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.

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.

Toxic leucoencephalopathy after 'chasing the dragon'.

Toxic leucoencephalopathy (TLE) is a rare neurological complication of heroin abuse. 'Chasing the dragon' is an inhalational mode of heroin abuse that originated in Southeast Asia. Intriguingly, no cases of TLE have been reported from this region, although the inhalational mode of heroin abuse is common. We herein report the case of a middle-aged man with a history of polysubstance abuse who presented with progressive neurological symptoms and progressed to an uncommunicative state. While the initial impression was that of iatrogenic parkinsonism, diffuse leucoencephalopathy with sparing of the cerebellum was noted on magnetic resonance imaging. In view of his history of inhalational heroin abuse close to the onset of the neurological symptoms, a diagnosis of TLE was made. No clinical improvement was noted with administration of a dopaminergic agent. This is the first known case of delayed TLE following heroin inhalation from Southeast Asia with the unusual feature of cerebellar sparing.

Comparison of the Montreal Cognitive Assessment and the Mini-Mental State Examination in detecting multi-domain mild cognitive impairment in a Chinese sub-sample drawn from a population-based study.

BACKGROUND: We examined the discriminant validity of the Montreal Cognitive Assessment (MoCA) and the Mini-Mental State Examination (MMSE) in detecting multiple-domain mild cognitive impairment (md-MCI) in a Chinese sub-sample drawn from elderly population-based study. METHODS: This study included Chinese participants from the Epidemiology of Dementia in Singapore (EDIS) study aged ≥ 60 years who underwent cognitive screening with the Abbreviated Mental Test and Progressive Forgetfulness Questionnaire. Screen-positive participants subsequently underwent MoCA, MMSE, and a comprehensive formal neuropsychological battery. MCI was defined by Petersen's criteria and further classified into single-domain MCI (sd-MCI) and md-MCI. Area under the receiver operating characteristic curve (AUC) with 95% confidence intervals (CIs) was computed for the MoCA and the MMSE in detecting md-MCI. RESULTS: A total of 300 participants were recruited: 128 (42.7%) were diagnosed with no cognitive impairment (NCI), 47 (15.7%) with sd-MCI, and 83 (28.0%) with md-MCI. Forty-one participants were excluded, 7 (2.3%) had dementia, and 34 (11.3%) had only objective cognitive impairment without subjective complaints. Although the MoCA had a significantly larger AUC than the MMSE (0.94 (95% CI = 0.91-0.97) vs. 0.91 (95% CI = 0.86-0.95), p= 0.04), at optimal cut-off points, the MoCA (19/20) was equivalent to the MMSE (25/26) in detecting md-MCI (sensitivity: 0.80 vs. 0.87, specificity: 0.92 vs. 0.80). CONCLUSION: Both screening tests had good discriminant validity and can be used in detecting md-MCI in a sub-sample of Chinese drawn from a population-based study.

Characteristics of probably benign breast MRI lesions.

OBJECTIVE: The purpose of our study was to describe the characteristics of probably benign breast MRI lesions and determine how these characteristics could be used to define the MRI BI-RADS 3 category. MATERIALS AND METHODS: We prospectively collected morphology and kinetic data on lesions assessed as BI-RADS 3 in 2,569 consecutive breast MRI examinations from January 2003 through November 2006. The clinical indications for MRI, follow-up assessments, and pathology findings through May 2008 were collected from clinical records. Data were linked to the regional tumor registry to identify cases of malignancy in patients who did not follow-up at our institution. Frequency of BI-RADS 3 and cancer yield were calculated. Characteristics of probably benign lesions were analyzed for predictors of malignancy. RESULTS: Three hundred sixty-two lesions were assessed as BI-RADS 3 in 260 (10.1%) of 2,569 examinations in 236 patients. The 362 lesions included 168 (46%) foci, 132 (36%) nonmasslike enhancements, and 62 (17%) masses. Delayed kinetic information was available in 275 lesions. The most suspicious delayed kinetic enhancement was persistent in 164 (60%) of 275, plateau in 47 (17%) of 275, and washout in 64 (23%) of 275. The cancer yield in patients with a BI-RADS 3 assessment was two (0.85%) of 236; both were ductal carcinoma in situ lesions. There were no malignancies in the 69 foci with 100% persistent enhancement. CONCLUSION: The characteristics of BI-RADS 3 lesions were highly variable in our population, and the risk of malignancy was low (0.85%). Assigning foci with 100% persistent enhancement to the BI-RADS 2 category can decrease the frequency of BI-RADS 3 assessment and maintain a likelihood of malignancy in less than 2% of cases.

Reversible cerebral vasoconstriction syndrome.

Reversible cerebral vasoconstriction syndromes (RCVS) are a group of disorders that have in common an acute presentation with headache, reversible vasoconstriction of cerebral arteries, with or without neurological signs and symptoms. In contrast to primary central nervous system vasculitis, they have a relatively benign course. We describe here a patient who was diagnosed with RCVS.

Stroke in women.

Stroke remains one of the leading causes of morbidity and mortality worldwide. Sexual differences in stroke have been recognized, though the mechanisms remain unclear. Women have a unique risk factor profile, especially so in the reproductively active age group. Exposure to oral contraceptives, hormone replacement therapy and a higher incidence of migraine and vasculitic disorders in women suggest that stroke would be common in women. Yet, the incidence of stroke remains higher in men across all ages, indicating a protective role of sex hormones. The differences in incidence and prevalence of stroke decreases as women age, confirming that hormones play a pivotal role in terms of normal physiology, disease and recovery. Recent evidence also points to sex based differences in response to therapy, in terms of acute management and prevention. Gender based differences in accessibility and provision of health care facilities add to the observed differences in terms of stroke outcome, though here women seem to fare worse than men. This review summarizes the observed sex differences in stroke, possible hormonal mechanisms that may explain the same and outlines recent patents and scope for future research in this field.