Atypical Presentation of Low-Grade Small Lymphocytic Lymphoma of the Lacrimal Sac.

Lymphoma of the lacrimal sac is uncommon and usually presents as a lacrimal sac mass, against a background of known systemic lymphoma. This study presents the case of a 70-year-old man with small lymphocytic lymphoma of the lacrimal sac and widespread systemic involvement presenting as common canalicular obstruction without a palpable mass or systemic symptoms.

Giant intracranial hemangioma in a neonate.

In this report we detail the case of an infant presenting with a giant intracranial congenital hemangioma and describe the clinical features and surgical management. Congenital hemangiomas are benign vascular tumors that typically present as skin lesions in neonates and infants. On rare occasions they present as intracranial tumors. The possibility that these tumors may undergo spontaneous regression poses a treatment dilemma.

Somatostatin Receptor PET/MR Imaging of Inflammation in Patients With Large Vessel Vasculitis and Atherosclerosis.

BACKGROUND: Assessing inflammatory disease activity in large vessel vasculitis (LVV) can be challenging by conventional measures. OBJECTIVES: We aimed to investigate somatostatin receptor 2 (SST2) as a novel inflammation-specific molecular imaging target in LVV. METHODS: In a prospective, observational cohort study, in vivo arterial SST2 expression was assessed by positron emission tomography/magnetic resonance imaging (PET/MRI) using 68Ga-DOTATATE and 18F-FET-ßAG-TOCA. Ex vivo mapping of the imaging target was performed using immunofluorescence microscopy; imaging mass cytometry; and bulk, single-cell, and single-nucleus RNA sequencing. RESULTS: Sixty-one participants (LVV: n = 27; recent atherosclerotic myocardial infarction of ≤2 weeks: n = 25; control subjects with an oncologic indication for imaging: n = 9) were included. Index vessel SST2 maximum tissue-to-blood ratio was 61.8% (P < 0.0001) higher in active/grumbling LVV than inactive LVV and 34.6% (P = 0.0002) higher than myocardial infarction, with good diagnostic accuracy (area under the curve: ≥0.86; P < 0.001 for both). Arterial SST2 signal was not elevated in any of the control subjects. SST2 PET/MRI was generally consistent with 18F-fluorodeoxyglucose PET/computed tomography imaging in LVV patients with contemporaneous clinical scans but with very low background signal in the brain and heart, allowing for unimpeded assessment of nearby coronary, myocardial, and intracranial artery involvement. Clinically effective treatment for LVV was associated with a 0.49 ± 0.24 (standard error of the mean [SEM]) (P = 0.04; 22.3%) reduction in the SST2 maximum tissue-to-blood ratio after 9.3 ± 3.2 months. SST2 expression was localized to macrophages, pericytes, and perivascular adipocytes in vasculitis specimens, with specific receptor binding confirmed by autoradiography. SSTR2-expressing macrophages coexpressed proinflammatory markers. CONCLUSIONS: SST2 PET/MRI holds major promise for diagnosis and therapeutic monitoring in LVV. (PET Imaging of Giant Cell and Takayasu Arteritis [PITA], NCT04071691; Residual Inflammation and Plaque Progression Long-Term Evaluation [RIPPLE], NCT04073810).

Biallelic variants in TAMM41 are associated with low muscle cardiolipin levels, leading to neonatal mitochondrial disease.

Mitochondrial disorders are clinically and genetically heterogeneous, with variants in mitochondrial or nuclear genes leading to varied clinical phenotypes. TAMM41 encodes a mitochondrial protein with cytidine diphosphate-diacylglycerol synthase activity: an essential early step in the biosynthesis of phosphatidylglycerol and cardiolipin. Cardiolipin is a mitochondria-specific phospholipid that is important for many mitochondrial processes. We report three unrelated individuals with mitochondrial disease that share clinical features, including lethargy at birth, hypotonia, developmental delay, myopathy, and ptosis. Whole exome and genome sequencing identified compound heterozygous variants in TAMM41 in each proband. Western blot analysis in fibroblasts showed a mild oxidative phosphorylation (OXPHOS) defect in only one of the three affected individuals. In skeletal muscle samples, however, there was severe loss of subunits of complexes I-IV and a decrease in fully assembled OXPHOS complexes I-V in two subjects as well as decreased TAMM41 protein levels. Similar to the tissue-specific observations on OXPHOS, cardiolipin levels were unchanged in subject fibroblasts but significantly decreased in the skeletal muscle of affected individuals. To assess the functional impact of the TAMM41 missense variants, the equivalent mutations were modeled in yeast. All three mutants failed to rescue the growth defect of the Δtam41 strains on non-fermentable (respiratory) medium compared with wild-type TAM41, confirming the pathogenicity of the variants. We establish that TAMM41 is an additional gene involved in mitochondrial phospholipid biosynthesis and modification and that its deficiency results in a mitochondrial disorder, though unlike families with pathogenic AGK (Sengers syndrome) and TAFAZZIN (Barth syndrome) variants, there was no evidence of cardiomyopathy.

Mechanisms and genetic determinants regulating sterol absorption, circulating LDL levels, and sterol elimination: implications for classification and disease risk.

This review integrates historical biochemical and modern genetic findings that underpin our understanding of the low-density lipoprotein (LDL) dyslipidemias that bear on human disease. These range from life-threatening conditions of infancy through severe coronary heart disease of young adulthood, to indolent disorders of middle- and old-age. We particularly focus on the biological aspects of those gene mutations and variants that impact on sterol absorption and hepatobiliary excretion via specific membrane transporter systems (NPC1L1, ABCG5/8); the incorporation of dietary sterols (MTP) and of de novo synthesized lipids (HMGCR, TRIB1) into apoB-containing lipoproteins (APOB) and their release into the circulation (ANGPTL3, SARA2, SORT1); and receptor-mediated uptake of LDL and of intestinal and hepatic-derived lipoprotein remnants (LDLR, APOB, APOE, LDLRAP1, PCSK9, IDOL). The insights gained from integrating the wealth of genetic data with biological processes have important implications for the classification of clinical and presymptomatic diagnoses of traditional LDL dyslipidemias, sitosterolemia, and newly emerging phenotypes, as well as their management through both nutritional and pharmaceutical means.

Internal auditory canal metastasis mimicking a vestibular schwannoma at presentation - a case report and review of the literature.

Metastasis to the internal auditory canal from breast carcinoma is extremely rare and difficult to diagnose. It radiologically mimics vestibular schwannoma and can occur as a first manifestation of systemic relapse after a long disease-free interval in patients previously treated for early breast cancer. The diagnosis is usually made retrospectively and the optimal management of such metastasis following complete resection remains undefined.

Amyotrophic lateral sclerosis with sensory neuropathy: part of a multisystem disorder?

Sensory involvement is thought not to be a feature of amyotrophic lateral sclerosis (ALS). However, in the setting of a specialist motor neuron disease clinic, we have identified five patients with sporadic ALS and a sensory neuropathy for which an alternative cause could not be identified. In three individuals, sensory nerve biopsy was performed, demonstrating axonal loss without features of an alternative aetiology. These findings support the hypothesis that ALS is a multisystem neurodegenerative disorder that may occasionally include sensory neuropathy among its non-motor features.

Reversible parkinsonism in a patient with progressive multifocal leucoencephalopathy.

A case of pathologically confirmed progressive multifocal leucoencephalopathy presenting with unilateral parkinsonism and cognitive decline that significantly improved over a 12-month period without any treatment is described. The patient had a background of chronic lymphocytic leukaemia, but had been in complete remission for 4 years at the time of diagnosis. This case is highly unusual not only in terms of the mode of clinical presentation in an apparently immunocompetent patient but also in that the patient spontaneously improved without any intervention. Progressive multifocal leucoencephalopathy should therefore be considered in the differential diagnosis of movement disorders developing in patients with a history of lymphoproliferative disease, even if they are in remission. Furthermore, such cases may not always require treatment, as the patient's immune system may overcome the viral disease process with spontaneous resolution of their neurological disorder.

Periocular Amyloidosis Manifesting as Pseudopemphigoid Treated With Mitomycin C.

PURPOSE: To describe an unusual cicatrizing manifestation of periocular amyloid and the utility of adjuvant antimetabolite therapy. METHODS: This is a case report of a 49-year old woman with progressive bilateral upper lid ptosis, who was found to have bilateral inferior forniceal masses with thickening of the conjunctiva. Conjunctival and eyelid biopsies showed evidence of amyloid deposition. Systemic evaluation did not reveal any evidence of systemic amyloidosis. Her blepharoptosis continued to deteriorate, and she underwent bilateral sequential upper lid ptosis correction surgery and debulking procedures. Subsequently, she developed severe and progressive cicatricial conjunctivitis with extensive symblepharon formation in all 4 fornices and restriction of ocular motility, simulating a clinical picture of ocular mucous membrane pemphigoid. RESULTS: She was treated surgically by division of symblepharon augmented with application of topical mitomycin C intraoperatively. This has been partially successful in freeing up differential movement between her lid and her eye and consequently improving eye protection and lubrication. CONCLUSIONS: Pseudopemphigoid represents a rare manifestation of periocular amyloid. Risks and benefits of surgical procedures in this context need to be carefully weighed to minimize the risk of secondary complications. Topical mitomycin C may be considered as a relatively safe adjunct in managing the cicatricial component of the disease.

Neuropathologic Characterization of Pontocerebellar Hypoplasia Type 6 Associated With Cardiomyopathy and Hydrops Fetalis and Severe Multisystem Respiratory Chain Deficiency due to Novel RARS2 Mutations.

Autosomal recessive mutations in the RARS2 gene encoding the mitochondrial arginyl-transfer RNA synthetase cause infantile-onset myoencephalopathy pontocerebellar hypoplasia type 6 (PCH6). We describe 2 sisters with novel compound heterozygous RARS2 mutations who presented perinatally with neurologic features typical of PCH6 but with additional features including cardiomyopathy, hydrops, and pulmonary hypoplasia and who died at 1 day and 14 days of age. Magnetic resonance imaging findings included marked cerebellar hypoplasia, gyral immaturity, punctate lesions in cerebral white matter, and unfused deep cerebral grey matter. Enzyme histochemistry of postmortem tissues revealed a near-global cytochrome c oxidase-deficiency; assessment of respiratory chain enzyme activities confirmed severe deficiencies involving complexes I, III, and IV. Molecular genetic studies revealed 2 RARS2 gene mutations: a c.1A>G, p.? variant predicted to abolish the initiator methionine, and a deep intronic c.613-3927C>T variant causing skipping of exons 6-8 in the mature RARS2 transcript. Neuropathologic investigation included low brain weights, small brainstem and cerebellum, deep cerebral white matter pathology, pontine nucleus neuron loss (in 1 sibling), and peripheral nerve pathology. Mitochondrial respiratory chain immunohistochemistry in brain tissues confirmed an absence of complexes I and IV immunoreactivity with sparing of mitochondrial numbers. These cases expand the clinical spectrum of RARS2 mutations, including antenatal features and widespread mitochondrial respiratory chain deficiencies in postmortem brain tissues.

Chromosomal imbalances in meningeal solitary fibrous tumors.

We present the results of a comparative genomic hybridization (CGH) analysis of three meningeal solitary fibrous tumors (SFT). One case showed loss of chromosome 3 and two tumors had deletions of the region 3p21-p26. Other chromosomal losses included 4p15, 8q22-q24, 10, 11q14-q25, 17q11- q23, 20, and 21 in one case each. In addition, there were gains of 18p11-p13 in one case, and 1p11-p36 and 20q11-q13 in another. To our knowledge, there are no previous CGH or cytogenetic data on meningeal SFT, and loss of material on chromosome 3 has not been described in SFT at other sites. Our findings are discussed in relation to published molecular genetic and cytogenetic data on meningioma and hemangiopericytoma, the two lesions with which meningeal SFT are most likely to be confused.

The genome of the sparganosis tapeworm Spirometra erinaceieuropaei isolated from the biopsy of a migrating brain lesion.

BACKGROUND: Sparganosis is an infection with a larval Diphyllobothriidea tapeworm. From a rare cerebral case presented at a clinic in the UK, DNA was recovered from a biopsy sample and used to determine the causative species as Spirometra erinaceieuropaei through sequencing of the cox1 gene. From the same DNA, we have produced a draft genome, the first of its kind for this species, and used it to perform a comparative genomics analysis and to investigate known and potential tapeworm drug targets in this tapeworm. RESULTS: The 1.26 Gb draft genome of S. erinaceieuropaei is currently the largest reported for any flatworm. Through investigation of ß-tubulin genes, we predict that S. erinaceieuropaei larvae are insensitive to the tapeworm drug albendazole. We find that many putative tapeworm drug targets are also present in S. erinaceieuropaei, allowing possible cross application of new drugs. In comparison to other sequenced tapeworm species we observe expansion of protease classes, and of Kuntiz-type protease inhibitors. Expanded gene families in this tapeworm also include those that are involved in processes that add post-translational diversity to the protein landscape, intracellular transport, transcriptional regulation and detoxification. CONCLUSIONS: The S. erinaceieuropaei genome begins to give us insight into an order of tapeworms previously uncharacterized at the genome-wide level. From a single clinical case we have begun to sketch a picture of the characteristics of these organisms. Finally, our work represents a significant technological achievement as we present a draft genome sequence of a rare tapeworm, and from a small amount of starting material.

Early-onset cataracts, spastic paraparesis, and ataxia caused by a novel mitochondrial tRNAGlu (MT-TE) gene mutation causing severe complex I deficiency: a clinical, molecular, and neuropathologic study.

Mitochondrial respiratory chain disease is associated with a spectrum of clinical presentations and considerable genetic heterogeneity. Here we report molecular genetic and neuropathologic findings from an adult with an unusual manifestation of mitochondrial DNA disease. Clinical features included early-onset cataracts, ataxia, and progressive paraparesis, with sequencing revealing the presence of a novel de novo m.14685G>A mitochondrial tRNA(Glu) (MT-TE) gene mutation. Muscle biopsy showed that 13% and 34% of muscle fibers lacked cytochrome c oxidase activity and complex I subunit expression, respectively. Biochemical studies confirmed a marked decrease in complex I activity. Neuropathologic investigation revealed a large cystic lesion affecting the left putamen, caudate nucleus, and internal capsule, with evidence of marked microvacuolation, neuron loss, perivascular lacunae, and blood vessel mineralization. The internal capsule showed focal axonal loss, whereas brainstem and spinal cord showed descending anterograde degeneration in medullary pyramids and corticospinal tracts. In agreement with muscle biopsy findings, reduced complex I immunoreactivity was detected in the remaining neuronal populations, particularly in the basal ganglia and cerebellum, correlating with the neurologic dysfunction exhibited by the patient. This study emphasizes the importance of molecular genetic and postmortem neuropathologic analyses for furthering our understanding of underlying mechanisms of mitochondrial disorders.

Abnormal prion protein in the pituitary in sporadic and variant Creutzfeldt-Jakob disease.

By using high-sensitivity Western blotting and immunohistochemistry, pituitary glands from patients with sporadic and variant Creutzfeldt-Jakob disease (sCJD and vCJD, respectively) were analysed for the presence of the protease-resistant form of the prion protein (PrPres). PrPres was detected in a greater proportion of vCJD pituitaries than sCJD pituitaries and was localized predominantly in the neurohypophysis. PrPres was also detected in a recurrent pituitary adenoma from an sCJD patient. Immunohistochemical analysis showed sparse positive labelling, predominantly in folliculostellate cells, in vCJD and sCJD adenohypophyses. The PrPres glycosylation pattern in the vCJD neurohypophyses showed a predominance of the unglycosylated band, which differed markedly from patterns found in all other vCJD tissues. The presence of PrPres in the pituitary of CJD patients at autopsy suggests that human growth hormone-related iatrogenic CJD may have indeed resulted from infectivity in collected pituitaries rather than necessarily from contamination of pituitary pools by adjacent brain tissue.