Revisiting the roles of glucose transporters in skeletal muscle physiology: is GLUT10 a novel player?

Skeletal muscle is the largest metabolic tissue responsible for systemic glucose handling. Glucose uptake into skeletal tissue is highly dynamic and delicately regulated, in part through the controlled expression and subcellular trafficking of multiple types of glucose transporters. Although the roles of GLUT4 in skeletal muscle metabolism are well established, the physiological significance of other, seemingly redundant, glucose transporters remain incompletely understood. Nonetheless, recent studies have shed light on the roles of several glucose transporters, such as GLUT1 and GLUT10, in skeletal muscle. Mice experiments suggest that GLUT10 could be a novel player in skeletal muscle metabolism in the context of mechanical overload, which is in line with the meta-analytical results of gene expression changes after resistance exercise in humans. Herein we discuss the knowns, unknowns, and implications of these recent findings.

Clinical manifestations of psychogenic non-epileptic seizures in children: Experiences from a single center.

BACKGROUND: This study aimed to determine the clinical features of psychogenic non-epileptic seizures (PNES) and to enhance the accuracy of the differential diagnosis of epilepsy. METHODS: This retrospective case series included patients diagnosed with PNES between December 2003 and February 2019 at Taipei Veterans General Hospital. We used International Classification of Diseases (10th revision) codes for screening, and relevant medical records were reviewed. Experienced pediatric neurologists diagnosed PNES based on clinical manifestations, and occasionally on confirmatory video-electroencephalography (EEG) or simultaneous scalp-EEG during the paroxysmal attack. General information, clinical manifestations, psychological conditions, and relevant laboratory or imaging test results were collected and analyzed. RESULTS: Twenty-six patients (mean age, 13 years 8 months) were evaluated, 9 male and 17 female. Ten patients with PNES had a previously established diagnosis of epilepsy. The duration between symptom onset and diagnosis ranged from 1 to 120 (mean, 21; median, 12) days. Sixteen patients showed possible causative psychosocial stressors. Multiple characteristic features or specific clinical manifestations of PNES-that usually differ from epileptic seizures-were observed in all patients with PNES. CONCLUSION: A detailed evaluation of clinical manifestations and medical history is important for the accurate diagnosis of PNES.

Cardiomyocyte Globotriaosylceramide Accumulation in Adult Male Patients with Fabry Disease and IVS4 + 919G>A GLA Mutation is Progressive with Age and Correlates with Left Ventricular Hypertrophy and Reduced Left Ventricular Ejection Fraction.

Background: While cardiovascular complications are the most common cause of mortality in Fabry disease, the relationship between globotriaosylceramide (GL-3) accumulation, the hallmark of Fabry cardiomyopathy, and cardiac hypertrophy has not been fully elucidated. Methods: We developed unbiased stereology protocols to quantify the ultrastrcture of Fabry cardiomyopathy. Endomyocardial biopsies from 10 adult male enzyme replacement therapy naïve Fabry patients with IVS4 + 919G>A GLA mutation were studied. The findings were correlated with cardiac MRI and clinical data. Results: Ultrastructural parameters showed significant relationships with key imaging and clinical and functional variables. Average cardiomyocyte volume and GL-3 volume per cardiomyocyte were progressively increased with age. Eighty-four percent of left ventricular mass index (LVMI) variability was explained by cardiomyocyte nuclear volume, age and plasma globotriaosylsphingosine with cardiomyocyte nuclear volume being the only independent predictor of LVMI. Septal thickness was directly and left ventricular ejection fraction (LVEF) was inversely correlated with cardiomyocyte GL-3 accumulation. Sixty-five percent of left ventricular ejection fraction (LVEF) variability was explained by cardiomyocyte GL3 volume, serum α-galactosidase-A activity and age with cardiomyocyte GL3 volume being the only independent predictor of LVEF. Residual α-galactosidase-A activity was directly correlated with myocardial microvasculature density. Conclusions: The unbiased stereological methods introduced in this study unraveled novel relationships between cardiomyocyte structure and important imaging and clinical parameters. These novel tools can help better understand Fabry cardiomyopathy pathophysiology.

Spontaneous Assembly and Three-Dimensional Stacking of Antiaromatic 5,15-Dioxaporphyrin on HOPG.

Antiaromatic compounds have recently received considerable attention because of their novel properties such as narrow HOMO-LUMO gaps and facile formation of mutual stacking. Here, the spontaneous assembly of antiaromatic meso-2-thienyl-substituted 5,15-dioxaporphyrin (DOP-1) is scrutinized at the liquid-solid interface by scanning tunneling microscopy (STM). Polymorphism in monolayers characterized by the orthogonal and parallel assemblies is found at the low concentration of 0.05 mM. The parallel assembly is more stable and dominantly formed at higher concentrations. Aggregation was observed at concentrations >0.2 mM, and the STM images of the aggregates implied the formation of stacked layers. The intrinsic electronic structures of the mutually stacked bilayer generated by applying an electric pulse to the monolayer were probed by scanning tunneling spectroscopy to reveal the narrowing of the HOMO-LUMO gap by about 20 % compared with the monolayer, thus suggesting significant molecular orbital interactions.

Role of Ketogenic Diets in Multiple Sclerosis and Related Animal Models: An Updated Review.

Prescribing a ketogenic diet (KD) is a century-old dietary intervention mainly used in the context of intractable epilepsy. The classic KD and its variants regained popularity in recent decades, and they are considered potentially beneficial in a variety of neurological conditions other than epilepsy. Many patients with multiple sclerosis (MS) have attempted diet modification for better control of their disease, although evidence thus far remains insufficient to recommend a specific diet for these patients. The results of 3 pilot clinical trials of KD therapy for MS, as well as several related studies, have been reported in recent years. The preliminary findings suggest that KD is safe, feasible, and potentially neuroprotective and disease-modifying for patients with MS. Research on corresponding rodent models has also lent support to the efficacy of KD in the prevention and treatment of experimental autoimmune encephalomyelitis and toxin-induced inflammatory demyelinating conditions in the brain. Furthermore, the animal studies have yielded mechanistic insights into the molecular mechanisms of KD action in relevant situations, paving the way for precision nutrition. Herein we review and synthesize recent advances and also identify unresolved issues, such as the roles of adipokines and gut microbiota, in this field. Hopefully this panoramic view of current understanding can inform future research directions and clinical practice with regard to KD in MS and related conditions.

Novel lissencephaly-associated DCX variants in the C-terminal DCX domain affect microtubule binding and dynamics.

OBJECTIVE: Pathogenic variants in DCX on the X chromosome lead to lissencephaly and subcortical band heterotopia (SBH), brain malformations caused by neuronal migration defects. Its product doublecortin (DCX) binds to microtubules to modulate microtubule polymerization. How pathogenic DCX variants affect these activities remains not fully investigated. METHODS: DCX variants were identified using whole exome and Sanger sequencing from six families with lissencephaly/SBH. We examined how these variants affect DCX functions using microtubule binding, regrowth, and colocalization assays. RESULTS: We found novel DCX variants p.Val177AlafsTer31 and p.Gly188Trp, as well as reported variants p.Arg196His, p.Lys202Met, and p.Thr203Ala. Incidentally, all of the missense variants were clustered on the C-terminal DCX domain. The microtubule binding ability was significantly decreased in p.Val177AlafsTer31, p.Gly188Trp, p.Lys202Met, and previously reported p.Asp262Gly variants. Furthermore, expression of p.Val177AlafsTer31, p.Gly188Trp, p.Arg196His, p.Lys202Met, and p.Asp262Gly variants hindered microtubule growth in cells. There were also decreases in the colocalization of p.Val177AlafsTer31, p.Thr203Ala, and p.Asp262Gly variants to microtubules. SIGNIFICANCE: Our results indicate that these variants in the C-terminal DCX domain altered microtubule binding and dynamics, which may underlie neuronal migration defects during brain development.

Indolent enhancing spinal lesions mimicking spinal metastasis in pediatric patients with malignant primary brain tumors.

Spinal metastasis from malignant primary brain tumors (MPBTs) in pediatric patients is rare and often appears as enhancing lesions on MRI. However, some indolent enhancing spinal lesions (IESLs) resulting from previous treatment mimic metastasis on MRI, leading to unnecessary investigation and treatment. In 2005-2020, we retrospectively enrolled 12 pediatric/young patients with clinical impression of spinal metastasis and pathological diagnosis of their spinal lesions. Three patients had MPBT with IESL, and 9 patients had malignant tumors with metastases. The histopathologic diagnosis of IESL was unremarkable marrow change. We evaluated their MRI, CT, and bone scan findings. The following imaging findings of IESL vs. spinal metastasis were noted: (1) IESLs appeared round/ovoid (3/3, 100%), whereas spinal metastasis appeared irregular (9/9, 100%) (P = 0.005); (2) target-shaped enhancement was noted in (3/3, 100%) vs. (0/9, 0%) of cases, respectively (P = 0.005); (3) pathologic fracture of the vertebral body was noted in (1/3, 33.3%) vs. (9/9, 100%) of cases, respectively (P = 0.045); (4) expansile vertebral shape was noted in (0/3, 0%) vs. (9/9, 100%) of cases, respectively (P = 0.005); (5) obliteration of the basivertebral vein was noted in (0/3, 0%) vs. (9/9, 100%) of cases, respectively (P = 0.005); and (6) osteoblastic change on CT was noted in (3/3, 100%) vs. (2/9, 22.2%) of cases, respectively (P = 0.034). IESL in pediatric patients with MPBT can be differentiated from metastasis based on their imaging characteristics. We suggest close follow-up rather than aggressive investigation and treatment for IESL.

Clinical spectrum and the comorbidities of Dravet syndrome in Taiwan and the possible molecular mechanisms.

Dravet syndrome (DS) is an uncommon epilepsy syndrome that may negatively affect the patients and their caregivers. However, reliable and valid measures of its impact on caregivers and the characteristics of patients with DS in Taiwan are lacking. This study aimed to describe the characteristics of patients with DS and concerns of their caregivers and establish a baseline frequency of disease characteristics using a cross-sectional survey in Taiwan. We assessed the caregivers of patients with DS using an online anonymous questionnaire. The seizure frequency decreased with age, although lacking statistical significance. Vaccines show no influence on the condition of patients with DS. Our findings revealed the highest impact on the domains affecting the caregivers' daily life, including additional household tasks, symptom observation, further medical plan, and financial issues. Caregivers also expressed concerns regarding the lack of independence/constant care, seizure control, speech/communication, and impacts on siblings because of long-term care of the patients in parents' absence. Our findings highlight the significant effects of caring for a child with DS on the lives of their caregivers in Taiwan; these findings will help raise awareness regarding the needs of these families. Furthermore, we discussed the possible pathophysiological mechanisms of associated comorbidities.

Hypothesis: Febrile infection-related epilepsy syndrome is a microglial NLRP3 inflammasome/IL-1 axis-driven autoinflammatory syndrome.

FIRES (febrile infection-related epilepsy syndrome) is a protracted neuroinflammatory condition of obscure cause. It mainly afflicts school-age children and often leads to permanent neurological sequelae. Most treatments to date have been of limited efficacy, while ketogenic diet and anti-interleukin-1 therapy appear beneficial for some patients. Research into this clinical entity is hampered by its rarity and complexity. Nonetheless, accumulating evidence derived from basic investigations and clinical observations converges to implicate the autoinflammatory nature of this syndrome. A closer analysis of current literature suggests that microglia and the NLRP3 inflammasome might be the pivotal cellular and molecular players in FIRES pathogenesis, respectively. Through evidence synthesis, herein we formulate the working hypothesis of overactivation of microglial NLRP3 inflammasome/interleukin-1 axis as the driving event in FIRES by creating a proinflammatory and proconvulsive milieu. The reverberation between neuroinflammation and seizure forms a vicious cycle. The unique properties of microglia might also contribute to unopposed IL-1 signalling and incessant sterile neuroinflammation in this context. The potential therapeutic relevance of the proposed conceptual framework is discussed.

Cognitive Assessment and Rehabilitation for Pediatric-Onset Multiple Sclerosis: A Scoping Review.

Cognitive impairment is increasingly recognized as an important clinical issue in pediatric multiple sclerosis (MS). However, variations regarding its assessment and remediation are noted in clinical arena. This scoping review aims to collate available evidence concerning cognitive assessment tool and cognitive rehabilitation for pediatric MS. We performed a systematic search of electronic databases (MEDLINE, PubMed, CINAHL Plus, and Web of Science) from inception to February 2020. Reference lists of included articles and trial registers were also searched. We included original studies published in English that addressed cognitive assessment tools or cognitive rehabilitation for pediatric-onset MS. Fourteen studies fulfilled our inclusion criteria. Among them, 11 studies evaluated the psychometric aspects of various cognitive assessment tools in the context of pediatric MS, and different neuro-cognitive domains were emphasized across studies. There were only three pilot studies reporting cognitive rehabilitation for pediatric-onset MS, all of which used home-based computerized programs targeting working memory and attention, respectively. Overall, more systematic research on cognitive assessment tools and rehabilitation for pediatric MS is needed to inform evidence-based practice. Computer-assisted cognitive assessment and rehabilitation appear feasible and deserve further studies.

Cardiac manifestations in patients with classical or cardiac subtype of Fabry disease.

BACKGROUND: Fabry disease (FD) is an X-linked lysosomal storage disorder engendered by a deficiency of the enzyme α-galactosidase A, leading to systemic accumulation of glycolipids. Studies have reported that the cardiac subtype of FD has a later onset and minimal extracardiac involvement. However, whether the severity of cardiac involvement differs between the classic and cardiac subtypes of FD remains unclear. METHODS: We enrolled consecutive patients with classic FD (n = 22; median age [25th-75th percentile], 47.0 [32.75-56.25] years; men, 72.7%) as well as age- and sex-matched patients with a later-onset cardiac subtype of FD who were selected from our cohort of patients with IVS4 919G>A mutation. FD was diagnosed on the basis of clinical symptoms/signs and pedigree screening of index case, plasma α-galactosidase activity, and molecular analysis. Data on clinical manifestations, laboratory findings, and echocardiogram findings were collected before enzyme replacement treatment. Disease severity was evaluated using the Mainz Severity Score Index score. RESULTS: All female patients demonstrated heterozygous mutations, with five, one, and four of them showing normal α-galactosidase activity, classic FD, and cardiac subtype of FD, respectively. The distributions of left ventricular performance indices and comorbidities, including hypertension, diabetes mellitus, and dyslipidemia, were similar between the two groups. Moreover, MSSI cardiovascular scores did not differ significantly between the groups (classic vs cardiac subtype, 10.0 [2.0-12.5] vs 10.5 [9.0-15.25]; p = 0.277). CONCLUSION: Cardiac manifestations are similar between patients with classic and cardiac subtype of FD.

Analysis of Renal and Cardiac Outcomes in Male Participants in the Fabry Outcome Survey Starting Agalsidase Alfa Enzyme Replacement Therapy Before and After 18 Years of Age.

PURPOSE: To determine the impact of initiating enzyme replacement therapy (ERT) with agalsidase alfa early in the course of Fabry disease, we evaluated renal and cardiac outcomes for ≤10 years after ERT initiation in males from the Fabry Outcome Survey (FOS). PATIENTS AND METHODS: Male patients from FOS were stratified into three cohorts by age at ERT initiation: ≤18 years (cohort 1), >18 and ≤30 years (cohort 2), and >30 years (cohort 3). Analysis included age at symptom onset, diagnosis, and ERT initiation; ERT duration; FOS-Mainz Severity Score Index (FOS-MSSI); estimated glomerular filtration rate (eGFR); proteinuria level; and left ventricular mass indexed to height (LVMI). Mixed-effect models estimated renal and cardiac outcomes during follow-up between and within cohorts. FINDINGS: The analysis included 560 male patients: 151 (27.0%) in cohort 1, 155 (27.7%) in cohort 2, and 254 (45.4%) in cohort 3. Mean±SD duration of ERT for cohorts 1, 2, and 3 was 6.3±4.3, 8.6±4.9, and 7.9±4.9 years, respectively. Mean±SD baseline FOS-MSSI scores increased with age from 9.8±7.2 in cohort 1 to 24.7±11.4 in cohort 3. Cohort 3 showed the lowest baseline mean±SD value for eGFR (87.1±29.0 mL/min/1.73m2) and highest baseline mean±SD values for proteinuria (801.9±952.6 mg/day) and LVMI (56.7±16.0 g/m2.7) among the three cohorts. Evaluation of mean annual rates of change in eGFR, proteinuria, and LVMI revealed no significant differences in any parameter for cohort 1. For cohort 2, proteinuria and LVMI remained stable, whereas eGFR significantly deteriorated annually (-1.12 mL/min/1.73m2; P<0.001). Cohort 3 demonstrated significant annual deteriorations in eGFR (-2.60 mL/min/1.73m2; P<0.001), proteinuria (+34.10 mg/day; P<0.001), and LVMI (+0.59 g/m2.7; P=0.001). IMPLICATIONS: Renal and/or cardiac disease progression appears attenuated in patients starting ERT in childhood or early adulthood versus patients starting ERT in later adulthood. These findings support early ERT initiation in Fabry disease. ClinicalTrials.gov identifier: NCT03289065.

The Fabry disease-causing mutation, GLA IVS4+919G>A, originated in Mainland China more than 800 years ago.

The Fabry disease-causing mutation, the GLA IVS4+919G>A (designated GLA IVS4), is very prevalent in patients with hypertrophic cardiomyopathy in Taiwan. This X-linked mutation has also been found in patients in Kyushu, Japan and Southeast Asia. To investigate the age and the possible ancestral origin of this mutation, a total of 33 male patients with the GLA IVS4+919G>A mutation, born in Taiwan, Japan, Singapore, Malaysia, Vietnam, and the Fujian and Guangdong provinces of China, were studied. Peripheral bloods were collected, and the Ilumina Infinium CoreExome-24 microarray was used for dense genotyping. A mutation-carrying haplotype was discovered which was shared by all 33 patients. This haplotype does not exist in 15 healthy persons without the mutation. Rather, a wide diversity of haplotypes was found in the vicinity of the mutation site, supporting the existence of a single founder of the GLA IVS4 mutation. The age of the founder mutation was estimated by the lengths of the mutation-carrying haplotypes based on the linkage-disequilibrium decay theory. The first, second, and third quartile of the age estimates are 800.7, 922.6, and 1068.4 years, respectively. We concluded that the GLA IVS4+919G>A mutation originated from a single mutational event that occurred in a Chinese chromosome more than 800 years ago.

Identification of lysosomal and extralysosomal globotriaosylceramide (Gb3) accumulations before the occurrence of typical pathological changes in the endomyocardial biopsies of Fabry disease patients.

PURPOSE: Evaluation standards and treatment initiation timing have been debated for a long time, particularly for late-onset Fabry disease (FD), because of its slow progression. However, early initiation of enzyme replacement therapy (ERT) for FD could be effective in stabilizing the disease progression and potentially preventing irreversible organ damage. We aimed to examine globotriaosylceramide (Gb3) deposits in patients' endomyocardial biopsies to understand the early pathogenesis of FD cardiomyopathy. METHODS: Immunofluorescent (IF) staining of Gb3 and lysosomal-associated membrane protein 1 (LAMP-1) was performed on endomyocardial biopsies of patients suspected of Fabry cardiomyopathy who had negative or only slight Gb3 accumulation determined by toluidine blue staining and electron microscopic examination. RESULTS: The IF staining results revealed that all patients examined had abundant Gb3 accumulation in their cardiomyocytes, including the ones who are negative for inclusion bodies. Furthermore, we found that early Gb3 deposits were mostly confined within lysosomes, while they appeared extralysosomally at a later stage. CONCLUSION: A significant amount of lysosomal Gb3 deposits could be detected by IF staining in cardiac tissue before the formation of inclusion bodies, suggesting the cardiomyocytes might have been experiencing cellular stress and damage early on, before the appearance of typical pathological changes of FD during the disease progression.

Vagus nerve stimulation for 6- to 12-year-old children with refractory epilepsy: Impact on seizure frequency and parenting stress index.

OBJECTIVES: Refractory epilepsy (RE) is frequently associated with neuropsychological impairment in children and may disrupt their social development. Vagus nerve stimulation (VNS) had been reported to have beneficial effects on behavioral outcomes. The aim of this study was to compare Parenting Stress Index (PSI) scores before and after VNS device implantation in children with RE, especially those who experienced seizure frequency reduction. METHODS: We conducted a one-group pretest-posttest study in school age children with RE. Seizure frequency and PSI were recorded at 12months after VNS device implantation. RESULTS: Treatment with VNS was significantly associated with reduced seizure frequency and parental stress as measured by PSI. Factors contributing to seizure frequency included idiopathic/cryptogenic etiology and neurobehavioral comorbidities. In children with reduced seizure frequency, statistically significant improvements in the child domain of the PSI on the subscales of mood and reinforces parent were found. In the parent domain, the scores for social isolation were reduced. CONCLUSIONS: Treatment with VNS was significantly associated with reduced seizure frequency and improved PSI scores, especially within the child domain on the mood and reinforces parent subscales. These findings suggest that VNS reduced not only seizure frequency but also the psychological burden on children with RE.

Functional and biological studies of α-galactosidase A variants with uncertain significance from newborn screening in Taiwan.

Fabry disease is an X-linked disorder resulted from deficiency of α-galactosidase A (GLA) activity. In Taiwan, a total of 792,247 newborns were screened from 2008 to 2014 in two newborn screening centers, and 13 variants of uncertain significance (VOUS) in the GLA gene were identified. To determine whether these variants were pathogenic or not, functional, biochemical, clinical and pedigree analyses were performed. In vitro functional assay was established through site-directed mutagenesis, and four in silico tools were used to predict pathogenesis. The enzyme activity of dried blood spots and plasma metabolite lyso-Gb3 level from subjects with the variants were measured. Additionally, clinical manifestations were evaluated extensively from the subjects and their relatives. Our results revealed that p.G104V, p.I232T, p.D322H, and p.G360C all exhibited relatively low residual enzyme activities and elevated plasma lyso-Gb3 level. These data strongly suggest that these Fabry mutations may cause classical or later-onset phenotypes. In contrast, neither significantly clinical symptoms nor elevated lyso-Gb3 level was found in cases with p.P60S, p.A108T, p.S304T, p.R356Q, and p.P362T variants, which may be non-pathogenic or milder forms of Fabry variants. More data need to be included for the patients with p.N53D, p.P210S, p.M296L, and p.K391T variants. The established system provides us more information to classify these GLA variants.

Improvement in the sensitivity of newborn screening for Fabry disease among females through the use of a high-throughput and cost-effective method, DNA mass spectrometry.

Many female carriers of Fabry disease are likely to develop severe morbidity and mortality. However, by our own estimation, around 80% of female newborns are missed by our current enzyme-based screening approach. Our team's aim was to develop an improved cost-effective screening method that is able to detect Fabry disease among female newborns. In Taiwan, based on a database of 916,000 newborns, ~98% of Fabry patients carry mutations out of a pool of only 21 pathogenic mutations. An Agena iPLEX platform was designed to detect these 21 pathogenic mutations using only a single-assay panel. A total of 54,791 female infants were screened and 136 female newborns with the IVS4 + 919G > A mutation and one female newborn with the c.656T > C mutation were identified. Using the current enzyme-based newborn screening approach as baseline, around 83% of female newborns are being missed. Through a family study of the IVS4 female newborns, 30 IVS4 adult family members were found to have left ventricular hypertrophy. Ten patients received endomyocardial biopsy and all were found to have significant globotriaosylceramide (Gb3) accumulation in their cardiomyocytes. All of these individuals now receive enzyme replacement therapy. We have demonstrated that the Agena iPLEX assay is a powerful tool for detecting females with Fabry disease. Furthermore, through this screening, we also have been able to identify many disease-onset adult family members who were originally undiagnosed for Fabry disease. This screening helps them to receive treatment in time before severe and irreversible cardiac damage has occurred.

Fabry disease: Review and experience during newborn screening.

Fabry disease (FD) is an X-linked lysosomal storage disease and is the result of mutation in the α-Galactosidase A gene; such mutations cause a deficiency in α-Galactosidase A enzyme and an accumulation of glycosphingolipid in tissue. Affected males with classic FD have little or no enzyme activity and have an early onset of symptoms and signs, including acroparesthesias, hypohidrosis, angiokeratomas, gastrointestinal dysfunction and/or a characteristic corneal dystrophy during childhood/adolescence. Males with late-onset FD who have residual enzyme activity develop progressive multi-systemic involvement that leads to renal failure and hypertrophic cardiomyopathy, as well as cerebrovascular disease; these events mostly occur during the fourth to seventh decades of life. Heterozygous females can develop vital organ damage that in turn causes severe morbidity and mortality; these symptoms may be as severe as those in affected males. For the treatable disease, this review aims to raise awareness of early recognition and further management of FD based on newborn screening. As newborn screening for FD has been implemented worldwide, it allows the early detection of individuals with Fabry mutations. Based on screening studies, the prevalence of the later-onset type FD is much higher than that of classical type FD. Newborn screening studies have also revealed that patients with FD may develop insidious but ongoing irreversible organ damage. The timing of enzyme replacement therapy, which is able to stabilize the progression of disease, is important in order to prevent irreversible organ damage. Therapies that may become available in the future include pharmacological chaperones and substrate reduction therapy, both of which are still under investigation as ways of improving the health of individuals with FD.

Muscle ultrasound: A useful tool in newborn screening for infantile onset pompe disease.

Our study aimed to evaluate the utility of muscle ultrasound in newborn screening of infantile-onset Pompe disease (IOPD) and to establish a system of severity grading. We retrospectively selected 35 patients with initial low acid alpha-glucosidase (GAA) activity and collected data including muscle ultrasound features, GAA gene mutation, activity/performance, and pathological and laboratory findings. The echogenicity of 6 muscles (the bilateral vastus intermedius, rectus femoris, and sartorius muscles) was compared to that of epimysium on ultrasound and rated either 1 (normal), 2 (mildly increased), or 3 (obviously increased). These grades were used to divide patients into 3 groups. IOPD was present in none of the grade-1 patients, 5 of 9 grade-2 patients, and 5 of 5 grade-3 patients (P < .001). Comparing grade-2 plus grade-3 patients to grade-1 patients, muscle ultrasound detected IOPD with a sensitivity and specificity of 100.0% (95% confidence interval [CI]: 69.2%-100%) and 84.0% (95% CI: 63.9%-95.5%), respectively. The mean number of affected muscles was larger in grade-3 patients than in grade-2 patients (4.2 vs. 2.0, P = .005). Mean alanine transaminase (ALT), aspartate transaminase (AST), creatine kinase (CK), and lactate dehydrogenase (LDH) levels were differed significantly different between grade-3 and grade-1 patients (P < .001). Because it permits direct visualization of injured muscles, muscle ultrasound can be used to screen for IOPD. Our echogenicity grades of muscle injury also correlate well with serum levels of muscle-injury biochemical markers.