Bone Marrow Transplant

Mucopolysaccharidosis type I-H (MPS I-H) is a rare lysosomal storage disorder caused by α-L-Iduronidase deficiency. Early haematopoietic stem cell transplantation (HSCT) is the sole available therapeutic option to preserve neurocognitive functions. We report long-term follow-up (median 9 years, interquartile range 8-16.5) for 51 MPS I-H patients who underwent HSCT between 1986 and 2018 in France. 4 patients died from complications of HSCT and one from disease progression. Complete chimerism and normal α-L-Iduronidase activity were obtained in 84% and 71% of patients respectively. No difference of outcomes was observed between bone marrow and cord blood stem cell sources. All patients acquired independent walking and 91% and 78% acquired intelligible language or reading and writing. Intelligence Quotient evaluation (n = 23) showed that 69% had IQ ≥ 70 at last follow-up. 58% of patients had normal or remedial schooling and 62% of the 13 adults had good socio-professional insertion. Skeletal dysplasia as well as vision and hearing impairments progressed despite HSCT, with significant disability. These results provide a long-term assessment of HSCT efficacy in MPS I-H and could be useful in the evaluation of novel promising treatments such as gene therapy

Lack of Long-Term Neurologic Efficacy of Zileuton in Sjögren–Larsson's Syndrome

International audienc

Diagnostic contribution of metabolic workup for neonatal inherited metabolic disorders in the absence of expanded newborn screening

Inherited metabolic disorders (IMDs) in neonates are a diagnostic and therapeutic challenge for the neonatologist, with the priority being to rapidly flag the treatable diseases. The objective of this study was to evaluate the contribution of targeted metabolic testing for diagnosing suspected IMDs on the basis of suggestive clinical setting or family history in neonates. We conducted an observational study over five years, from January 1st, 2010 to December 31, 2014 in the neonatal intensive care unit (NICU) at Robert Debré University Hospital, Paris, France. We assessed the number of neonates for whom a metabolic testing was performed, the indication for each metabolic test and the diagnostic yield of this selected metabolic workup for diagnosing an IMD. Metabolic testing comprised at least one of the following testings: plasma, urine or cerebrospinal fluid amino acids, urine organic acids, plasma acylcarnitine profile, and urine mucopolysaccharides and oligosaccharides. 11,301 neonates were admitted at the neonatal ICU during the study period. One hundred and ninety six neonates underwent metabolic testing. Eleven cases of IMDs were diagnosed. This diagnostic approach allowed the diagnosis, treatment and survival of 4 neonates (maple syrup urine disease, propionic acidemia, carnitine-acylcarnitine translocase deficiency and type 1 tyrosinemia). In total, metabolic testing was performed for 1.7% of the total number of neonates admitted in the NICU over the study period. These included 23% finally unaffected neonates with transient abnormalities, 5.6% neonates suffering from an identified IMD, 45.4% neonates suffering from a non-metabolic identified disease and 26% neonates with chronic abnormalities but for whom no final causal diagnosis could be made. In conclusion, as expected, such a metabolic targeted workup allowed the diagnosis of classical neonatal onset IMDs in symptomatic newborns. However, this workup remained normal or unspecific for 94.4% of the tested patients. It allowed excluding an IMD in 68.4% of the tested neonates. In spite of the high rate of normal results, such a strategy seems acceptable due to the severity of the symptoms and the need for immediate treatment when available in neonatal IMDs. However, its cost-effectiveness remains low especially in a clinically targeted population in a country where newborn screening is still unavailable for IMDs except for phenylketonuria in 2019

Cerliponase alfa changes the natural history of children with neuronal ceroid lipofuscinosis type 2: The first French cohort

International audienc

Argininosuccinic aciduria: from identification to management of paucisymptomatic late onset forms

Background: Argininosuccinic aciduria, the second most common urea cycle disorder (UCD) is due to argininosuccinate lyase (ASL) deficiency. Neonatal onset forms are characterized by hyperammonemic comas. Late onset ASL patients exhibit variable symptoms ranging from intermittent hyperammonemia to unspecific psychomotor delay, behavioral and cognitive disturbances. Systemic hypertension, brittle hair or liver fibrosis are specific findings compared with other UCDs that can occur independently of hyperammonemia. Objective: To report two atypical late onset forms of argininosuccinic aciduria. Case reports: Patient 1 presented with myoclonic epilepsy and mild psychomotor delay at the age of 3. Clinical examination revealed hepatomegaly that prompted to perform a metabolic workup. The latter found argininosuccinic acid (ASA) accumulation in body fluids without hyperammonemia or liver dysfunction. ASA level in cerebrospinal fluid (CSF) was 3.6 fold higher than in blood. Patient 2 presented with acute episodes of apnea, cyanosis and hypertonia at age 3 months. Clinical findings revealed mild hepatomegaly and hypotonia. High ASA level was detected in blood and urine, without hyperammonemia. Low protein diet and arginine supplementation were introduced, resulting in decreased blood ASA levels in both patients who exhibited moderate neurodevelopmental delay. Discussion and conclusion: Nonspecific symptoms may occur in late onset ASL patients and time for metabolic screening is a challenge. In particular, myoclonic epilepsy is an unusual initial presentation. Increased ASA level in CSF combined with reported nitric oxide (NO) deficiency despite arginine supplementation may contribute to neurotoxicity. While protein restriction and arginine supplementation can decrease hyperammonemia if present and limit blood ASA accumulation, the impact of treatment on the neurological disease remains questionable. Recent data suggest that ASL patients might benefit from NO supplementation

Transition in health care from childhood to adulthood for lysosomal diseases patients in France, current state and priorities: The TENALYS study

International audienc

Is time since hip fracture influencing the discrimination between fractured and nonfractured subjects as assessed at the calcaneum by three technologically different quantitative ultrasound devices?

Because quantitative ultrasound (QUS) instruments from different manufacturers have significant technical differences, it is difficult to assess whether all of them can discriminate similarly between osteoporotic fractures and age-matched controls. Thus, to avoid any bias, reliable comparative assessment of the QUS devices should be carried out on the same population. Few studies have fulfilled this condition. Another source of variability in cross-sectional studies in which fractured and nonfractured subjects are compared is the time since osteoporotic fracture. Our study evaluated the ability of three calcaneal QUS devices to discriminate patients with osteoporotic hip fracture from control subjects, using the same population. In addition, a subset of patients was re-measured about 9 months after the hip replacement surgery to check how the time since fracture affects the discriminatory ability of the different QUS devices. Fifty postmenopausal hip-fractured patients and 46 postmenopausal age-matched controls were included in this study and measured on three QUS devices, as well as 50 young healthy controls to calculate the T-score. Odds ratio results showed that a decrease in UBIS trade mark BUA of 1 SD was associated with a significant increase in fracture risk (odds ratio adjusted = 2.30) comparable with Sahara broadband ultrasound attenuation (BUA) (OR adj. = 2.30), and Achilles BUA (OR adj. = 3.5). However, given the large overlap between the 95% intervals of each OR and for the areas under ROC curves, no significant difference was found between them. In the subset of 15 hip-fractured subjects, no significant differences were found between ultrasound parameters of the first visit and 9 months after except for the heel width (soft tissue variation). Odds ratio and areas under the curve (AUC) tend to increase from visit 1 to 2 for the BUA and decrease substantially for the SOS for all but the Lunar Achilles+. Nonsignificant correlation was found between the absolute difference of the ultrasound parameters measured at the two visits and the time since fracture, except for the Sahara SOS (r = 0.45; P < 0.04). In conclusion, no significant differences between QUS technologies were observed in their positive and significant ability to discriminate hip-fractured patient from controls. However, this statement is shadowed when taking into account the time since fracture which seems to negatively influence results obtained on dry versus wet QUS systems. As a result, it is advisable that such parameters would be taken into account when designing a study aimed to demonstrate the discriminatory ability of heel ultrasound between normal and hip-fractured patients

Philosophie, Phänomenologie und Psychologie. Husserl und der “zeitgemäße Anachronismus” der Phänomenologie der Gestaltpsychologie

Often there has been seen connections and continuity between the phenomenology of Husserl and the epistemological orientation of representatives of Gestalt psychology. In fact the two methodological procedures are quite different. In the era of Weimarer Republic the Berlin School used a combination of empirical research, philosophical reflexion, phenomenology and physiology, those conceptions – derived from the work of Stumpf – were their methodological guidelines until World War II. Compared to the ‘pure’ phenomenology and epistemology in times of the Weimarer Republic the gestalt phenomenology can be seen as ‘impure’ and ‘anachronistic’. In this paper the characteristics and the actuality of this ‘anachronism’ are discussed