Molecular Diagnosis of Pompe Disease in the Genomic Era: Correlation with Acid Alpha-Glucosidase Activity in Dried Blood Spots.

Measurement of alpha-glucosidase activity on dried blood spots has been the main method to screen for Pompe disease, but a paradigm shift has been observed in recent years with the incorporation of gene panels and exome sequencing in molecular diagnostic laboratories. An 89-gene panel has been available to Canadian physicians since 2017 and was analyzed in 2030 patients with a suspected muscle disease. Acid alpha-glucosidase activity was measured in parallel in dried blood spots from 1430 patients. Pompe disease was diagnosed in 14 patients, representing 0.69% of our cohort. In 7 other patients, low enzyme activities overlapping those of Pompe disease cases were attributable to the presence of pseudodeficiency alleles. Only two other patients had enzymatic activity in the Pompe disease range, and a single heterozygous pathogenic variant was identified. It is possible that a second variant could have been missed; we suggest that RNA analysis should be considered in such cases. With gene panel testing increasingly being performed as a first-tier analysis of patients with suspected muscle disorders, our study supports the relevance of performing reflex enzymatic activity assay in selected patients, such as those with a single GAA variant identified and those in whom the observed genotype is of uncertain clinical significance.

Low prevalence of bilateral (presumed nutritional) optic neuropathy as a cause of blindness in the Gambia.

OBJECTIVE: Previous reports of epidemics of optic neuropathy in Africa have mainly focused on eastern and central areas. Our study aimed to measure the prevalence of optic neuropathy in The Gambia, a West African country, and compare this prevalence with a simultaneously occurring epidemic of optic neuropathy, now considered endemic, in Tanzania. METHODS: The sample population, derived from the Gambian National Blindness Survey (1996), was selected using simple random sampling. Thirty-three cases of low vision/blindness were identified where optic neuropathy was the sole cause of visual loss. Within a month, 31 cases were located and these patients underwent ophthalmic and peripheral nerve assessment and completed lifestyle questionnaires. RESULTS: Five of the 31 individuals were found to have bilateral symmetrical optic neuropathy. Although it was not possible to fully ascertain etiology, the phenotype is compatible with epidemic, presumed nutritional, optic neuropathy described in Tanzania. Comparative prevalence data suggest a prevalence of 0.07% in The Gambia based on a total sample size of 6873 vs 2.4% in Tanzania. CONCLUSION: Our data indicate that bilateral optic neuropathy is nonepidemic in The Gambia. Rare vitamin B12 and folate deficiencies reported in rural Gambians may explain the low prevalence because previous epidemics were due to nutrient deficiency. Our study is the only available estimate of epidemic optic neuropathy in The Gambia and, as such, provides an important contribution to our knowledge in identifying characteristics that may cause specific populations to be more susceptible to this public health burden.

Low folate status and indoor pollution are risk factors for endemic optic neuropathy in Tanzania.

AIMS: Bilateral optic neuropathy in Dar-es-Salaam, Tanzania was first reported as an epidemic in 1988. Now argued to be endemic in 2010, the aetiology remains unclear. The authors investigated the hypothesis that low folate and vitamin B12 status are associated with optic neuropathy, and also sought to investigate whether mercury, commonly used drugs, dietary factors and indoor pollution may also be risk factors. METHODS: 57 cases and 102 controls were recruited from two tertiary referral centres in Dar-es-Salaam. Data were collected on demographic characteristics, diet, medication history and HIV status. Folate and vitamin B12 (holo-transcobalamin) were measured in stored serum samples. Exposure to mercury was assessed from concentrations in random urine samples. RESULTS: Cooking indoors more than twice per week (OR 54.48 (95% CI 9.30 to 319.10)) and indoor use of charcoal or firewood (OR 21.20 (95% CI 2.51 to 179.36)) increased the risk of optic neuropathy. Risk was reduced in those with a higher folate status (highest versus lowest quartile OR=0.11 (95% CI 0.02 to 0.51)) and higher protein intakes (OR=0.84 (95% CI 0.72 to 0.96). No association was found with mercury exposure or any common drug or food commodity. CONCLUSION: This study presents the first direct evidence of low folate status and indoor pollution in the aetiology of endemic bilateral optic neuropathy in Tanzania.

Epidemic optic neuropathy is evident in the Somalian population.

BACKGROUND: Optic neuropathy epidemics have proven to be a serious public health problem around the world. Recently, documented outbreaks have occurred in Cuba and Tanzania, with almost identical clinical presentation. Investigations of both epidemics have implicated nutritional deficiencies as part of a multifactorial etiology, and thus, it is proposed that there may be many undetected epidemics in other food-deprived nations. Somalia, a country subject to prolonged droughts and civil war, may be at particular risk of nutritional deficits. We conducted a case series in Mogadishu, the Somalian capital, with the aim of identifying and characterizing any cases of epidemic optic neuropathy. METHODS: Cases were recruited at the Al-Noor Eye Hospital, Mogadishu, between 2002 and 2004. Individuals were screened by trained ophthalmic nurses, and a full ophthalmic examination was undertaken by an experienced ophthalmologist. Patients also completed a lifestyle questionnaire to identify any common risk factors. RESULTS: One hundred five acute cases of optic neuropathy were identified. Progression from hyperemia to pallor of the optic discs and greatest visual loss occurred over the first month. Our findings are similar to those reported in the Tanzanian epidemic, including involvement of young patients (mean age: 24 ± 5.3 years) and evidence of peripheral neuropathy. CONCLUSION: Epidemic levels of optic neuropathy are evident in Somalia. The extent of visual loss in the first month emphasizes the need to initiate treatment early in the course of the disease. Training and establishing health surveillance systems in community clinics may form a central component to this strategy.

Confirming statements about pictures of natural scenes: evidence of the processing of gist from eye movements.

Combined displays of graphics and text, such as figure captions in newspapers and books, lead to distinctive inspection patterns, or scanpaths. Readers characteristically look very briefly at the picture, and then read the caption, and then look again at the picture. The initial inspection of the picture is the focus of interest in the present experiment, in which we attempted to modify the inspection by giving participants advance knowledge of the subject of a sentence (the cued object) that was to be verified or denied on the basis of whether it correctly described some aspect of the scene shown in the picture. Eye fixations were recorded while the viewers looked at the picture and the sentence in whatever sequence they chose. By allowing viewers to know the subject of the sentence in advance, we asked whether patterns of fixations on the sentence and on the second inspection of the picture would reflect prior knowledge of the focus of the sentence. Providing advance information did not influence eye movements while reading the sentence. It did, however, increase the number of fixations in the initial inspection of the picture, and it also reduced the number and duration of the fixations on the pictures overall. The results suggest that cueing participants to the object allowed increased coding in the initial inspection of the picture, though the benefit of such coding only becomes apparent when the picture is inspected for the second time.