Distal hereditary motor neuropathies (dHMN) are a group of heterogeneous diseases and previous studies have reported that the compound heterozygous recessive MME variants cause dHMN. Our study found a novel homozygous MME variant and a reported compound heterozygous MME variant in two Chinese families, respectively. Next-generation sequencing and nerve conduction studies were performed for two probands. The probands in two families presented with the muscle weakness and wasting of both lower limbs and carried a c.2122 A > T (p.K708*) and c.1342 C > T&c.2071_2072delinsTT (p.R448*&p.A691L) variant, respectively. Prominently axonal impairment of motor nerves and slight involvement of sensory nerves were observed in nerve conduction study. Our study reported a \"novel\" nonsense mutation and a missense variant of autosomal recessive late-onset dHMN and reviewed reported MME variants associated with dHMN phenotype.

BACKGROUND: Cobalamin C is the most common inborn error of intracellular cobalamin metabolism caused by biallelic pathogenic variants in the MMACHC gene, leading to impaired conversion of dietary vitamin B12 into its two metabolically active forms, methylcobalamin and adenosylcobalamin. Biochemical hallmarks are elevated plasma total homocysteine (HCYs) and low methionine accompanied by methylmalonic aciduria. This study aimed to evaluate the clinical, biochemical, and molecular analysis of Pakistani patients with CblC defect.
METHODS: Medical charts, urine organic acid (UOA) chromatograms, plasma amino acid levels, plasma tHcy and MMACHC gene results of patients presenting at the Biochemical Genetics Clinic, AKUH from 2013-2021 were reviewed. Details were collected on a pre-structured questionnaire. SPSS 22 was used for data analysis.
RESULTS: CblC was found in 33 cases (Male:Female 19:14). The median age of symptoms onset and diagnosis were 300 (IQR:135-1800) and 1380 (IQR: 240-2730) days. The most common clinical features were cognitive impairment (n = 29), seizures (n = 23), motor developmental delay (n = 20), hypotonia (n = 17), and sparse/hypopigmented scalp hair (n = 16). The MMACHC gene sequencing revealed homozygous pathogenic variant c.394C > T, (p.Arg132*) in 32 patients, whereas c.609G > A, (p.TRP203*) in one patient whose ancestors had settled in Pakistan from China decades ago. The median age of treatment initiation was 1530 (IQR: 240-2790). The median pre-treatment HCYs levels were 134 (IQR:87.2-155.5) compared to post-treatment levels of 33.3 (IQR: 27.3-44.95) umol/L.
CONCLUSIONS: Thirty-three cases of CblC defect from a single center underscores a significant number of the disorder within Pakistan. Late diagnosis emphasizes the need for increased clinical awareness and adequate diagnostic facilities.

BACKGROUND: Recent studies show that cognitive impairment is more prevalent in older patients with Multiple Sclerosis (MS). However, whether this is the result of several years of a chronic disease or specific age-related changes is still unclear. Therefore, we aim to assess the outcomes in both classic and social cognition in late-onset MS (LOMS) and compare them to adult-onset MS (AOMS) when accounting for age and disease duration.
METHODS: In this cross-sectional study, a group of 27 LOMS patients (age of disease onset >50 years) was compared with patients with AOMS (age of disease onset between 18 and 50 years). Patients with AOMS were grouped based on age (AOAMS, n = 27) and on disease duration (AODMS, n = 27) in order that these variables are matched with LOMS. Their cognitive performance was evaluated using the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) and the Revised \"Reading the Mind in the Eyes\" Test (RMET). Clinical and demographic variables were collected and analysed.
RESULTS: In general, both classic and social cognitive performance was inferior in the LOMS group when accounting for age and disease duration. We found a statistically significant negative correlation between age of disease onset and performance in all cognitive domains except for verbal memory. The presence of at least one vascular risk factor (VRF) was associated with slower information-processing speed (SDMT) (p = 0.006) and poorer RMET performance (p = 0.020).
CONCLUSIONS: A later age of MS is associated with worse cognitive functioning possibly due to the loss of neuroplasticity in an already aged brain.
CONCLUSIONS: Patients with LOMS have worse cognitive outcomes than AOMS in both classic and social domains, especially when associated with the presence of VRF. Hence, health care providers and patients should not undervalue the importance of cognitive stimulating activities, management of VFR and socialization in this specific group of patients.

A medical condition known as angioedema is characterized by sudden swelling of the mucosa, subcutaneous tissue, dermis, and submucosal tissues. If airway obstruction results in respiratory distress, this condition may be fatal. Histamine, bradykinin, and leukotrienes are just a few of the complex chemotactic mediators that play a role in the pathophysiology of angioedema and can lead to fluid buildup in deeper skin layers. Many things, such as medication side effects, genetic disorders, and allergic reactions, can cause angioedema. Olanzapine, an atypical antipsychotic mainly used to treat a few mental disorders, is one notable drug linked to angioedema. Angioedema is a documented side effect of olanzapine, albeit rare. Although the exact mechanism by which olanzapine causes angioedema is unknown, immunological-mediated or idiosyncratic reactions are thought to be involved. This study aims to review the current literature on the association between olanzapine and angioedema, including potential mechanisms of action and implications for clinical management. The possible risk factors, presentation, diagnosis, and treatment options for olanzapine-induced angioedema will also be discussed.

UNASSIGNED: Describe the clinical features and management of this uncommon case of late-onset Capsular bag distension syndrome that occurred 33 years after cataract surgery.
UNASSIGNED: An 87-year-old male was referred to our clinic complaining of blurred and gradual, painless reduction in vision in his left eye over the past year. A complete ophthalmological examination, Ultrasound biomicroscopy (UBM), anterior segment optical coherence tomography (AS-OCT), and optical biometry were performed to confirm the diagnosis. A 25-gauge pars plana vitrectomy combined with posterior capsulotomy was performed. The aspirated fluid was sent for microbiological analyses. After surgery, the patient\'s visual acuity returned to previous values, and anterior chamber depth slightly deepened. Samples taken were negative for bacteria.
UNASSIGNED: Late-onset Capsular bag distension syndrome may occur up to 33 years following cataract surgery. A surgical approach offers the advantage of complete clearance of the turbid fluid, also removing the residual cortical material and enabling microbial and pathological testing.

Spastic paraplegia type 4 (SPG4), the predominant form of Autosomal Dominant Hereditary spastic paraplegia (AD-HSP), is characterized by variants in the SPAST gene. This study reports a unique case of a late-onset SPG4 in a Han Chinese male, manifesting primarily as gait disturbances from lower extremity spasticity. Uncovered through whole-genome sequencing, a previously undocumented frameshift variant, c.1545dupA in exon 14 of the SPAST gene, was identified. Notably, this variant was absent in asymptomatic parents with confirmed paternity and maternity status, suggesting a de novo variant occurrence. This discovery emphasizes the potential of de novo variants to exhibit a late-onset pure pattern, extending the SPG4 variant spectrum, and consideration of such variants should be given in HSP patients with a negative family history.

This study aimed to explore the different characteristics between early-onset severe preeclampsia (ESPE) and late-onset severe preeclampsia (LSPE) to improve pregnancy outcomes. We performed a retrospective cohort study between January 2016 and December 2021. Eligible hospitalized pregnant women with severe preeclampsia were assigned into the early-onset or late-onset group, depending on the gestational age at the time of severe preeclampsia onset (< or ≥ 34 gestational weeks, respectively). The clinical characteristics, laboratory results, maternal complications, and fetal and neonatal outcomes were recorded and compared between the two groups. A total of 1,238 pregnant women were included, with 525 in the early-onset group and 713 in the late-onset group. The late-onset group had more cases of gestational diabetes, whereas the early-onset group had a higher blood pressure, showed more proteinuria, had more liver and renal damage, exhibited more serious adverse maternal, fetal, and neonatal outcomes, was more likely to be admitted to the intensive care unit, and required longer hospital stays (all P < 0.05). In addition, the early-onset group had fewer prenatal care appointments and was more often transferred from a primary or secondary care hospital. The logistic regression analysis showed that a weekly weight gain of > 100 g was a risk factor for ESPE and that fewer prenatal care appointments were a risk factor for ESPE in pregnant women with female fetuses. Moreover, logistic regression analysis indicated that nulliparity and gestational diabetes during the current pregnancy were risk factors for LSPE. In conclusion, compared with the women with LSPE, those with ESPE usually had worse maternal, fetal, and neonatal outcomes. More frequent prenatal screening and care should be provided for pregnant women with high-risk factors.

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Some patients with primary progressive aphasia (PPA) demonstrate only anomia. The lack of longitudinal observations of anomic PPA precluded us from determining whether progressive anomic aphasia was simply an early stage of semantic or logopenic variants, or a relatively independent variant. Herein, we report the 10-year clinical course of a patient with PPA who presented with pure anomic aphasia for 9 years. He is a right-handed man with anomia, who noticed word-finding difficulty at age 73. He was admitted to the hospital at age 77. On admission, the patient showed pure anomic aphasia with preserved other language function. Episodic memory and visuospatial function were preserved. Magnetic resonance imaging (MRI) revealed left temporal lobe atrophy. At 82 years of age, the patient presented with pure anomic aphasia. At 83 years old, he showed mild impairment in word comprehension and semantic memory, in addition to anomia. MRI demonstrated further atrophy in the bilateral anterior temporal lobes, predominantly on the left side. This case suggests the possibility of slowly progressive, late-onset anomic PPA, which could be differentiated from the early stage of semantic or logopenic variants.

UNASSIGNED: Patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) usually present with multisystemic dysfunction with a wide range of clinical manifestations. When the tests for common mitochondrial DNA (mtDNA) point mutations are negative and the mtDNA defects hypothesis remains, urine epithelial cells can be used to screen the mitochondrial genome for unknown mutations to confirm the diagnosis.
UNASSIGNED: A 66-year-old Chinese woman presented with symptoms of MELAS and was initially misdiagnosed with acute encephalitis at another institution. Although genetic analysis of blood lymphocyte DNA was negative, brain imaging, including magnetic resonance imaging, magnetic resonance spectroscopy, and clinical and laboratory findings, were all suggestive of MELAS. Finally, the patient was eventually diagnosed with MELAS with the mtDNA 5783G>A mutation in the MT-TC gene with a urinary sediment genetic test.
UNASSIGNED: This case report expands the genetic repertoire associated with MELAS syndrome and highlights the importance that full mtDNA sequencing should be warranted beside the analysis of classical variants when a mitochondrial disorder is highly suspected. Furthermore, urine sediment genetic testing has played a crucial role in the diagnosis of MELAS.