GBA1 as a risk gene for osteoporosis in the specific populations and its role in the development of Gaucher disease.

BACKGROUND: Osteoporosis and its primary complication, fragility fractures, contribute to substantial global morbidity and mortality. Gaucher disease (GD) is caused by glucocerebrosidase (GBA1) deficiency, leading to skeletal complications. This study aimed to investigate the impact of the GBA1 gene on osteoporosis progression in GD patients and the specific populations. METHODS: We selected 8115 patients with osteoporosis (T-score ≤ - 2.5) and 55,942 healthy individuals (T-score > - 1) from a clinical database (N = 95,223). Monocytes from GD patients were evaluated in relation to endoplasmic reticulum (ER) stress, inflammasome activation, and osteoclastogenesis. An in vitro model of GD patient's cells treated with adeno-associated virus 9 (AAV9)-GBA1 to assess GBA1 enzyme activity, chitotriosidase activity, ER stress, and osteoclast differentiation. Longitudinal dual-energy X-ray absorptiometry (DXA) data tracking bone density in patients with Gaucher disease (GD) undergoing enzyme replacement therapy (ERT) over an extended period. RESULTS: The GBA1 gene variant rs11264345 was significantly associated [P < 0.002, Odds Ratio (OR) = 1.06] with an increased risk of bone disease. Upregulation of Calnexin, NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) and Apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) was positively associated with osteoclastogenesis in patients with GD. In vitro AAV9-GBA1 treatment of GD patient cells led to enhanced GBA1 enzyme activity, reduced chitotriosidase activity, diminished ER stress, and decreased osteoclast differentiation. Long-term bone density data suggests that initiating ERT earlier in GD leads to greater improvements in bone density. CONCLUSIONS: Elevated ER stress and inflammasome activation are indicative of osteoporosis development, suggesting the need for clinical monitoring of patients with GD. Furthermore, disease-associated variant in the GBA1 gene may constitute a risk factor predisposing specific populations to osteoporosis.

A practical synthesis of nitrone-derived C5a-functionalized isofagomines as protein stabilizers to treat Gaucher disease.

Isofagomine (IFG) and its analogues possess promising glycosidase inhibitory activities. However, a flexible synthetic strategy toward both C5a-functionalized IFGs remains to be explored. Here we show a practical synthesis of C5a-S and R aminomethyl IFG-based derivatives via the diastereoselective addition of cyanide to cyclic nitrone 1. Nitrone 1 was conveniently prepared on a gram scale and in high yield from inexpensive (-)-diethyl D-tartrate via a straightforward method, with a stereoselective Michael addition of a nitroolefin and a Nef reaction as key steps. A 268-membered library (134 × 2) of the C5a-functionalized derivatives was submitted to enzyme- or cell-based bio-evaluations, which resulted in the identification of a promising ß-glucocerebrosidase (GCase) stabilizer demonstrating a 2.7-fold enhancement at 25 nM in p.Asn370Ser GCase activity and a 13-fold increase at 1 µM in recombinant human GCase activity in Gaucher cell lines.

Twelve-year review of galactosemia newborn screening in Taiwan: Evolving methods and insights.

Background: Galactosemia was introduced into Taiwan's routine newborn screening (NBS) program in 1985. This study presents a 12-year experience, emphasizing disease diagnosis and screening performance. Method: NBS for galactosemia utilized dried blood spot samples taken 48-72 h post-delivery, with total galactose (TGal) level as the primary marker. Newborns with critical TGal levels were referred immediately, while those with borderline TGal underwent a recall test. GALT activity measurement was applied simultaneously as the second-tier marker. Further confirmatory tests, such as whole exome sequencing (WES), were conducted upon referral. Results: From January 1st, 2011, to December 31st, 2022, 51 cases were identified from 817,906 newborns. Of these, nine individuals had persistently elevated TGal. Diagnoses included one case of GALT deficiency, one of GALM deficiency, and seven of GALE deficiencies. Notably, the classic galactosemia patient (GALT deficiency) presented with extreme high TGal and was referred to the hospital for diet management immediately. All affected patients were instructed to adopt a galactose-restricted diet. By the median age of 2.5 years, all exhibited normal development and liver function. Conclusion: The incidence of classical galactosemia and its variants is extremely low in Taiwan. Incorporating WES into NBS has improved our ability to detect various galactosemia forms, enriching our understanding of the genetic underpinnings. While these newly discovered forms often present with milder initial elevations in TGal, specific biochemical investigations and regular monitoring are essential to understanding the long-term implications and outcomes.

Gene therapy corrects the neurological deficits of mice with sialidosis.

Patients with sialidosis (mucolipidosis type I) type I typically present with myoclonus, seizures, ataxia, cherry-red spots, and blindness because of mutations in the neuraminidase 1 (NEU1) gene. Currently, there is no treatment for sialidosis. In this study, we developed an adeno-associated virus (AAV)-mediated gene therapy for a Neu1 knockout (Neu1-/-) mouse model of sialidosis. The vector, AAV9-P3-NP, included the human NEU1 promoter, NEU1 cDNA, IRES, and CTSA cDNA. Untreated Neu1-/- mice showed astrogliosis and microglial LAMP1 accumulation in the nervous system, including brain, spinal cord, and dorsal root ganglion, together with impaired motor function. Coexpression of NEU1 and protective protein/cathepsin A (PPCA) in neonatal Neu1-/- mice by intracerebroventricular injection, and less effective by facial vein injection, decreased astrogliosis and LAMP1 accumulation in the nervous system and improved rotarod performance of the treated mice. Facial vein injection also improved the grip strength and survival of Neu1-/- mice. Therefore, cerebrospinal fluid delivery of AAV9-P3-NP, which corrects the neurological deficits of mice with sialidosis, could be a suitable treatment for patients with sialidosis type I. After intracerebroventricular or facial vein injection of AAV vectors, NEU1 and PPCA are expressed together. PPCA-protected NEU1 is then sent to lysosomes, where ß-Gal binds to this complex to form a multienzyme complex in order to execute its function.

Ethnically unique disease burden and limitations of current expanded carrier screening panels.

OBJECTIVES: The purpose of the study is to identify the recessive diseases currently affecting real-world pediatric patients in Taiwan, and whether current extended carrier screening panels have the coverage and detective power to identify the pathogenic variants in the carrier parents. METHODS: A total of 132 trio-samples were collected from May 2017 to March 2022. The participants were parents of pediatric intensive care unit patients who were critically ill or infants with abnormal newborn screening results. A retrospective carrier screening scheme was applied to analyze only the carrier status of pathogenic or likely pathogenic recessive variants resulting in diseases in their children. The recessive disorders diagnosed in our cohort were compared with the gene content in commercial panels. RESULTS: Mutations in COQ4, PEX1, OTC, and IKBKG were the most frequently identified. In the parents of 44 children with confirmed diagnoses of recessive diseases, 47 (53.40%) screened positive for being the carriers of the same recessive disorders diagnosed in their children. The commercial panels covered 35.13% to 54.05% of the disorders diagnosed in this cohort. CONCLUSION: Clinicians and genetic counselors should be aware of the limitations of current extended carrier screening and interpret negative screening results with caution. Future panels should also consider genes with ethnically unique mutations such as pathogenic variants of the COQ4 gene in the East Asian population.

Life-Saving Treatments for Spinal Muscular Atrophy: Global Access and Availability.

Background and Objectives: Spinal muscular atrophy (SMA) is a neurodegenerative disorder manifesting with progressive muscle weakness and atrophy. SMA type 1 used to be fatal within the first 2 years of life, but is now treatable with therapies targeting splicing modification and gene replacement. Nusinersen, risdiplam, and onasemnogene abeparvovec-xioi improve survival, motor strength, endurance, and ability to thrive, allowing many patients to potentially attain a normal life; all have been recently approved by major regulatory agencies. Although these therapies have revolutionized the world of SMA, they are associated with a high economic burden, and access to these therapies is limited in some countries. The primary objective of this study was to compare the availability and implementation of treatment of SMA from different regions of the world. Methods: In this qualitative study, we surveyed health care providers from 21 countries regarding their experiences caring for patients with SMA. The main outcome measures were provider survey responses on newborn screening, drug availability/access, barriers to treatment, and related questions. Results: Twenty-four providers from 21 countries with decades of experience (mean 26 years) in treating patients with SMA responded to the survey. Nusinersen was the most available therapy for SMA. Our survey showed that while genetic testing is usually available, newborn screening is still unavailable in many countries. The provider-reported treatment cost also varied between countries, and economic burden was a major barrier in treating patients with SMA. Discussion: Overall, this survey highlights the global inequality in managing patients with SMA. The spread of newborn screening is essential in ensuring improved access to care for patients with SMA. With the advancement of neurotherapeutics, more genetic diseases will soon be treatable, and addressing the global inequality in clinical care will require novel approaches to mitigate such inequality in the future.

Higher dose alglucosidase alfa is associated with improved overall survival in infantile-onset Pompe disease (IOPD): data from the Pompe Registry.

BACKGROUND: Studies indicate that doses of alglucosidase alfa (ALGLU) higher than label dose (20 mg/kg every other week) improve clinical outcomes in infantile-onset Pompe disease (IOPD). We investigated data from the Pompe Registry to determine the association between ALGLU dose and survival in IOPD. RESULTS: We included 332 IOPD patients from the Registry as of January 2022 who had cardiomyopathy and were first treated at age < 1 year. We used Cox proportional hazards models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between ALGLU as a time-varying exposure and survival, adjusting for age at first treatment, sex, and cross-reactive immunologic material (CRIM)/immune tolerance induction (ITI) status. Dose was measured as average relative dose received over time (in multiples of label dose, range > 0 to 4 times label dose), current dose, and lagged dose. 81% patients received label dose at treatment initiation. Over time, 52% received a higher dose. Higher ALGLU dose over time was associated with improved survival: adjusted HR 0.40 (95% CI 0.22-0.73, p = 0.003) per 1-unit increase in average relative dose, with similar results for invasive ventilation-free survival (adjusted HR 0.48, 95% CI 0.28-0.84; p = 0.010). The association was consistent in patients first treated before or after 3 months of age and did not vary significantly by CRIM status. Results for current and lagged dose were similar to average dose. CONCLUSIONS: Higher ALGLU doses were associated with significantly improved overall and invasive ventilator-free survival in IOPD. Results were consistent across sensitivity analyses.

Late-onset symptomatic hyperprolactinemia in 6-pyruvoyl-tetrahydropterin synthase deficiency.

BACKGROUND: Tetrahydrobiopterin (BH4) deficiency caused by 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency is a rare disorder that is one of the major causes of hyperphenylalaninemia in Taiwan. METHODS: In this study, we reviewed the clinical courses of 12 adolescent and adult patients (7 females and 5 males) with PTPS deficiency. RESULTS: The patients were treated shortly after diagnosis through newborn screening with a combination of BH4, levodopa/carbidopa, and 5-OH-tryptophan. Their plasma phenylalanine and tyrosine levels were well controlled, and their prolactin levels were also decreased after treatment. However, their prolactin levels gradually rose as they grew into puberty, and at a current age of 27.5 [interquartile range (IQR 7.9)] years, five of the 12 patients had either highly elevated prolactin levels (> 100 ng/mL in one male patient, normal reference values, male < 11 ng/mL, female < 17 ng/mL) or symptoms, including irregular menstruation, amenorrhea, and breast swelling (in four female patients). The dosage of levodopa in these five patients (14.3 (IQR 3.0) mg/kg/day) was slightly higher than that in the other patients (p = 0.05). Magnetic resonance imaging studies did not reveal an increase in the size of the anterior pituitary gland, although a Rathke cleft cyst was found in one patient. Two patients received cabergoline treatment, which promptly lowered prolactin levels and relieved symptoms. CONCLUSIONS: Hyperprolactinemia is common in female patients with PTPS deficiency, especially after puberty. A long-acting dopamine agonist, such as cabergoline, may be a necessary adjunctive treatment for most patients with BH4 deficiency.

Precocious puberty in patients with Pompe disease.

Introduction: The life expectancy of Pompe disease patients has increased due to improved neonatal screening and enzyme replacement therapy. Nevertheless, the potential effect of frequent medical device exposure on pubertal development in these patients is not well understood, so further investigation is warranted. Methods: In this cross-sectional study, we assessed the growth and puberty of nine Pompe disease patients. In addition, to determine the effects of frequent plastic medical device exposure in these patients, we measured urinary phthalate metabolites before and one day after enzyme replacement therapy. Results: Five out of nine patients (55%) with Pompe disease on enzyme replacement therapy had precocious puberty. Patients with precocious puberty had significantly shorter predicted adult heights compared to those with normal puberty (p = 0.014). The levels of mono-2-ethylhexyl phthalate (MEHP) and mono(2-ethyl-5-carboxypentyl) phthalate (MECPP) increased after enzyme replacement therapy, but the average levels of phthalate metabolites did not significantly differ between patients with normal and precocious puberty. Conclusion: Pompe disease patients on enzyme replacement therapy tend to have precocious puberty, which may reduce their adult height. There are no significant differences in urinary phthalate metabolites between normal and precocious puberty patients. Regular follow-up of growth and puberty in Pompe disease patients is important to improve their health outcomes.

Aromatic l-amino acid decarboxylase deficiency in Taiwan.

Aromatic l-amino acid decarboxylase (AADC) deficiency is a rare inherited disorder that affects neurotransmitter biosynthesis. A DDC founder mutation c.714 + 4A > T (IVS6 + 4A > T) is prevalent in the Chinese population. This study investigated the epidemiology of AADC deficiency in Taiwan by analyzing data from National Taiwan University Hospital (NTUH), a central institution for diagnosing and treating the disease. From January 2000 to March 2023, 77 patients with AADC deficiency visited NTUH. Among them, eight were international patients seeking a second opinion, and another two had one or both non-Chinese parents; all others were ethnically Chinese. The c.714 + 4A > T mutation accounted for 85% of all mutated alleles, and 94% of patients exhibited a severe phenotype. Of the 77 patients, 31 received gene therapy at a mean age of 3.76 years (1.62-8.49) through clinical trials, and their current ages were significantly older than those of the remaining patients. Although the combined incidence of AADC deficiency in this study (1:66491 for 2004 and later) was lower than that reported in newborn screening (1:31997 to 1:42662), case surges coincided with the launch of clinical trials and the implementation of newborn screening. Currently, many young patients are awaiting for treatment.

Changing clinical manifestations of Gaucher disease in Taiwan.

BACKGROUND: Gaucher disease (GD) is a lysosomal storage disorder characterized by deficient glucocerebrosidase activity that results from biallelic mutations in the GBA1 gene. Its phenotypic variability allows GD to be classified into 3 subtypes based on the presence and extent of neurological manifestations. Enzyme replacement therapy (ERT) has been available for all patients with GD in Taiwan since 1998. Newborn screening (NBS) for GD has been available since 2015. This study attempted to unveil the clinical features of patients diagnosed with GD during different eras in Taiwan. MATERIALS AND METHODS: Data from the health records of two tertiary hospitals responsible for two-thirds of the patients with GD in Taiwan were used. The study population included all patients identified as having GD between 1998, and April 2022, in these two hospitals for review. A total of 42 individuals were included, six of whom were diagnosed by NBS. RESULTS: Our cohort presented a higher proportion of GD3 individuals, both by clinical suspicion and by NBS diagnosis, than that reported worldwide. The major subtypes that were recognized following NBS diagnosis were GD2 and GD3. The majority of GD patients carry at least one p.Leu483Pro variant. The 5-year survival rates were 0% for GD2 patients and 100% for patients with other subtypes. Patients diagnosed during the post-NBS era were free of symptoms on initial presentation, except for those with the GD2 subtype. For those diagnosed earlier, ERT was shown to be effective in terms of improved hemograms and prevented bone crises. However, the neurological symptoms in GD3 patients progressed despite ERT intervention. CONCLUSION: ERT is essential in reversing the hematological presentations and preventing the skeletal complications of GD. Timely diagnosis of GD with NBS allows for early intervention with ERT to prevent disease progression and complications. However, the need for effective intervention for neurological dysfunction remains unmet.

Phenotypic Heterogeneity in Patients with Mutations in the Mitochondrial Complex I Assembly Gene NDUFAF5.

BACKGROUND: Rare mutations in NADH:ubiquinone oxidoreductase complex assembly factor 5 (NDUFAF5) are linked to Leigh syndrome. OBJECTIVE: We aimed to describe clinical characteristics and functional findings in a patient cohort with NDUFAF5 mutations. METHODS: Patients with biallelic NDUFAF5 mutations were recruited from multi-centers in Taiwan. Clinical, laboratory, radiological, and follow-up features were recorded and mitochondrial assays were performed in patients' skin fibroblasts. RESULTS: Nine patients from seven unrelated pedigrees were enrolled, eight homozygous for c.836 T > G (p.Met279Arg) in NDUFAF5 and one compound heterozygous for p.Met279Arg. Onset age had a bimodal distribution. The early-onset group (age <3 years) presented with psychomotor delay, seizure, respiratory failure, and hyponatremia. The late-onset group (age ≥5 years) presented with normal development, but slowly progressive dystonia. Combing 25 previously described patients, the p.Met279Arg variant was exclusively identified in Chinese ancestry. Compared with other groups, patients with late-onset homozygous p.Met279Arg were older at onset (P = 0.008), had less developmental delay (P = 0.01), less hyponatremia (P = 0.01), and better prognosis with preserved ambulatory function into early adulthood (P = 0.01). Bilateral basal ganglia necrosis was a common radiological feature, but brainstem and spinal cord involvement was more common with early-onset patients (P = 0.02). A modifier gene analysis showed higher concomitant mutation burden in early-versus late-onset p.Met279Arg homozygous cases (P = 0.04), consistent with more impaired mitochondrial function in fibroblasts from an early-onset case than a late-onset patient. CONCLUSIONS: The p.Met279Arg variant is a common mutation in our population with phenotypic heterogeneity and divergent prognosis based on age at onset. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Consensus recommendations for the treatment and management of patients with Fabry disease on migalastat: a modified Delphi study.

Objective: Fabry disease is a progressive disorder caused by deficiency of the α-galactosidase A enzyme (α-Gal A), leading to multisystemic organ damage with heterogenous clinical presentation. The addition of the oral chaperone therapy migalastat to the available treatment options for Fabry disease is not yet universally reflected in all treatment guidelines. These consensus recommendations are intended to provide guidance for the treatment and monitoring of patients with Fabry disease receiving migalastat. Methods: A modified Delphi process was conducted to determine consensus on treatment decisions and monitoring of patients with Fabry disease receiving migalastat. The multidisciplinary panel comprised 14 expert physicians across nine specialties and two patients with Fabry disease. Two rounds of Delphi surveys were completed and recommendations on the use of biomarkers, multidisciplinary monitoring, and treatment decisions were generated based on statements that reached consensus. Results: The expert panel reached consensus agreement on 49 of 54 statements, including 16 that reached consensus in round 1. Statements that reached consensus agreement are summarized in recommendations for migalastat treatment and monitoring, including baseline and follow-up assessments and frequency. All patients with Fabry disease and an amenable mutation may initiate migalastat treatment if they have evidence of Fabry-related symptoms and/or organ involvement. Treatment decisions should include holistic assessment of the patient, considering clinical symptoms and organ involvement as well as patient-reported outcomes and patient preference. The reliability of α-Gal A and globotriaosylsphingosine as pharmacodynamic response biomarkers remains unclear. Conclusion: These recommendations build on previously published guidelines to highlight the importance of holistic, multidisciplinary monitoring for patients with Fabry disease receiving migalastat, in addition to shared decision-making regarding treatments and monitoring throughout the patient journey. GRAPHICAL ABSTRACT.

Curated incidence of lysosomal storage diseases from the Taiwan Biobank.

Lysosomal storage diseases (LSDs) are a group of metabolic disorders resulting from a deficiency in one of the lysosomal hydrolases. Most LSDs are inherited in an autosomal or X-linked recessive manner. As LSDs are rare, their true incidence in Taiwan remains unknown. In this study, we used high-coverage whole-genome sequencing data from 1,495 Taiwanese individuals obtained from the Taiwan Biobank. We found 3826 variants in 71 genes responsible for autosomal recessive LSDs. We first excluded benign variants by allele frequency and other criteria. As a result, 270 variants were considered disease-causing. We curated these variants using published guidelines from the American College of Medical Genetics and Genomics (ACMG). Our results revealed a combined incidence rate of 13 per 100,000 (conservative estimation by pathologic and likely pathogenic variants; 95% CI 6.92-22.23) to 94 per 100,000 (extended estimation by the inclusion of variants of unknown significance; 95% CI 75.96-115.03) among 71 autosomal recessive disease-associated genes. The conservative estimations were similar to those in published clinical data. No disease-causing mutations were found for 18 other diseases; thus, these diseases are likely extremely rare in Taiwan. The study results are important for designing screening and treatment methods for LSDs in Taiwan and demonstrate the importance of mutation curation to avoid overestimating disease incidences from genomic data.

Loss of Flot2 expression in deep cerebellar nuclei neurons of mice with Niemann-Pick disease type C.

Niemann-Pick disease type C (NPC) is caused by a deficiency of the NPC1 or NPC2 gene, leading to storages of unesterified cholesterol and sphingolipids. Cerebellar ataxia is a main symptom of NPC and the deep cerebellar nuclei (DCN) is the sole signal output of the cerebellum. In this study, we explored the pathological changes in DCN neurons of Npc1 knockout mice (Npc1-). We first demonstrated that DCN neurons of Npc1- mice had prominent ganglioside GM2 accumulation in the late endosomes but not in the lysosomes. More importantly, Flot2 expression, a marker for the lipid rafts, was lost. Single-nucleus RNA sequencing analysis revealed a generalized reduction in gene expression in DCN neurons, though Camk1d, encoding one of the Ca2+/calmodulin-dependent protein kinases (CaMKs), increased in expression. We treated Npc1- mice with CaMK inhibitor KN-93, but CaMK1D expression increased further. We also fed Npc1- mice with two medications for NPC. We found that miglustat, a sphingolipid synthesis inhibitor, increased the expression of Flot2. Moreover, N-acetyl l-leucine (NALL), an experimental medicine for NPC, recovered Flot2 expression. Therefore, our data suggest that in Npc1- mice, GM2 sequestration and the loss of lipid rafts lead to cell dysfunction and symptoms of NPC.

Streamlined determination of 3-O-methyldopa in dried blood spots: Prospective screening for aromatic l-amino-acid decarboxylase deficiency.

BACKGROUND: Aromatic L-amino-acid decarboxylase (AADC) deficiency diagnosis is often delayed by low disease awareness and specific laboratory examinations. We demonstrated that an elevated concentration of L-dopa metabolite 3-O-methyldopa (3-OMD) in dried blood spots could be integrated into a newborn screening program to detect AADC deficiency. METHODS: DBS samples for amino acid and acylcarnitine analysis using NeoBase™2 reagents were also analyzed for the 3-OMD concentration using 13C6-phenylalanine as an internal standard. For samples exceeding the pre-defined cutoffs, an additional spot was punched from the original filter paper for second-tier 3-OMD measurement by high performance liquid chromatography (HPLC)-MS/MS assay. Newborns with a 3-OMD concentration exceeding 500 ng/mL were referred for confirmatory testing. RESULTS: From Feb. 2020 to Dec. 2022, 157,371 newborns were screened for AADC deficiency. Eight newborns exhibited an elevated 3-OMD concentration (839-5170 ng/mL). Among them, six newborns were confirmed to carry two pathogenic DDC variants, indicating an incidence of AADC deficiency of ∼1:26,000 (95% confidence interval: 1 in 12,021 to 1 in 57,228). During the follow-up period, all six patients developed typical symptoms of AADC deficiency. CONCLUSION: The screening for 3-OMD, a target for AADC deficiency, could be easily integrated into the existing newborn screening programs and facilitate the future application for early diagnosis and effective treatment.

Bedtime extended release cornstarch improves biochemical profile and sleep quality for patients with glycogen storage disease type Ia.

BACKGROUND: Patients with glycogen storage disease type Ia (GSDIa) are prone to hypoglycemia. Uncooked cornstarch (CS) is the treatment, but maintaining nighttime blood glucose levels is still difficult. METHODS: The study enrolled patients with GSDIa to investigate the benefits of bedtime extended release CS (ER-CS, Glycosade®) versus regular CS. The daytime CS schedule was not altered. A 7-day continuous glucose monitoring (CGM) was performed at the baseline and 12 weeks after using ER-CS. Biochemical profile, sleep quality (Pittsburgh Sleep Quality Index, PSQI), and quality of life (SF-36 questionnaire) were measured at the baseline and 24 weeks after using ER-CS. RESULTS: Nine patients (9 to 33 years of age) were enrolled. Compared with the baseline (80.0 ± 6.33 mg/dL), the 12-week evaluations revealed higher mean morning glucose levels (86.5 ± 8.26 mg/dL, p = 0.015). Twenty-four weeks after the use of bedtime ER-CS, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels both decreased (from 69.3 ± 77.8 to 41.1 ± 40.4 U/L and from 78.8 ± 99.6 to 37.8 ± 28.81 U/L, respectively, p = 0.013 for both analyses), and sleep and fasting time both elongated (from 7.8 ± 0.87 to 8.6 ± 1.02 h and from 6.5 ± 1.22 to 7.6 ± 1.02 h, respectively, p = 0.011 for both analyses). The mean PSQI score in the five adult patients decreased significantly (from 5.8 ± 1.29 to 3.0 ± 1.71, p = 0.042). CONCLUSION: This study provides evidence of clinically meaningful improvements by shifting only bedtime regular CS to ER-CS in patients with GSDIa. As ER-CS is considerably more expensive than regular CS, this approach presents a cost-effective alternative.

Prevalence of DDC genotypes in patients with aromatic L-amino acid decarboxylase (AADC) deficiency and in silico prediction of structural protein changes.

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive genetic disorder affecting the biosynthesis of dopamine, a precursor of both norepinephrine and epinephrine, and serotonin. Diagnosis is based on the analysis of CSF or plasma metabolites, AADC activity in plasma and genetic testing for variants in the DDC gene. The exact prevalence of AADC deficiency, the number of patients, and the variant and genotype prevalence are not known. Here, we present the DDC variant (n = 143) and genotype (n = 151) prevalence of 348 patients with AADC deficiency, 121 of whom were previously not reported. In addition, we report 26 new DDC variants, classify them according to the ACMG/AMP/ACGS recommendations for pathogenicity and score them based on the predicted structural effect. The splice variant c.714+4A>T, with a founder effect in Taiwan and China, was the most common variant (allele frequency = 32.4%), and c.[714+4A>T];[714+4A>T] was the most common genotype (genotype frequency = 21.3%). Approximately 90% of genotypes had variants classified as pathogenic or likely pathogenic, while 7% had one VUS allele and 3% had two VUS alleles. Only one benign variant was reported. Homozygous and compound heterozygous genotypes were interpreted in terms of AADC protein and categorized as: i) devoid of full-length AADC, ii) bearing one type of AADC homodimeric variant or iii) producing an AADC protein population composed of two homodimeric and one heterodimeric variant. Based on structural features, a score was attributed for all homodimers, and a tentative prediction was advanced for the heterodimer. Almost all AADC protein variants were pathogenic or likely pathogenic.

Efficacy and Safety of Avalglucosidase Alfa in Patients With Late-Onset Pompe Disease After 97 Weeks: A Phase 3 Randomized Clinical Trial.

Importance: In the previously reported Comparative Enzyme Replacement Trial With neoGAA Versus rhGAA (COMET) trial, avalglucosidase alfa treatment for 49 weeks showed clinically meaningful improvements in upright forced vital capacity (FVC) percent predicted and 6-minute walk test (6MWT) compared with alglucosidase alfa. Objective: To report avalglucosidase alfa treatment outcomes during the COMET trial extension. Design, Setting, and Participants: This phase 3 double-blind randomized clinical trial with crossover in the extension period enrolled patients 3 years and older with previously untreated late-onset Pompe disease (LOPD) between November 2, 2016, and February 10, 2021, with primary analysis after 49 weeks. Patients were treated at 55 referral centers in 20 countries. Efficacy outcomes were assessed at 97 weeks and safety outcomes to last follow-up, with data cutoff at February 10, 2021. Data were analyzed from May to June 2021. Interventions: Random assignment (1:1) to receive 20 mg/kg of avalglucosidase alfa or alglucosidase alfa by intravenous infusion every other week for 49 weeks; thereafter, all patients received 20 mg/kg of avalglucosidase alfa every other week. Main Outcomes and Measures: The primary outcome was the least squares (LS) mean change from baseline in FVC percent predicted. Secondary outcomes included the LS mean change from baseline in 6MWT, muscle strength, motor function, quality of life, and disease biomarkers. Safety and tolerability were also assessed. Results: Of 100 participants from the double-blind treatment period, 95 entered the extension period. Of these, 51 (54%) were men, and the mean (range) age was 48.3 (10-79) years. At the start of this study, mean upright FVC percent predicted was similar between treatment arms, and 6MWT distance was greater in the avalglucosidase alfa arm. From baseline to week 97, LS mean (SE) FVC percent predicted increased by 2.65 (1.05) for those who continued avalglucosidase alfa and 0.36 (1.12) for those who switched to avalglucosidase alfa. The LS mean (SE) 6MWT distance increased by 18.60 (12.01) m and 4.56 (12.44) m, respectively. For participants who switched to avalglucosidase alfa, FVC percent predicted remained stable (LS mean [SE] change from week 49 to 97, 0.09 [0.88]) and 6MWT distance improved (LS mean [SE] change from week 49 to 97, 5.33 [10.81] m). Potentially treatment-related adverse events were reported in 29 patients (56.9%) who continued avalglucosidase alfa and in 25 patients (56.8%) who switched. Conclusions and Relevance: In this randomized clinical trial extension, maintenance of positive clinical outcomes was demonstrated for patients continuing avalglucosidase alfa treatment and, to a lesser extent, patients who switched from alglucosidase alfa. No new safety concerns were observed. Trial Registration: ClinicalTrials.gov Identifier: NCT02782741.