired activity of the lysosomal hydrolase N-acetylglucosamine- 1-phosphotransferase, a key enzyme in the synthesis of the mannose-6-phosphate targeting signals on lysosomal enzymes. Patients with MLII alpha/beta present coarse facial features, cessation of statural growth, important skeletal manifestations, impaired neuromotor development and cardiorespiratory involvement. All children appear to have cardiac involvement, but severe dilated cardiomyopathy is uncommon. In this report we describe the case of an 11-month-old girl who is affected by a MLII. Analysis of the GNPTAB gene identified at a heterozygous level the previously described gene variants c. 2693delA p(Lys898Serfs*13) and c. 2956C>T p(Arg986Cys). Her main clinical features were coarse face with gingival hypertrophy, dysostosis multiplex, recurrent respiratory infection and an early onset of dilated cardiomyopathy, an uncommon feature for MLII. To our knowledge, dilated cardiomyopathy has been previously described in literature in only two cases of MLII and in one patient affected by MLIII., (Copyright 2020 Biolife Sas. www.biolifesas.org.)

Lysosomal storage diseases (LSDs) include a heterogeneous group of rare, inborn, metabolic diseases characterized by deficiency of lysosomal enzymes or of other proteins involved in lysosomal function, leading to multi organ system substrates accumulation, with consequent multi systemic clinical presentation. Cardiac disease is particularly important in some group of LSDs as glycogen storage diseases (Pompe), mucopolysaccharidoses and in glycosphingolipidoses (Anderson-Fabry disease and less frequently Gaucher disease). Various cardiac manifestations may be observed including hypertrophic and dilated cardiomyopathy, coronary artery disease and valvular disease. The availability of enzyme replacement therapy (ERT) has changed the natural history of some LSDs such as Pompe disease, thanks to the significant effects on cardiological involvement. In other LSDs such as MPSs or Fabry disease, ERT has been shown to stabilize or slow the progression of heart damage. This imposes the need for a timely diagnosis that allows a rapid onset of ERT., (Copyright 2020 Biolife Sas. www.biolifesas.org.)

Mucopolysaccharidosis type II or Hunter syndrome is an X-linked lysosomal storage disease caused by a mutation in the gene encoding the lysosomal enzyme iduronate-2-sulfatase. The consequent enzyme deficiency causes a progressive, multisystem accumulation of glycosaminoglycans, which is the cause of the clinical manifestations involving also Central Nervous System for patients with the severe form of disease. The limits of the currently available therapies for Hunter syndrome, hematopoietic stem cell transplantation and recombinant enzyme replacement therapy, mainly regarding brain achievement, have encouraged several studies which recognized gene therapy as a potential therapeutic option for this condition. In vitro studies firstly aimed at the demonstration that viral vector- mediated IDS gene expression could lead to high levels of enzyme activity in transduced cells. The encouraging results obtained allowed the realization of many preclinical studies investigating the utilization of gene therapy vectors in animal models of Mucopolysaccharidosis II, together with a phase I clinical trial approved for Hunter patients affected by the mild form of the disease. Together to in vivo studies in which recombinant vectors are directly administered, systematically or by direct injection into Central Nervous System, also ex vivo gene therapy, consisting in transplantation of autologous hematopoietic stem cells, modified in vitro, into the animal or patient, has been tested. A wider clinical application of the results obtained so far is essential to ensure that gene therapy can be definitively validated as a therapeutic option available and usable for this rare but life-threatening disorder., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

The Norrbottnian type of Gaucher disease (GD), as described many years ago, is due to a unique neuronopathic variant (c.1448T>G; L444P) that may have appeared during or before the sixteenth century in northern Sweden. It is a well-defined nosological entity with a characteristic course of clinical manifestations. In particular, Norrbottnian patients described in Sweden and Poland seem to share identical clinical histories characterized by the early onset of significant hepatosplenomegaly, often requiring splenectomy at an early age. Neurological involvement generally appears during the first or second decade of life, and includes horizontal gaze palsy, epilepsy, myoclonic movements, ataxia, dementia and cognitive impairment. Osteopenia occurs primarily in the spine, causing a severe and progressive thoracic kyphosis, although the involvement of other skeletal sites cannot be excluded. Here, we report on four Gaucher type 3 patients with Southern Italian ancestry presenting with clinical features and disease progression comparable to those of the 'Norrbottnian' Swedish phenotype, particularly regarding skeletal involvement with poor responsiveness to any therapeutical approach. Although a common ancestry among Southern Italian and Swedish Norrbottnian GD patients could not be investigated, the genotype [L444P]+[L444P] is the most frequently encountered in Southern Italy.

Background: The variants of neuronopathic Gaucher disease may be viewed as a clinical phenotypic continuum divided into acute and chronic forms. The chronic neuronopathic form of Gaucher disease is characterized by a later onset of neurological symptoms and protracted neurological and visceral involvement. The first-choice treatment for nonneuronopathic Gaucher disease is enzyme replacement therapy with recombinant analogues of the deficient human enzyme glucocerebrosidase. Enzyme replacement therapy has been shown to improve hematological and bone manifestations associated with Gaucher disease, but, as with most proteins, recombinant enzymes cannot cross the blood-brain barrier, which prevents effects on neurological manifestations. Substrate reduction therapy with miglustat (N-butyldeoxynojirimycin) inhibits glucosylceramide synthase, which catalyzes the first step in glycosphingolipid synthesis. Because miglustat can cross the blood-brain barrier, it has been suggested that, combined with enzyme replacement therapy, it might be effective in treating neurological symptoms in patients with neuronopathic Gaucher disease., Case Presentation: We report observed effects of combined enzyme replacement therapy and substrate reduction therapy in a 7-year-old Caucasian boy with neuronopathic Gaucher disease who was homozygous for L444P mutations. He had received enzyme replacement therapy from the age of 18 months, and concomitant miglustat treatment was commenced, with dosing according to body surface area uptitrated over 1 month with dietary modifications when he reached the age of 30 months. He experienced mild diarrhea after commencing miglustat therapy, which decreased in frequency/severity over time. His splenomegaly was reduced, and his hematological values and plasma angiotensin-converting enzyme activity normalized. Plasma chitotriosidase also showed substantial and sustained decreases. After 5 years of combination therapy, the patient showed no signs of neurological impairment., Conclusions: This case supports the concept that oral miglustat in combination with intravenous enzyme replacement therapy may be beneficial in preventing neurological signs in patients with chronic neuronopathic Gaucher disease. The importance of dietary modifications has also been confirmed. Further follow-up studies are needed to better define the therapeutic effect of combined treatment in this Gaucher disease subtype.

Background: Osteopetrosis is a rare genetic disorder characterized by increased bone density due to a defective osteoclast's bone resorption. Three clinical forms can be identified based on severity, age of onset and inheritance: the dominant benign form (ADO), the intermediate form (IRO) and the recessive severe form (ARO). Several genes have been involved in the pathogenesis of these different types of osteopetrosis. Many experimental evidences point out on a specific role for CLCN7, the gene encoding the chloride channel protein subunit alfa and for TCIRG1, the gene encoding an osteoclast specific subunit of the vacuolar proton pump. Mutations in CLCN7 gene have been associated to the complete spectrum of osteopetrosis ranging from ARO to IRO and even to ADO type II. On the other hand, mutations in TCIRG1 gene account for more than 50% of cases of ARO. It is then evident that the malignant osteopetrosis is characterized by a great molecular and clinical heterogeneity often making the final diagnosis difficult to achieve., Methods: We performed a complete clinical, biochemical and molecular analysis by PCR and direct sequencing, of a novel case of osteopetrosis with inconsistent clinical phenotype., Results: The patient, who cannot be ascribed to any of the ADO, ARO or IRO groups, carried two novel mutations in compound heterozygosis in the CLCN7 gene. The first was the missense mutation c. 948C > T on exon 10 that produces an Arg to Cys change, while the second was the IVS11 + 5G > A splicing mutation that resides on the donor splice site of intron 11 and distrupts the canonical splice site., Conclusion: Our data a) Demonstrate that the unusual clinical presentation observed in our patient with a mild clinical onset evolving towards a more serious clinical picture, is associated to two novel mutations on CLCN7 gene. b) Support the already described clinical and molecular heterogeneity of the malignant osteopetrosis c) Suggest that, performing a molecular diagnosis of osteopetrosis with inconsistent clinical presentation these two novel mutations have to be first considered.

We report a new case of 8q interstitial duplication in a patient with dysmorphic features, umbilical hernia, cryptorchidism, short stature, congenital heart defect and mild mental retardation (MR). Chromosome analysis with high resolution QFQ bands showed 46,XY, 8q+, which was interpreted as a partial duplication of the distal long arm of chromosome 8 (q22 → qter). This chromosomal aberration was further characterized using fluorescence in situ hybridization (FISH) analyses with multiple DNA probes and array-CGH (Comparative Genomic Hybridization) experiment which demonstrated a de novo direct duplication (8)(q22.2-q24.3). We have compared this case with other partially trisomic 8q patients reported in literature and highlighted the common clinical features in 8q22-8q24 duplication syndrome., (Published by Elsevier Masson SAS.)

Background: The co-existence of two genetically distinct metabolic disorders in the same patient has rarely been reported. Phenylketonuria (PKU) is an inborn error of the metabolism resulting from a phenylalanine hydroxylase deficiency. Fabry disease (FD) is an X-linked lysosomal storage disorder due to a deficiency of the enzyme alpha-galactosidase A., Case Presentation: We report a case of a 3 year- old boy affected by classic PKU and FD, both confirmed by molecular data. The FD was suspected at the age of 21 months on the presence of non-specific GI symptoms (severe abdominal pain and periodically appearance of not specific episodes of gastroenteritis) apparently non related to PKU., Conclusion: This is the first report of co-existence of FD and PKU, two different congenital inborn of metabolism and in consideration of the prevalence of each disease this chance association is a very unusual event. The co-existence of this diseases made very difficult the correct interpretation of clinical symptoms as lack of appetite, severe abdominal pain and non-specific gastroenteritis episodes. Furthermore, this case report helps to define the early clinical phenotype of FD.

Deficiency of dihydropteridine reductase causes a variant form of phenylketonuria associated with a devastating neurological disease characterized by mental retardation, hypokinesis and other features relating to basal ganglia disorder. Hyperphenylalaninaemias with tetrahydrobiopterin deficiency make up about 1-3% of all hyperphenylalaninaemias. We describe three patients from Calabria, a southern region of Italy, who have a dihydropteridine reductase deficiency, caused by the same mutation (p.L14P) also found in the nearby region of Sicily. We report the evolution of clinical and biochemical data during the treatment of these patients where we used prolactin serum determination to adapt the specific therapy. This report suggests that serum prolactin levels can be a good biomarker for optimal dosage of hydroxylated precursors in long-term treatment monitoring.

We report a female patient with a 46,XX,der(8)t(1;8)(q42.1;p23.3) karyotype who had a mild phenotype characterised by a few subtle dysmorphic features and mild developmental retardation, probably resulting from trisomy 1q42-->qter. The deletion on the short arm of the chromosome 8 appeared to be confined to the distal chromosomal segment.