Genetic etiology and clinical challenges of phenylketonuria.

This review discusses the epidemiology, pathophysiology, genetic etiology, and management of phenylketonuria (PKU). PKU, an autosomal recessive disease, is an inborn error of phenylalanine (Phe) metabolism caused by pathogenic variants in the phenylalanine hydroxylase (PAH) gene. The prevalence of PKU varies widely among ethnicities and geographic regions, affecting approximately 1 in 24,000 individuals worldwide. Deficiency in the PAH enzyme or, in rare cases, the cofactor tetrahydrobiopterin results in high blood Phe concentrations, causing brain dysfunction. Untreated PKU, also known as PAH deficiency, results in severe and irreversible intellectual disability, epilepsy, behavioral disorders, and clinical features such as acquired microcephaly, seizures, psychological signs, and generalized hypopigmentation of skin (including hair and eyes). Severe phenotypes are classic PKU, and less severe forms of PAH deficiency are moderate PKU, mild PKU, mild hyperphenylalaninaemia (HPA), or benign HPA. Early diagnosis and intervention must start shortly after birth to prevent major cognitive and neurological effects. Dietary treatment, including natural protein restriction and Phe-free supplements, must be used to maintain blood Phe concentrations of 120-360 µmol/L throughout the life span. Additional treatments include the casein glycomacropeptide (GMP), which contains very limited aromatic amino acids and may improve immunological function, and large neutral amino acid (LNAA) supplementation to prevent plasma Phe transport into the brain. The synthetic BH4 analog, sapropterin hydrochloride (i.e., Kuvan®, BioMarin), is another potential treatment that activates residual PAH, thus decreasing Phe concentrations in the blood of PKU patients. Moreover, daily subcutaneous injection of pegylated Phe ammonia-lyase (i.e., pegvaliase; PALYNZIQ®, BioMarin) has promised gene therapy in recent clinical trials, and mRNA approaches are also being studied.

Pain Management in Breast Cancer Patients: A Multidisciplinary Approach.

Pain is a significant problem and is one of the most invalidating symptoms in breast cancer (BC) patients that would negatively affect the functional status and the Quality of Life (QoL). Pain management in BC patients requires thorough patient evaluation and critical assessment of pain. The actual cause for the pain must be recognized, so management can be tailored to each patient. This review aims to discuss various treatment modalities employed for effectively managing pain in BC patients. Pharmacotherapy makes up the cornerstone of the management of pain in BC patients. Both opioid and non-opioid analgesics are utilized. The WHO recommends a method called "by the ladder" for managing pain in BC patients where analgesics are used in ascending order. In comprehensive pain management (CPM), non-pharmacologic therapies are gaining wide acceptance and popularity, including complementary and alternative medicine (CAM), procedural and psychosocial interventions. Procedural interventions are usually used in case of severe pain refractory to pharmacological therapy. Techniques, such as radiotherapy, neurectomy, and nerve blocks, are effective in managing cancer pain. However, CAM therapies in BC pain management need to be guided by enough scientific evidence, decision-making, and medical judgment of regulatory bodies. BC pain management is based on careful routine pain assessments and appropriate patient evaluation both physically and psychologically. Pain control is one of the methods to improve the QoL of BC patients. Both pharmacological and non-pharmacological therapies are accessible to patients today, but they should be used with caution to minimize toxicity and increase effectiveness. The use of any pain management intervention should be based on proper scientific evidence and collective medical judgment.