Clinical and molecular characteristics of mitochondrial DNA depletion syndrome associated with neonatal cholestasis and liver failure.

OBJECTIVE: To determine the frequency of mitochondrial DNA depletion syndrome (MDS) in infants with cholestasis and liver failure and to further clarify the clinical, biochemical, radiologic, histopathologic, and molecular features associated with MDS due to deoxyguanosine kinase (DGUOK) and MPV17 gene mutations. STUDY DESIGN: We studied 20 infants with suspected hepatocerebral MDS referred to our tertiary care center between 2007 and 2013. Genomic DNA was isolated from blood leukocytes, liver, and/or skeletal muscle samples by standard methods. Mitochondrial DNA copy number relative to nuclear DNA levels was determined in muscle and/or liver DNA using real-time quantitative polymerase chain reaction and compared with age-matched controls. Nuclear candidate genes, including polymerase γ, MPV17, and DGUOK were sequenced using standard analyses. RESULTS: We identified pathogenic MPV17 and DGUOK mutations in 11 infants (6 females) representing 2.5% of the 450 cases of infantile cholestasis and 22% of the 50 cases of infantile liver failure referred to our center during the study period. All of the 11 patients manifested cholestasis that was followed by a rapidly progressive liver failure and death before 2 years of life. Mitochondrial DNA depletion was demonstrated in liver or muscle for 8 out of the 11 cases where tissue was available. Seven patients had mutations in the MPV17 gene (3 novel mutations), 4 patients had DGUOK mutations (of which 2 were novel mutations). CONCLUSION: Mutations in the MPV17 and DGUOK genes are present in a significant percentage of infants with liver failure and are associated with poor prognosis.

Severe infantile encephalomyopathy caused by a mutation in COX6B1, a nucleus-encoded subunit of cytochrome c oxidase.

Cytochrome c oxidase (COX) deficiency, one of the most common respiratory-chain defects in humans, has been associated with mutations in either mitochondrial DNA genes or nucleus-encoded proteins that are not part in but promote the biogenesis of COX. Mutations of nucleus-encoded structural subunits were sought for but never found in COX-defective patients, leading to the conjecture that they may be incompatible with extra-uterine survival. We report a disease-associated mutation in one such subunit, COX6B1. Nuclear-encoded COX genes should be reconsidered and included in the diagnostic mutational screening of human disorders related to COX deficiency.

Nonaneurysmal Perimesencephalic Subarachnoid Hemorrhage as an Atypical Initial Presentation of Cerebral Venous Sinus Thrombosis: A Case Report.

BACKGROUND Subarachnoid hemorrhage is rarely the first presentation of cerebral venous sinus thrombosis. This case study emphasizes the presentation of perimesencephalic subarachnoid hemorrhage due to cerebral venous sinus thrombosis and the importance of neurovascular imaging for reliable diagnosis of nonaneurysmal perimesencephalic subarachnoid hemorrhage due to cerebral venous sinus thrombosis. CASE REPORT We describe a case of cerebral venous sinus thrombosis manifesting initially as subarachnoid hemorrhage. Non-contrast computed tomography showed evidence of subarachnoid hemorrhage involving the prepontine and suprasellar cisterns. Cerebral convexities were totally spared while parenchymal microbleeding was observed in the midbrain. The diagnosis was confirmed by magnetic resonance arteriography and venography. Treatment included low molecular weight heparin and warfarin therapy to restore the international normalization ratio of the patient to 2.5, followed by oral warfarin therapy for 3 months. CONCLUSIONS Cerebral venous sinus thrombosis manifesting initially as subarachnoid hemorrhage is rare. Subarachnoid hemorrhage caused by cerebral venous sinus thrombosis has been reported previously to be confined to the cerebral convexities, sparing the basal cistern. However, this is not always the case where the radiological confirmation suggests the occurrence of nonaneurysmal perimesencephalic subarachnoid hemorrhage.

An Unusual Cause of Cauda Equina Syndrome: Lumbar Epidural Venous Engorgement.

BACKGROUND Epidural venous plexus (EVP) engorgement occurs due to many conditions, so it can be easily misdiagnosed. This becomes problematic when the diagnosis requires prompt treatment for a good outcome, especially when it results in cauda equina syndrome (CES). We report a case of extensive iliocaval thrombosis leading to epidural venous plexus and ascending lumbar vein engorgement as an outcome of deep venous thrombosis (DVT) due to probable adverse effects of oral combined contraceptive pills (OCCP). CASE REPORT A 42-year-old woman presented to a rural medical facility with bilateral lower-limb swelling and skin darkening for 2 days. She was transferred to a tertiary medical facility where her condition deteriorated to severe CES. A lower-limbs ultrasonography confirmed the presence of extensive DVT extending to the lower segment of the inferior vena cava. Spine magnetic resonance imaging showed abnormal enhancement of the conus medullaris with thick enhanced cauda equina nerve roots, consistent with a possible case of Guillain-Barré syndrome. However, there was engorgement of the EVP extending to the ascending lumbar, azygos, and hemiazygos veins, which was misdiagnosed. The patient was managed immediately with low-molecular-weight heparin and steroids. She died 4 weeks after admission due to hospital-acquired pneumonia and acute respiratory distress syndrome, probably due to the high dose of steroids. CONCLUSIONS Acute CES has a wide differential diagnosis. This report describes an unusual cause of CES and emphasizes the importance of early recognition to avoid misdiagnosis and management delay. Early identification of this clinical entity markedly decreases morbidity and mortality and thus improves the prognosis. Likewise, underlying causing factors such as venous congestion due to OCCP-related DVT should be considered in the diagnosis.

Primary Occipital Ewing's Sarcoma with Subsequent Spinal Seeding.

Ewing's sarcoma is a primary bone cancer that mainly affects the long bones. This malignancy is particularly common in pediatric patients. Primary cranial involvement accounts for 1% of cases, with occipital involvement considered extremely rare. In this case study, primary occipital Ewing's sarcoma with a posterior fossa mass and subsequent relapse resulting in spinal seeding is reported. A 3-year-old patient presented with a 1-year history of left-sided headaches, localized over the occipital bone with progressive torticollis. Computed tomography (CT) imaging showed a mass in the left posterior fossa compressing the brainstem. The patient then underwent surgical excision followed by adjuvant chemoradiation therapy. Two years later, the patient presented with severe lower back pain and urinary incontinence. Whole-spine magnetic resonance imaging (MRI) showed cerebrospinal fluid (CSF) seeding from the L5 to the S4 vertebrae. Primary cranial Ewing's sarcoma is considered in the differential diagnosis of children with extra-axial posterior fossa mass associated with destructive permeative bone lesions. Although primary cranial Ewing's sarcoma typically has good prognosis, our patient developed metastasis in the lower spine. Therefore, with CNS Ewing's sarcoma, screening of the entire neural axis should be taken into consideration for early detection of CSF seeding metastasis in order to decrease the associated morbidity and mortality.

Homonymous Superior Quadrantanopia due to Erdheim-Chester Disease with Asymptomatic Pituitary Involvement.

Polyostotic sclerosing histiocytosis, also known as Erdheim-Chester disease (ECD), is a rare form of non-Langerhans histiocytosis. ECD has wide clinical spectrums which mainly affect skeletal, neurological, dermatological, retroperitoneal, cardiac, and pulmonary manifestations. Here we describe a case of ECD in a 45-year-old female who presented initially with bilateral knee pain and homonymous superior quadrantanopia progressed to ophthalmoplegia and complete visual loss of the left eye over a period of one year. Plain X-ray of both knees showed bilateral patchy sclerosis of the distal femur and upper parts of the tibiae. Initial brain magnetic resonance imaging (MRI) showed bilateral enhancing masses in the temporal lobes anterior to the temporal horns, thickening of the pituitary stalk, partially empty sella, and involvement of the left cavernous sinus one year later. Our case is a peculiar case of ECD initially presented with unilateral homonymous superior quadrantanopia due to involvement of the visual apparatus in the mesial temporal lobe which progressed to unilateral ophthalmoplegia and total visual loss secondary to involvement of the cavernous sinus. Thus, the diagnosis of ECD should be kept in mind in the presence of bilateral bone sclerotic lesions.

Isolated brain stem tuberculoma presenting with one and a half syndrome.

In this report, we describe a patient with left conjugate gaze palsy and internuclear ophthalmoplegia on the opposite gaze one-and-a-half-syndrome [11/2 syndrome]. Magnetic resonance imaging of the brain showed nodular enhancing brain stem lesions. After excluding other potential diseases, tuberculoma was thought to be the underlying etiology. Recovery was achieved 8 weeks after initiation of anti-tuberculous anti-TB therapy. The isolated nature of the tuberculoma and the association with this rare syndrome is highlighted.

Neuromyelitis optica.

Neuromyelitis optica disease is characterized by simultaneous or successive attacks involving both the optics nerves and spinal cord without any evidence of the disease elsewhere. We report a 22-year-old Saudi woman with relapsing neuromyelitis optica disease. She had all the clinical, cerebrospinal fluid, and radiological features that differ from primary demyelinating disease. However, our patient responded well to long-term corticosteroid therapy and azathioprine with improvement in her expanded disability status scale, and ambulation. In addition, no acute relapses occurred with significant improvement on magnetic resonance imaging lesions and favorable outcome.