Towards needed improvements in inherited metabolic medicine in adulthood: The SIMMESN adult metabolic working group and MetabERN Joint Position Statement.

Inherited metabolic disorders (IMDs), previously considered as a paediatric sub-specialisation are more and more prevalent in adults, thanks to improved survival, and the expansion of diagnostic tools detecting attenuated-late onset forms in adulthood. Italy is one of the countries with the highest number of IMDs screened by dry blood spots in neonates, allowing them to receive early treatments and to reach adult age. Despite this, awareness of IMDs is still low by the adult medical community, with difficulties in transition and transfer of patients to adult services and unmet patient needs. In 2022, a collaboration between the adult metabolic working group of the Italian Society for the Study of Inherited Metabolic Disorders and Neonatal Screening (SIMMESN) and the European Reference Network for Hereditary Metabolic Disorders (MetabERN) was established to face problems linked to IMDs in adulthood. "The Statement of Udine" was developed to guide further steps towards improvements in inherited metabolic medicine in adults, referencing the experience from the UK. The aim of this paper is to present "The Statement of Udine" explaining its background and its possible applications.

Incidence and risk factors for development of left ventricular hypertrophy in Fabry disease.

BACKGROUND: Left ventricular hypertrophy (LVH) is the principal cardiac manifestation of Fabry disease (FD). This study aimed to determine the incidence and predictors of LVH development in a contemporary cohort of patients with FD and no LVH at baseline evaluation. METHODS: Consecutively referred adult (aged ≥16 years) patients with FD were enrolled into an observational cohort study. Patients were prospectively followed in a specialist cardiomyopathy centre and the primary endpoint was the first detection of LVH (left ventricular mass index (LVMi) ≥115 g/m2 in men and ≥95 g/m2 in women). RESULTS: From a cohort of 393 patients, 214 (aged 35.8±13.8 years; 61 (29%) males) had no LVH at first evaluation. During a median follow-up of 9.4 years (IQR 4.7-12.7), 55 patients (24.6%) developed LVH. The estimated incidence of LVH was 11.3% (95% CI 6.5% to 16.1%) at 5 years, 29.1% (95% CI 21.5% to 36.7%) at 10 years and 45.0% (95% CI 33.8% to 62.4%) at 15 years of follow-up. On multivariable analysis, independent predictors for LVH development were age (HR 1.04 (95% CI 1.02 to 1.06) per 1-year increase, p<0.001), male sex (HR 2.90 (95% CI 1.66 to 5.09), p<0.001) and an abnormal ECG (HR 3.10 (95% CI 1.72 to 5.57), p<0.001). The annual rate of change in LVMi was +2.77 (IQR 1.45-4.62) g/m2/year in males and +1.38 (IQR 0.09-2.85) g/m2/year in females (p<0.001). CONCLUSIONS: Approximately one-quarter of patients with FD developed LVH during follow-up. Age, male sex and ECG abnormalities were associated with a higher risk of developing LVH in patients with FD.

Brain function in classic galactosemia, a galactosemia network (GalNet) members review.

Classic galactosemia (CG, OMIM #230400, ORPHA: 79,239) is a hereditary disorder of galactose metabolism that, despite treatment with galactose restriction, affects brain function in 85% of the patients. Problems with cognitive function, neuropsychological/social emotional difficulties, neurological symptoms, and abnormalities in neuroimaging and electrophysiological assessments are frequently reported in this group of patients, with an enormous individual variability. In this review, we describe the role of impaired galactose metabolism on brain dysfunction based on state of the art knowledge. Several proposed disease mechanisms are discussed, as well as the time of damage and potential treatment options. Furthermore, we combine data from longitudinal, cross-sectional and retrospective studies with the observations of specialist teams treating this disease to depict the brain disease course over time. Based on current data and insights, the majority of patients do not exhibit cognitive decline. A subset of patients, often with early onset cerebral and cerebellar volume loss, can nevertheless experience neurological worsening. While a large number of patients with CG suffer from anxiety and depression, the increased complaints about memory loss, anxiety and depression at an older age are likely multifactorial in origin.

Arginine:glycine amidinotransferase (AGAT) deficiency: an easy-to-miss treatable adult-onset myopathy.

Arginine:glycine amidinotransferase (AGAT) deficiency is an ultrarare disorder of creatine metabolism, presenting with developmental delay, characteristic biochemical findings and muscle weakness. Most known cases have been identified and treated in early childhood. We describe a 27-year-old woman with learning difficulties and significant myopathy who was diagnosed through genetic investigation in adulthood. Treatment with creatine (10-15 g/day) led to a significant and rapid improvement of muscle strength. A literature review of the few reported adult cases confirms that progressive myopathy is a prominent feature that responds well to creatine supplementation. AGAT deficiency, a partially treatable condition, should be considered in the differential diagnosis of a genetic myopathy, particularly in people with developmental delay and progressive myopathy.

Raised CK and acute kidney injury following intense exercise in three patients with a history of exercise intolerance due to homozygous mutations in SLC2A9.

Acute rhabdomyolysis (AR) leading to acute kidney injury has many underlying etiologies, however, when the primary trigger is exercise, the most usual underlying cause is either a genetic muscle disorder or unaccustomed intense exercise in a healthy individual. Three adult men presented with a history of exercise intolerance and episodes of acute renal impairment following intense exercise, thought to be due to AR in the case of two, and dehydration in one. The baseline serum CK was mildly raised between attacks in all three patients and acutely raised during attacks in two of the three patients. Following referral to a specialized neuromuscular centre, further investigation identified very low serum urate (<12 umol/L). In all three men, genetic studies confirmed homozygous mutations in SLC2A9, which encodes for facilitated glucose transporter member 9 (GLUT9), a major regulator of urate homeostasis. Hereditary hypouricaemia should be considered in people presenting with acute kidney injury related to intense exercise. Serum urate evaluation is a useful screening test best undertaken after recovery.