Multisystem pathology in McLeod syndrome.

We present a comprehensive characterization of clinical, neuropathological, and multisystem features of a man with genetically confirmed McLeod neuroacanthocytosis syndrome, including video and autopsy findings. A 61-year-old man presented with a movement disorder and behavioral change. Examination showed dystonic choreiform movements in all four limbs, reduced deep-tendon reflexes, and wide-based gait. He had oromandibular dyskinesia causing severe dysphagia. Elevated serum creatinine kinase (CK) was first noted in his thirties, but investigations, including muscle biopsy at that time, were inconclusive. Brain magnetic resonance imaging showed white matter volume loss, atrophic basal ganglia, and chronic small vessel ischemia. Despite raised CK, electromyography did not show myopathic changes. Exome gene panel testing was negative, but targeted genetic analysis revealed a hemizygous pathogenic variant in the XK gene c.895C > T p.(Gln299Ter), consistent with a diagnosis of McLeod syndrome. The patient died of sepsis, and autopsy showed astrocytic gliosis and atrophy of the basal ganglia, diffuse iron deposition in the putamen, and mild Alzheimer's pathology. Muscle pathology was indicative of mild chronic neurogenic atrophy without overt myopathic features. He had non-specific cardiomyopathy and splenomegaly. McLeod syndrome is an ultra-rare neurodegenerative disorder caused by X-linked recessive mutations in the XK gene. Diagnosis has management implications since patients are at risk of severe transfusion reactions and cardiac complications. When a clinical diagnosis is suspected, candidate genes should be interrogated rather than solely relying on exome panels.

A rare presentation of rapidly progressing myopathy in an adolescent.

We present a case of severe juvenile dermatomyositis with limited response to steroids in an adolescent who developed symptoms within hours after receiving Pfizer BNT162b2 coronavirus disease 2019 vaccine. The patient presented with severe weakness of proximal muscles, dyspnoea, and tachycardia. His muscle enzymes were raised, and he was diagnosed with severe juvenile dermatomyositis following magnetic resonance imaging and muscle biopsy. His management was challenging, requiring multidisciplinary input, and difficult decisions with regard to the appropriate immunomodulatory treatments. The patient had to undergo escalating immunosuppressive treatments before he began to recover clinically and biochemically. To our knowledge, this is the first case in an adolescent although a few cases of similar presentations following coronavirus disease 2019 vaccination have been reported in adults. Elucidating the potential relationship of the vaccine with this severe myopathy in an adolescent is important for global vaccination policies, but avoiding the conflation of association with causation is also crucial in the context of the pandemic.

The Role of Sural Nerve Biopsy in the Diagnosis of Vasculitis.

OBJECTIVE: The diagnostic yield of sural nerve biopsy (SNB) in vasculitis is uncertain. Our aim was to document relevant characteristics of patients undergoing SNB in the investigation of vasculitis; determine the diagnostic yield; relate positive biopsy findings to patient demographic, laboratory, and clinical variables; and to calculate the rate of surgical complications. METHODS: Patients with suspected vasculitis that underwent SNB as part of diagnostic evaluation at academic medical centers in Sweden and the United Kingdom were identified by searching local pathology databases and clinic registers. A structured review of medical case records and pathology reports was conducted. Histological findings were categorized as definite, probable, or no vasculitis in accordance with the 2015 Brighton Collaboration reinterpretation and update of the Peripheral Nerve Society guidelines for vasculitic neuropathy. Definite and probable findings were considered positive for vasculitis. RESULTS: Ninety-one patients that underwent SNB were identified (45% female). Forty (44%) patients showed histological evidence of vasculitis: 14 definite and 26 probable. A concomitant muscle biopsy conducted in 10 patients did not contribute to the diagnostic yield. Positive antineutrophil cytoplasmic antibody test, organ involvement other than the nervous system, and a longer biopsy sample were associated with a positive biopsy. The reported surgical complication rate was 15%. CONCLUSION: SNB of sufficient length is a useful procedure to confirm a diagnosis of vasculitis.

Heterozygous frameshift variants in HNRNPA2B1 cause early-onset oculopharyngeal muscular dystrophy.

Missense variants in RNA-binding proteins (RBPs) underlie a spectrum of disease phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, and inclusion body myopathy. Here, we present ten independent families with a severe, progressive muscular dystrophy, reminiscent of oculopharyngeal muscular dystrophy (OPMD) but of much earlier onset, caused by heterozygous frameshift variants in the RBP hnRNPA2/B1. All disease-causing frameshift mutations abolish the native stop codon and extend the reading frame, creating novel transcripts that escape nonsense-mediated decay and are translated to produce hnRNPA2/B1 protein with the same neomorphic C-terminal sequence. In contrast to previously reported disease-causing missense variants in HNRNPA2B1, these frameshift variants do not increase the propensity of hnRNPA2 protein to fibrillize. Rather, the frameshift variants have reduced affinity for the nuclear import receptor karyopherin ß2, resulting in cytoplasmic accumulation of hnRNPA2 protein in cells and in animal models that recapitulate the human pathology. Thus, we expand the phenotypes associated with HNRNPA2B1 to include an early-onset form of OPMD caused by frameshift variants that alter its nucleocytoplasmic transport dynamics.

Complex spinal fixation of a cervical vertebra Brown tumour: report of an unusual case.

Brown tumours affecting the cervical spine are a rare but recognised complication of renal failure-related secondary hyperparathyroidism. We present a case of a 26 year-old female with radiculopathy who was managed successfully with 360° cervical spine fixation and parathyroidectomy.

AL amyloidosis presenting with limb girdle myopathy.

An elderly Caucasian man presented with a 10-month history of proximal myopathy and dysphagia. His serum creatine kinase (CK) was elevated at 877 U/L (normal 40-320) and electromyography confirmed a myopathic process. Blood and urine tests suggested myeloma; bone marrow examination showed 30% plasma cells and stained positive for amyloid. The muscle biopsy was initially reported as normal but in the light of the bone marrow report, the biopsy specimen was stained for amyloid, which was positive. We diagnosed systemic amyloidosis causing a myopathy and have started treatment for myeloma.

Identification of Prdm genes in human corneal endothelium.

Corneal endothelial cells (CECs) are essential for maintaining corneal stromal hydration and ensuring its transparency, which is necessary for normal vision. Dysfunction of CECs leads to stromal decompensation, loss of transparency and corneal blindness. Corneal endothelium has low proliferative potential compared to surface epithelial cells leading to poor regeneration of CEC following injury. Additionally, the tissue exhibits age related decline in endothelial cell density with re-organisation of the cell layer, but no regeneration. The mechanisms which control proliferation and differentiation of neural crest derived CEC progenitors are yet to be clearly elucidated. Prdm (Positive regulatory domain) family of transcriptional regulators and chromatin modifiers are important for driving differentiation of a variety of cellular types. Many Prdm proteins are expressed in specific precursor cell populations and are necessary for their progression to a fully differentiated phenotype. In the present work, we sought to identify members of the Prdm gene family which are specifically expressed in human (h) CECs with a view to begin addressing their potential roles in CEC biology, focussing especially on Prdm 4 and 5 genes. By performing semi-quantitative reverse transcription coupled to PCR amplification we found that in addition to Prdm4 and Prdm5, Prdm2 and Prdm10 genes are expressed in hCECs. We further found that cultured primary hCECs or immortalised HCEC-12 cells express all of the Prdm genes found in CECs, but also express additional Prdm transcripts. This difference is most pronounced between Prdm gene expression patterns of CECs isolated from healthy human corneas and immortalised HCEC-12 cells. We further investigated Prdm 4 and Prdm 5 protein expression in cultured primary hCECs and HCEC-12 cells as well as in a human cadaveric whole cornea. Both Prdm 4 and Prdm 5 are expressed in human corneal endothelium, primary hCECs and in HCECs-12 cells, characterised by expression of the Na+/K+-ATPase. We observed that both proteins exhibit cytosolic (intracellular, but non-nuclear and distinct from extracellular fluid) as well as nuclear localisation within the endothelial layer, with Prdm 5 being more concentrated in the nuclei of the endothelial cells than Prdm 4. Thus, our work identifies novel Prdm genes specifically expressed in corneal endothelial cells which may be important in the control of CEC differentiation and proliferation.

Minimally Invasive Excision of Lumbar Tophaceous Gout: Case Report.

BACKGROUND: Symptomatic spinal gout is relatively rare. Open laminectomy, with or without fusion, has been so far the standard treatment for symptomatic spinal gout. We describe here the first case of spinal tophaceus gout treated with minimally invasive surgery. METHODS: A 60-year-old patient, morbidly obese, with no previous history of gout, presented with neurogenic claudication due to severe lumbar canal stenosis at L3/4. Surgery was performed through a minimally invasive approach, using tubular retractors. During surgery, an extradural mass with a thin capsule and containing white "chalky" partially calcified material, slightly adherent to and compressing the theca, was removed. RESULTS: There were no intra- or perioperative complications. Surgery successfully improved the functional status, with a significant increase in walking distance and no residual leg pain or neurogenic claudication. Histopathology confirmed the diagnosis of spinal tophaceous gout. CONCLUSIONS/LEVEL OF EVIDENCE: Although spinal gout is usually responsive to medical treatment, surgery is often the first line treatment, particularly in patients with neurological deficits. Would surgery be indicated, we believe that minimally invasive surgery can be effective in treating symptomatic spinal tophaceous gout. Level of Evidence: Class IV.

Successful treatment of residual pituitary adenoma in persistent acromegaly following localisation by 11C-methionine PET co-registered with MRI.

OBJECTIVE: To determine if functional imaging using 11C-methionine positron emission tomography co-registered with 3D gradient echo MRI (Met-PET/MRI), can identify sites of residual active tumour in treated acromegaly, and discriminate these from post-treatment change, to allow further targeted treatment. DESIGN/METHODS: Twenty-six patients with persistent acromegaly after previous treatment, in whom MRI appearances were considered indeterminate, were referred to our centre for further evaluation over a 4.5-year period. Met-PET/MRI was performed in each case, and findings were used to decide regarding adjunctive therapy. Four patients with clinical and biochemical remission after transsphenoidal surgery (TSS), but in whom residual tumour was suspected on post-operative MRI, were also studied. RESULTS: Met-PET/MRI demonstrated tracer uptake only within the normal gland in the four patients who had achieved complete remission after primary surgery. In contrast, in 26 patients with active acromegaly, Met-PET/MRI localised sites of abnormal tracer uptake in all but one case. Based on these findings, fourteen subjects underwent endoscopic TSS, leading to a marked improvement in (n = 7), or complete resolution of (n = 7), residual acromegaly. One patient received stereotactic radiosurgery and two patients with cavernous sinus invasion were treated with image-guided fractionated radiotherapy, with good disease control. Three subjects await further intervention. Five patients chose to receive adjunctive medical therapy. Only one patient developed additional pituitary deficits after Met-PET/MRI-guided TSS. CONCLUSIONS: In patients with persistent acromegaly after primary therapy, Met-PET/MRI can help identify the site(s) of residual pituitary adenoma when MRI appearances are inconclusive and direct further targeted intervention (surgery or radiotherapy).

Germinoma of the medulla oblongata - A case report.

We describe a case of primary intracranial medulla oblongata germinoma in a 23-year-old female who presented with deteriorating balance and mobility. Imaging demonstrated an exophytic lesion arising from the dorsal medulla oblongata and extending into the fourth ventricle. The tissue sample was obtained via suboccipital craniotomy and a diagnosis of a primary medullary germinoma was made. The patient underwent whole craniospinal axis radiotherapy and remains well and recurrence-free at 1-year follow up.

Rosette-forming glioneuronal tumor with dissemination throughout the ventricular system: a case report.

A 33-year-old female was found to have a rosette-forming glioneuronal tumor (RGNT) occurring within the fourth ventricle with multifocal extension to the third and lateral ventricles. She presented with headaches, blurred vision, nausea, and intermittent dizziness. A brain magnetic resonance imaging (MRI) scan showed hydrocephalus and multifocal nodules throughout the ventricular system with the largest mass occupying the fourth ventricle. An endoscopic third ventriculostomy and biopsy were performed. Histological examination demonstrated a glioneuronal neoplasm with the characteristic features of RGNT. While the histopathological features of our case are well in accord with those reported in the literature, the multifocal intraventricular growth pattern has only been described twice before. Moreover, RGNT of the fourth ventricle with dissemination throughout the supratentorial ventricles has only been described once before. Long-term studies are required to assess the best treatment modalities and clinical behavior of this extremely rare disseminated RGNT entity.

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.

Considerations in establishing a post-mortem brain and tissue bank for the study of myalgic encephalomyelitis/chronic fatigue syndrome: a proposed protocol.

BACKGROUND: Our aim, having previously investigated through a qualitative study involving extensive discussions with experts and patients the issues involved in establishing and maintaining a disease specific brain and tissue bank for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), was to develop a protocol for a UK ME/CFS repository of high quality human tissue from well characterised subjects with ME/CFS and controls suitable for a broad range of research applications. This would involve a specific donor program coupled with rapid tissue collection and processing, supplemented by comprehensive prospectively collected clinical, laboratory and self-assessment data from cases and controls. FINDINGS: We reviewed the operations of existing tissue banks from published literature and from their internal protocols and standard operating procedures (SOPs). On this basis, we developed the protocol presented here, which was designed to meet high technical and ethical standards and legal requirements and was based on recommendations of the MRC UK Brain Banks Network. The facility would be most efficient and cost-effective if incorporated into an existing tissue bank. Tissue collection would be rapid and follow robust protocols to ensure preservation sufficient for a wide range of research uses. A central tissue bank would have resources both for wide-scale donor recruitment and rapid response to donor death for prompt harvesting and processing of tissue. CONCLUSION: An ME/CFS brain and tissue bank could be established using this protocol. Success would depend on careful consideration of logistic, technical, legal and ethical issues, continuous consultation with patients and the donor population, and a sustainable model of funding ideally involving research councils, health services, and patient charities. This initiative could revolutionise the understanding of this still poorly-understood disease and enhance development of diagnostic biomarkers and treatments.

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.

Glioblastomas with oligodendroglial component have the same clinical phenotype as classical glioblastomas.

INTRODUCTION: Glioblastomas are the commonest primary brain tumour and are considered one of the most heterogeneous tumour types. The introduction of a glioblastoma with oligodendroglial component (GBM + O) in the latest WHO Classification of Tumours of the Central Nervous System (1) was to help with this. There has been conflicting evidence as to whether this tumour conferred a better prognosis than classical glioblastoma (GBM). The aim of this study was to study the clinical phenotype of these GBM + O tumours and compare it to the classical GBM. MATERIALS AND METHODS: All patients with histological evidence of a glioblastoma between 1st January 2007 and 31st January 2011 were identified from the Neuropathology Database. Clinical and radiological details were obtained for all patients. The overall survival of patients who were treated with chemoradiotherapy was obtained and the GBM + O cohort compared to the classical GBM cohort. RESULTS: Three hundred and ninety-six patients with newly diagnosed glioblastomas were identified: 294 (74.2%) had classical GBM and 102 (25.6%) had GBM + O. The two cohorts presented at a similar age (61.1 years GBM + O vs. 63.2 years GBM; P = 0.09) and were matched for sex and side of the tumour. GBM + O were more likely to be located in the frontal lobes (38.2% for GBM + O vs. 27.2% for GBM: P = 0.04). In the group that was treated with chemoradiotherapy the overall survival was similar (median survival GBM + O 361 days vs. 379 days GBM; Log Rank 0.61, P = 0.43). CONCLUSION: The presence of an oligodendroglial component does not confer any improvement in survival and has a similar clinical phenotype to classical GBMs.

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.

Neurenteric cyst of the anterior cranial fossa: case report and literature review.

Intracranial neurenteric cysts are rare congenital lesions that typically occur in the posterior fossa. We report a case of a 70-year-old gentleman presenting with gait disturbance, found to have a neurenteric cyst primarily arising from and expanding the sella turcica. A review of the literature revealed 27 reports of supratentorial neurenteric cysts. Clinical presentation, radiological characteristics, treatment, prognosis and embryological origin are discussed. Intracranial neurenteric cysts should be included in the differential with any well-demarcated cystic lesion without enhancement on magnetic resonance imaging (MRI). Complete surgical excision is the treatment of choice, with good prognosis.

Paravertebral cervical chordoma--a case report.

Chordomas constitute <5% of vertebral column tumours and a third of these arise in the upper cervical spine and tend to be clival - usually midline, with occasional eccentric extension. We report a case of cervical chordoma presenting as a lateral neck mass and discuss its origin, diagnosis and management.

Mitochondrial transfer RNA(Phe) mutation associated with a progressive neurodegenerative disorder characterized by psychiatric disturbance, dementia, and akinesia-rigidity.

BACKGROUND: Mitochondrial diseases are characterized by wide phenotypic and genetic variability, but presentations in adults with akinetic rigidity and hyperkinetic movement disorders are rare. OBJECTIVES: To describe clinically a subject with progressive neurodegeneration characterized by psychosis, dementia, and akinesia-rigidity, and to associate this phenotype with a novel mitochondrial transfer RNA(Phe) (tRNA(Phe)) (MTTF) mutation. DESIGN, SETTING, AND PATIENT: Case description and detailed laboratory investigations of a 57-year-old woman at a university teaching hospital and a specialist mitochondrial diagnostic laboratory. RESULTS: Histopathological findings indicated that an underlying mitochondrial abnormality was responsible for the subject's progressive neurological disorder, with mitochondrial genome sequencing revealing a novel m.586G>A MTTF mutation. CONCLUSIONS: The clinical phenotypes associated with mitochondrial disorders may include akinesia-rigidity and psychosis. Our findings further broaden the spectrum of neurological disease associated with mitochondrial tRNA(Phe) mutations.