Based on experiences from everyday clinical practice and indications from the literature, the menstrual cycle might impact on metabolic stability in patients with urea cycle disorders and organic acidurias. However, this connection has not yet been systematically investigated.Phenylketonuria (PKU) as the most prevalent inborn error of metabolism with its easily determinable biomarker is a suitable model disease to shed light on this question. In ten patients with classic PKU on a low protein diet and on an amino acid mixture, phenylalanine (Phe) was measured from dried blood spots twice a week for 6 months. During this time, the patients documented their menstrual cycle and filled in nutrition protocols since it is known that the menstrual cycle also influences nutritional behavior. Based on this cohort, we found a significant correlation between the phases of the menstrual cycle and Phe concentration, with the lowest concentrations in the early luteal phase and the highest in the early follicular phase, during menstrual bleeding. This effect did not appear to be due to a change in eating behavior, as both protein and calorie intake were not significantly different in relation to the menstrual cycle. Since the increase in Phe began before menstrual bleeding, it does also not appear to be a pure effect of catabolism due to bleeding. Further studies will be required to identify the cause of this effect and to develop possible therapeutic strategies.

Newborn screening is an essential public health strategy that aims to detect a range of conditions, including inborn errors of metabolism, in neonates shortly after birth. The timely identification is crucial due to the asymptomatic nature of many conditions at birth, but which can lead to significant health complications if left untreated. Through this study, we aimed to investigate the incidence of IEMs screened by the Qatar National Newborn Screening Program. We retrospectively analyzed a total of 351,223 newborns screened from 2010 to 2023. The incidence for the studied IEMs was calculated and correlated with demographics, consanguinity, and family history. In addition, the diagnostic yield of different tests utilized was assessed. Our study revealed a total of 318 positive cases with IEMs, and a significantly high incidence of 1:1105 for IEMs in Qatar. Classical Homocystinuria was the most frequently detected condition, with a cumulative incidence of 1:6754 live births, linked to the founder variant p. Arg336Cys in the CBS gene. Aminoacidopathies were the most prevalent category, followed by fatty acid oxidation disorders, organic acidurias, biotinidase deficiency, and urea cycle disorders. Genetic testing showed a high diagnostic yield of 90%. Of the 60 cases that underwent targeted variant testing, 98% were confirmed, while 90% of the 59 cases tested by single gene testing were confirmed. Our study provides the incidence rates of IEMs in Qatar and novel insights that could facilitate setting up/developing IEM incidence-reducing strategies and improving outcomes for affected newborns and their families.

L-2-hydroxyglutaric aciduria (L2HGA) is a hereditary metabolic disorder characterized by the accumulation of L-2-hydroxyglutaric acid in body fluids, particularly in cerebrospinal fluid, which disrupts neuron function in the central nervous system and triggers oxidative stress. It can cause seizures, developmental disorders, and behavioral abnormalities. The study retrospectively evaluated the demographic information, initial symptoms, clinical characteristics, cranial magnetic resonance imaging (MRI) findings, and post-treatment biochemical changes of 10 cases diagnosed with L2HGA. The study included five paediatric and five adult cases with a molecular diagnosis of L2HGA. The mean age at diagnosis was 10.1 years. Convulsion was identified as the primary presenting symptom in 70 % of cases. We identified intellectual disability in 80 % of our cases. In addition to the classic cranial MRI findings of subcortical white matter involvement, basal ganglia involvement was detected in 60 % of cases. We found that 2-hydroxyglutaric acid levels in urine organic acid analysis were significantly decreased riboflavin and carnitine post-treatment, with a mean decrease of 133.89 ± 101.43 mmol/mol creatinine (p=0.017). The most common missense variant identified in the L2HGDH gene was c.905C>T (p.Pro302Leu), occurring at a frequency of 50 % (5/10). The cases did not report significant improvement in their symptoms with treatment. L2HGA is a rare metabolic disorder that is more common in communities where consanguineous marriages are prevalent. Early diagnosis enables early treatment and protection of the brain from oxidative stress. As more cases are reported publicly, studies on genotype-phenotype relationships will yield more significant findings.

Inherited metabolic diseases (IMDs) represent a major clinical challenge, especially during the neonatal and infant periods. They require tailored and long-term nutritional management to ensure proper growth and development. Protein substitutes are essential in the dietary treatment of IMDs, particularly aminoacidopathies, organic acidemias, and urea cycle disorders. In Italy, a variety of PSs is available for infants with IMDs requiring a controlled protein and/or amino acid intake; however, differences in their nutritional composition may impact clinical outcomes. This study aims to examine and compare the nutritional composition of infant PSs (IPSs) available on the Italian market, focusing on macronutrients, micronutrients, and functional components. The analysis targets products used in the dietary management of aminoacidopathies, organic acidemias, and urea cycle disorders during the first year of life. We compared the nutritional composition of products intended for healthy infants, considering the Commission Delegated Regulation (EU) 2016/127 and Commission Delegated Regulation (EU) 2016/128. Phenylketonuria is excluded from this analysis, as it has been recently addressed in another paper. For each condition, there are only two products available, except for isovaleric aciduria and urea cycle disorders, which have only one product. The results indicate higher energy, linoleic, and alpha-linolenic acid content (+9%, +55%, and +290% compared to the maximum reference value), and lower levels of lactose, vitamin D, choline, selenium, and iodine (-92%, -34%, -37%, -12%, and -39% compared to the minimum reference value) for several IPSs. The analysis revealed the presence of docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) in all IPSs, while half of them contain arachidonic acid (ARA). This study represents the first comprehensive comparison of the nutritional profiles of IPSs for IMDs on the Italian market. The results identify potential areas for optimization, aiming to provide adequate levels of micronutrients, essential fatty acids, and functional ingredients, such as biotics, to support gut health, immune function, and neurodevelopment.

Inborn errors of metabolism (IEMs) are traditionally the domain of pediatricians and internists for metabolic diseases. In general, neurologists only become involved when these disorders are complicated by neurologic symptoms such as seizures, developmental delay, or motor problems. However, in recent years and mainly due to the successes of next-generation sequencing, the number of IEMs primarily presenting with neurologic symptoms and not detected by classic biochemical testing has grown significantly. This in particular relates to disorders in the biosynthesis of amino acids. Therefore, I will start by discussing defects in the synthesis pathways of the amino acids serine, glutamine, proline, and asparagine. In these disorders, the amino acid can be low in body fluids with biochemical testing, but more frequently are completely normal and although are in different metabolic pathways, they share many clinical features such as hypomyelination and white matter abnormalities. Next, I will discuss classic amino acid disorders and organic acid disorders due to defects in breakdown pathways characterized by elevations of key metabolites in body fluids and associated with neurologic abnormalities and white matter changes on MRI. Individuals with clinical manifestations of isovaleric acidemia (IVA) have either classic IVA identified on newborn screening or classic IVA with a later diagnosis due to a missed diagnosis or later onset of clinical manifestations. Classic IVA is characterized by acute metabolic decompensations (vomiting, poor feeding, lethargy, hypotonia, seizures, and a distinct odor of sweaty feet). Acute metabolic decompensations are typically triggered by fasting, (febrile) illness (especially gastroenteritis), or increased protein intake. Clinical deterioration often occurs within hours to days after birth. Additional manifestations of classic IVA include developmental delay, intellectual disability and/or impaired cognition, epilepsy, and movement disorder (tremor, dysmetria, extrapyramidal movements). Early treatment in those identified by newborn screening can significantly reduce morbidity and mortality in individuals with classic IVA. The diagnosis of classic IVA is established in a proband by identification of C5-carnitine metabolites by tandem mass spectrometry and isovalerylglycine (IVG) and 3-hydroxyisovaleric acid (3-HIVA) on analysis of urinary organic acids by gas chromatography-mass spectrometry, or identification of biallelic pathogenic variants in IVD by molecular genetic testing. Targeted therapy: Low-leucine/protein-reduced diet and the supplementation of a leucine-free formula in infants or leucine-free amino acid mixture in older children; carnitine and/or glycine supplementation. Supportive care: Routine daily treatment includes education of affected individuals and caregivers about the natural history, maintenance and emergency treatment, prognosis, and risks of acute encephalopathic crises; emergency treatment letter and MedicAlert®; management of movement disorder per neurologist; physical therapy and aggressive rehabilitation therapy for gross motor delay; notify metabolic center prior to planned surgeries; consult metabolic disease specialist with any emergency surgery/procedure. Emergency outpatient treatment includes carbohydrate supplementation orally or via tube feeding, transient reduction of natural protein intake, elevation of carnitine supplementation, and glycine; antipyretics for fever; antiemetics for vomiting. Acute inpatient treatment includes stopping protein intake, intravenous glucose, and hydration with normal saline; adjusting treatments for new or evolving neurologic manifestations; consider buffers as needed for life-threatening metabolic acidosis; nitrogen scavengers for hyperammonemia. Surveillance: Quantitative analysis of plasma amino acids at least every three months until age one year, every six months from age one to six years, and annually in those age six years and older; blood gases, albumin, calcium, phosphate, parathyroid hormone, complete blood count, and vitamin B12 at least annually in those on a protein-restricted diet; measurement of growth and head circumference at each visit throughout childhood; monitor weight throughout adulthood; monitor developmental milestones at each visit; neuropsychological testing and standardized quality-of-life assessments as needed; assessment of movement disorder at each visit. Agents/circumstances to avoid: Excess of dietary protein or protein malnutrition inducing catabolic state; prolonged fasting; catabolism during illness. Evaluation of relatives at risk: Biochemical or molecular genetic testing of all at-risk sibs of any age is warranted to allow for early diagnosis and treatment of classic IVA. Classic IVA is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an IVD pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the IVD pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.