Congenital hyperinsulinism of a large Italian cohort: a retrospective study.

INTRODUCTION: To evaluate and describe the diagnostic process, medical, nutritional and surgical approach, and neurological outcome, we report data from a large Italian cohort of patients with Congenital hyperinsulinism (CHI). METHODS: We retrospectively analyzed 154 CHI patients admitted to Ospedale Pediatrico Bambino Gesù from 1985 to 2022. RESULTS: Hypoglycemia occurred within the first year of life in 85.5% of patients, median time to diagnosis was 1 day (IQR 14 days). Ninety-two percent of patients were treated with diazoxide, 66.9% were responsive. Octreotide was administered to 28.6% of patients, 61.4% were responsive. Forty percent of patients were off-therapy, mostly from diazoxide. Thirty-four percent of patients carried mutations in ABCC8, 12.6% were syndromic, and 9.2% were transient CHI. Surgery was performed in 23/47 diazoxide-unresponsive and 2/95 diazoxide-responsive patients: 64.0% were focal at histology. Combining data from genetics, pancreatic venous sampling, 18F-DOPA PET/CT and histology, 80.6% resulted diffuse, 16.7% focal, and 2.8% atypical CHI. Post-surgical diabetes developed in 6 patients. Neurocognitive evaluation revealed developmental delay or intellectual disability in 15.7% of 70 patients, mostly of a mild degree. Epilepsy was documented in 13.7% of 139 patients. CONCLUSION: Our diagnostic and therapeutic results are mainly consistent with the international indications and the CHI Global Registry data, with relatively low rates of neurological outcomes. Good outcomes were likely associated with early diagnosis and prompt management of patients because the majority of patients were diagnosed within 2 weeks. Remarkably, it is of utmost importance to spread the knowledge and refer CHI patients to multidisciplinary expert centers.

Availability of psychological resources for parents receiving communication of positivity at newborn screening for metabolic diseases in Italy.

Receiving information in the case of a positive or false-positive expanded newborn screening (ENBS) result for metabolic diseases is a stressful event. The availability of psychological support to families is crucial across the different communication steps and is recommended by different guidelines and position papers. However, more information is needed about the availability of psychological resources in the ENBS process. This national survey aimed to provide an overview of the availability of psychological resources for parents who received communication of positivity at the ENBS in the 23 Italian centers and how the support is provided to parents. An online survey was sent to the Heads of the ENBS centers asking about the availability of a clinical psychologist, their involvement in the ENBS process, and an estimation of parents receiving psychological support. More than 60% of the centers report having a clinical psychologist in the ENBS team; however, in more than 50% of cases, the psychologist does not participate in the consultation with parents (nor for the first consultation post-positivity or at confirmation of diagnosis). Furthermore, nearly 60% of the centers reported the experience of parental rejection of psychological sessions.  Conclusion: There is a need for harmonization among the Italian ENBS centers concerning the availability of psychological resources and how these resources are provided to families. Parents' needs remained only partially fulfilled. What is Known: • Receiving communication of positivity at the ENBS can be highly stressful for parents and requires adequate psychological support. • The guidelines recommend psychological support for parents during the ENBS process. What is New: • Only 14/23 (60.9%) of Italian ENBS centers have a clinical psychologist within the team. • In half of the consultations with parents receiving communication of positivity, the clinical psychologist is never involved.

The impact of liver transplantation on health-related quality of life in (acute) intoxication-type inborn errors of metabolism.

Organic acidurias (OAs), urea-cycle disorders (UCDs), and maple syrup urine disease (MSUD) belong to the category of intoxication-type inborn errors of metabolism (IT-IEM). Liver transplantation (LTx) is increasingly utilized in IT-IEM. However, its impact has been mainly focused on clinical outcome measures and rarely on health-related quality of life (HRQoL). Aim of the study was to investigate the impact of LTx on HrQoL in IT-IEMs. This single center prospective study involved 32 patients (15 OA, 11 UCD, 6 MSUD; median age at LTx 3.0 years, range 0.8-26.0). HRQoL was assessed pre/post transplantation by PedsQL-General Module 4.0 and by MetabQoL 1.0, a specifically designed tool for IT-IEM. PedsQL highlighted significant post-LTx improvements in total and physical functioning in both patients' and parents' scores. According to age at transplantation (≤3 vs. >3 years), younger patients showed higher post-LTx scores on Physical (p = 0.03), Social (p < 0.001), and Total (p =0.007) functioning. MetabQoL confirmed significant post-LTx changes in Total and Physical functioning in both patients and parents scores (p ≤ 0.009). Differently from PedsQL, MetabQoL Mental (patients p = 0.013, parents p = 0.03) and Social scores (patients p = 0.02, parents p = 0.012) were significantly higher post-LTx. Significant improvements (p = 0.001-0.04) were also detected both in self- and proxy-reports for almost all MetabQoL subscales. This study shows the importance of assessing the impact of transplantation on HrQoL, a meaningful outcome reflecting patients' wellbeing. LTx is associated with significant improvements of HrQol in both self- and parent-reports. The comparison between PedsQL-GM and MetabQoL highlighted that MetabQoL demonstrated higher sensitivity in the assessment of disease-specific domains than the generic PedsQL tool.

Neurologic outcome following liver transplantation for methylmalonic aciduria.

Liver and liver/kidney transplantation are increasingly used in methylmalonic aciduria, but little is known on their impact on CNS. The effect of transplantation on neurological outcome was prospectively assessed in six patients pre- and post-transplant by clinical evaluation and by measuring disease biomarkers in plasma and CSF, in combination with psychometric tests and brain MRI studies. Primary (methylmalonic- and methylcitric acid) and secondary biomarkers (glycine and glutamine) significantly improved in plasma, while they remained unchanged in CSF. Differently, biomarkers of mitochondrial dysfunction (lactate, alanine, and related ratios) significantly decreased in CSF. Neurocognitive evaluation documented significant higher post-transplant developmental/cognitive scores and maturation of executive functions corresponding to improvement of brain atrophy, cortical thickness, and white matter maturation indexes at MRI. Three patients presented post-transplantation reversible neurological events, which were differentiated, by means of biochemical and neuroradiological evaluations, into calcineurin inhibitor-induced neurotoxicity and metabolic stroke-like episode. Our study shows that transplantation has a beneficial impact on neurological outcome in methylmalonic aciduria. Early transplantation is recommended due to the high risk of long-term complications, high disease burden, and low quality of life.

Expert opinion of an Italian working group on the assessment of cognitive, psychological, and neurological outcomes in pediatric, adolescent, and adult patients with phenylketonuria.

Phenylketonuria (PKU) is an inherited metabolic disease characterized by a defective conversion of phenylalanine (Phe) to tyrosine, potentially leading to Phe accumulation in the brain. Dietary restriction since birth has led to normal cognitive development. However, PKU patients can still develop cognitive or behavioral abnormalities and subtle neurological deficits. Despite the increasing evidence in the field, the assessment of neurocognitive, psychopathological, and neurological follow-up of PKU patients at different ages is still debated. The high interindividual variability in the cognitive outcome of PKU patients makes the specificity of the neurocognitive and behavioral assessment extremely challenging. In the present paper, a multidisciplinary panel of Italian PKU experts discussed different tools available for cognitive, psychopathological, and neurological assessment at different ages based on the existing literature and daily clinical practice. This study aims to provide evidence and a real-life-based framework for a specific clinical assessment of pediatric, adolescent, and adult patients affected by PKU.

Ketogenic diet as elective treatment in patients with drug-unresponsive hyperinsulinemic hypoglycemia caused by glucokinase mutations.

BACKGROUND: Hyperinsulinemic hypoglycemia (HI) is the most frequent cause of recurrent hypoglycemia in children. Despite diagnostic and therapeutic advances, it remains an important cause of morbidity, leading to neurological complications, such as psychomotor retardation and epilepsy. Patients with diffuse drug-unresponsive HI manifest neurological impairment and neurobehavioral problems, even though surgically treated with a near-total pancreatectomy. Based on the analogies between HI and GLUT1 deficiency, both presenting with neuroglycopenia and lack of alternative cerebral energy sources, we administered a ketogenic diet (KD) in three drug-unresponsive GCK-HI patients with the aim of preserving neurodevelopment and avoiding the need of a near-total pancreatectomy. They presented recurrent symptomatic hypoglycemia, intellectual disability and refractory epilepsy. Patients were treated with classical KD for 79, 27 and 18 months, respectively. RESULTS: All patients became asymptomatic in a few days and showed an important improvement of the alert state. Epilepsy disappeared and no appearance of novel hypoglycemic lesions was detected with a brain MRI. Cognitive and adaptive abilities rapidly improved and normalized. IQ rose significantly from 81 to 111 (p = 0.04) in patient 1, from 82 vs 95 (p = 0.04) in patient 2, from 60 to 90 (p = 0.04) in patient 3. CONCLUSIONS: We demonstrated the safety and efficacy of KD in the treatment of drug-unresponsive GCK-HI at a short and long-term. The neuroprotective effects of KD determined the recovery from epilepsy and intellectual disabilities and averted the need of a near-total pancreatectomy. All patients and their families reported an improvement of physical and psychosocial well-being, with a substantial improvement of their quality of life. These results might change the course and the quality of life of these patients and their families, having a relevant impact on human lives. Therefore, KD might be considered the elective treatment in unresponsive forms of GCK-HI.

Ketogenic diet in a patient with congenital hyperinsulinism: a novel approach to prevent brain damage.

BACKGROUND: Congenital hyperinsulinism (CHI) is the most frequent cause of hypoglycemia in children. In addition to increased peripheral glucose utilization, dysregulated insulin secretion induces profound hypoglycemia and neuroglycopenia by inhibiting glycogenolysis, gluconeogenesis and lipolysis. This results in the shortage of all cerebral energy substrates (glucose, lactate and ketones), and can lead to severe neurological sequelae. Patients with CHI unresponsive to medical treatment can be subjected to near-total pancreatectomy with increased risk of secondary diabetes. Ketogenic diet (KD), by reproducing a fasting-like condition in which body fuel mainly derives from beta-oxidation, is intended to provide alternative cerebral substrates such ketone bodies. We took advantage of known protective effect of KD on neuronal damage associated with GLUT1 deficiency, a disorder of impaired glucose transport across the blood-brain barrier, and administered KD in a patient with drug-unresponsive CHI, with the aim of providing to neurons an energy source alternative to glucose. METHODS: A child with drug-resistant, long-standing CHI caused by a spontaneous GCK activating mutation (p.Val455Met) suffered from epilepsy and showed neurodevelopmental abnormalities. After attempting various therapeutic regimes without success, near-total pancreatectomy was suggested to parents, who asked for other options. Therefore, we proposed KD in combination with insulin-suppressing drugs. RESULTS: We administered KD for 2 years. Soon after the first six months, the patient was free of epileptic crises, presented normalization of EEG, and showed a marked recover in psychological development and quality of life. CONCLUSIONS: KD could represent an effective treatment to support brain function in selected cases of CHI.

Long term follow-up to evaluate the efficacy of miglustat treatment in Italian patients with Niemann-Pick disease type C.

BACKGROUND: Twenty-five patients with Niemann Pick disease type C (age range: 7 months to 44 years) were enrolled in an Italian independent multicenter trial and treated with miglustat for periods from 48 to 96 months. METHODS: Based on the age at onset of neurological manifestations patients' phenotypes were classified as: adult (n = 6), juvenile (n = 9), late infantile (n = 6), early infantile (n = 2). Two patients had an exclusively visceral phenotype. We clinically evaluated patients' neurological involvement, giving a score of severity ranging from 0 (best) to 3 (worst) for gait abnormalities, dystonia, dysmetria, dysarthria, and developmental delay/cognitive impairment, and from 0 to 4 for dysphagia. We calculated a mean composite severity score transforming the original scores proportionally to range from 0 to 1 to summarize the clinical picture of patients and monitor their clinical course. RESULTS: We compared the results after 24 months of treatment in 23 patients showing neurological manifestations. Stabilization or improvement of all parameters was observed in the majority of patients. With the exception of developmental delay/cognitive impairment, these results persisted after 48-96 months in 41 - 55% of the patients (dystonia: 55%, dysarthria: 50%, gait abnormalities: 43%, dysmetria: 41%, respectively). After 24 months of therapy the majority of the evaluable patients (n = 20), demonstrated a stabilization or improvement in the ability to swallow four substances of different consistency (water: 65%, purée: 58%, little pasta: 60%, biscuit: 55%). These results persisted after 48-96 months in 40-50% of patients, with the exception of water swallowing. Stabilization or improvement of the composite severity score was detected in the majority (57%) of 7 patients who were treated early (within 3.5 years from onset) and rarely in patients who received treatment later. CONCLUSIONS: The results of this study suggest that miglustat treatment can improve or stabilize neurological manifestations, at least for a period of time; the severity of clinical conditions at the beginning of treatment can influence the rate of disease progression. This conclusion applies particularly to patients with juvenile or adult onset of the disease. TRIAL REGISTRATION: EudraCT number 2006-005842-35.

Cognitive findings and behavior in children and adolescents with phenylketonuria.

OBJECTIVE: The primary aim of this study was to assess cognitive development, in particular that of executive functions (EFs), and behavioral findings for patients with early treated phenylketonuria (PKU). Furthermore, we evaluated the relationships of our findings with plasma levels of Phe and adherence to dietary prescriptions. METHODS: A cross-sectional design was adopted. Patients who had early treated PKU, who were older than 4 years, and who were regularly seen by a physician were enrolled in the study. Cognitive development was assessed with Wechsler Scales appropriate to the chronological age of subjects in the study. Executive functions were assessed using the Tower of London test, and behavioral findings were quantified with the Child Behavior Checklist. RESULTS: Thirty-five patients were enrolled (mean age 11.5 years, SD ± 6.2). The mean Full Scale intelligence quotient was in the normal range (93.4 ± 17.4), without significant difference between the verbal intelligence quotient (mean, 94.3 ± 16.1) and performance intelligence quotient (mean, 93.9 ± 18.0). The majority of patients showed a deficit within the EF domain of cognitive abilities (mean lower than 1.8 SD of the normal mean), 8 of them showing a score <2 SD lower than the normal mean. Internalizing problems were also observed in 12 patients (38.7%) and were higher in adherent patients and in patients with a lower intelligence quotient. CONCLUSION: After early diagnosis and treatment of PKU, residual problems can be found in EFs of patients not achieving satisfactory Phe levels, while scores of internalizing behaviors were higher in compliant patients.