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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

Background: Adult patients with adrenoleukodystrophy have a poor prognosis owing to development of adrenomyeloneuropathy. Additionally, a large proportion of patients with adrenomyeloneuropathy develop life-threatening progressive cerebral adrenoleukodystrophy. Leriglitazone is a novel selective peroxisome proliferator-activated receptor gamma agonist that regulates expression of key genes that contribute to neuroinflammatory and neurodegenerative processes implicated in adrenoleukodystrophy disease progression. We aimed to assess the effect of leriglitazone on clinical, imaging, and biochemical markers of disease progression in adults with adrenomyeloneuropathy. Methods: ADVANCE was a 96-week, randomised, double-blind, placebo-controlled, phase 2–3 trial done at ten hospitals in France, Germany, Hungary, Italy, the Netherlands, Spain, the UK, and the USA. Ambulatory men aged 18–65 years with adrenomyeloneuropathy without gadolinium enhancing lesions suggestive of progressive cerebral adrenoleukodystrophy were randomly assigned (2:1 without stratification) to receive daily oral suspensions of leriglitazone (150 mg starting dose; between baseline and week 12, doses were increased or decreased to achieve plasma concentrations of 200 μg·h/mL [SD 20%]) or placebo by means of an interactive response system and a computer-generated sequence. Investigators and patients were masked to group assignment. The primary efficacy endpoint was change from baseline in the Six-Minute Walk Test distance at week 96, analysed in the full-analysis set by means of a mixed model for repeated measures with restricted maximum likelihood and baseline value as a covariate. Adverse events were also assessed in the full-analysis set. This study was registered with ClinicalTrials.gov, NCT03231878; the primary study is complete; patients had the option to continue treatment in an open-label extension, which is ongoing. Findings: Between Dec 8, 2017, and Oct 16, 2018, of 136 patients screened, 116 were randomly assigned; 62 [81%] of 77 patients receiving leriglitazone and 34 [87%] of 39 receiving placebo completed treatment. There was no between-group difference in the primary endpoint (mean [SD] change from baseline leriglitazone: –27·7 [41·4] m; placebo: –30·3 [60·5] m; least-squares mean difference –1·2 m; 95% CI –22·6 to 20·2; p=0·91). The most common treatment emergent adverse events in both the leriglitazone and placebo groups were weight gain (54 [70%] of 77 vs nine [23%] of 39 patients, respectively) and peripheral oedema (49 [64%] of 77 vs seven [18%] of 39). There were no deaths. Serious treatment-emergent adverse events occurred in 14 (18%) of 77 patients receiving leriglitazone and ten (26%) of 39 patients receiving placebo. The most common serious treatment emergent adverse event, clinically progressive cerebral adrenoleukodystrophy, occurred in six [5%] of 116 patients, all of whom were in the placebo group. Interpretation: The primary endpoint was not met, but leriglitazone was generally well tolerated and rates of adverse events were in line with the expected safety profile for this drug class. The finding that cerebral adrenoleukodystrophy, a life-threatening event for patients with adrenomyeloneuropathy, occurred only in patients in the placebo group supports further investigation of whether leriglitazone might slow the progression of cerebral adrenoleukodystrophy. Funding: Minoryx Therapeutics.

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.

Introduction Fabry disease (FD) is an X-linked lysosomal storage disorder resulting in vascular glycosphingolipid accumulation and increased stroke risk. MRI findings associated with FD include white matter hyperintensities (WMH) and cerebral microbleeds (CMBs), suggesting the presence of cerebral small vessel disease. MRI-visible perivascular spaces (PVS) are another promising marker of small vessel disease associated with impaired interstitial fluid drainage. We investigated the association of PVS severity and anatomical distribution with FD. Patients and methods We compared patients with genetically proven FD to healthy controls. PVS, WMH, lacunes and CMBs were rated on standardised sequences using validated criteria and scales, blinded to diagnosis. A trained observer (using a validated rating scale), quantified the total severity of PVS. We used logistic regression to investigate the association of severe PVS with FD. Results We included 33 FD patients (median age 44, 44.1% male) and 20 healthy controls (median age 33.5, 50% male). Adjusting for age and sex, FD was associated with more severe basal ganglia PVS (odds ratio (OR) 5.80, 95% CI 1.03–32.7) and higher total PVS score (OR 4.03, 95% CI 1.36–11.89). Compared with controls, participants with FD had: higher WMH volume (median 495.03 mm3 vs 0, p = 0.0008), more CMBs (21.21% vs none, p = 0.04), and a higher prevalence of lacunes (21.21% vs. 5%, p = 0.23). Conclusions PVS scores are more severe in FD than control subjects. Our findings have potential relevance for FD diagnosis and suggest that impaired interstitial fluid drainage might be a mechanism of white matter injury in FD.

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.

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.