A novel variant in the tropomyosin 3 gene presenting as an adult-onset distal myopathy - a case report.

BACKGROUND: We report a patient with a novel c.737 C > T variant (p.Ser246Leu) of the TPM3 gene presenting with adult-onset distal myopathy. CASE PRESENTATION: A 35-year-old Chinese male patient presented with a history of progressive finger weakness. Physical examination revealed differential finger extension weakness, together with predominant finger abduction, elbow flexion, ankle dorsiflexion and toe extension weakness. Muscle MRI showed disproportionate fatty infiltration of the glutei, sartorius and extensor digitorum longus muscles without significant wasting. Muscle biopsy and ultrastructural examination showed a non-specific myopathic pattern without nemaline or cap inclusions. Genetic sequencing revealed a novel heterozygous p.Ser246Leu variant (c.737C>T) of the TPM3 gene which is predicted to be pathogenic. This variant is located in the area of the TPM3 gene where the protein product interacts with actin at position Asp25 of actin. Mutations of TPM3 in these loci have been shown to alter the sensitivity of thin filaments to the influx of calcium ions. CONCLUSION: This report further expands the phenotypic spectrum of myopathies associated with TPM3 mutations, as mutations in TPM3 had not previously been reported with adult-onset distal myopathy. We also discuss the interpretation of variants of unknown significance in patients with TPM3 mutations and summarise the typical muscle MRI findings of patients with TPM3 mutations.

Unique Clinical, Radiological and Histopathological Characteristics of a Southeast Asian Cohort of Patients with Limb-Girdle Muscular Dystrophy 2G/LGMD-R7-Telethonin-Related.

AIM: We describe a cohort of five patients with limb-girdle muscular dystrophy (LGMD) 2G/LGMD-R7 in a South-east Asian cohort. BACKGROUND: LGMD2G/LGMD-R7-telethonin-related is caused by mutations in the TCAP gene that encodes for telethonin. METHODS: We identified consecutive patients with LGMD2G/LGMD-R7-telethonin-related, diagnosed at the National Neuroscience Institute (NNI) and National University Hospital (NUH) between January 2000 and June 2021. RESULTS: At onset, three patients presented with proximal lower limb weakness, one patient presented with Achilles tendon contractures, and one patient presented with delayed gross motor milestones. At last follow up, three patients had a limb girdle pattern of muscle weakness and two had a facioscapular humeral pattern of weakness. Whole body muscle MRI performed for one patient with a facioscapular-humeral pattern of weakness showed a pattern of muscle atrophy similar to facioscapular-humeral dystrophy. One patient had histological features consistent with myofibrillar myopathy; electron microscopy confirmed the disruption of myofibrillar architecture. One patients also had reduced staining to telethonin antibody on immunohistochemistry. CONCLUSION: We report the unique clinical and histological features of a Southeast Asian cohort of five patients with LGMD2G/LGMD-R7-telethonin-related muscular dystrophy and further expand its clinical and histopathological spectrum.

Should Aquaporin-4 Antibody Test Be Performed in all Patients With Isolated Optic Neuritis?

BACKGROUND: Optic neuritis (ON) may be the initial manifestation of neuromyelitis optica spectrum disorder (NMOSD). Aquaporin-4 antibody (AQP4 Ab) is used to diagnose NMOSD. This has implications on prognosis and is important for optimal management. We aim to evaluate if clinical features can distinguish AQP4 Ab seropositive and seronegative ON patients. METHODS: We reviewed patients with first episode of isolated ON from Tan Tock Seng Hospital and Singapore National Eye Centre who tested for AQP4 Ab from 2008 to 2017. Demographic and clinical data were compared between seropositive and seronegative patients. RESULTS: Among 106 patients (120 eyes) with first episode of isolated ON, 23 (26 eyes; 22%) were AQP4 Ab positive and 83 (94 eyes; 78%) were AQP4 Ab negative. At presentation, AQP4 Ab positive patients had older mean onset age (47.9 ± 13.6 vs 36.8 ± 12.6 years, P < 0.001), worse nadir VA (OR 1.714; 95% CI, 1.36 to 2.16; P < 0.001), less optic disc swelling (OR 5.04; 95% CI, 1.682 to 15.073; p = 0.004), and higher proportions of concomitant anti-Ro antibody (17% vs 4%, p = 0.038) and anti-La antibody (17% vs 1%, p = 0.008). More AQP4 Ab positive patients received steroid-sparing immunosuppressants (74% vs 19%, p < 0.001) and plasma exchange (13% vs 0%, p = 0.009). AQP4 Ab positive patients had worse mean logMAR VA (visual acuity) at 12 months (0.70 ± 0.3 vs 0.29 ± 0.5, p = 0.051) and 36 months (0.37±0.4 vs 0.14 ± 0.2, p = 0.048) follow-up. CONCLUSION: Other than older onset age and retrobulbar optic neuritis, clinical features are non-discriminatory for NMOSD. We propose a low threshold for AQP4 Ab serology testing in inflammatory ON patients, particularly in high NMOSD prevalence populations, to minimize diagnostic and treatment delays.

Acute to Subacute Atraumatic Entrapment Neuropathies in Patients With CMT1A: A Report of a Distinct Phenotypic Variant of CMT1A.

Charcot-Marie-Tooth type 1A (CMT1A) is typically characterised as a childhood-onset, symmetrical, length-dependent polyneuropathy with a gradual progressive clinical course. Acute to subacute neurological deterioration in CMT1A is rare, and has been reported secondary to overlap pathologies including inflammatory neuropathy. We identified two patients with CMT1A who presented with acute to subacute, atraumatic, entrapment neuropathies as an initial symptom. A superimposed inflammatory neuropathy was excluded. Both patients had a diffuse demyelinating polyneuropathy, with markedly low motor nerve conduction velocities (<20 m/s). In both patients, we demonstrated symptomatic and asymptomatic partial conduction blocks at multiple entrapment sites. Nerve ultrasound findings in our patients demonstrated marked diffuse nerve enlargement, more pronounced at non-entrapment sites compared to entrapment sites. We discuss ways to distinguish this condition from its other differentials. We propose pathophysiological mechanisms underlying this condition. We propose that CMT1A with acute to subacute, atraumatic, entrapment neuropathies to be a distinct phenotypic variant of CMT1A.

Staging model for amyotrophic lateral sclerosis in Singapore.

Introduction: A clinical-based staging model would guide physicians in the prompt management of the evolving symptoms and functional needs of patients with amyotrophic lateral sclerosis (ALS). Methods: We aimed to delineate the clinical trajectory of ALS in Singapore and test the degree of congruity of King's College staging for ALS (King's staging) among Singapore patients. In this retrospective cohort study, clinical milestones used for staging were identical to King's staging: stage 1 corresponded to symptom onset; stage 2A corresponded to diagnosis; stage 2B corresponded to two central nervous system (CNS) regions; stage 3B corresponded to three CNS regions; stage 4A corresponded to requirement of supportive enteric feeding; and stage 4B corresponded to requirement of non-invasive ventilation, of which bulbar, diaphragmatic, upper and lower limb pyramidal involvements each constituted one CNS region. Standardised timings from disease onset (0) to death (1) among Singapore patients with ALS were measured. Results: 46 patients with ALS were reviewed. Results were largely congruous with King's staging. Results for patients with limb-onset ALS were: diagnosis (0.35); two CNS region involvement (0.42); three CNS region involvement (0.63); diaphragmatic involvement (0.81); and bulbar involvement (0.73). Results for patients with bulbar-onset ALS were: diagnosis (0.14); two CNS region involvement (0.28); three CNS region involvement (0.42); diaphragmatic involvement (0.62); and bulbar involvement (0.67). Conclusion: King's staging can be used to model ALS trajectory in Singapore due to the large degree of congruity seen. Easily remembered and accessible knowledge of ALS staging will allow prompt management of the evolving needs of patients with ALS.

Hereditary Transthyretin Amyloidosis- Clinical and Genetic Characteristics of a Multiracial South-East Asian Cohort in Singapore.

BACKGROUND AND AIMS: Studies of hereditary transthyretin amyloidosis (ATTRv amyloidosis) in South-East Asia are underrepresented in the literature. We report the unique phenotypic and genetic characteristics of this disorder in a multiracial South-East Asian cohort. METHODS: Patients with genetically proven ATTRv amyloidosis were identified over a 13-year period (2007-2020) at the National Neuroscience Institute, Singapore. Clinical, laboratory, genotypic and electrophysiological features were retrospectively reviewed. RESULTS: 29 patients comprising Chinese, Malay, Burmese, Vietnamese and Indonesians with ATTRv amyloidosis were identified. Somatic neuropathy was the most common initial presentation, followed by carpal tunnel syndrome, autonomic dysfunction and cardiac dysfunction. ATTR-A97S (p.Ala117Ser) was the most common variant found in 14 patients, constituting 66.7%of ethnic Chinese patients and 48.3%of the entire cohort. Five patients had early-onset disease (age < 50 years) with the following variants: ATTR-V30M (p.Val50Met), ATTR-G47A (p.Gly67Ala), ATTR-S50I (p.Ser70Ile) and ATTR-A97S (p.Ala117Ser); one patient with ATTR-A97S (p.Ala117Ser) had isolated unilateral carpal tunnel syndrome with amyloid deposits identified on histological examination of the transverse carpal ligament. All early-onset patients had a positive parental history; two patients, with ATTR-S50I (p.Ser70Ile) and ATTR-Ala97Ser (p.Ala117Ser) respectively, demonstrated anticipation with mother-to-daughter inheritance. Amongst the 24 patients with late-onset disease (age≥50 years), two patients had novel variants, ATTR-G66D (p.Glu86Asp) and ATTR-A81V (p.Ala101Val) that were confirmed to be pathogenic based on the histological identification of transthyretin amyloid. Other identified variants included ATTR-V30M (p.Val50Met), ATTR-R34T (p.Arg54Thr), ATTR-S50I (p.Ser70Ile), ATTR-H88R (p.His108Arg) and ATTR-A97S (p.Ala117Ser). CONCLUSION: Our study further expands the genotypic and phenotypic knowledge regarding ATTRv amyloidosis.

Clinical practice with steroid therapy for Duchenne muscular dystrophy: An expert survey in Asia and Oceania.

BACKGROUND: Several studies on clinical practice for Duchenne muscular dystrophy (DMD) have been conducted in Western countries. However, there have been only a few similar studies in Asia and Oceania. Here, we investigate the steroid therapy-related clinical practice for DMD among the local experts. In 2015, we conducted a DMD expert survey in Asia and Oceania to acquire information regarding patients with DMD and to assess current clinical practice with the cooperation of Asian and Oceanian Myology Centre, a neuromuscular disease research network. RESULTS: We obtained survey responses from 87 out of 148 clinicians (62%) from 13 countries and regions. In China, 1385 DMD patients were followed-up by 5 respondent neurologists, and 84% were between 0 and 9 years of age (15% were 10-19 years, 1% > 19 years). While in Japan, 1032 patients were followed-up by 20 clinicians, and the age distribution was similar between the 3 groups (27% were 0-9 years, 35% were 10-19 years, 38% were >19 years). Most respondent clinicians (91%) were aware of DMD standard of care recommendations. Daily prednisolone/prednisone administration was used most frequently at initiation (N = 45, 64%). Inconsistent opinion on steroid therapy after loss of ambulation and medication for bone protection was observed. CONCLUSIONS: Rare disease research infrastructures have been underdeveloped in many of Asian and Oceanian countries. In this situation, our results show the snapshots of current medical situation and clinical practice in DMD. For further epidemiological studies, expansion of DMD registries is necessary.

Mutational spectrum of dystrophinopathies in Singapore: Insights for genetic diagnosis and precision therapy.

Duchenne and Becker muscular dystrophies (DMD/BMD) are X-linked recessive disorders caused by mutations in the DMD gene. Emerging therapies targeting patients with specific mutations are now becoming a reality for many of these patients. Precise molecular diagnosis is essential to facilitate the identification of possible new treatments for patients in the local context. In this study, we screened 145 dystrophinopathic patients in Singapore and assessed their molecular status for eligibility to current emerging genetic therapies. Overall, 140 (96.5%) of all patients harbored pathogenic DMD mutations comprising 95 exonic deletions (65.5%), 14 exonic duplications (9.7%), and 31 pathogenic small mutations (21.4%). Nonsense and frameshift mutations constitute 83.9% of all the small mutations. We found 71% (103/145) of all Singaporean dystrophinopathy patients to be theoretically amenable for exon skipping, either through skipping of single (53.1%) or multiple exons (17.9%). This approach is applicable to 81.1% (77/95) of patients carrying deletions and 83.9% (26/31) of those with small mutations. Eteplirsen induced skipping of exon 51 is applicable to 12.4% of local patients. Nonsense read-through therapy was found to be applicable in another 12.4% of all patients. Mutation screening is crucial for providing insights into the underlying genetic signature of the disease in the local population and contributes toward existing information on DMD mutations in Asia and globally. This will guide future targeted drug development and clinical trial planning for this disease.

Phenotypic and molecular features underlying neurodegeneration of motor neurons derived from spinal and bulbar muscular atrophy patients.

Spinal and bulbar muscular atrophy (SBMA) is a neurodegenerative disease caused by the expansion of polyglutamine region in the androgen receptor. To gain insights into mechanisms of SBMA, four wild-type and five SBMA iPSC lines were differentiated to spinal motor neurons (sMNs) with high efficiency. SBMA sMNs showed neurite defects, reduced sMN survival and decreased protein synthesis levels. Microarray analysis revealed a dysregulation in various neuronal-related signalling pathways in SBMA sMNs. Strikingly, FAM135B a novel gene of unknown function, was found drastically downregulated in SBMA sMNs. Knockdown of FAM135B in wild-type sMNs reduced their survival and contributed to neurite defects, similar to SBMA sMNs, suggesting a functional role of FAM135B in SBMA. The degenerative phenotypes and dysregulated genes revealed could be potential therapeutic targets for SBMA.

Distinction between anti-VGKC-complex seropositive patients with and without anti-LGI1/CASPR2 antibodies.

BACKGROUND: To identify clinical and paraclinical differences between anti-voltage-gated potassium channel (VGKC)-complex seropositive patients with and without anti-leucine-rich glioma-inactivated protein 1 (LGI1)/contactin-associated protein-like 2 (CASPR2) antibodies (Abs). METHODS: We performed a retrospective analysis of 50 anti-VGKC-complex seropositive patients from January 2013 to September 2016, and tested them for anti-LGI1/CASPR2 Abs. Comparative analysis was performed between anti-LGI1/CASPR2 seropositive and 'double negative' patients. RESULTS: Seven patients had anti-LGI1/CASPR2 Abs while 43 patients were 'double negative' for these 2 Abs. Three 'double negative' patients had other neuronal surface Abs and were excluded from analysis. Compared to 'double negative' patients, a higher proportion of anti-LGI1/CASPR2 seropositive patients had complex partial seizures (5/7 vs 5/40; p = .003), limbic encephalitis (4/7 vs 2/40; p = .003), hippocampal imaging abnormalities (5/7 vs 3/39; p < .001), temporal epileptiform activity/electrographic seizures (4/6 vs 4/27; p = .020), tumours (3/7 vs 0/40; p = .002), and received acute immunotherapy (5/7 vs 6/40; p = .005) and maintenance immunotherapy (5/7 vs 4/40; p = .001). Anti-LGI1/CASPR2 seropositive patients had higher anti-VGKC-complex Abs levels (median 2857 pM [range 933-6730] vs 165 pM [104-1065]; p < .001). In contrast, a higher proportion of 'double negative' patients had non-specific behavioral disorders (20/40 vs 0/7; p = .015), and 13 of 40 (32.5%) had alternative organic diagnoses. CONCLUSION: In anti-VGKC-complex seropositive patients, we identified features in patients with anti-LGI1/CASPR2 Abs distinct from 'double negative' patients, and found that 'double negative' patients were associated with non-specific clinical features and had a high rate of alternative diagnosis. These findings demonstrate the limited utility of anti-VGKC-complex Abs testing in suspected neurological autoimmunity.

Generation of sibling-matched induced pluripotent stem cell lines from spinal and bulbar muscular atrophy patients.

Spinal and bulbar muscular atrophy (SBMA) is a neurodegenerative disease caused by the expansion of CAG repeats in the Androgen Receptor gene (AR). We report the generation of induced pluripotent stem cell (iPSC) lines from two SBMA patients and their healthy siblings. The SBMA and healthy iPSC lines retain the number of AR CAG repeats, express pluripotency markers and are able to differentiate into the three germ layers. The iPSC lines are also free of Sendai virus transgenes and have normal karyotypes. The SBMA iPSC lines with their sibling-matched controls would serve as useful tools to study SBMA disease mechanism.

Neurological manifestations of primary Sjogren's syndrome.

PURPOSE OF REVIEW: This review summarizes our current understanding of the neurological manifestations of primary Sjogren's syndrome (PSS), their pathophysiology, and treatment. RECENT FINDINGS: Prevalence of neurological manifestations in PSS varies widely from 10 to 60%, with pure or predominantly sensory polyneuropathies as the most common neurologic manifestation (e.g. sensory ataxic or small fiber sensory painful neuropathy). Mononeuropathy multiplex, polyradiculopathy, symptomatic dysautonomia, cranial neuropathy, myopathy, and central nervous system involvement are less common. PSS-associated sensory neuropathy is often the presenting feature of Sjogren's syndrome and, therefore, a high index of suspicion is required, particularly in female patients with nonlength-dependent, painful, or ataxic sensory neuropathies or those with trigeminal sensory and autonomic involvement. The pathophysiological basis of PSS-associated neuropathy is still unclear. Dorsal root ganglionitis and peripheral nerve vasculitis have been observed on histological examination of biopsy and autopsy samples. A few studies have explored the fundamental role of humoral autoimmune mechanisms. Small, uncontrolled, treatment trials with numerous immunomodulatory agents have reported variable benefit in PSS-associated neuropathy, particularly corticosteroids for mononeuritis multiplex and intravenous immunoglobulin for small fiber or sensory ataxic neuropathy. SUMMARY: The clinical and histological spectrum of neurological manifestations of Sjogren's syndrome is becoming clear. The field needs further exploration of basic neuroimmunological mechanisms of neural injury, and controlled treatment trials.

Superior sagittal sinus thrombosis: subtle signs on neuroimaging.

INTRODUCTION: The aim of this study was to review the clinical, computed tomography (CT) and magnetic resonance imaging (MRI) diagnosis and the frequency of positive neuroimaging findings in patients with cerebral venous thrombosis (CVT) involving the superior sagittal sinus. MATERIALS AND METHODS: A clinical and radiological database of patients with final diagnosis of CVT was compiled from the inpatient hospital information service of a tertiary neurological hospital over 5 years. CT and MRI studies in 22 patients were retrospectively examined for direct signs of venous sinus thrombosis and for complications of CVT. The diagnosis of CVT before and after CT and MRI was reviewed. RESULTS: Clinical diagnosis of possible CVT was suspected in only 1 patient. When the diagnosis was not suspected, CT diagnosis was difficult and there was a high false negative rate of 52.6%. MRI fared better, but the false negative rate was still 11%. Directs signs of venous sinus thrombosis such as the triangle sign, empty delta sign on CT and loss of the normal flow voids on MRI, could be retrospectively detected in 57.9%, 100% and 100% of patients respectively. Although 4 patients presented with subarachnoid haemorrhage, these direct signs were present in 3 patients. CONCLUSION: Clinical diagnosis of CVT is rarely suspected before CT and MRI, and although subtle positive signs are often present, these may not be appreciated unless there is a high index of suspicion or image review at multidisciplinary team meetings.