Janice Brewer

Two Australian families with inclusion-body myopathy, Paget's disease of bone and frontotemporal dementia: novel clinical and genetic findings

We report the first Australian families with inclusion-body myopathy, Pagets disease of the bone and frontotemporal dementia (IBMPFD). The clinical characteristics of the two pedigrees are described including a previously undescribed phenotypic feature of pyramidal tract dysfunction in one family member. A novel mutation in the valosin-containing protein (VCP) gene (p.Arg155Leu) was found in one family while the other family had a previously reported mutation (p.Leu198Trp). Our findings broaden the phenotypic spectrum of IBMPFD and further emphasise the resemblance to amyotrophic lateral sclerosis in some cases.

Mutations in HSPB8 causing a new phenotype of distal myopathy and motor neuropathy.

Objective: To report novel disease and pathology due to HSPB8 mutations in 2 families with autosomal dominant distal neuromuscular disease showing both myofibrillar and rimmed vacuolar myopathy together with neurogenic changes. Methods: We performed whole-exome sequencing (WES) in tandem with linkage analysis and candidate gene approach as well as targeted next-generation sequencing (tNGS) to identify causative mutations in 2 families with dominant rimmed vacuolar myopathy and a motor neuropathy. Pathogenic variants and familial segregation were confirmed using Sanger sequencing. Results: WES and tNGS identified a heterozygous change in HSPB8 in both families: c.421A > G p.K141E in family 1 and c.151insC p.P173SfsX43 in family 2. Affected patients had a distal myopathy that showed myofibrillar aggregates and rimmed vacuoles combined with a clear neurogenic component both on biopsy and neurophysiologic studies. MRI of lower limb muscles demonstrated diffuse tissue changes early in the disease stage progressing later to fatty replacement typical of a myopathy. Conclusion: We expand the understanding of disease mechanisms, tissue involvement, and phenotypic outcome of HSPB8 mutations. HSPB8 is part of the chaperone-assisted selective autophagy (CASA) complex previously only associated with Charcot-Marie-Tooth type 2L (OMIM 60673) and distal hereditary motor neuronopathy type IIa. However, we now demonstrate that patients can develop a myopathy with histologic features of myofibrillar myopathy with aggregates and rimmed vacuoles, similar to the pathology in myopathies due to gene defects in other compounds of the CASA complex such as BAG3 and DNAJB6 after developing the early neurogenic effects.

Brain histopathology in three cases of Susac's syndrome: implications for lesion pathogenesis and treatment

Susacs syndrome (SS) is the triad of encephalopathy, branch retinal artery occlusions and sensorineural hearing loss. While rare, it has become increasingly recognised since characteristic ‘snowball’ corpus callosum lesions were appreciated on MRI.1 We present clinical and histopathological findings on three patients with SS. Our findings demonstrate a T-cell-mediated inflammatory contribution to lesion pathogenesis. Treatment with the tumour necrosis factor (TNF) inhibitor, infliximab was beneficial in two patients, including in one previously reported,2 and in another who failed rituximab. This report provides a histological rationale for the observed benefit of infliximab, and suggests that infliximab should be considered as an adjunct therapy in patients with refractory SS. Three patients with SS most recently diagnosed among the authors’ practices who had undergone brain biopsy as part of their diagnostic clinical workup were identified. The clinical features, radiology, treatment and outcomes for the three patients are presented as online supplementary data (tables S1–S5 and figures S1 and S2). Extensive serum autoantibody screening was negative. Headache was present in all patients, highlighting the fact that it is a common manifestation of encephalopathy in SS. All three cases reported relatively non-specific auditory and visual symptoms, emphasising that fluorescein angiography±audiology testing should be considered in the diagnostic workup of patients with unexplained encephalopathy. Two patients underwent cerebellar biopsies and one a frontal lobe biopsy. One biopsy was from a treatment-naive patient (case 1). All contained variable numbers of wedge-shaped microinfarcts surrounded by microglia. In cerebellar biopsies (cases 1 and 3), …

Adult onset leucodystrophy with neuroaxonal spheroids and pigmented glia (ALSP): report of a new kindred

Adult onset leucodystrophy with neuroaxonal spheroids and pigmented glia (ALSP) is a progressive and fatal white matter degenerative disease which typically affects adults in their fourth or fifth decades. ALSP is a newly proposed diagnostic moniker [1], which encompasses two previously separate entities with similar clinical, imaging and pathological features – hereditary diffuse leucoencephalopathy with axonal spheroids (HDLS) and familial pigmented orthochromatic leucodystrophy (POLD) [1–4]. The definitive diagnosis of ALSP requires neuropathological confirmation, as there is significant variation in reported radiological and clinical features, even within the same kindred, as well as overlap with other adult-onset white matter diseases [5]. Patients often present with early neuropsychiatric symptoms, particularly depression and anxiety [6]. There is progressive cognitive decline, which may be misdiagnosed as Alzheimer disease or frontotemporal dementia, progressive motor impairment and/or epilepsy. Death typically ensues within 10 years. The neuropathological hallmarks of ALSP are a widespread central myelin degeneration with sparing of subcortical U-fibres, the presence of axonal spheroids, and nonmetachromatic sudanophilic lipopigment within macrophages and glial cells [3,4]. A recent review identified only 20 characterized ALSP families (12 HDLS and eight POLD) [1]. We present a new kindred affected by ALSP; affected individuals span three generations and several continents. The proband was a 62-year-old right-handed man of Indian origin, who presented with gradual onset of ataxia of gait and dysarthria that began some 5 years previously. There was accompanying emotional lability and prominent frontal dysexecutive syndrome resulting in retirement as an academic. At presentation, the patient was confined to a wheelchair due to ataxia of gait and spasticity. Physical examination revealed severe cognitive deficit (Folstein minimental score of 18/30), prominent frontal release reflexes and a spastic dysarthria with normal language. There was marked ocular motor apraxia, mild bilateral facial and bulbar weakness, increased tone and decreased deep tendon reflexes in all limbs, with extensor plantar responses. There was a moderate degree of weakness in a pyramidal distribution in the arms and legs. Progressive dysarthria and impairment of sphincter control resulted in admission to hospital 3 years later, with insertion of a percutaneous gastrostomy required to maintain nutrition and hydration. The patient died 10 years following initial presentation, from septicaemia secondary to pneumonia. Significant investigations revealed normal general biochemistry and haematology. In addition, other normal tests included a short synacthen test, serum lactate and pyruvate, leucocyte arylsulphatase A, plasma very long chain fatty acids, serum cysteine, vasculitic screen, and urinary amino and organic acids. Cerebrospinal fluid examination was acellular with an elevated protein 1.76 g/dl, normal glucose and no evidence of oligoclonal bands. Magnetic resonance imaging of the brain demonstrated a mild degree of atrophy with markedly abnormal white matter supratentorially, sparing the cortex and deep grey matter structures (Figure 1). Lamin B1 gene testing was negative. The proband’s father and paternal uncle had both experienced similar symptoms in their fifth decade, and died of the disease at age 62 and 48 years respectively. Two siblings, a brother and a sister, also died of a similar disease at ages 60 and 73 years. One sister died at an early age in a traffic accident, while one brother is unaffected at age 73 years. Three nephews also appear affected by a similar disease (Figure 2). At autopsy, there was marked muscular wasting of both upper and lower limbs. Bronchopneumonia was confirmed as the immediate cause of death. The brain weighed 1216 g, and showed marked atrophy of the frontoparietal region and lateral cerebellar hemispheres, with moderate atrophy of other cortical regions. The cut surface revealed severe degenerative changes of the subcortical white matter and corpus callosum. The white matter was semitranslucent and gelatinous, and shrunk away from the cut surface. There was macroscopic sparing of the subcortical U-fibres. The cortical ribbon and basal ganglia were unremarkable.

‘Ancient’ schwannoma of the orbit

A 65‐year‐old woman presented with a 3 month history of right eye discomfort and protrusion. Examination revealed right proptosis with hypoglobus and diplopia in extremes of upgaze. Computed tomographic scanning revealed a large extraconal mass in the superotemporal orbit. The mass was excised through an extended superior skin crease incision. Histopathology revealed a benign tumour of Schwann cell origin showing advanced cystic degeneration, the so‐called ‘ancient schwannoma’. The authors could find only two previously reported cases of such tumours arising in the orbit.

Tuberculous osteomyelitis diagnosed following an incidental finding on bone scintigraphy

A 47-year-old Sri Lankan man was diagnosed with diabetic neuropathic ulceration of the left hallux. Technetium-99m scintigraphy showed increased uptake corresponding to the ulcer. However an incidental finding of increased uptake was also noted in the right distal tibia (figure 1). The patient had no localising symptoms on the right. His medical history was significant for type 2 diabetes requiring …

50. Pineal mixed germ cell tumour: A case report and literature riview

Introduction Primary germ cell tumour in the pineal region is very rare among all primary intracranial neoplasms, accounting for approximately 2% of these tumours. Mixed germ cell tumours are one of the six histologic subtypes which account for 10–13% of pineal germ cell tumours. Case report We present a case of mixed germ cell tumour in an 18-year-old male. He presented with a long history of confusion, memory loss, occasional headaches and diabetes insipidus. Neurological examination revealed Parinauds syndrome. The MRI scan demonstrated a complex pineal region lesion with a large component of fat. Histologically, the tumour was shown to be a mixed germ cell tumour with germinoma accounting for greater than 95% and mature teratoma for less than 5% of the biopsies. Discussion In summary, a rare case of pineal mixed germ cell tumour is presented and the literature is reviewed.

21. Audit of primary brain tumours at royal north shore hospital from 2007 to 2011

Accurate pathological diagnosis and classification of brain tumours guides therapy and underpins translational research. We reviewed the pathological diagnosis of all primary brain tumours undergoing resection or biopsy at the Royal North Shore Hospital, an adult tertiary referral institution with a catchment population of 1.2 million during the period 2007 to 2011. Patients age ranged from 15 to 92. There were 779 cases, comprising 382 (49.04%) astrocytic, 11 (1.41%) oligoastrocytic, 35 (4.49%) oligodendroglial (0.13%) choroid plexus, 7 (0.90%) embryonal, 34 (4.36%) ependymal, 14 (1.80%) haemangioblastoma, 276 (35.43%) meningeal, 11 (1.41%) 15 (1.93%) neuronal and mixed neuronal-glial, 35 (4.49%) and 1 (0.13%) pineal. Of the astrocytic tumours 84% were glioblastoma, 10.5% anaplastic astrocytoma, 3% diffuse astrocytoma and 2% pilocytic astrocytoma. Meningeal tumours were subtyped into the following breakdowns: (72%) meningioma, (19%) atypical meningioma, (4.8%) haemangio-pericytoma, (2.8%) anaplastic meningioma, (0.7%) papillary, meningioma, (0.7%) anaplastic haemangiopericytoma and (0.34%) rhabdoid meningioma. Oligodendroglial tumours were subtyped into the following breakdowns: (74%) anaplastic oligodendroglioma, (26%) oligo-dendroglioma. Ependymal tumours were broken down into the following subcategories: (62%) ependymoma, (32%) myxopapillary ependymoma, (3%) anaplastic ependymoma and (3%) subependymoma. The incidence of most tumour subtypes in our audit was comparable to published rates in large-scale hospital-based studies. The most notable exception to this was the unusually high proportion of glioblastomas and haemangioblastomas which occurred at a rate that was double that seen in similar studies presumably because of a referral bias towards this quaternary centre.

Differences in the Pathological Diagnosis and Repeat Craniotomy Rates in Cerebral Tumors Undergoing Biopsy or Resection in an Urban Versus Regional Center

AbstractPrimary intracranial tumors occur with an incidence of between 2.5 and 6 per 100,000 individuals. They require specialist expertise for investigation and management including input from radiology, pathology, neurosurgery, and oncology. Therefore, most patients with intracranial neoplasia are investigated and managed in larger hospitals. The geographically dispersed population of Australia has facilitated the development of neurosurgical units in regional areas. However, major metropolitan hospitals are over-represented compared with regional centers in most research cohorts. We therefore sought to investigate the spectrum of intracranial neoplasms undergoing biopsy and surgery at a major regional center in Australia and to compare the demographic and pathological features to similar cohorts treated in major metropolitan hospitals.We searched the pathological databases of both a major regional pathology provider and a major metropolitan pathology practice, which provides surgical pathology services for both a large private and a large public neurosurgical hospital, to identify all cerebral tumors undergoing biopsy or resection over a 14-year period (calendar years 2001 and 2014).In all, 3717 cerebral tumors were identified. Among them, 51% were from an urban private hospital, 33% from an urban public hospital, and 16% from a regional public hospital. Overall, one-third of them were neuroepithelial in origin, a quarter metastatic disease, a fifth meningeal, and one-tenth were pituitary adenomas. The regional center treated a higher proportion of metastatic tumors and less meningeal tumors compared with the urban center. Additionally, patients were less likely to undergo a second operation in the regional center (P < 0.001). The differences give an important insight into the burden of neurosurgical disease in regional Australia, and how it differs from that encountered in large metropolitan centers.

15. A twin with a mole! A case report of an extremely rare condition of molar pregnancy with a coexisting fetus progressing to a viable infant

Introduction Molar pregnancy with a coexisting twin fetus is an extreme rarity. The incidence of such an occurrence ranges from 1 in 10,000 to 100,000 pregnancies and this may increase with the greater use of assisted reproductive techniques. The management of these pregnancies is difficult due to complications such as fetal death, vaginal bleeding, pre-eclampsia and an increase risk for persistent trophoblastic disease. Delivery of a viable term normal infant from this combination is even rarer. Case report We report a case of molar pregnancy in a 36-year-old woman with a coexisting twin fetus which progressed to delivery of a viable healthy infant at term gestation. The submitted specimen was a twin placenta comprising two separate discs joined by a dividing membrane. One of the discs was pale yellow and small. Vesicles were not evident macroscopically. Microscopic examination showed a dichorionic diamniotic twin gestation. The placenta of the viable term gestation showed no significant abnormality while the separate yellow disc showed changes of hydatidiform mole with extensive infarct-like necrosis. Discussion Molar pregnancy with a coexisting twin fetus progressing to a healthy infant is an extremely rare entity. The management guidelines for decision making are limited as there are only a few published reports in the literature. We present this case report to highlight the existence of this extremely rare entity. In addition, it demonstrates that, despite the presence of a coexisting molar gestation, the non-molar gestation may progress to delivery of a normal healthy term infant.