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Abstract Background Alpha-mannosidosis is a rare autosomal recessive lysosomal storage disorder (LSD) caused by reduced activity of alpha-mannosidase. Clinical manifestations include skeletal dysmorphism, mental impairment, hearing loss and recurrent infections. The severe type of the disease leads to early childhood death, while patients with milder forms can live into adulthood. There are no mortality studies to date. This study aimed to investigate the age at death and the causes of death of patients with alpha-mannosidosis who had not received disease-modifying treatment. Methods Clinicians and LSD patient organisations (POs) from 33 countries were invited to complete a questionnaire between April–May 2021. Cause of death and age at death was available for 15 patients. A literature review identified seven deceased patients that met the inclusion criteria. Results Median age at death for patients reported by clinicians/POs was 45 years (mean 40.3 ± 13.2, range 18–56, n = 15); 53% were female. One death occurred during the patient’s second decade of life, and 14 out of 15 deaths (93.3%) during or after the patients’ third decade, including four (26.7%) during their sixth decade. Median age at death for patients identified from the literature was 4.3 years (mean 15.7 ± 17.0, range 2.2–41, n = 7); two were female. Four of the seven patients (57.1%) died within the first decade of life. Seven of 15 deaths (46.7%) reported by clinicians/POs were recorded as pneumonia and three (20.0%) as cancer. Other causes of death included acute renal failure due to sepsis after intestinal perforation, decrease of red blood cells of unknown origin, kidney failure with systemic lupus erythematosus, aortic valve insufficiency leading to heart failure, and dehydration due to catatonia. Three out of seven causes of death (42.9%) reported in the literature were associated with septicaemia, two (28.6%) with respiratory failure and one to pneumonia following aspiration. Conclusions This study suggests that pneumonia has been the primary cause of death during recent decades in untreated patients with alpha-mannosidosis, followed by cancer. Determining the causes of mortality and life expectancy in these patients is crucial to further improve our understanding of the natural history of alpha-mannosidosis.

Abstract Background Pompe disease (PD) is a disorder of glycogen metabolism conditioning a progressive and life conditioning myopathy. Enzyme replacement therapy (ERT) is currently the best treatment option for PD, but is not resolutive. While other potential therapeutic approaches have been reported before, these have never been tried as co- treatments. L-alanine oral supplementation (LAOS) has been proven to reduce muscle breakdown: we hereby report the first case of supplementation on a PD patient on ERT. Case presentation F. is a 9 y.o. infantile onset Pompe Disease (IOPD) girl ERT-treated since age 1 developing a progressive myopathy. We started her on LAOS and performed assessments at baseline, 6 and 9 months. At baseline, F.’s weight, height and BMI were within normal ranges, while body composition showed low fat mass -FM and high resting energy expenditure—REE levels. After LAOS, a progressive FM increase and REE reduction could be observed both at 6 and 9 months. Conclusions ERT is not curative for PD patients thus additional treatments could be considered to improve outcomes. Our patient showed physical signs of inability to accumulate energy when exclusively on ERT, while FM increase and REE reduction occurred when supplemented with LAOS, likely reflecting anabolic pathways’ implementation. This is the first case reporting potential LAOS benefits in PD-on ERT patients. Longitudinal case control studies are yet needed to evaluate possible efficacy of combined LAOS And ERT treatment in PD patients.