Background/Objectives: Glycogen storage disease type IX (GSD IX) is a group of inherited metabolic disorders caused by phosphorylase kinase deficiency affecting the liver or muscle. Despite being relatively common among GSDs, GSD IX remains underexplored. Methods: A systematic review of GSD IX was conducted per PRISMA guidelines using SCOPUS and PubMed, registered with PROSPERO. Inclusion focused on human clinical studies published up to 31 December 2024. Results: A total of 400 patients with GSD IX were analyzed: 274 IXa (mean age at diagnosis 5.1 years), 72 IXc (mean age at diagnosis 4.9 years), 39 IXb (mean age at diagnosis 4.2 years), and 15 IXd (mean age at diagnosis 44.9 years). Hepatomegaly was commonly reported in types IXa, IXb, and especially IXc (91.7%), but was rare in IXd. Elevated transaminases were frequently observed in types IXa, IXb, and particularly IXc, while uncommon in IXd. Fasting hypoglycemia was occasionally observed in types IXa and IXb, more frequently in IXc (52.7%), and was not reported in IXd. Growth delay or short stature was observed in a substantial proportion of patients with types IXa (43.8%), IXb, and IXc, but was rare in IXd. Muscle involvement was prominent in IXd, with all patients showing elevated CPK (mean 1011 U/L). Neurological involvement was infrequently reported in types IXa and IXc. Conclusions: This systematic review includes the most extensive clinical case history of GSD IX described in the literature. The clinical spectrum of GSD IX varies widely among subtypes, with IXc being the most aggressive. While liver forms are generally present in early childhood, muscle-type IXd shows delayed onset and milder symptoms, often leading to diagnostic delays. For diagnosis, it is essential not to underestimate key clinical features such as hepatic involvement and hypoglycemia in a child under 5 years of age. Other manifestations, including the as-yet unexplored systemic involvement of bone and kidney, remain insufficiently understood and require further investigation. Next-generation sequencing has improved diagnostic precision over traditional biopsy. Dietary management, including uncooked cornstarch, Glycosade^®, and high-protein intake, remains the cornerstone of treatment. However, there is a paucity of well-designed, evidence-based studies to determine the most effective therapeutic approach. Despite its historically perceived benign course, the broad phenotypic variability of GSD IX, including progressive liver involvement and potential neurological complications, highlights its substantial clinical relevance and underscores the need for accurate diagnostic classification and long-term multidisciplinary follow-up.

Background: Expanded Newborn Screening (ENS) allows the early identification of many inherited metabolic diseases (IMDs) for which timely treatment can modify the natural history. For most IMDs, diagnosis by ENS is pre-clinical. However, clinical symptoms may emerge for certain conditions before screening results become available. Methods: We describe six cases of patients with early-onset IMDs born between 2013 and 2023, who were admitted or transferred to Sant’Orsola University Hospital in Bologna (Italy). Results: Over the study period, 379,013 newborns underwent ENS in the Italian region of Emilia-Romagna. Excluding cases of congenital hypothyroidism, pre-clinical diagnoses from ENS were 410. In addition, six cases of IMD presented with early-onset clinical symptomatology, an antecedent to the outcome of newborn screening (incidence over 11 years of 1.58 cases per 100,000 infants). Among these patients, three were diagnosed with Urea Cycle Disorders (UCDs)—two with Citrullinemia type I (CIT1) and one with Argininosuccinic Acidemia (ASA); two were diagnosed with Methylmalonic Acidemia (MMA); and one was found to have Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCADD). Conclusions: Our 11-year experience with ENS has shown that clinical onset can occur between the second and fourth day of life, though rare. Even if dried blood spot (DBS) collection was performed 24–48 h after birth, the time required for sample transportation and processing would still delay result availability, making early intervention unlikely. Therefore, our experience supports performing ENS at 48–72 h, as currently implemented in Italy, while also highlighting the advantages and limitations of earlier screening.

Background/Objectives: Biotinidase deficiency (BD) is a treatable autosomal recessive disorder included in many newborn screening (NBS) programs. The importance of early diagnosis and treatment is now well established. However, recent studies are emerging on the possibility of increased enzyme activity with age, an observation that raises questions about the long-term validity of the initial classification of these patients. This study aimed to assess the incidence, genetic and clinical features, and, notably, the longitudinal enzymatic trajectory of BD in a cohort identified by NBS in Emilia-Romagna, Italy, with implications for diagnostic re-evaluation and therapeutic decisions. Methods: A retrospective and prospective analysis was conducted on 64 infants recalled after NBS for suspected BD between 2016 and 2020. Biochemical, molecular, and clinical data were collected, and biotinidase (BTD) activity was monitored longitudinally. Affected individuals were supplemented with biotin and followed clinically for at least 5 years. Results: Thirty-one patients were diagnosed with BD (30 partial, 1 profound; incidence 1:5448). A significant and sustained increase in BTD activity was observed from diagnosis through early childhood (p < 0.001 up to 60 months), particularly among patients carrying the p.Asp444His variant. This enzymatic trend suggests a potential remodulation of biochemical classification over time. Genotype–phenotype concordance was high (92%), and clinical outcomes were favorable across the cohort. Conclusions: This study provides new evidence that BTD activity in patients with BD increases progressively, supporting the concept of age-dependent enzyme recovery. Our results support the need for systematic re-evaluation of diagnosis and treatment, especially at 12 months of age, and particularly in patients with evidence of partial activity deficiency and the p.Asp444His mutation.

Background: At the onset of Type 1 Diabetes (T1D), international guidelines recommend initiating subcutaneous insulin therapy within a wide dosage range (0.5–1 IU/kg/day), as insulin requirement (IR) varies greatly based on several factors, including age, pubertal status, and the presence of diabetic ketoacidosis (DKA). In clinical practice, some individuals require higher-than-expected IR, leading to prolonged hospitalization. This study aimed to identify predictive factors for elevated IR at T1D onset. Methods: We conducted a retrospective observational study including 218 children and adolescents diagnosed with T1D between January 2010 and September 2020. Clinical and laboratory parameters were collected. IR was defined as the highest daily subcutaneous insulin dose (IU/kg/day) during hospitalization, after resolution of DKA. Results: As expected, DKA severity and HbA1c levels were associated with increased IR. However, the strongest independent predictor in the multivariate model was serum triglyceride level (β = 0.27, p < 0.001), with an adjusted R² of 0.37. No evidence of multicollinearity was detected, and ROC analysis yielded an AUC of approximately 0.70. Conclusions: Hypertriglyceridemia at T1D onset is independently associated with higher IR, regardless of DKA severity. Early recognition of this marker could help optimize insulin dosing, improve metabolic stabilization, and potentially shorten hospital stays.

Background/Objectives: Glycogen storage disease type IX (GSD IX) is an inherited metabolic disorder characterized by marked clinical heterogeneity and variable severity. Dietary therapy is considered the cornerstone of management, but evidence on treatment strategies, efficacy, and safety remains limited. This study aimed to systematically synthesize available data on therapeutic approaches and clinical outcomes in GSD IX. Methods: A focused analysis of treatment-related data was conducted from a previously performed PRISMA-based systematic review. Clinical studies reporting treatment and follow-up data in genetically confirmed GSD IX patients were included. Results: Among 400 patients identified in the original review, 129 from 26 studies had treatment and follow-up data available. Dietary management combined with uncooked cornstarch (UCCS) was the most common approach (96.1%), with highly heterogeneous protocols. Hepatic manifestations improved in 59/129 (45.7%) of patients, and hypoglycemia in 45/129 (34.9%). Growth outcomes were variable, with catch-up growth in 14.0% and persistent impairment in 19.4%, although data were often missing. Muscle involvement was rarely assessed. No treatment-related adverse events were reported. However, disease-related complications were described, including liver cirrhosis, neurological involvement, osteopenia/osteoporosis, and two deaths in GSD IXa patients. Conclusions: Dietary therapy combined with UCCS remains the mainstay of treatment in GSD IX and is associated with improvement in key clinical domains. However, evidence is limited, heterogeneous, and largely based on small studies. Data on modified cornstarch formulations, such as Glycosade^®, are scarce. Prospective studies and standardized treatment protocols are needed to support evidence-based management.