Natural History of Leigh Syndrome: A Study of Disease Burden and Progression.

OBJECTIVE: This observational cohort study aims to quantify disease burden over time, establish disease progression rates, and identify factors that may determine the disease course of Leigh syndrome. METHODS: Seventy-two Leigh syndrome children who completed the Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) at baseline at 3.7 years (interquartile range [IQR] = 2.0-7.6) and follow-up assessments at 7.5 years (IQR = 3.7-11.0) in clinics were enrolled. Eighty-two percent of this cohort had a confirmed genetic diagnosis, with pathogenic variants in the MT-ATP6 and SURF1 genes being the most common cause. The total NPMDS scores denoted mild (0-14), moderate (15-25), and severe (>25) disease burden. Detailed clinical, neuroradiological, and molecular genetic findings were also analyzed. RESULTS: The median total NPMDS scores rose significantly (Z = -6.9, p < 0.001), and the percentage of children with severe disease burden doubled (22% → 42%) over 2.6 years of follow-up. Poor function (especially mobility, self-care, communication, feeding, and education) and extrapyramidal features contributed significantly to the disease burden (τb  ≈ 0.45-0.68, p < 0.001). These children also deteriorated to wheelchair dependence (31% → 57%), exclusive enteral feeding (22% → 46%), and one-to-one assistance for self-care (25% → 43%) during the study period. Twelve children (17%) died after their last NPMDS scores were recorded. These children had higher follow-up NPMDS scores (disease burden; p < 0.001) and steeper increase in NPMDS score per annum (disease progression; p < 0.001). Other predictors of poor outcomes include SURF1 gene variants (p < 0.001) and bilateral caudate changes on neuroimaging (p < 0.01). INTERPRETATION: This study has objectively defined the disease burden and progression of Leigh syndrome. Our analysis has also uncovered potential influences on the trajectory of this neurodegenerative condition. ANN NEUROL 2022;91:117-130.

Relative acidic compartment volume as a lysosomal storage disorder-associated biomarker.

Lysosomal storage disorders (LSDs) occur at a frequency of 1 in every 5,000 live births and are a common cause of pediatric neurodegenerative disease. The relatively small number of patients with LSDs and lack of validated biomarkers are substantial challenges for clinical trial design. Here, we evaluated the use of a commercially available fluorescent probe, Lysotracker, that can be used to measure the relative acidic compartment volume of circulating B cells as a potentially universal biomarker for LSDs. We validated this metric in a mouse model of the LSD Niemann-Pick type C1 disease (NPC1) and in a prospective 5-year international study of NPC patients. Pediatric NPC subjects had elevated acidic compartment volume that correlated with age-adjusted clinical severity and was reduced in response to therapy with miglustat, a European Medicines Agency­approved drug that has been shown to reduce NPC1-associated neuropathology. Measurement of relative acidic compartment volume was also useful for monitoring therapeutic responses of an NPC2 patient after bone marrow transplantation. Furthermore, this metric identified a potential adverse event in NPC1 patients receiving i.v. cyclodextrin therapy. Our data indicate that relative acidic compartment volume may be a useful biomarker to aid diagnosis, clinical monitoring, and evaluation of therapeutic responses in patients with lysosomal disorders.

Altered distribution and function of natural killer cells in murine and human Niemann-Pick disease type C1.

Niemann-Pick type C (NPC) is a neurodegenerative lysosomal storage disorder caused by defects in the lysosomal proteins NPC1 or NPC2. NPC cells are characterized by reduced lysosomal calcium levels and impaired sphingosine transport from lysosomes. Natural killer (NK) cells kill virally infected/transformed cells via degranulation of lysosome-related organelles. Their trafficking from lymphoid tissues into the circulation is dependent on sphingosine-1-phosphate (S1P) gradients, sensed by S1P receptor 5 (S1P5). We hypothesized that NK-cell function and trafficking could be affected in NPC disease due to the combined effects of the lysosomal calcium defect and sphingosine storage. In an NPC1 mouse model, we found the frequency of NK cells was altered and phenocopied S1P5-deficient mice, consistent with defects in S1P levels. NK cells from NPC1 mice also had a defect in cytotoxicity due to a failure in degranulation of cytotoxic granules, which was associated with reduced lysosomal calcium levels. Affected NPC1 patients and NPC1 heterozygote carriers had reduced NK-cell numbers in their blood and showed similar phenotypic and developmental changes to those observed in the NPC1 mouse. These findings highlight the effects of lysosomal storage on the peripheral immune system.

SURF1 deficiency: a multi-centre natural history study.

BACKGROUND: SURF1 deficiency, a monogenic mitochondrial disorder, is the most frequent cause of cytochrome c oxidase (COX) deficient Leigh syndrome (LS). We report the first natural history study of SURF1 deficiency. METHODS: We conducted a multi-centre case notes review of 44 SURF1-deficient patients from ten different UK centres and two Australian centres. Survival data for LRPPRC-deficient LS and nuclear-encoded complex I-deficient LS patients were obtained from previous publications. The survival of SURF1-deficient patients was compared with these two groups using Kaplan-Meier survival analysis and logrank test. RESULTS: The majority of patients (32/44, 73%) presented in infancy (median 9.5 months). Frequent symptoms were poor weight gain (95%, median age 10 months), hypotonia (93%, median age 14 months), poor feeding/vomiting (89%, median age 10 months), developmental delay (88%, median age 14 months), developmental regression (71%, median age 19 months), movement disorder (52%, median age 24 months), oculomotor involvement (52%, median age 29 months) and central respiratory failure (78%, median age 31 months). Hypertrichosis (41%), optic atrophy (23%), encephalopathy (20%), seizures (14%) and cardiomyopathy (2%) were observed less frequently. CONCLUSIONS: SURF1-deficient patients have a homogeneous clinical and biochemical phenotype. Early recognition is essential to expedite diagnosis and enable prenatal diagnosis.

Invariant natural killer T cells are not affected by lysosomal storage in patients with Niemann-Pick disease type C.

Invariant natural killer T (iNKT) cells are a specialised subset of T cells that are restricted to the MHC class I like molecule, CD1d. The ligands for iNKT cells are lipids, with the canonical superagonist being α-galactosylceramide, a non-mammalian glycosphingolipid. Trafficking of CD1d through the lysosome is required for the development of murine iNKT cells. Niemann-Pick type C (NPC) disease is a lysosomal storage disorder caused by dysfunction in either of two lysosomal proteins, NPC1 or NPC2, resulting in the storage of multiple lipids, including glycosphingolipids. In the NPC1 mouse model, iNKT cells are virtually undetectable, which is likely due to the inability of CD1d to be loaded with the selecting ligand due to defective lysosomal function and/or CD1d trafficking. However, in this study we have found that in NPC1 patients iNKT cells are present at normal frequencies, with no phenotypic or functional differences. In addi-tion, antigen-presenting cells derived from NPC1 patients are functionally competent to present several different CD1d/iNKT-cell ligands. This further supports the hypothesis that there are different trafficking requirements for the development of murine and human iNKT cells, and a functional lysosomal/late-endosomal compartment is not required for human iNKT-cell development.

Using path analysis to understand parents' perceptions of their children's weight, physical activity and eating habits in the Champlain region of Ontario.

INTRODUCTION: Parents have a fundamental role in promoting the healthy weight of their children. OBJECTIVES: To determine parental perceptions of their child's body weight, eating and physical activity (PA) behaviours, and to test a predictive model of parental perceptions regarding their child's PA and healthy eating behaviours. METHODS: A random-digit telephone survey was conducted among parents of children four to 12 years of age living in the Champlain region of Ontario. Descriptive statistics were used to summarize the responses. Path analysis was used to identify predictors of parental perceptions of PA and healthy eating. RESULTS: The study sample consisted of 1940 parents/caregivers. Only 0.2% of parents reported their child as being obese; 8.6% reported their child as being overweight. Most parents perceived their child to be physically active and eating healthily. Approximately 25% of parents reported that their child spent 2 h/day or more in front of a screen, and that their child consumed less than three servings of fruits and vegetables daily, and regularly consumed fast food. Variables that correlated with PA perceptions included time spent reading/doing homework, interest in PA, perceived importance of PA, frequency of PA, level of parental PA, participation in organized sport, child weight and parental concern for weight. Variables that predicted perceptions regarding healthy eating were parental education, household income, preparation of home-cooked meals, fruit and vegetable intake, and concern for and influence on the child's weight. CONCLUSIONS: Parents in the present study sample did not appear to understand, or had little knowledge of the recommendations for PA and healthy eating in children. Parents appeared to base their judgment of healthy levels of PA or healthy eating behaviours using minimal criteria; these criteria are inconsistent with those used by health professionals to define adequate PA and healthy eating. The present survey highlights an important knowledge gap between scientific opinion and parental perceptions of the criteria for healthy PA and eating behaviours.