The Asian Fabry Cardiomyopathy High-Risk Screening Study 2 (ASIAN-FAME-2): Prevalence of Fabry Disease in Patients with Left Ventricular Hypertrophy.

Background: Fabry disease (FD) is a rare X-linked lysosomal storage disorder that commonly manifests cardiovascular complications. We aimed to assess the prevalence of FD in a Chinese population with left ventricular hypertrophy (LVH) whilst implementing a gender-specific screening approach. Methods: Patients with LVH, defined as a maximum thickness of the left ventricular septal/posterior wall ≥ 13 mm, were considered eligible. All patients with hypertrophic cardiomyopathy (HCM) were excluded. Plasma α-galactosidase (α-GLA) enzyme activity was assessed using a dried blood spot test. Males with low enzyme activity underwent genetic testing to confirm a diagnosis of FD whereas females were screened for both α-GLA and globotriaosylsphingosine concentration and underwent genetic analysis of the GLA gene only if testing positive for ≥1 parameter. Results: 426 unrelated patients (age = 64.6 ± 13.0 years; female: male = 113:313) were evaluated. FD was diagnosed in 3 unrelated patients (age = 69.0 ± 3.5 years, female: male = 1:2) and 1 related female subject (age = 43 years). Genetic analyses confirmed the late-onset cardiac variant GLA c.640-801G>A (n = 3) and the missense variant c.869T>C associated with classic FD (n = 1). Cardiac complications were the only significant findings associated with the late-onset c.640-801G>A mutation, manifesting as mild or severe concentric LVH. In contrast, the classic c.869T>C mutation FD exhibited multisystemic manifestations in addition to severe concentric LVH. Conclusions: The prevalence of FD is lower in Chinese patients with LVH when HCM is excluded. The pathological variant c.640-801G>A remains the most common cause of late-onset FD, while the detection of FD in females can be improved by utilizing a gender-specific screening method.

Changes in forced vital capacity over ≤ 13 years among patients with late-onset Pompe disease treated with alglucosidase alfa: new modeling of real-world data from the Pompe Registry.

BACKGROUND: Chronic respiratory insufficiency from progressive muscle weakness causes morbidity and mortality in late-onset Pompe disease (LOPD). Previous Pompe Registry (NCT00231400) analyses for ≤ 5 years' alglucosidase alfa treatment showed a single linear time trend of stable forced vital capacity (FVC) % predicted. METHODS: To assess longer term Pompe Registry data, piecewise linear mixed model regression analyses estimated FVC% predicted trajectories in invasive-ventilator-free patients with LOPD aged ≥ 5 years. We estimated annual FVC change 0-6 months, > 6 months-5 years, and > 5-13 years from treatment initiation, adjusting for baseline age, sex, and non-invasive ventilation. FINDINGS: Among 485 patients (4612 FVC measurements; 8.3 years median follow-up), median ages at symptom onset, diagnosis, and alglucosidase alfa initiation were 34.3, 41.1, and 44.9 years, respectively. FVC% increased during the first 6 months' treatment (slope 1.83%/year; 95% confidence interval: 0.66, 3.01; P = 0.0023), then modestly declined -0.54%/year (-0.79, -0.30; P < 0.0001) during > 6 months-5 years, and -1.00%/year (-1.36, -0.63; P < 0.0001) during > 5-13 years. The latter two periods' slopes were not significantly different from each other (Pdifference = 0.0654) and were less steep than published natural history slopes (-1% to -4.6%/year). Estimated individual slopes were ≥ 0%/year in 96.1%, 30.3%, and 13.2% of patients during the 0-6 month, > 6 month-5 year, and > 5-13 year periods, respectively. CONCLUSION: These real-world data indicate an alglucosidase alfa benefit on FVC trajectory that persists at least 13 years compared with published natural history data. Nevertheless, unmet need remains since most individuals demonstrate lung function decline 5 years after initiating treatment. Whether altered FVC trajectory impacts respiratory failure incidence remains undetermined. TRIAL REGISTRATION: This study was registered (NCT00231400) on ClinicalTrials.gov on September 30, 2005, retrospectively registered.

Impact of renal function variability on long-term prognosis in ischemic stroke patients with atrial fibrillation.

Background: Although renal dysfunction is associated with adverse clinical outcomes in patients with atrial fibrillation (AF) following stroke, the impact of renal function variability is unclear. Aim: This study aimed to assess the association between renal function variability and various adverse clinical outcomes in patients with transient ischemic attack (TIA)/ischemic stroke and atrial fibrillation (AF). Methods: We conducted a population-based study and retrospectively identified patients hospitalized with a diagnosis of TIA/ischemic stroke and AF during 2016-2020 using the Clinical Data Analysis and Reporting System of Hong Kong. Serial serum creatinine tested upon the onset of TIA/ischemic stroke and during their subsequent follow-up was collected. Renal function variability was calculated using the coefficient of variation of the estimated glomerular filtration rate (eGFR). Clinical endpoints that occurred during the study period were captured and included ischemic stroke/systemic embolism, intracerebral hemorrhage (ICH), total bleeding, major adverse cardiovascular events (MACE), cardiovascular, non-cardiovascular, and all-cause mortality. Competing risk regression and Cox proportional hazard regression models were used to assess the associations of renal function variability with the outcomes of interest. Results: A total of 3,809 patients (mean age 80 ± 10 years, 43% men) who satisfied the inclusion and exclusion criteria were followed up for a mean of 2.5 ± 1.5 years (9,523 patient-years). The mean eGFR was 66 ± 22 mL/min/1.73 m2 at baseline, and the median number of renal function tests per patient during the follow-up period was 20 (interquartile range 11-35). After accounting for potential confounders, a greater eGFR variability was associated with increased risks of recurrent ischemic stroke/systemic embolism [fully adjusted subdistribution hazard ratio 1.11, 95% confidence interval (CI) 1.03-1.20], ICH (1.17, 1.01-1.36), total bleeding (1.13, 1.06-1.21), MACE (1.22, 1.15-1.30), cardiovascular (1.49, 1.32-1.69), non-cardiovascular (1.43, 1.35-1.52), and all-cause mortality (fully adjusted hazard ratio 1.44, 1.39-1.50). Conclusion: Visit-to-visit renal function variability is independently associated with adverse clinical outcomes in TIA/ischemic stroke patients with AF. Further large-scale studies are needed to validate our results.

SCN4A-related congenital myopathy in a Han Chinese patient: A case report and literature review.

SCN4A mutations have been shown to be associated with myotonia, paramyotonia congenita, and periodic paralyses. More recently, loss-of-function variants in the SCN4A gene were also noted to be associated with rarer, autosomal recessive forms of congenital myasthenic syndrome and congenital myopathy. Diagnosis is challenging as the initial clinical presentation and histological features on muscle biopsies are non-specific. We report a Han Chinese patient presented with congenital myopathy with two missense SCN4A variants. The patient had an antenatal history of reduced fetal movements, polyhydramnios and a very preterm birth. At birth, she was noted to have low Apgar score, respiratory distress syndrome and hypotonia. Delayed motor development was noted in early childhood. Dysmorphic features such as an elongated face, dolichocephaly and high arched palate were present. At 16 years of age, the patient developed progressive muscle weakness and was wheelchair-bound by age 20. Muscle biopsy revealed non-specific changes only. Targeted hereditary myopathy panel testing by next generation sequencing revealed two previously unreported missense variants c.1841A > T p.(Asn614Ile) and c.4420G > A p.(Ala1474Thr) in the SCN4A gene. The clinical features of SCN4A-related congenital myopathy and myasthenic syndrome were reviewed. This case exemplifies the utility of next generation sequencing in the diagnosis of undifferentiated muscle disease.

Impulse control and related behavioral disorders (ICRD) in Idiopathic Parkinson's Disease treated with different dopamine agonists in Hong Kong: Is any dopamine agonist better?

Objective: To assess the incidence of Impulse control and related behavioral disorders (ICRD) in Chinese Idiopathic Parkinson Disease (IPD) patients treated with different dopamine agonists (DA), and their clinical characteristics and associated risk factors. Methods: This was an observational cohort study based on clinical interviews and medical records of IPD patients treated with DA for >6 months in three hospitals in Hong Kong. The short version of Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease (QUIP-S) was used to screen for ICRD. ICRD incidence among different DA, clinical characteristics and risk factors were examined. Results: Incidence of ICRD was analyzed in 311 patients taking their first, single DA. 43 patients (13.8 %) developed ICRD. The mean duration of IPD was 8.5 ± 5.6 years and median HY stage was 2.5. Bromocriptine and rotigotine users had lower ICRD incidence rate. Both pramipexole [adjusted HR 7.28 (2.46-21.54), p < 0.001] and ropinirole [adjusted HR 6.53 (2.67-15.99), p < 0.001] were independently associated with higher risk of ICRD compared to bromocriptine in multivariate analysis. Similarly, pramipexole and ropinirole appeared to carry higher risk compared to rotigotine but did not reach statistical significance. Male [adjusted HR 2.24 (1.07-4.72), p = 0.033], younger IPD onset [adjusted HR 2.99 (1.44-6.19) for onset < 50 year, p = 0.003] and history of psychiatric disorders [adjusted HR 2.80 (1.39-5.62), p = 0.004] were other independent risk factors. Conclusion: Bromocriptine and probably rotigotine carried a lower ICRD risk compared to pramipexole and ropinirole.

Basilar artery diameter as neuroimaging biomarker in Chinese Fabry disease patients.

BACKGROUND: Fabry disease (FD) is an X-linked lysosomal storage disease resulting from mutations of α-galactosidase A gene, and has been emphasized as one of the etiologies of young stroke and leukoencephalopathy. Vertebrobasilar dolichoectasia (VBD) is a highlighted finding in FD. We aim to examine the utility of VBD in Chinese FD by comparing the differences in basilar artery (BA) diameter of Chinese FD patients against age-matched controls with and without stroke. METHODS: This was a matched case-control study involving 37 Chinese FD patients. The BA diameters were evaluated on axial T2-weighted magnetic resonance imaging and compared to two age-and-gender matched control groups, one with stroke and one without. The association between BA diameter and stroke occurrences and white matter hyperintensities (WMH) were analyzed among all FD patients. RESULTS: Patients with FD had significantly increased BA diameter compared to controls with and without stroke (p < 0.001). A BA diameter of 4.16 mm could distinguish FD from controls in the stroke subgroup (ROC AUC 0.870, p = 0.001, sensitivity 80% specificity 100%), and with a cut-off of 3.21 mm in the non-stroke subgroup (ROC AUC 0.846, p < 0.001, sensitivity 77.8% specificity 88.9%). Larger BA diameter had more stroke occurrences and was moderately associated with heavier WMH load in terms of higher total FAZEKAS scores. (Spearman's rho = 0.423, p = 0.011). CONCLUSION: VBD was also present in Chinese FD patients. BA diameter has high diagnostic utility in identifying FD from a mixed cohort of stroke and normal controls, and carried predictive value in evaluating neurological complications of FD.

Mitochondrial diseases in Hong Kong: prevalence, clinical characteristics and genetic landscape.

OBJECTIVE: To determine the prevalence of mitochondrial diseases (MD) in Hong Kong (HK) and to evaluate the clinical characteristics and genetic landscape of MD patients in the region. METHODS: This study retrospectively reviewed the phenotypic and molecular characteristics of MD patients from participating public hospitals in HK between January 1985 to October 2020. Molecularly and/or enzymatically confirmed MD cases of any age were recruited via the Clinical Analysis and Reporting System (CDARS) using relevant keywords and/or International Classification of Disease (ICD) codes under the HK Hospital Authority or through the personal recollection of treating clinicians among the investigators. RESULTS: A total of 119 MD patients were recruited and analyzed in the study. The point prevalence of MD in HK was 1.02 in 100,000 people (95% confidence interval 0.81-1.28 in 100,000). 110 patients had molecularly proven MD and the other nine were diagnosed by OXPHOS enzymology analysis or mitochondrial DNA depletion analysis with unknown molecular basis. Pathogenic variants in the mitochondrial genome (72 patients) were more prevalent than those in the nuclear genome (38 patients) in our cohort. The most commonly involved organ system at disease onset was the neurological system, in which developmental delay, seizures or epilepsy, and stroke-like episodes were the most frequently reported presentations. The mortality rate in our cohort was 37%. CONCLUSION: This study is a territory-wide overview of the clinical and genetic characteristics of MD patients in a Chinese population, providing the first available prevalence rate of MD in Hong Kong. The findings of this study aim to facilitate future in-depth evaluation of MD and lay the foundation to establish a local MD registry.

Neurological manifestations in m.3243A>G-related disease triggered by metformin.

INTRODUCTION: m.3243A>G-related disease has multi-systemic manifestations including diabetes mellitus. It is uncertain whether metformin would trigger neurological manifestations of this disease. This study aims to review the diagnosis and management of m.3243A>G-related diabetes genetically confirmed by our laboratory and to evaluate the risk of metformin use triggering neurological manifestations. METHODS: Cases with m.3243A>G detected between 2009 and 2020 were reviewed. Cases with diabetes mellitus were included. Cases with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) before diabetes onset were excluded. Odds ratio was calculated for association between metformin use and newly developed neurological manifestations. RESULTS: Sixteen patients were identified. Odds ratio for metformin use was 3.50 [0.37-33.0; p = 0.3287]. One illustrative case with clear causal relationship between metformin use and neurological manifestations was described in detail. CONCLUSION: m.3243A>G-related diabetes mellitus is underdiagnosed. Red flags including positive family history, short stature, low body weight and hearing loss are often overlooked. Early diagnosis allows regular systemic assessment. In the era of precision medicine and novel therapies, it is prudent to avoid metformin as it could trigger neurological manifestations in this condition. Coenzyme Q10, DPP-IV inhibitors, SGLT2 inhibitors and GLP-1 receptor agonists may be considered.

High Prevalence of Late-Onset Fabry Cardiomyopathy in a Cohort of 499 Non-Selective Patients with Left Ventricular Hypertrophy: The Asian Fabry Cardiomyopathy High-Risk Screening Study (ASIAN-FAME).

Left ventricular hypertrophy (LVH) caused by cardiac variant Fabry disease (FD) is typically late-onset and may mimic LVH caused by abnormal loading conditions. We aimed to determine the prevalence of FD in a non-selective patient population of everyday practice presenting with LVH, including those with hypertension and valve disease. We measured plasma alpha-galactosidase A activity using dried blood spot tests in 499 (age = 66 ± 13 years; 336 men) Hong Kong Chinese patients with LVH defined as maximal LV septal/posterior wall thickness ≥13 mm on echocardiography. Patients with low enzyme activity underwent mutation analysis of the GLA gene. Eight (age = 53-74 years; all men) unrelated patients (1.6%) had low plasma alpha-galactosidase A activity (0.57 ± 0.27 µmol/L wb/hr) and all were confirmed to have the GLA IVS4 + 919G > A mutation. FD patients presented with heart failure (n = 5), heart block (n = 2), ventricular tachycardia (n = 1), chest pain (n = 3), and/or murmur (n = 1). Uncontrolled hypertension (n = 4) and/or severe mitral/aortic valve pathology (n = 2) were frequent. Ethnic subgroups included Teochew (n = 5), Canton (n = 2), and Wenzhou (n = 1). Endomyocardial biopsy (n = 6) revealed hypertrophic myocytes with vacuolization and dense lamellar bodies. Late-onset IVS4 + 919G > A FD is prevalent among Chinese LVH patients, and should be considered as a cause of LVH in adult patients even when hypertension and/or valve pathology are present.

Screening for Fabry Disease in patients with unexplained left ventricular hypertrophy.

Fabry Disease (FD) is a systemic disorder that can result in cardiovascular, renal, and neurovascular disease leading to reduced life expectancy. FD should be considered in the differential of all patients with unexplained left ventricular hypertrophy (LVH). We therefore performed a prospective screening study in Edmonton and Hong Kong using Dried Blood Spot (DBS) testing on patients with undiagnosed LVH. Participants found to have unexplained LVH on echocardiography were invited to participate and subsequently subjected to DBS testing. DBS testing was used to measure α-galactosidase (α-GAL) enzyme activity and for mutation analysis of the α-galactosidase (GLA) gene, both of which are required to make a diagnosis of FD. DBS testing was performed as a screening tool on patients (n = 266) in Edmonton and Hong Kong, allowing for detection of five patients with FD (2% prevalence of FD) and one patient with hydroxychloroquine-induced phenocopy. Left ventricular mass index (LVMI) by GLA genotype showed a higher LVMI in patients with IVS4 + 919G > A mutations compared to those without the mutation. Two patients were initiated on ERT and hydroxychloroquine was discontinued in the patient with a phenocopy of FD. Overall, we detected FD in 2% of our screening cohort using DBS testing as an effective and easy to administer screening tool in patients with unexplained LVH. Utilizing DBS testing to screen for FD in patients with otherwise undiagnosed LVH is clinically important due to the availability of effective therapies and the value of cascade screening in extended families.

Two related Chinese Fabry disease patients with a p.N215S pathological variant who presented with nephropathy.

Fabry disease is an X-linked lysosomal storage disease resulting from a mutation in the GLA gene that encodes α-galactosidase A. The p.N215S (c.644A > G [p.Asn215Ser]) genotype is the most common later-onset variant reported in individuals of European or North American descent. It is usually referred to as a cardiac variant, although manifestations in other organ systems have been observed. In this report, we describe a nephropathy presentation in two related Chinese Fabry disease patients with p.N215S.

Clinical and pathological characterization of FLNC-related myofibrillar myopathy caused by founder variant c.8129G>A in Hong Kong Chinese.

FLNC-related myofibrillar myopathy could manifest as autosomal dominant late-onset slowly progressive proximal muscle weakness; involvements of cardiac and/or respiratory functions are common. We describe 34 patients in nine families of FLNC-related myofibrillar myopathy in Hong Kong ethnic Chinese diagnosed over the last 12 years, in whom the same pathogenic variant c.8129G>A (p.Trp2710*) was detected. Twenty-six patients were symptomatic when diagnosed; four patients died of pneumonia and/or respiratory failure. Abnormal amorphous material or granulofilamentous masses were detected in half of the cases, with mitochondrial abnormalities noted in two-thirds. We also show by haplotype analysis the founder effect associated with this Hong Kong variant, which might have occurred 42 to 71 generations ago or around Tang and Song dynasties, and underlain a higher incidence of myofibrillar myopathy among Hong Kong Chinese. The late-onset nature and slowly progressive course of the highly penetrant condition could have significant impact on the family members, and an early diagnosis could benefit the whole family. Considering another neighboring founder variant in FLNC in German patients, we advocate development of specific therapies such as chaperone-based or antisense oligonucleotide strategies for this particular type of myopathy.

Genetic diagnosis of CADASIL in three Hong Kong Chinese patients: A novel mutation within the intracellular domain of NOTCH3.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an adult onset hereditary stroke syndrome characterized by recurrent stroke and progressive cognitive impairment caused by NOTCH3 mutations. We report here the clinical and molecular findings of three unrelated Hong Kong Chinese families with CADASIL syndrome. Sanger sequencing of genomic DNA revealed a novel heterozygous variant NM_000435.2(NOTCH3):c.[5903_5904insATAA];[5903_5904=] NP_000426.2:p.(Asp1969∗);(Asp1969=) and two previously reported heterozygous mutations NM_000435.2(NOTCH3):c.[328C>T];[328C=] NP_000426.2:p.[(Arg110Cys)];[(Arg110=)] and NM_000435.2(NOTCH3):c.[580T>A];[580T=] NP_000426.2:p.(Cys194Ser);(Cys194=) in the three families respectively. Molecular basis of CADASIL in these three patients were further established. Genetic analysis provides a reliable method for confirming the diagnosis of CADASIL and enables proper genetic counseling and cascade testing.

Improvement of bone mineral density after enzyme replacement therapy in Chinese late-onset Pompe disease patients.

OBJECTIVE: Late-onset Pompe disease (LOPD) is a lysosomal storage disease resulted from deficiency of the enzyme acid α-glucosidase. Patients usually develop a limb-girdle pattern of myopathy and respiratory impairment, and enzyme replacement therapy (ERT) is the only specific treatment available. Recently, LOPD has been associated with low bone mineral density (BMD), but the effect of ERT on BMD is inconclusive. In this report we described our early observations on the change of BMD after ERT in Chinese LOPD patients. RESULTS: We studied four Chinese LOPD patients with different severities of myopathy. All were underweight, and three had osteoporosis at baseline. We found significant weight gain in three patients after ERT and all four patients showed improvement in BMD. The biggest improvement, 84.4% increase in BMD, was seen in a lady with the most prominent weight recovery. Our results suggest that ERT improves BMD in Chinese LOPD and weight gain could be a major contributor to this effect.

DRESS syndrome: A case of cross-reactivity with lacosamide?

A 42-year-old patient with epilepsy was admitted to the hospital for fever and generalized skin rash. He has known allergy to phenytoin. Valproate was started in 2012, but failed to control his seizure despite gradual increase in dosage. Phenobarbitone was added 16 days before admission and was stopped on admission. He was treated with beta-lactam antibiotics. The rash subsided gradually after the cessation of phenobarbitone. Lacosamide was subsequently added for seizure control. Unfortunately, he developed drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome soon after introduction of lacosamide that required the use of systemic steroid for acute hepatitis. A cross-reactivity with lacosamide was suspected in view of the rapid onset of DRESS syndrome after the initial rash resolution and soon after the introduction of lacosamide. We postulated that the rapid onset of DRESS syndrome may be related to the aromatic ring that is in common among phenytoin, phenobarbitone, and lacosamide.

Clinical manifestation of late onset Pompe disease patients in Hong Kong.

Late onset Pompe disease is a rare inherited metabolic disease with diverse clinical manifestation. However, there is a lack of local data in Hong Kong. We aimed at performing an in-depth review of natural history of all patients in Hong Kong. Eleven patients were diagnosed to have the disease in Hong Kong from 2000 to 2013. All case records were reviewed and face-to-face interviews were conducted to complete a questionnaire regarding the clinical manifestation and diagnosis of the disease. The estimated birth incidence was 1/300,000. The age of diagnosis ranged from 9 to 44 years; all patients were ethnic Chinese. The median ages of first symptoms and first medical attention were 20.5(6-44) and 29(9-44) years respectively. The most common initial complaint was decreased exercise tolerance. Two patients' first complaint was difficulty with getting up from lying position and failure to perform sit up. The mean time from first medical attention to diagnosis was 1.3 years but one patient was diagnosed 8 years later. Half of the patients sought medical attention due to progressive shortness of breath and all of them developed type 2 respiratory failure requiring ventilator support during the first admission. Two patients became chair-bound and seven patients required assisted ventilation. Late onset Pompe disease tends to have an earlier and more aggressive clinical presentation in Chinese and lower birth incidence was found in Hong Kong.

Young-onset parkinsonism in a Hong Kong Chinese man with adult-onset Hallervorden-Spatz syndrome.

Neurodegeneration with brain iron accumulation (NBIA) is a heterogeneous group of disorders varied in genetic etiologies, clinical presentations, and radiological features. NBIA is an iron homeostasis disorder with progressive iron accumulation in the central nervous systems and is clinically characterized by extrapyramidal movement abnormalities, retinal pigmentary changes, and cognitive impairment. Panthothenate kinase-associated neurodegeneration (Hallervorden-Spatz disease) is the commonest disorder of NBIA with a prevalence of one-three per million. Clinically, it is classified into early-onset childhood, atypical late-onset, and adult-onset type. Adult-onset type is rarer. We report the first case of adult-onset panthothenate kinase-associated neurodegeneration in Hong Kong in a 28-year-old Chinese man who presented with pure young-onset parkinsonism. Magnetic resonance imaging (MRI) of the brain showed the presence of eye-of-the-tiger sign. Two compound heterozygous mutations PANK2 NM_153638.2: c.445G > T; NP_705902.2: p.E149X and PANK2 NM_153638.2: c.1133A > G; NP_705902.2: p.D378G were detected. Parkinsonism per se is a very heterogeneous phenotypic group. In view of the readily available genetic analysis of PANK2, panthothenate kinase-associated neurodegeneration should be considered in adult patients with young-onset parkinsonism with or without the eye-of-the-tiger sign. The exact diagnosis offers a different management approach and genetic counseling. NBIA is likely under- or misdiagnosed in Hong Kong Chinese.