Objectives Propionic acidemia (PA) is an autosomal recessive multisystem disorder caused by the deficiency of propionyl-CoA carboxylase, encoded by PCCA and PCCB genes. This retrospective study presents the clinical and laboratory characteristics of PA patients followed up in our center. Methods Included in the study were 50 patients diagnosed in a single center with propionic acidemia between 1984 and 2020, whose electronic and written hospital records regarding demographic, clinical, and laboratory features, along with diagnostic and therapeutic approaches, were reviewed retrospectively. Results This cohort had a median age at diagnosis of 18 days and 91.1 % (n=41) were born at term. Consanguinity was notably prevalent (91.1 %), and a family history of PA was reported in 14 % of cases. No significant relationships were observed between clinical and laboratory parameters and mortality. Laboratory findings at the time of diagnosis revealed significant metabolic abnormalities, including low levels of free carnitine, elevated C3 propionyl carnitine, and varied amino acid imbalances. Twenty-three patients exhibited developmental delay and/or intellectual disability. Brain magnetic resonance imaging unveiled white matter involvement and ventricular dilatation in 9/25 patients. Furthermore, dilated cardiomyopathy (26 %) was noted in patients who had cardiac assessments. Among the study cohort, 27 patients survived, 23 patients died during follow-up. No significant relationships were observed between clinical and laboratory parameters and mortality. Conclusions Despite improvements in the understanding of the pathophysiology and advances in diagnostic and treatment approaches, propionic acidemia and its long-term complications can still lead to severe consequences. This comprehensive evaluation offers valuable insights into the multifaceted nature of PA.

Objective: Despite overlapping features, these 2 groups of disorders may exhibit distinct clinical and biochemical profiles. This study aimed to evaluate and compare the clinical presentation, laboratory findings, neuroimaging characteristics, genotypic spectrum, and clinical outcomes of patients with ketogenesis and ketolysis defects. Materials and Methods: Thirty patients diagnosed between 1986 and 2023 were retrospectively reviewed. Diagnosis was confirmed by clinical findings, biochemical, and genetic/enzymatic testing. Data included demographic details, clinical manifestations, neurodevelopmental status, laboratory results, imaging findings, genetic information, and treatments. Results: Of the 30 patients, 13 (43.3%) were diagnosed with 3-hydroxy-3-methylglutaryl-CoA lyase deficiency (HMGCLD), 14 (46.7%) with 2-methylacetoacetyl-coenzyme A thiolase deficiency (MATD), and 3 (10%) with succinyl-CoA:3-ketoacid CoA transferase deficiency (SCOTD). Patients with ketolysis defects presented at a later median age (210 vs. 30 days, P < .009) and exhibited more profound metabolic acidosis (pH 7.06 ± 0.18 vs. 7.26 ± 0.12, P = .028). Common presenting symptoms included vomiting in 25 (83.3%), hypoglycemia in 9 (33.3%), and seizures in 5 (16.6%). Leigh-like neuroimaging findings were observed in 3 HMGCLD patients. Biallelic pathogenic variants in HMGCL, ACAT1, or OXCT1 were identified in 14 patients. Dialysis was required in 1 MATD and 1 SCOTD case. Excluding those lost to follow-up, the mortality rates among the remaining 18 patients were 1/8, 12.5% in 2/9 HMGCLD, and 22.2% in MATD. One of the patients with SCOTD was alive at the time of the last follow-up. Conclusion: Patients with ketolysis defects are more likely to present later and with severe metabolic acidosis, occasionally requiring renal replacement therapy. Delayed diagnosis may hinder timely intervention, potentially contributing to increased mortality.

Background: It has been reported that phenylalanine (Phe)-restricted diets may have negative effects on bone health in patients with classical phenylketonuria (cPKU). We aimed to evaluate bone mineral density (BMD) in adults with cPKU and determine the risk factors associated with low BMD. Methods: Eighty adult patients with cPKU were examined, including 41 women and 39 men. The age range was 18.3-39.4 years (median 22.8). The femoral and lumbar BMD were measured by dual energy X-ray absorptiometry. The patients were evaluated in two groups with low (Z-score <=-2) and normal BMD (Z-score > -2). Results: Low BMD was detected in 20 patients (25%). The low BMD group had significantly more males (75% vs 40%, p < 0.01) and lower mean body mass index (BMI, 22.4 vs 24.5 kg/m2, p = 0.02). Paradoxically, mean blood calcium and 25-hydroxy vitamin D levels were higher in the low BMD group, but only marginally (10.0 vs 9.8 mg/dl and 25.1 vs 21.0 g/L respectively, p < 0.05). The groups did not differ significantly with regards to age, mean Phe levels at diagnosis, median Phe levels above the age of 12 years, other nutritional parameters or vitamin-mineral supplementation. There was no history of clinical fractures. Discussion: Although osteopenia, osteoporosis and low BMD have been reported in PKU, conflicting data also exist. Our study of a large adult cPKU cohort strongly supports previously published limited data that suggest male sex and low BMI confer a higher risk for low BMD in cPKU; and age, Phe levels and dietary adherence do not. In our study, although the patients were young, low BMD was quite common (25%). Bone health should be evaluated even in young adults with cPKU, especially in males and those with low BMI, regardless of treatment compliance and vitamin-mineral status. Prospective studies reporting on clinical outcomes such as bone pain or fractures will be valuable in the coming years.

BACKGROUND:Phenylketonuria is an autosomal recessive disorder characterized by the deficiency of phenylalanine hydroxylase, which converts phenylalanine into tyrosine. Diagnosis and prompt initiation of appropriate treatment shortly after birth are important for achieving optimal outcomes in phenylketonuria. IDMP-PKU is an ongoing study to gain insight into the patient journey and identify the unmet needs and areas for improvement in diagnosis, treatment, and follow-up of PKU in Türkiye. AIM:To present the rationale and design of the IDMP-PKU study, as well as the findings from an interim analysis, describing baseline demographic, diagnosis, family history, and genetic testing data for 1553 children enrolled in the study. METHOD:This is a multicenter, observational registry-based study, conducted in 3 tertiary pediatric metabolic clinics in Türkiye. The study provides a descriptive analysis of baseline demographic, diagnosis, family history, and genetic testing data of study population. RESULTS:The study included 1,553 patients (median age: 10 (IQR 5-18) years; 37.1% classical PKU) from 90% of the cities in Türkiye, diagnosed between 1981 and 2022. Parental consanguinity was reported in 43.5% of families (27.1% first cousins). The most frequently detected allelic variant was c.1066-11G > A (IVS-10-11G > A) (22.8%). Homozygous mutations were more common in patients with parental consanguinity (76.8% vs 17.1%; p < 0.001). The median time to diagnosis improved to 21 days after the implementation of the national newborn screening (NBS) program in December 2006 but 28.6% of patients were diagnosed after one month of age. Low level of maternal education was associated with longer time to diagnosis (p < 0.001). CONCLUSIONS:Implementation of national NBS has contributed to earlier identification of patients with PKU. Increasing the number of screening laboratories and pediatric metabolic clinics will speed up the diagnostic process and help achieve the guideline-recommended time for diagnosis and initiation of treatment. In countries with high rates of consanguineous marriages, increasing public awareness of PKU and genetic counselling before marriage will be valuable in reducing the prevalence of PKU.

Objective. Phenylketonuria (PKU) is a prevalent inherited metabolic disorder, resulting from biallelic pathogenic variants in the PAH gene. This study aimed to assess the clinical characteristics of 1103 infants referred to a single center due to positive newborn screening (NBS) tests for PKU, providing insights into screening and diagnosis. Methods. The health records of infants who were referred with suspicion of PKU through the Turkish national NBS program to a single referral center between January 2016 and January 2023 were retrospectively reviewed. The study analyzed demographic data, clinical findings, and diagnostic results from hospital records. Logistic regression analysis identified significant predictors of age at admission. Results. This study highlights significant regional differences within Türkiye regarding DBS collection, result reporting, and age at admission. Significant delays in age at admission (expressed as median, [Q1-Q3]) were noted in the Eastern Anatolia (34 days [27-42]), Southeastern Anatolia [34 days (25-42)], and Black Sea regions [26 days (19-33)]. Out of the referred infants, 5.1% and 2.4% had transient tyrosinemia and transient hyperphenylalaninemia, respectively, and these transient conditions were more prevalent among neonates with a history of jaundice. Phenylalanine level was normal in 38.1% of the patients and was considered false positive. Among the 26 (2.36%) patients admitted after 90 days (late admissions), there were 2 PKU patients with untreated Phe levels >20 mg/dL (n=2). Among the 140 infants requiring treatment, 1.43% (n=2) were late admissions (>90 days). A history of PKU in the family and higher initial Phe levels were associated with earlier admissions. Conclusion. This comprehensive analysis underscores the need to enhance NBS programs, particularly in regions with identified delays. Improving healthcare infrastructure, increasing awareness, and implementing targeted health policies are crucial for timely diagnosis and treatment. Future research should address regional disparities and optimize screening protocols to improve outcomes for affected infants.

In phenylketonuria (PKU), natural protein intake is thought to increase with age, particularly during childhood and adolescence. Longitudinal dietary intake data are scarce and lifelong phenylalanine tolerance remains unknown. Nine centres managing PKU in Europe and Turkey participated in a retrospective study. Data were collected from dietetic records between 2012 and 2018 on phenylalanine (Phe), natural protein, and protein substitute intake. A total of 1323 patients (age range: 1–57 y; 51% male) participated. Dietary intake data were available on 1163 (88%) patients. Patient numbers ranged from 59 to 320 in each centre. A total of 625 (47%) had classical PKU (cPKU), n = 357 (27%) had mild PKU (mPKU), n = 325 (25%) had hyperphenylalaninemia (HPA), and n = 16 (1%) were unknown. The mean percentage of blood Phe levels within target ranged from 65 ± 54% to 88 ± 49%. When intake was expressed as g/day, the mean Phe/natural protein and protein equivalent from protein substitute gradually increased during childhood, reaching a peak in adolescence, and then remained consistent during adulthood. When intake was expressed per kg body weight (g/kg/day), there was a decline in Phe/natural protein, protein equivalent from protein substitute, and total protein with increasing age. Overall, the mean daily intake (kg/day) was as follows: Phe, 904 mg ± 761 (22 ± 23 mg/kg/day), natural protein 19 g ± 16 (0.5 g/kg/day ± 0.5), protein equivalent from protein substitute 39 g ± 22 (1.1 g/kg/day ± 0.6), and total protein 59 g ± 21 (1.7 g/kg/day ± 0.6). Natural protein tolerance was similar between males and females. Patients with mPKU tolerated around 50% less Phe/natural protein than HPA, but 50% more than cPKU. Higher intakes of natural protein were observed in Southern Europe, with a higher prevalence of HPA and mPKU compared with patients from Northern European centres. Natural protein intake doubled with sapropterin usage. In sapropterin-responsive patients, 31% no longer used protein substitutes. Close monitoring and optimisation of protein intake prescriptions are needed, along with future guidelines specifically for different age groups and severities.

Objectives: The MetabQoL 1.0 is the first disease-specific health related quality of life (HrQoL) questionnaire for patients with intoxication-type inherited metabolic disorders. Our aim was to assess the validity and reliability of the MetabQoL 1.0, and to investigate neuropsychiatric burden in our patient population. Methods: Data from 29 patients followed at a single center, aged between 8 and 18 years with the diagnosis of methylmalonic acidemia (MMA), propionic acidemia (PA) or isovaleric acidemia (IVA), and their parents were included. The Pediatric Quality of Life Inventory (PedsQoL) was used to evaluate the validity and reliability of MetabQoL 1.0.Results: The MetabQoL 1.0 was shown to be valid and reliable (Cronbach's alpha: 0.64-0.9). Fourteen out of the 22 patients (63.6%) formally evaluated had neurological findings. Of note, 17 out of 20 patients (85%) had a psychiatric disorder when evaluated formally by a child and adolescent psychiatrist. The median mental scores of the MetabQoL 1.0 proxy report were significantly higher than those of the self report (p = 0.023). Patients with neonatal-onset disease had higher MetabQoL 1.0 proxy physical (p = 0.008), mental (p = 0.042), total scores (p = 0.022); and self report social (p = 0.007) and total scores (p = 0.043) than those with later onset disease.Conclusions: This study continues to prove that the MetabQoL 1.0 is an effective tool to measure what matters in intoxication-type inherited metabolic disorders. Our results highlight the importance of clinical assessment complemented by patient reported outcomes which further expands the evaluation toolbox of inherited metabolic diseases.

Background/aim:Pompe disease (acid maltase deficiency, glycogen storage disease type II, OMIM #606800) is an autosomal recessive disorder characterized by lysosomal acid-α-glucosidase deficiency. The infantile-onset type of the disease is mainly characterized by cardiomegaly, hypotonia, and a high mortality rate. This study aimed to create a national consensus about infantile-onset Pompe disease (IOPD) to raise awareness among clinicians and standardize diagnosis and treatment approaches in Türkiye. Materials and methods:The Gazi University Division of Metabolic Diseases and Nutrition developed this expert opinion consensus and expanded it to include metabolism specialists across Türkiye. A systematic literature review was performed, and the Delphi method was used to evaluate the results. Results:Seventeen conclusive questions were produced about clinical presentation, diagnosis, and treatment, and 14 reached a consensus. Consensus was reached that general hypotonia is one of the most important findings, and agreement was also achieved on the starting dose of treatment for presymptomatic patients. The contributors agreed that gene therapy is a good treatment option for IOPD in the future. Conclusion:The topics related to this consensus will help physicians in Türkiye and elsewhere with high incidence rates of IOPD, especially regarding diagnosis and treatment decisions.

Objective: To evaluate clinical characteristics and long-term outcomes in patients with guanidinoacetate methyltransferase (GAMT) deficiency with a special emphasis on seizures and electroencephalography (EEG) findings. Methods: We retrospectively analyzed the clinical and molecular characteristics, seizure types, EEG findings, neuroimaging features, clinical severity scores, and treatment outcomes in six patients diagnosed with GAMT deficiency. Results: Median age at presentation and diagnosis were 11.5 months (8-12 months) and 63 months (18 months -11 years), respectively. Median duration of follow-up was 14 years. Global developmental delay (6/6) and seizures (5/6) were the most common symptoms. Four patients presented with febrile seizures. The age at seizure-onset ranged between 8 months and 4 years. Most common seizure types were generalized tonic seizures (n = 4) and motor seizures resulting in drop attacks (n = 3). Slow background activity (n = 5) and generalized irregular sharp and slow waves (n = 3) were the most common EEG findings. Burst-suppression and electrical status epilepticus during slow-wave sleep (ESES) pattern was present in one patient. Three of six patients had drug-resistant epilepsy. Post-treatment clinical severity scores showed improvement regarding movement disorders and epilepsy. All patients were seizure-free in the follow-up. Conclusions: Epilepsy is one of the main symptoms in GAMT deficiency with various seizure types and nonspecific EEG findings. Early diagnosis and initiation of treatment are crucial for better seizure and cognitive outcomes. This long-term follow up study highlights to include cerebral creatine deficiency syndromes in the differential diagnosis of patients with global developmental delay and epilepsy and describes the course under treatment.

Background: In 2011, a European phenylketonuria (PKU) survey reported that the blood phenylalanine (Phe) levels were well controlled in early life but deteriorated with age. Other studies have shown similar results across the globe. Different target blood Phe levels have been used throughout the years, and, in 2017, the European PKU guidelines defined new targets for blood Phe levels. This study aimed to evaluate blood Phe control in patients with PKU across Europe. Methods: nine centres managing PKU in Europe and Turkey participated. Data were collected retrospectively from medical and dietetic records between 2012 and 2018 on blood Phe levels, PKU severity, and medications. Results: A total of 1323 patients (age range:1–57, 51% male) participated. Patient numbers ranged from 59 to 320 in each centre. The most common phenotype was classical PKU (n = 625, 48%), followed by mild PKU (n = 357, 27%) and hyperphenylalaninemia (HPA) (n = 325, 25%). The mean percentage of blood Phe levels within the target range ranged from 65 ± 54% to 88 ± 49% for all centres. The percentage of Phe levels within the target range declined with increasing age (<2 years: 89%; 2–5 years: 84%; 6–12 years: 73%; 13–18 years: 85%; 19–30 years: 64%; 31–40 years: 59%; and ≥41 years: 40%). The mean blood Phe levels were significantly lower and the percentage within the target range was significantly higher (p < 0.001) in patients with HPA (290 ± 325 μmol/L; 96 ± 24%) and mild PKU (365 ± 224 μmol/L; 77 ± 36%) compared to classical PKU (458 ± 350 μmol/L, 54 ± 46%). There was no difference between males and females in the mean blood Phe levels (p = 0.939), but the percentage of Phe levels within the target range was higher in females among school-age children (6–12 years; 83% in females vs. 78% in males; p = 0.005), adolescents (13–18 years; 62% in females vs. 59% in males; p = 0.034) and adults (31–40 years; 65% in females vs. 41% in males; p < 0.001 and >41 years; 43% in females vs. 28% in males; p < 0.001). Patients treated with sapropterin (n = 222) had statistically significantly lower Phe levels compared to diet-only-treated patients (mean 391 ± 334 μmol/L; percentage within target 84 ± 39% vs. 406 ± 334 μmol/L; 73 ± 41%; p < 0.001), although a blood Phe mean difference of 15 µmol/L may not be clinically relevant. An increased frequency of blood Phe monitoring was associated with better metabolic control (p < 0.05). The mean blood Phe (% Phe levels within target) from blood Phe samples collected weekly was 271 ± 204 μmol/L, (81 ± 33%); for once every 2 weeks, it was 376 ± 262 μmol/L, (78 ± 42%); for once every 4 weeks, it was 426 ± 282 μmol/L, (71 ± 50%); and less than monthly samples, it was 534 ± 468 μmol/L, (70 ± 58%). Conclusions: Overall, blood Phe control deteriorated with age. A higher frequency of blood sampling was associated with better blood Phe control with less variability. The severity of PKU and the available treatments and resources may impact the blood Phe control achieved by each treatment centre.

Objective: Phenylketonuria is a metabolic disorder resulting from mutations in the PAH gene, causing elevated blood phenylalanine (Phe) levels which can lead to severe neurological damage if untreated. The primary treatment is a lifelong low-protein diet with amino acid substitutes and micronutrient supplements. During the COVID-19 pandemic, classical phenylketonuria (PKU) patients faced significant challenges, including restricted access to routine care like clinical visits and metabolic control monitoring. The aim of the this study was to examine the disruptions in outpatient visits, the variances in pre- and post-pandemic Phe levels, and clinical severity among patients who contracted COVID-19. Material and Methods: Starting from the pandemic date of March 11, 2020, demographic data, laboratory characteristics, and details about COVID-19 infection were retrospectively reviewed for classical PKU patients with accessible electronic records from March 2018 to March 2022. Results: When the median blood Phe levels before and after the pandemic were compared, a significant difference was found. We observed that adult patients diagnosed with classical PKU often defaulted on their follow-up appointments. Conclusion: The COVID-19 pandemic significantly disrupted the follow-up and management of classical PKU patients. However, no severe COVID-19 cases were reported among this population, suggesting they did not face an increased risk from the infection. This study emphasizes the critical need to develop robust strategies for patient engagement and follow-up, especially for adult classical PKU patients who are at risk of discontinuing routine care.

Background: Old age, obesity, and certain chronic conditions are among the risk factors for severe COVID-19. More information is needed on whether inherited metabolic disorders (IMD) confer risk of more severe COVID-19. We aimed to establish COVID-19 severity and associated risk factors in patients with IMD currently followed at a single metabolic center.Methods: Among all IMD patients followed at a single metabolic referral center who had at least one clinic visit since 2018, those with accessible medical records were reviewed for SARS-CoV-2 tests. COVID-19 severity was classified according to the WHO recommendations, and IMD as per the international classification of IMD.Results: Among the 1841 patients with IMD, 248 (13.5%) had tested positive for COVID-19, 223 of whom gave consent for inclusion in the study (131 children and 92 adults). Phenylalanine hydroxylase (48.4%) and biotini-dase (12.1%) deficiencies were the most common diagnoses, followed by mucopolysaccharidoses (7.2%). 38.1% had comorbidities, such as neurologic disabilities (22%) or obesity (9.4%). The majority of COVID-19 episodes were asymptomatic (16.1%) or mild (77.6%), but 6 patients (2.7%) each had moderate and severe COVID-19, and two (0.9%) had critical COVID-19, both of whom died. 3 patients had an acute metabolic decompensation during the infection. Two children developed multisystem inflammatory syndrome (MIS-C). Long COVID symp-toms were present in 25.2%. Presence of comorbidities was significantly associated with more severe COVID-19 in adults with IMD (p < 0.01), but not in children (p = 0.45). Compared to other categories of IMD, complex mol-ecule degradation disorders were significantly associated with more severe COVID-19 in children (p < 0.01); such a significant IMD category distinction was not found in adults.Discussion: This is the largest study on COVID-19 in IMD patients relying on real-word data and objective defini-tions, and not on merely expert opinions or physician surveys. COVID-19 severity and long COVID incidence in IMD are probably similar to the general population, and the risk of acute metabolic decompensation is not likely to be greater than that in other acute infections. Disease category (complex molecule degradation) in children, and comorbidities in adults may be associated with COVID-19 severity in IMD. Additionally, the first documented accounts of COVID-19 in 27 different IMD are recorded. The high occurrence of MIS-C may be coincidental, but warrants further study.(c) 2023 Elsevier Inc. All rights reserved.

Multiple acyl-coenzyme A dehydrogenase deficiency (MADD) is of special interest because the late-onset myopathic form of the disease is often dramatically riboflavin-responsive (RR). After our group's recent publication including 19 patients with RR-MADD, we continued to encounter late-diagnosed patients and aimed to describe the characteristics of the recent patients we diagnosed with RR-MADD. Patients diagnosed with RR-MADD since January 2019 were included. Clinical, laboratory and molecular genetic characteristics were evaluated retrospectively from hospital records. Three patients at the ages of 12 (P1, M), 13 (P2, F) and 16 (P3, F) years were diagnosed during the study period. The age at onset was 9-14 years. All had vomiting, fatigue, myalgia, proximal muscle weakness (with predominant involvement of neck extensors) and weight loss, but the main presenting complaints were diverse (vomiting, neck pain, and headache). Swallowing (P2) and breathing (P2, P3) difficulties were also present. Peak serum creatine kinase (CK) levels (359-1932 U/L; N≤ 145 U/L) were above the normal range, but P1 occasionally had normal CK. P1 also had hyperammonemia and significant lactic acidosis, but lactic acidosis was mild-moderate in P2 and P3. Urinary organic acid analysis revealed significant elevations of glutaric acid, 2-hydroxyglutaric acid, ethylmalonic acid, dicarboxylic acids and acylglycine derivatives and acylcarnitine profiling from dried blood spots showed elevated long-chain acylcarnitines in all patients, and medium-chain acylcarnitines in one. Treatment only with riboflavin (300 mg/d) and coenzyme Q10 (200 mg/d) resulted in complete resolution of symptoms in all patients within 2-7 days. Sequencing of ETFDH gene revealed homozygosity of the founder variant c.1130T>C (p.Leu377Pro) in P1 and P2, but was non-diagnostic in P3, for whom whole exome sequencing for the investigation of other MADD genes is underway. There is an overlap of these new patients with our previously reported RR-MADD cohort. Diverse, systemic and non-specific presentations, obscurity of myopathy are the key challenges defining diagnostic delay. Metabolic work-up of this treatable myopathy should be considered for preventing life-threatening complications and significant morbidity. Multiple acyl-coenzyme A dehydrogenase deficiency (MADD) is of special interest because the late-onset myopathic form of the disease is often dramatically riboflavin-responsive (RR). After our group's recent publication including 19 patients with RR-MADD, we continued to encounter late-diagnosed patients and aimed to describe the characteristics of the recent patients we diagnosed with RR-MADD. Patients diagnosed with RR-MADD since January 2019 were included. Clinical, laboratory and molecular genetic characteristics were evaluated retrospectively from hospital records. Three patients at the ages of 12 (P1, M), 13 (P2, F) and 16 (P3, F) years were diagnosed during the study period. The age at onset was 9-14 years. All had vomiting, fatigue, myalgia, proximal muscle weakness (with predominant involvement of neck extensors) and weight loss, but the main presenting complaints were diverse (vomiting, neck pain, and headache). Swallowing (P2) and breathing (P2, P3) difficulties were also present. Peak serum creatine kinase (CK) levels (359-1932 U/L; N≤ 145 U/L) were above the normal range, but P1 occasionally had normal CK. P1 also had hyperammonemia and significant lactic acidosis, but lactic acidosis was mild-moderate in P2 and P3. Urinary organic acid analysis revealed significant elevations of glutaric acid, 2-hydroxyglutaric acid, ethylmalonic acid, dicarboxylic acids and acylglycine derivatives and acylcarnitine profiling from dried blood spots showed elevated long-chain acylcarnitines in all patients, and medium-chain acylcarnitines in one. Treatment only with riboflavin (300 mg/d) and coenzyme Q10 (200 mg/d) resulted in complete resolution of symptoms in all patients within 2-7 days. Sequencing of ETFDH gene revealed homozygosity of the founder variant c.1130T>C (p.Leu377Pro) in P1 and P2, but was non-diagnostic in P3, for whom whole exome sequencing for the investigation of other MADD genes is underway. There is an overlap of these new patients with our previously reported RR-MADD cohort. Diverse, systemic and non-specific presentations, obscurity of myopathy are the key challenges defining diagnostic delay. Metabolic work-up of this treatable myopathy should be considered for preventing life-threatening complications and significant morbidity.

Metabolic myopathies are among the treatable causes of rhabdomyolysis and myoglobinuria. Carnitine palmitoyl transferase 2 (CPT II) deficiency is one of the most common causes of recurrent myoglobinuria in adults. It is an inherited disorder of fatty acid oxidation pathway, commonly associated with elevated acylcarnitine levels. In this case report, we present a 49-year-old male patient who developed acute kidney injury after rhabdomyolysis and was thus diagnosed with CPT2 deficiency after his first episode of rhabdomyolysis. Inborn errors of metabolism should be kept in mind in patients with rhabdomyolysis. Acylcarnitine profile may be normal in CPT II deficiency, even during an acute attack, and molecular genetic diagnostics should be applied if there is high index of clinical suspicion.

Background: Phenylalanine (Phe)-restricted diet is associated with lower quality of life for patients with phenylketonuria (PKU), and a concern for caregivers of recently-diagnosed infants. Sapropterin is an oral drug used as an alternative or adjunct to dietary treatment. We have observed that some of the young infants initially managed successfully with sapropterin monotherapy have required dietary treatment in long-term follow-up. We aimed to determine the baseline factors associated with future initiation of dietary treatment in these patients.Methods: Data were obtained retrospectively from the medical records of 80 PKU patients started on sapropterin monotherapy before 3 months of age between 2011 and 2021.Results: The patients were followed for a median of 3.9 years (Q1-Q3: 2.5-5.75 years). Sapropterin was tapered down and discontinued in 5 patients (6.3%) as their Phe levels remained below 360 mu mol/L without treatment. Sapropterin monotherapy was sufficient in 62 patients (77.5%), while 13 (16.2%) required dietary treatment. Phe and tyrosine (Tyr) levels, and Phe:Tyr ratios differed significantly among the patients maintained on sapropterin monotherapy and those started on dietary treatment, but the Phe:Tyr ratio at diagnosis was the most important independent baseline variable (OR: 1.61, 95% CI: 1.15-2.27, p = 0.006), with Phe:Tyr ratio at diagnosis >5.25 associated with dietary treatment (sensitivity: 90.0%, specificity: 81.8%). Genotypic phenotype value (GPV), unavailable at baseline, was also associated with dietary treatment (median GPV 9.2 vs. 3.8, p = 0.006), but some genotypes were not specific to the final treatment modality.Discussion: We propose that the Phe:Tyr ratio at diagnosis is an important indicator to predict dietary requirement in young infants initially managed with sapropterin monotherapy.

Abstract Objectives Neonatal-onset organic acidemias (OAs) account for 80% of neonatal intensive care unit (NICU) admissions due to inborn errors of metabolism. The aim of this study is to analyze clinical features and follow-up of neonates diagnosed with OAs in a metabolic referral center, focusing on perinatal characteristics and the impact of first the metabolic crisis on long-term outcome. Methods Perinatal features, clinical and laboratory characteristics on admission and follow-up of 108 neonates diagnosed with OAs were retrospectively analyzed. Global developmental delay, abnormal electroencephalogram (EEG) or brain magnetic resonance imaging (MRI), chronic complications, and overall mortality. Associations between clinical findings on admission and outcome measures were evaluated. Results Most prevalent OA was maple syrup urine disease (MSUD) (34.3%). Neonates with methylmalonic acidemia (MMA) had significantly lower birth weight (p<0.001). Metabolic acidosis with increased anion gap was more frequent in MMA and propionic acidemia (PA) (p=0.003). 89.1% of OAs were admitted for recurrent metabolic crisis. 46% had chronic non-neurologic complications; 19.3% of MMA had chronic kidney disease. Abnormal findings were present in 26/34 of EEG, 19/29 of MRI studies, and 32/33 of developmental screening tests. Metabolic acidosis on admission was associated with increased incidence of abnormal EEG (p=0.005) and overall mortality (p<0.001). Severe hyperammonemia in MMA was associated with overall mortality (33.3%) (p=0.047). Patients diagnosed between 2007–2017 had lower overall mortality compared to earlier years (p<0.001). Conclusions Metabolic acidosis and hyperammonemia are emerging predictors of poor outcome and mortality. Based on a large number of infants from a single center, survival in neonatal-onset OA has increased over the course of 30 years, but long-term complications and neurodevelopmental results remain similar. While prompt onset of more effective treatment may improve survival, newer treatment modalities are urgently needed for prevention and treatment of chronic complications.

The authors declare no conflict of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.

Tyrosinemia type III is an extremely rare autosomal recessive disease, with only 19 patients yet reported. It is caused by a deficiency of the 4-hydroxyphenylpyruvate dioxygenase enzyme, resulting from biallelic mutations in the HPD gene. Although the clinical spectrum of the disease is not fully known, most patients present with neurodevelopmental symptoms. We report on a 20-month-old patient who was investigated due to developmental delay and dysmorphic features. The girl had a novel splice-site mutation in the HPD gene and ventriculomegaly in cranial imaging, which was not previously associated with tyrosinemia type III. Our patient had mild subjective improvement in social skills and language development after dietary therapy was started and her tyrosine levels decreased. We also summarize clinical, biochemical, and genetic findings of previously published patients with biallelic HPD mutations.

To the Editor: We read the recent society position paper by Squires et al (1) on pediatric acute liver failure (ALF) with great interest and were delighted to see the comprehensive discussion of inherited metabolic disorders; however, we are concerned that their recommendation of “L-carnitine administration enterally or intravenously at a dose of 100 mg kg–1 day–1” during acute decompensations of fatty acid oxidation disorders (FAOD) (1), referring to the 2005 editorial by Alonso (2), is outdated, and may be potentially harmful for some patients with FAOD. FAOD are autosomal recessive disorders caused by defects in the carnitine cycle or the mitochondrial fatty acid b-oxidation pathway. L-Carnitine replacement at 100 mgkg−1 day−1, and even higher doses is indicated and unequivocally effective in systemic primary carnitine deficiency, which can present with hypoketotic hypoglycemia, hyper-ammonemia, hepatomegaly, and ALF in infants, or with dilated cardiomyopathy and muscle weakness later in life (3). Although other FAOD have similar clinical manifestations, the biochemical signatures and treatment approaches differ significantly. Long-chain acylcarnitines (>14 carbon atoms) are cardio-toxins with arrhythmogenic and negative inotropic potential (4). Deficiencies of carnitine:acylcarnitine translocase (CACT), carnitine palmitoyltransferase II (CPT2), very long-chain acyl-CoA dehydrogenase (VLCAD), long-chain hydroxyacyl-CoA dehydrogenase (LCHAD), electron transport flavoprotein (ETF) and ETF:u-biquinone oxidoreductase are the FAOD that cause elevations of long-chain fatty acids and long-chain acylcarnitines (5). Supplemented l-carnitine can bind these fatty acids to form more long-chain acylcarnitines, further increasing the potential cardiotoxicity. In fact, a 2009 consensus statement on long-chain fatty acid oxidation defects not only points out that there is no evidence supporting the benefit of L-carnitine in the long-term treatment of these disorders, but also refers to the potential for adverse effects, and recommends that supplementation should be avoided at times of acute metabolic derangement (6), to which ALF would be an apt example. A recent evidence- and consensus-based guideline on VLCAD deficiency reiterates this concern, stating that l-carnitine supplementation at a low dose (10–25 mgkg–1 day–1) may be considered if the patient is well and free carnitine concentration is <10 μmol/L (7). Although we do recognize that these statements are still controversial and partly based on expert opinion, a general recommendation for L-carnitine supplementation at a dose of 100 mgkg–1 day–1 could bear significant harm without much benefit for patients with long-chain FAOD. We would advise a more individualized approach and a much lower dose (if any), based on free carnitine levels and the subtype ofFAOD. Ifpatients withlong-chain FAOD are receiving L-carnitine supplementation, cardiac monitoring and close follow-up of free carnitine and long-chain acylcarnitine levels are warranted. Consultation to biochemical geneticists or metabolic pediatricians could also help in the management of individuals with these intricate and multifaceted disorders.

Objective: Phosphomannomutase 2 deficiency (PMM2-CDG) is a disorder of protein N-glycosylation with a wide clinical spectrum. Hypoglycemia is rarely reported in PMM2-CDG. In this study, we evaluated cause, treatment options and outcomes in cases with hypoglycemia in the course of PMM2-CDG. Methods: Clinical records of patients followed with PMM2-CDG within the last two decades were reviewed. Medical data of patients with hypoglycemia were evaluated in more detail. Demographic and clinical findings, organ involvement and laboratory investigations at time of hypoglycemia were recorded. Time of first attack of hypoglycemia, cause, treatment modalities, duration of hypoglycemia (permanent/transient), and duration of treatment, as well as outcome were also recorded. Other published cases with PMM2-CDG and hypoglycemia are also reviewed in order to elucidate characteristics as well as pathophysiology of hypoglycemia. Results: Nine patients with PMM2-CDG were reviewed, and hypoglycemia was present in three cases. All three had hyperinsulinism as the cause of hypoglycemia. In the first two cases reported here, serum insulin level concurrent with hypoglycemic episodes was elevated, and glucose response was exaggerated during glucagon test, favoring hyperinsulinism. However, in the third case, the serum insulin level at time of hypoglycemia was not so high but hypoglycemia responded well to diazoxide. Hyperinsulinism was permanent in two of these three cases. No genotype-phenotype correlation was observed with respect to hyperinsulinism. Conclusion: The main cause of hypoglycemia in PMM2-CDG appears to be hyperinsulinism. Although insulin levels at the time of hypoglycemia may not be very high, hypoglycemia in patients with PMM2 responds well to diazoxide.