Consensus guidelines for the monitoring and management of metachromatic leukodystrophy in the United States.

Metachromatic leukodystrophy (MLD) is a fatal, progressive neurodegenerative disorder caused by biallelic pathogenic mutations in the ARSA (Arylsulfatase A) gene. With the advent of presymptomatic diagnosis and the availability of therapies with a narrow window for intervention, it is critical to define a standardized approach to diagnosis, presymptomatic monitoring, and clinical care. To meet the needs of the MLD community, a panel of MLD experts was established to develop disease-specific guidelines based on healthcare resources in the United States. This group developed a consensus opinion for best-practice recommendations, as follows: (i) Diagnosis should include both genetic and biochemical testing; (ii) Early diagnosis and treatment for MLD is associated with improved clinical outcomes; (iii) The panel supported the development of newborn screening to accelerate the time to diagnosis and treatment; (iv) Clinical management of MLD should include specialists familiar with the disease who are able to follow patients longitudinally; (v) In early onset MLD, including late infantile and early juvenile subtypes, ex vivo gene therapy should be considered for presymptomatic patients where available; (vi) In late-onset MLD, including late juvenile and adult subtypes, hematopoietic cell transplant (HCT) should be considered for patients with no or minimal disease involvement. This document summarizes current guidance on the presymptomatic monitoring of children affected by MLD as well as the clinical management of symptomatic patients. Future data-driven evidence and evolution of these recommendations will be important to stratify clinical treatment options and improve clinical care.

Progressive encephalopathy after routine 4-month immunizations in a patient with NAXD genetic variant.

Metabolic pathways are known to generate byproducts-some of which have no clear metabolic function and some of which are toxic. Nicotinamide adenine dinucleotide phosphate hydrate (NAD(P)HX) is a toxic metabolite that is produced by stressors such as a fever, infection, or physical stress. Nicotinamide adenine dinucleotide phosphate hydrate dehydratase (NAXD) and nicotinamide adenine dinucleotide phosphate hydrate epimerase (NAXE) are part of the nicotinamide repair system that function to break down this toxic metabolite. Deficiency of NAXD and NAXE interrupts the critical intracellular repair of NAD(P)HX and allows for its accumulation. Clinically, deficiency of NAXE manifests as progressive, early onset encephalopathy with brain edema and/or leukoencephalopathy (PEBEL) 1, while deficiency of NAXD manifests as PEBEL2. In this report, we describe a case of probable PEBEL2 in a patient with a variant of unknown significance (c.362C>T, p.121L) in the NAXD gene who presented after routine immunizations with significant skin findings and in the absence of fevers.

Neurological manifestations in PMM2-congenital disorders of glycosylation (PMM2-CDG): Insights into clinico-radiological characteristics, recommendations for follow-up, and future directions.

PURPOSE: In the absence of prospective data on neurological symptoms, disease outcome, or guidelines for system specific management in phosphomannomutase 2-congenital disorders of glycosylation (PMM2-CDG), we aimed to collect and review natural history data. METHODS: Fifty-one molecularly confirmed individuals with PMM2-CDG enrolled in the Frontiers of Congenital Disorders of Glycosylation natural history study were reviewed. In addition, we prospectively reviewed a smaller cohort of these individuals with PMM2-CDG on off-label acetazolamide treatment. RESULTS: Mean age at diagnosis was 28.04 months. Developmental delay is a constant phenotype. Neurological manifestation included ataxia (90.2%), myopathy (82.4%), seizures (56.9%), neuropathy (52.9%), microcephaly (19.1%), extrapyramidal symptoms (27.5%), stroke-like episodes (SLE) (15.7%), and spasticity (13.7%). Progressive cerebellar atrophy is the characteristic neuroimaging finding. Additionally, supratentorial white matter changes were noted in adult age. No correlation was observed between the seizure severity and SLE risk, although all patients with SLE have had seizures in the past. "Off-label" acetazolamide therapy in a smaller sub-cohort resulted in improvement in speech fluency but did not show statistically significant improvement in objective ataxia scores. CONCLUSION: Clinical and radiological findings suggest both neurodevelopmental and neurodegenerative pathophysiology. Seizures may manifest at any age and are responsive to levetiracetam monotherapy in most cases. Febrile seizure is the most common trigger for SLEs. Acetazolamide is well tolerated.

Hematopoietic cell transplantation for sialidosis type I.

We report the clinical and laboratory follow-up data of an adolescent female with Type I Sialidosis who underwent bone marrow transplant (BMT). After BMT, plasma and urine biomarkers responded concurrently with engraftment. Neuropsychiatry data showed preservation in some domains, but she did have overall decline in motor performance. Sialidosis is a very rare lysosomal condition, and we believe this to be the first report of a case of Type I Sialidosis undergoing BMT.

Clinical disease characteristics of patients with Niemann-Pick Disease Type C: findings from the International Niemann-Pick Disease Registry (INPDR).

BACKGROUND: Niemann-Pick Disease Type C (NPC) is an autosomal recessive rare disease characterised by progressive neurovisceral manifestations. The collection of on-going large-scale NPC clinical data may generate better understandings of the natural history of the disease. Here we report NPC patient data from the International Niemann-Pick Disease Registry (INPDR). METHOD: The INPDR is a web-based, patient-led independent registry for the collection of prospective and retrospective clinical data from Niemann-Pick Disease patients. Baseline data from NPC patients enrolled into the INPDR from September 2014 to December 2019 was extracted to analyse the demographic, genetic and clinical features of the disease. RESULTS: A total of 203 NPC patients from six European countries were included in this study. The mean age (SD) at diagnosis was 11.2 years (14.2). Among enrolled patients, 168 had known neurological manifestations: 43 (24.2%) had early-infantile onset, 47 (26.4%) had late-infantile onset, 41 (23.0%) had juvenile onset, and 37 (20.8%) had adult onset. 10 (5.6%) patients had the neonatal rapidly fatal systemic form. Among the 97 patients with identified NPC1 variants, the most common variant was the c. 3182T > C variant responsible for the p.lle1061Thr protein change, reported in 35.1% (N = 34) of patients. The frequencies of hepatomegaly and neonatal jaundice were greatest in patients with early-infantile and late-infantile neurological onset. Splenomegaly was the most commonly reported observation, including 80% of adult-onset patients. The most commonly reported neurological manifestations were cognitive impairment (78.5%), dysarthria (75.9%), ataxia (75.9%), vertical supranuclear gaze palsy (70.9%) and dysphagia (69.6%). A 6-domain composite disability scale was used to calculate the overall disability score for each neurological form. Across all with neurological onset, the majority of patients showed moderate to severe impairments in all domains, except for 'swallowing' and 'seizure'. The age at diagnosis and death increased with increased age of neurological symptom onset. Miglustat use was recorded in 62.4% of patients and the most common symptomatic therapies used by patients were antiepileptics (32.9%), antidepressants (11.8%) and antacids (9.4%). CONCLUSION: The proportion of participants at each age of neurological onset was relatively equal across the cohort. Neurological manifestations, such as ataxia, dysphagia, and dysarthria, were frequently observed across all age categories.

Current directions in tau research: Highlights from Tau 2020.

Studies supporting a strong association between tau deposition and neuronal loss, neurodegeneration, and cognitive decline have heightened the allure of tau and tau-related mechanisms as therapeutic targets. In February 2020, leading tau experts from around the world convened for the first-ever Tau2020 Global Conference in Washington, DC, co-organized and cosponsored by the Rainwater Charitable Foundation, the Alzheimer's Association, and CurePSP. Representing academia, industry, government, and the philanthropic sector, presenters and attendees discussed recent advances and current directions in tau research. The meeting provided a unique opportunity to move tau research forward by fostering global partnerships among academia, industry, and other stakeholders and by providing support for new drug discovery programs, groundbreaking research, and emerging tau researchers. The meeting also provided an opportunity for experts to present critical research-advancing tools and insights that are now rapidly accelerating the pace of tau research.

International consensus on clinical severity scale use in evaluating Niemann-Pick disease Type C in paediatric and adult patients: results from a Delphi Study.

BACKGROUND: Several scales have been developed in the past two decades to evaluate Niemann-Pick disease Type C (NPC) severity in clinical practice and trials. However, a lack of clarity concerning which scale to use in each setting is preventing the use of standardised assessments across the world, resulting in incomparable data sets and clinical trial outcome measures. This study aimed to establish agreed approaches for the use of NPC severity scales in clinical practice and research. METHODS: A Delphi method of consensus development was used, comprising three survey rounds. In Round 1, participants were asked nine multiple-choice and open-ended questions to gather opinions on the six severity scales and domains. In Rounds 2 and 3, questions aimed to gain consensus on the opinions revealed in Round 1 using a typical Likert scale. RESULTS: Nineteen experts, active in NPC paediatric and adult research and treatment, participated in this study. Of these, 16/19 completed Rounds 1 and 2 and 19/19 completed Round 3. Consensus (defined as ≥ 70% agreement or neutrality, given the study aim to identify the severity scales that the clinical community would accept for international consistency) was achieved for 66.7% of the multiple-choice questions in Round 2 and 83% of the multiple-choice questions in Round 3. Consensus was almost reached (68%) on the use of the 5-domain NPCCSS scale as the first choice in clinical practice. Consensus was reached (74%) for the 17-domain NPCCSS scale as the first choice in clinical trial settings, but the domains measured in the 5-domain scale should be prioritised as the primary endpoints. Experts called for educational and training materials on how to apply the NPCCSS (17- and 5-domains) for clinicians working in NPC. CONCLUSIONS: In achieving a consensus on the use of the 17-domain NPCCSS scale as the first choice for assessing clinical severity of NPC in clinical trial settings but prioritising the domains in the 5-domain NPCCSS scale for routine clinical practice, this study can help to inform future discussion around the use of the existing NPC clinical severity scales. For routine clinical practice, the study helps provide clarity on which scale is favoured by a significant proportion of a representative body of experts, in this case, the 5-domain NPCCSS scale.

Impacts and Burden of Niemann pick Type-C: a patient and caregiver perspective.

BACKGROUND: Niemann-Pick disease type C (NPC) is a debilitating condition that impacts patients' and caregivers' quality of life (QOL) and reduces the patient's life expectancy. Since there is little qualitative research from the perspective of patients and family caregivers, this study explored the impact of NPC on patients' and caregivers' daily lives to understand the burden of disease. RESULTS: A survey of caregivers for patients with NPC and adult patients with NPC (n = 49; patient age: 13 months-65 years) assessed NPC severity, importance of NPC symptoms, and how symptoms impacted patients' and caregivers' activities of daily living (ADLs) and health-related QOL (HRQOL). Follow-up interviews with a subset of survey participants (n = 28) explored the ranking of NPC symptom importance and impact on ADLs and HRQOL. Findings indicated that the most important manifestations of NPC were ambulation, swallowing, speech, fine motor skills, and cognition, which were those that had the most significant impact on ADLs and HRQOL. A wide range of ADLs were affected by NPC, mainly eating/drinking and the ability to perform daily tasks, including self-care, communicating, participating in school or work, and moving indoors as well as outside the home. Along with these impacts, there was an increased risk of experiencing dangerous or life-threatening situations leading to loss of patient independence and additional caregiver burden, often requiring changes in lifestyle such as giving up work. All aspects of patients' and caregivers' HRQOL were affected. Participants reported feelings of social isolation, loss of enjoyment in activities (patients), and feelings of sadness or worry (caregivers). CONCLUSIONS: Ambulation, swallowing, speech, fine motor skills, and cognition are important manifestations of NPC. ADLs and HRQOL were impaired in the majority of patients as well as their caregivers. The findings were independent of current age, age of onset of symptoms, and level of NPC disease-related disability; however, the impact increased at higher levels of disease disability. Knowing the impact of NPC on patients and caregivers is important for understanding the lived experience of NPC and for identifying potential areas of support.

Acetylation turns leucine into a drug by membrane transporter switching.

Small changes to molecules can have profound effects on their pharmacological activity as exemplified by the addition of the two-carbon acetyl group to make drugs more effective by enhancing their pharmacokinetic or pharmacodynamic properties. N-acetyl-D,L-leucine is approved in France for vertigo and its L-enantiomer is being developed as a drug for rare and common neurological disorders. However, the precise mechanistic details of how acetylation converts leucine into a drug are unknown. Here we show that acetylation of leucine switches its uptake into cells from the L-type amino acid transporter (LAT1) used by leucine to organic anion transporters (OAT1 and OAT3) and the monocarboxylate transporter type 1 (MCT1). Both the kinetics of MCT1 (lower affinity compared to LAT1) and the ubiquitous tissue expression of MCT1 make it well suited for uptake and distribution of N-acetyl-L-leucine. MCT1-mediated uptake of a N-acetyl-L-leucine as a prodrug of leucine bypasses LAT1, the rate-limiting step in activation of leucine-mediated signalling and metabolic process inside cells such as mTOR. Converting an amino acid into an anion through acetylation reveals a way for the rational design of drugs to target anion transporters.

Efficacy and safety of arimoclomol in Niemann-Pick disease type C: Results from a double-blind, randomised, placebo-controlled, multinational phase 2/3 trial of a novel treatment.

Niemann-Pick disease type C (NPC) is a rare, genetic, progressive neurodegenerative disorder with high unmet medical need. We investigated the safety and efficacy of arimoclomol, which amplifies the heat shock response to target NPC protein misfolding and improve lysosomal function, in patients with NPC. In a 12-month, prospective, randomised, double-blind, placebo-controlled, phase 2/3 trial (ClinicalTrials.gov identifier: NCT02612129), patients (2-18 years) were randomised 2:1 to arimoclomol:placebo, stratified by miglustat use. Routine clinical care was maintained. Arimoclomol was administered orally three times daily. The primary endpoint was change in 5-domain NPC Clinical Severity Scale (NPCCSS) score from baseline to 12 months. Fifty patients enrolled; 42 completed. At month 12, the mean progression from baseline in the 5-domain NPCCSS was 0.76 with arimoclomol vs 2.15 with placebo. A statistically significant treatment difference in favour of arimoclomol of -1.40 (95% confidence interval: -2.76, -0.03; P = .046) was observed, corresponding to a 65% reduction in annual disease progression. In the prespecified subgroup of patients receiving miglustat as routine care, arimoclomol resulted in stabilisation of disease severity over 12 months with a treatment difference of -2.06 in favour of arimoclomol (P = .006). Adverse events occurred in 30/34 patients (88.2%) receiving arimoclomol and 12/16 (75.0%) receiving placebo. Fewer patients had serious adverse events with arimoclomol (5/34, 14.7%) vs placebo (5/16, 31.3%). Treatment-related serious adverse events (n = 2) included urticaria and angioedema. Arimoclomol provided a significant and clinically meaningful treatment effect in NPC and was well tolerated.

Should patients with Phosphomannomutase 2-CDG (PMM2-CDG) be screened for adrenal insufficiency?

PMM2-CDG is the most common congenital disorder of glycosylation (CDG) accounting for almost 65% of known CDG cases affecting N-glycosylation. Abnormalities in N-glycosylation could have a negative impact on many endocrine axes. There is very little known on the effect of impaired N-glycosylation on the hypothalamic-pituitary-adrenal axis function and whether CDG patients are at risk of secondary adrenal insufficiency and decreased adrenal cortisol production. Cortisol and ACTH concentrations were simultaneously measured between 7:44 am to 1 pm in forty-three subjects (20 female, median age 12.8 years, range 0.1 to 48.6 years) participating in an ongoing international, multi-center Natural History study for PMM2-CDG (ClinicalTrials.gov Identifier: NCT03173300). Of the 43 subjects, 11 (25.6%) had cortisol below 5 µg/dl and low to normal ACTH levels, suggestive of secondary adrenal insufficiency. Two of the 11 subjects have confirmed central adrenal insufficiency and are on hydrocortisone replacement and/or stress dosing during illness; 3 had normal and 1 had subnormal cortisol response to ACTH low-dose stimulation test but has not yet been started on therapy; the remaining 5 have upcoming stimulation testing planned. Our findings suggest that patients with PMM2-CDG may be at risk for adrenal insufficiency. Monitoring of morning cortisol and ACTH levels should be part of the standard care in patients with PMM2-CDG.

Free sialic acid storage disorder: Progress and promise.

Lysosomal free sialic acid storage disorder (FSASD) is an extremely rare, autosomal recessive, neurodegenerative, multisystemic disorder caused by defects in the lysosomal sialic acid membrane exporter SLC17A5 (sialin). SLC17A5 defects cause free sialic acid and some other acidic hexoses to accumulate in lysosomes, resulting in enlarged lysosomes in some cell types and 10-100-fold increased urinary excretion of free sialic acid. Clinical features of FSASD include coarse facial features, organomegaly, and progressive neurodegenerative symptoms with cognitive impairment, cerebellar ataxia and muscular hypotonia. Central hypomyelination with cerebellar atrophy and thinning of the corpus callosum are also prominent disease features. Around 200 FSASD cases are reported worldwide, with the clinical spectrum ranging from a severe infantile onset form, often lethal in early childhood, to a mild, less severe form with subjects living into adulthood, also called Salla disease. The pathobiology of FSASD remains poorly understood and FSASD is likely underdiagnosed. Known patients have experienced a diagnostic delay due to the rarity of the disorder, absence of routine urine sialic acid testing, and non-specific clinical symptoms, including developmental delay, ataxia and infantile hypomyelination. There is no approved therapy for FSASD. We initiated a multidisciplinary collaborative effort involving worldwide academic clinical and scientific FSASD experts, the National Institutes of Health (USA), and the FSASD patient advocacy group (Salla Treatment and Research [S.T.A.R.] Foundation) to overcome the scientific, clinical and financial challenges facing the development of new treatments for FSASD. We aim to collect data that incentivize industry to further develop, obtain approval for, and commercialize FSASD treatments. This review summarizes current aspects of FSASD diagnosis, prevalence, etiology, and disease models, as well as challenges on the path to therapeutic approaches for FSASD.

Spontaneous improvement of carbohydrate-deficient transferrin in PMM2-CDG without mannose observed in CDG natural history study.

A recent report on long-term dietary mannose supplementation in phosphomannomutase 2 deficiency (PMM2-CDG) claimed improved glycosylation and called for double-blind randomized study of the dietary supplement in PMM2-CDG patients. A lack of efficacy of short-term mannose supplementation in multiple prior reports challenge this study's conclusions. Additionally, some CDG types have previously been reported to demonstrate spontaneous improvement in glycosylated biomarkers, including transferrin. We have likewise observed improvements in transferrin glycosylation without mannose supplementation. This observation questions the reliability of transferrin as a therapeutic outcome measure in clinical trials for PMM2-CDG. We are concerned that renewed focus on mannose therapy in PMM2-CDG will detract from clinical trials of more promising therapies. Approaches to increase efficiency of clinical trials and ultimately improve patients' lives requires prospective natural history studies and identification of reliable biomarkers linked to clinical outcomes in CDG. Collaborations with patients and families are essential to identifying meaningful study outcomes.