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Purpose: This trial aimed to assess the efficacy and safety of olipudase alfa enzyme replacement therapy for non–central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) in adults. Methods: A phase 2/3, 52 week, international, double-blind, placebo-controlled trial (ASCEND; NCT02004691/EudraCT 2015-000371-26) enrolled 36 adults with ASMD randomized 1:1 to receive olipudase alfa or placebo intravenously every 2 weeks with intrapatient dose escalation to 3 mg/kg. Primary efficacy endpoints were percent change from baseline to week 52 in percent predicted diffusing capacity of the lung for carbon monoxide and spleen volume (combined with splenomegaly-related score in the United States). Other outcomes included liver volume/function/sphingomyelin content, pulmonary imaging/function, platelet levels, lipid profiles, and pharmacodynamics. Results: Least square mean percent change from baseline to week 52 favored olipudase alfa over placebo for percent predicted diffusing capacity of the lung for carbon monoxide (22% vs 3.0% increases, P =.0004), spleen volume (39% decrease vs 0.5% increase, P

Adrenomyeloneuropathy (AMN) is a rare inherited condition where affected individuals develop slowly progressive spastic paraparesis with a gradual decline in walking ability. There is no cure for AMN and treatment focuses on supportive measures and aids. One treatment option is functional electrical stimulation (FES), a treatment, approved by The National Institute for Health and Care Excellence (NICE), for managing foot drop in upper motor neuron disorders. Limited evidence exists for its use in AMN patients. We describe the effects of FES in an individual case and more broadly within a cohort of 21 patients successfully treated with FES. Patients with AMN referred for FES typically report frequent falls (71%) and foot drop (57%) as the most common barriers to walking. When using FES, walking speed at baseline (0.70 m/s [SD = 0.2]) was maintained at the 2‐year review (0.68 m/s [SD = 0.2]) with a persistent orthotic effect (improvement in walking speed when device on vs. off) seen from wearing FES over the same 2‐year period (11%–19%). Patient walking satisfaction (visual analogue scale: 0 – very dissatisfied; 10 – very satisfied) was also greater when comparing no‐FES versus FES over the same period (Year 1: 2.5 vs. 7.7; Year 2: 2.1 vs. 6.1). FES is not effective in all patients. Twelve patients referred found no benefit from the device; although there was no clear evidence, this was related to the degree of AMN associated peripheral neuropathy. However, FES is a safe, cost‐effective treatment option and should be considered, along with assessment in a multidisciplinary clinic, for all AMN patients with walking difficulties.

IntroductionArgininosuccinate lyase is integral to the urea cycle, which enables nitrogen waste and biosynthesis of arginine, a precursor of nitric oxide. Inherited argininosuccinate lyase deficiency causes argininosuccinic aciduria, the second most common urea cycle defect and an inherited model of systemic nitric oxide deficiency. Patients present with developmental delay, epilepsy and movement disorder. Here we aim to characterise epilepsy, a common and neurodebilitating complication in argininosuccinic aciduria.Patients and MethodsWe conducted a retrospective study in seven tertiary metabolic centres in the UK, Italy and Canada from 2020 to 2022 to assess the phenotype of epilepsy in ASA and correlate it with clinical, biochemical, radiological and electroencephalographic data.ResultsThirty-seven patients aged 1 to 31 years old were included. Twenty-two (60%) patients presented epilepsy. Median age at epilepsy-onset was 24 months. Generalized tonic clonic and focal seizures were most common in early-onset patients whilst atypical absences were predominant in late-onset patients. Seventeen patients (77%) required antiseizure medications and 6 (27%) had partially controlled or refractory epilepsy. Epileptic patients presented with a severe neurodebilitating disease with higher rates of speech delay (p=0.04) and autism spectrum disorders (p=0.01) and more frequent arginine supplementation (p=0.01) compared to non-epileptic patients. Neonatal seizures were not associated with a higher risk of developing epilepsy. Biomarkers of ureagenesis did not differ between epileptic and non-epileptic patients. Epilepsy-onset in early infancy (p=0.05) and electroencephalographic background asymmetry (p=0.0007) were significant predictors of partially controlled or refractory epilepsy.ConclusionsEpilepsy in argininosuccinic aciduria is frequent, polymorphic, associated with more frequent neurodevelopmental complications. We identified prognostic factors for pharmacoresistance in epilepsy. This study does not support defective ureagenesis as prominent in the pathophysiology of epilepsy but suggests roles of arginine toxicity and central dopamine deficiency.Key PointsEpilepsy in ASA is frequent, polymorphic, occurring in early childhood and associated with a more severe neurodevelopmental phenotype.Early-onset epilepsy and electroencephalographic background asymmetry are prognostic for pharmaco-resistance of epilepsy in ASA.Hyperammonaemia is suggested not to be the primary pathophysiological mechanism for epileptogenesis in ASA.Central dopamine deficiency is suggested to have a role in pathophysiology of epilepsy in ASA.Arginine-related neurotoxicity is suggested to be associated with increased in frequency and severity of epilepsy in ASA.

Previous studies have suggested that cognitive and psychosocial underfunctioning in early-treated adults with phenylketonuria (PKU) may be explained by suboptimal adherence to dietary treatments, however, these studies often employ small samples, with different outcome measures, definitions and cut-offs. Samples have also tended to comprise participants with a limited range of blood phenylalanine concentrations, and often individuals who may not have been treated early enough to avoid neurological damage. In this study, we explore the impact of lifetime dietary control, as indicated by blood phenylalanine concentrations in childhood, adolescence and adulthood, on long-term cognitive and psychosocial outcomes in a large sample of adults with PKU who were diagnosed by neonatal screening and commenced on dietary treatment within the first month of life. One hundred and fifty-four participants underwent cognitive testing, assessing attention, learning, working memory, language, executive functioning and processing speed. One hundred and forty-nine completed measures of psychosocial functioning, documenting educational, occupational, quality of life, emotional and social outcomes which were compared with a group of healthy controls. Many adults with PKU demonstrated cognitive impairments, most frequently affecting processing speed (23%), executive function (20%) and learning (12%). Cognitive outcomes were related to measures of historic metabolic control, but only processing speed was significantly related to phenylalanine concentration at the time of testing after controlling for historic levels. Adults with PKU did not, however, differ from controls in educational, occupational, quality of life or emotional outcomes, or on a measure of family functioning, and showed only minor differences in relationship style. These findings have implications for patient counselling and decisions regarding the management of PKU in adulthood.

Cerebral white matter pathology is a common CNS manifestation of Fabry disease, visualized as white matter hyperintensities on MRI in 42–81% of patients. Diffusion tensor imaging (DTI) MRI is a sensitive technique to quantify microstructural damage within the white matter with potential value as a disease biomarker. We evaluated the pattern of DTI abnormalities in Fabry disease, and their correlations with cognitive impairment, mood, anxiety, disease severity and plasma lyso-Gb3 levels in 31 patients with genetically proven Fabry disease and 19 age-matched healthy control subjects. We obtained average values of fractional anisotropy and mean diffusivity within the white matter and performed voxelwise analysis with tract-based spatial statistics. Using a standardized neuropsychological test battery, we assessed processing speed, executive function, anxiety, depression and disease severity. The mean age (% male) was 44.1 (45%) for patients with Fabry disease and 37.4 (53%) for the healthy control group. In patients with Fabry disease, compared to healthy controls the mean average white matter fractional anisotropy was lower in [0.423 (standard deviation, SD 0.023) versus 0.446 (SD 0.016), P = 0.002] while mean average white matter mean diffusivity was higher (749 × 10−6 mm2/s (SD 32 × 10−6) versus 720 × 10−6 mm2/s (SD 21 × 10−6), P = 0.004]. Voxelwise statistics showed that the diffusion abnormalities for both fractional anisotropy and mean diffusivity were anatomically widespread. A lesion probability map showed that white matter hyperintensities also had a wide anatomical distribution with a predilection for the posterior centrum semiovale. However, diffusion abnormalities in Fabry disease were not restricted to lesional tissue; compared to healthy controls, the normal appearing white matter in patients with Fabry disease had reduced fractional anisotropy [0.422 (SD 0.022) versus 0.443 (SD 0.017) P = 0.003] and increased mean diffusivity [747 × 10−6 mm2/s (SD 26 × 10−6) versus 723 × 10−6 mm2/s (SD 22 × 10−6), P = 0.008]. Within patients, average white matter fractional anisotropy and white matter lesion volume showed statistically significant correlations with Digit Symbol Coding Test score (r = 0.558, P = 0.001; and r = −0.633, P ≤ 0.001, respectively). Average white matter fractional anisotropy correlated with the overall Mainz Severity Score Index (r = −0.661, P ≤ 0.001), while average white matter mean diffusivity showed a strong correlation with plasma lyso-Gb3 levels (r = 0.559, P = 0.001). Our findings using DTI confirm widespread areas of microstructural white matter disruption in Fabry disease, extending beyond white matter hyperintensities seen on conventional MRI. Moreover, diffusion measures show strong correlations with cognition (processing speed), clinical disease severity and a putative plasma biomarker of disease activity, making them promising quantitative biomarkers for monitoring Fabry disease severity and progression.

Hyperammonaemia is often encountered in acute neurology and can be the cause of acute or chronic neurological symptoms. Patients with hyperammonaemia may present with seizures or encephalopathy, or may be entirely asymptomatic. The underlying causes are diverse but often straightforward to diagnose, although sometimes require specialist investigations. Haemodialysis or haemo(dia)filtration is the first-line treatment for acute severe hyperammonaemia (of any cause) in an adult. Here we discuss our approach to adult patients with hyperammonaemia identified by a neurologist.

Adult metabolic medicine (AMM) is an expanding medical subspecialty, due to the increasing number of adult patients with inherited metabolic diseases (IMD). However, a formal training and postgraduate education in this field is not available in the majority of countries. Existing adult metabolic specialists (AMS) come from many different backgrounds. The aim of this survey was to assess the state of play as regards education and training in AMM worldwide. Members of the Society for the Study of Inborn Error of Metabolism adult metabolic group (n = 89) were asked to take part in this survey. Forty‐two AMS (47.2%) from 18 different countries completed the questionnaire. The most common specialties were internal medicine (38.1%), endocrinology (26.2%), genetics (21.4%), and neurology (21.4%). Ninety‐five percent of respondents considered that practical clinical experience had contributed importantly for their professional development, while only 27% felt the same for formal academic education. The current state of available education and training was judged as generally poor or fair (73% of the respondents). The most suggested ways of improving education and training in AMM were: to facilitate international internships; to implement courses on adult‐IMD; and to create a formal academic education. The skills considered most important for AMS were: recognition of signs and symptoms of diseases, knowledge of the available treatments, and ability to perform a correct follow up. In conclusion, worldwide, current available education and training in AMM is considered inadequate. This survey emphasizes the need for development of new, formal training opportunities to improve knowledge, and competence in this rapidly expanding field.

Background Niemann-Pick disease type C (NPC) is a lysosomal storage disease with a heterogeneous neurodegenerative clinical course. Multiple therapies are in clinical trials and inclusion criteria are currently mainly based on age and neurological signs, not taking into consideration differential individual rates of disease progression. Results In this study, we have evaluated a simple metric, denoted annual severity increment score (ASIS), that measures rate of disease progression and could easily be used in clinical practice. We show that ASIS is stable over several years and can be used to stratify patients for clinical trials. It achieves greater homogeneity of the study cohort relative to age-based inclusion and provides an evidence-based approach for establishing inclusion/exclusion criteria. In addition, we show that ASIS has prognostic value and demonstrate that treatment with an experimental therapy - acetyl-DL-leucine - is associated with a reduction in ASIS scores. Conclusion ASIS has the potential to be a useful metric for clinical monitoring, trial recruitment, for prognosis and measuring response to therapy. Electronic supplementary material The online version of this article (10.1186/s13023-018-0880-9) contains supplementary material, which is available to authorized users.

The kidney is affected in a number of inherited metabolic disorders. This chapter focuses on several in which renal disease is usually not the primary clinical manifestation, meaning that there are often other multisystem features and biochemical markers which aid diagnosis. They are rare, but important as early diagnosis and appropriate treatment can often improve outcome.