Francesca Menni

Background and ObjectivesEnzyme replacement therapy has not only significantly improved motor outcome and survival in patients with classic infantile Pompe disease, but also revealed previously unr...

Background Neurodevelopmental disorders, hypotonia, microcephaly or macrocephaly, poor growth and distinctive facial traits are some of the most common reasons to refer a child to an expert consultant. But which expert? A priori response might not be always predictable. Clinical experience teaches that it is not unusual to come across a metabolic diagnosis in a patient suspected of a genetic condition and vice versa. Still, although phenotypically convergent, genetic and metabolic disorders strongly diverge on therapeutic availability. In such an entangled scenario, new sequencing technologies may bring to light further uncertainties, detecting variants that often need a clinical confirm to be interpreted. Methods. In order to explore clinical convergence among metabolic and genetic disorders we present a cases’ collection of patients wrongly referred to metabolic disorder clinic or to medical genetic service in a third level Center in the North of Italy. Results. Data gained from this retrospective review demonstrate the striking importance of multi-disciplinary management of complex pediatric cases. Conclusions. In Hub Hospitals and in rare diseases’ Centers, it appears mandatory to promote a side by side collaboration embracing pediatricians, clinical geneticists and laboratory in order to take an all-around point of view of undiagnosed patients. What falls out of our competence might fall out of our view as well.

Background: Newborn screening (NBS) is a preventive healthcare program aiming at identifying the inborn errors of metabolism (IEMs) in asymptomatic infants to reduce the risk of severe complications. The aim of this study was to report the first years (2016–2020) of the expanded NBS program in the Lombardy region, Italy. Methods: Dried blood spots were collected from newborns’ heels at 48–72 h after birth. FIA-MS/MS was performed to evaluate specific biochemical markers. Genetic confirmation was achieved via Sanger or NGS on newborns and reported to a clinical reference center (CRC). Results: A total of 343,507 newborns were tested; 1414/343,507 resulted as positive to NBS and were reported to the CRC. A total of 209 newborns were diagnosed with IEMs: 206 infants received a diagnosis of IEM through NBS, confirmed by genetic analysis; three neonates were not positive to NBS but were subsequentially diagnosed with IEMs. A total of 1208/343,507 were false positive cases. Twenty-seven types of IEMs were diagnosed in 209 patients: 111 newborns were affected by aminoacidemias, 11 by urea cycle disorders, 27 by organic acidemias, 34 by fatty acid oxidation disorders, and 26 by secondary conditions. Conclusions: We report here for the first time the IEM incidence and distribution in the Lombardy region in the first five years of NBS.

Background: Receiving communication of positivity for metabolic diseases at Expanded Newborn Screening can be extremely stressful for parents, both in case of false positive and true positive cases. However, little is known about the predictors of distress and differential impact on mothers and fathers.Methods: In this longitudinal study, 169 fathers and 171 mothers referred to one of the Italian metabolic centres for communication of positivity completed a survey including General Health Questionnaire-12, Emotion Thermometers (measuring stress, anxiety, depression, anger and need for help), Impact of Event Scale–Revised, Multidimensional Scale of Perceived Social Support and Emotion Regulation Questionnaire. Perceived severity and control of the children’s health were also assessed. The survey was completed in person after the first session at metabolic centres and online after 1, 3 and 6 months.Results: Nearly 80% of parents reported a clinical level of distress and anxiety after the communication of positivity, one-third of them reported post-traumatic symptoms and more than half of parents reported a need for help. After 6 months, there are still more than 30% of parents with a clinical level of distress and anxiety, 6% with post-traumatic symptoms and more than 20% who continue to express a need for help. No gender difference was reported and no differences emerged between pre-COVID-19 and post-COVID-19 periods for parental distress and post-traumatic symptoms.Social support, perceived severity and control of the child’s health—but not gender or previous parental experience—predicted the post-traumatic symptoms at baseline while at 6 months the only significant predictor was perceived severity.Conclusion: Adequate psychological support should be provided from the initial communication for both parents and for true positive, false positive and variants of uncertain significance/heterozygous carrier cases.

Background/Objective: Lysosomal storage diseases (LSDs) are a group of rare, inborn, metabolic errors characterized by deficiencies in normal lysosomal function and by the intralysosomal accumulation of undegraded substrates, resulting in the damage of multiple organ systems. The spectrum of clinical manifestations is extremely heterogeneous. LSD diagnosis and management still present many issues. Methods: A group of Italian experts and patients’ representatives met to discuss some critical aspects, and among the most impactful are early diagnosis, the transition of the patient from pediatric to adult age, territorial management, and the multidisciplinary approach. Results: Possible solutions to diagnostic delays may be a widespread newborn screening and screening programs on selected populations. The lack of a structured transition process could be helped by the drafting of shared diagnostic and therapeutic care pathways beyond the availability of databases accessible to the different levels that manage a patient. Territorial management could benefit from telemedicine, but a homogeneous diffusion of home therapy, not yet everywhere possible, is essential. A fundamental role is played by the patient associations, which should be increasingly involved in the political choices. It is also crucial to create structured multidisciplinary teams of experts for disease management and comorbidities. A transversal need appears to be greater training on LSDs. In Italy, the “Statement of Udine” was developed to guide further steps towards improvements in inherited metabolic medicine in adults, referencing the experience from the United Kingdom. Conclusions: Much can be done for the early diagnosis and management of LSDs with an effective treatment, but many aspects need improvement for the overall management of the patient. An investment in dedicated resources, formal recognition, and training is needed to address these unmet needs.

Idiopathic intracranial hypertension (IIH), also known as pseudotumour cerebri syndrome (PTCS), is characterized by the presence of signs and symptoms of raised intracranial pressure without evidence of any intracranial structural cause and with normal cerebrospinal fluid microscopy and biochemistry. Obesity, various systemic diseases and endocrine conditions, and a number of medications are known to be risk factors for PTCS. The medications commonly associated with PTCS are amiodarone, antibiotics, corticosteroids, cyclosporine, growth hormone, oral contraceptives, vitamin A analogues, lithium, phenytoin, NSAIDs, leuprolide acetate, and some neuroleptic drugs. In relation to antibiotics, quinolones may cause intracranial hypertension, and most reported cases of quinolone-induced intracranial hypertension were associated with nalidixic acid, ciprofloxacin, ofloxacin, or pefloxacin. Literature reports of levofloxacin-induced PTCS are rare. Some authors recently hypothesized that Mycoplasma pneumoniae may trigger PTCS. We report on a 14-year-old overweight White Italian boy who suffered headache, diplopia, and severe bilateral papilloedema after a Mycoplasma pneumoniae infection, exacerbated on levofloxacin intake. A spontaneous improvement in headache and a reduction in diplopia was seen during hospitalisation. Oral acetazolamide therapy led to the regression of papilloedema in about five months. No permanent eye damage has been observed in our patient to date. PTCS pathophysiology may be multifactorial and its specific features and severity may be a consequence of both constitutional and acquired factors interacting synergistically. It may be useful for paediatricians to know that some antibiotics may have the potential to precipitate PTCS in patients who already have an increased CSF pressure due to a transitory imbalanced CSF circulation caused by infections such as Mycoplasma pneumoniae, with headache being the first and most sensitive, but also the least specific, symptom.

Enzyme replacement therapy (ERT) has deeply modified the clinical history of Infantile Onset Pompe Disease (IOPD). However, its long-term effectiveness is still not completely defined. Available data shows a close relationship between clinical outcome and patients’ cross-reactive immunological status (CRIM), being CRIM-negative status a negative prognostic factor. At the same time limited data are available on the long-term treatment in CRIM-positive infants. A retrospective multicentre observational study was designed to analyse the long-term effectiveness of ERT in IOPD. Thirteen Italian centres spread throughout the country were involved and a cohort of 28 patients (15 females, 13 males, born in the period: February 2002–January 2013) was enrolled. IOPD diagnosis was based on clinical symptoms, enzymatic and molecular analysis. All patients received ERT within the first year of life. Clinical, laboratory, and functional data (motor, cardiac and respiratory) were collected and followed for a median period of 71 months (5 years 11 months). Median age at onset, diagnosis and start of ERT were 2, 3 and 4 months, respectively. CRIM status was available for 24/28 patients: 17/24 (71%) were CRIM-positive. Nineteen patients (67%) survived > 2 years: 4 were CRIM-negative, 14 CRIM-positive and one unknown. Six patients (5 CRIM-positive and one unknown) never needed ventilation support (21,4%) and seven (6 CRIM-positive and one unknown: 25%) developed independent ambulation although one subsequently lost this function. Brain imaging study was performed in 6 patients and showed peri-ventricular white matter abnormalities in all of them. Clinical follow-up confirmed the better prognosis for CRIM-positive patients, though a slow, progressive worsening of motor and/or respiratory functions was detected in 8 patients. These data are the result of the longest independent retrospective study on ERT in IOPD reported so far outside clinical trials. The data obtained confirmed the better outcome of the CRIM-positive patients but at the same time, showed the inability of the current therapeutic approach to reverse or stabilize the disease progression. The results also evidenced the involvement of central nervous system in Pompe disease. To better understand the disease clinical history and to improve treatment efficacy larger multicentre studies are needed as well as the development of new therapeutic approaches.

Correction to: Journal of Human Genetics advance online publication 27 July 2017; https://doi.org/10.1038/jhg.2017.78