Lack of mitochondrial complex I assembly factor NDUFAF2 results in a distinctive infantile-onset brainstem neurodegenerative disease with early lethality.

BACKGROUND: Congenital disorders of the mitochondrial respiratory chain are a heterogeneous group of inborn errors of metabolism. Among them, NADH:ubiquinone oxidoreductase (complex I, CI) deficiency is the most common. Biallelic pathogenic variants in NDUFAF2, encoding the nuclear assembly CI factor NDUFAF2, were initially reported to cause progressive encephalopathy beginning in infancy. Since the initial report in 2005, less than a dozen patients with NDUFAF2-related disease have been reported. METHODS: Clinical, biochemical, and neuroradiological features of four new patients residing in Northern Israel were collected during 2016-2022 at Emek Medical Center. Enzymatic activities of the five respiratory-chain complexes were determined in isolated fibroblast mitochondria by spectrophotometric methods. Western blot analyses were conducted with anti-human NDUFAF2 antibody; antibody against the mitochondrial marker VDAC1 was used as a loading control. Genetic studies were performed by chromosome microarray analysis using Affymetrix CytoScan 750 K arrays. RESULTS: All four patients presented with infantile-onset growth retardation, ophthalmological impairments with nystagmus, strabismus (starting between 5 and 9 months), and further progressed to life-threatening episodes of apnea usually triggered by trivial febrile illnesses (between 10 and 18 months) with gradual loss of acquired developmental milestones (3 of 4 patients). Serial magnetic-resonance imaging studies in two of the four patients showed a progressive pattern of abnormal T2-weighted hyperintense signals involving primarily the brainstem, the upper cervical cord, and later, the basal ganglia and thalami. Magnetic-resonance spectroscopy in one patient showed an increased lactate peak. Disease progression was marked by ventilatory dependency and early lethality. 3 of the 4 patients tested, harbored a homozygous 142-kb partial interstitial deletion that omits exons 2-4 of NDUFAF2. Mitochondrial CI activity was significantly decreased in the only patient tested. Western blot analysis disclosed the absence of NDUFAF2 protein compared to normal controls. In addition, we reviewed all 10 previously reported NDUFAF2-deficient cases to better characterize the disease. CONCLUSIONS: Biallelic loss-of-function mutations in NDUFAF2 result in a distinctive phenotype in the spectrum of Leigh syndrome with clinical and neuroradiological features that are primarily attributed to progressive brainstem damage.

Neovascular Glaucoma as a Presenting Sign of Catastrophic Antiphospholipid Syndrome with a "Catastrophic" Heart Valve Finding.

We aimed to describe a case of neovascular glaucoma (NVG) as a first presenting sign of catastrophic antiphospholipid syndrome (CAPS) with heart valve aseptic vegetations known as Libman-Sacks endocarditis. A 39-year-old man was referred for left eye decreased visual acuity and pain, upon examination left eye high intraocular pressure; rubeosis iridis of both eyes (BE); and prominent retinal ischemia. Clinical and fluorescein angiography findings established the diagnosis of left eye NVG with vaso-occlusive disease in BE. Magnetic resonance imaging of the head showed widespread ischemic lesions and hemorrhagic foci. The transesophageal echocardiogram showed 2 big mitral valve lesions consistent with the diagnosis of Libman-Sacks endocarditis. Laboratory and clinical diagnosis of CAPS and suspected SLE was confirmed, and treatment with anticoagulants and IV steroids was initiated. This case demonstrates that severe vaso-occlusive retinopathy with severe brain ischemia should raise the suspicion of systemic autoimmune pro-coagulative diseases with heart valve aseptic vegetations.

Traumatic Optic Neuropathy and Monocular Blindness following Transnasal Penetrating Optic Canal Injury by a Wooden Foreign Body.

PURPOSE: To report a case of right eye blindness due to a penetrating injury in the contralateral nostril. METHODS: This is a case report of a 67-year-old patient who presented to the emergency room complaining of transient blurred vision in his right eye after falling on a small branch with no apparent injury besides minor lacerations. The following day, the patient experienced blindness in the right eye. Physical examination revealed small lacerations on his left forehead and optic neuropathy on the right side with no other obvious discerning physical or imaging abnormalities. RESULTS: After elevated suspicion and reassessment of the neuroimaging findings, a radiolucent track was observed in the nasal cavity, continuing up from the left nostril to the right optic nerve. Transnasal endoscopic surgery was performed and a long wooden branch was removed from the nasal cavity. CONCLUSION: A nasally penetrating wooden foreign body can cause traumatic optic neuropathy and vision loss on the unaffected side and can be very difficult to locate and image without any clear external evidence as to its presence. This case highlights the importance of maintaining a high level of suspicion in these types of cases.

Postzygotic HRAS mutation causing both keratinocytic epidermal nevus and thymoma and associated with bone dysplasia and hypophosphatemia due to elevated FGF23.

INTRODUCTION: Epidermal nevus syndrome is a rare group of disorders characterized by the combination of congenital epidermal nevi and extracutaneous features, including skeletal, neurological, ocular, and other systemic findings. We report a case of keratinocytic epidermal nevus syndrome that includes a thymoma, bone dysplasia, and hypophosphatemia with elevated fibroblast growth factor 23 (FGF23) levels associated with postzygotic HRAS mutation. CASE REPORT: A 14-year-old boy was admitted due to recent limping. The physical examination revealed multiple right-sided linear epidermal nevi along Blaschko's lines. Magnetic resonance imaging showed cystic lesions in cervical bones and thymoma, and x-ray examination showed cystic lesions in the hands. Biochemical studies demonstrated severe hypophosphatemia, normocalcemia, high normal PTH, low 25-hydroxyvitamin D and low 1,25-dihydroxyvitamin D levels. The serum FGF23 C-terminal level was normal, but the intact FGF23 level was found to be elevated. Genetic evaluation revealed a heterozygote mutation in the HRAS gene in both the keratinocytic epidermal nevus and thymoma but not in DNA extracted from blood lymphocytes, thus establishing the mutation as postzygotic. DISCUSSION: Postzygotic mutations in HRAS lead to elevation of FGF23 levels, as found in mutated PHEX, FGF23, DMP1, and ENPP1 genes, which lead to hypophosphatemia. CONCLUSION: An identical postzygotic HRAS mutation was shown to be present in both keratinocytic epidermal nevus and thymoma and to be associated with bone lesions and hypophosphatemia due to elevated FGF23 levels. These may all be related to the HRAS mutation.

Chest pain unit in an internal medicine department: comparison of a year with the facility to a year without.

BACKGROUND: Chest pain is one of the most common reasons for emergency department visits and hospital admissions. Chest pain units (CPU) are being incorporated in tertiary hospitals for rapid and effective management of patients with chest pain. In Israel prior to 2010, only one chest pain unit existed in a tertiary hospital. OBJECTIVES: To report our first year experience with a CPU located in an internal medicine department as compared to the year before establishment of the CPU. METHODS: We retrospectively evaluated the medical records of consecutive patients who were admitted to our internal medicine department for the investigation of chest pain for 2 different years: a year before and a year after the establishment of the CPU in the department. We focused on the patients' characteristics and the impact of the CPU regarding the investigational modalities used and the length of in-hospital stay. RESULTS: In the year before establishment of the CPU, 258 patients were admitted to our department with chest pain, compared to 417 patients admitted to the CPU in the first year of its operation. All patients were followed for serial electrocardiographic and cardiac enzyme testing. All CPU patients (100%) underwent investigation compared to only 171 patients (66%) in the pre-CPU year. During the year pre-CPU, 164 non-invasive tests were performed (0.64 tests per patient) compared to 506 tests (1.2 tests/patient) in the CPU population. Coronary arteriography was performed in 35 patients (14%) during the pre-CPU year, mostly as the first test performed, compared to 61 patients (15%) during the CPU year, mostly as a second test, with only 5 procedures (1.1%) being the first test performed. The length of hospitalization was significantly shorter during the CPU year, 37.8 +/- 29.4 hours compared to 66.8 +/- 46 hours in the pre-CPU year. CONCLUSIONS: Establishment of a CPU in an internal medicine department significantly decreased the need for invasive coronary arteriography as the first modality for investigating patients admitted with chest pain, significantly decreased the need for invasive procedures (especially where no intervention was performed), and significantly shortened the hospitalization period. CPU is an effective facility for rapid and effective investigation of patients admitted with chest pain.

Forty- versus 20-minute trials of the maintenance of wakefulness test regimen for licensing of drivers.

STUDY OBJECTIVES: Objective assessment of the ability to maintain wakefulness, although very important, is still equivocal. A recent study from our lab has shown that the Maintenance of Wakefulness Test (MWT), when performed with the 20-minute protocol (MWT20), is unreliable in assessing patients who are highly motivated to maintain wakefulness. In this study, we sought to examine whether the 40-minute protocol (MWT40) is a better tool in assessing such individuals. METHODS: One hundred sixty-four consecutive subjects referred to our sleep lab by the Medical Institute for Driving Safety were studied. All subjects underwent a full-night polysomnogram followed by an MWT, 4 trials of 40 minutes each. All subjects knew that if they failed the wakefulness test their driving license would be revoked. RESULTS: Forty-one subjects out of 164 (25%) fell asleep at least once. Of 39 subjects with severe obstructive sleep apnea, (respiratory disturbance index > 40/h), 19 fell asleep (48.7%). Of 13 subjects with a minimum oxygen saturation level below 65%, 7 fell asleep (53%). In the MWT20, only 7% of patients with severe obstructive sleep apnea fell asleep at least once. CONCLUSIONS: We conclude that the MWT40 is superior to the MWT20 in detecting difficulties maintaining wakefulness in a highly motivated population. However, our results yield a significantly lower detection of difficulties maintaining wakefulness than those reported in healthy subjects, suggesting that the MWT40 is also highly affected by motivation. We believe that, for a highly motivated population (such as for a driver's license validation), different average sleep-latency threshold should be used than in general population.

The 20-min trial of the maintenance of wakefulness test is profoundly affected by motivation.

Assessment of the ability to maintain wakefulness, although very important both for research and for clinical purposes, is still equivocal. The current gold standard is considered the Maintenance of Wakefulness Test (MWT), although there are two different potential protocols to perform it and the normal reference range has been determined on selected populations. The effect of potential "penalty" on failing the test (i.e., presenting sleepiness) has not been seriously studied. We therefore planned this study to examine the effect of motivation on the MWT results in a potentially sleepy population. We hypothesized that with the knowledge that participants may lose their driving license if they fail the test, the results would indicate significantly less sleepiness than reported for other populations. Fifty-four consecutive subjects at high risk of sleepiness referred to the sleep laboratory for evaluation of their ability to maintain wakefulness were studied. All were referred by the National Council for Driving Safety, knowing that if they failed the test, their driving license would not be renewed. Referral reasons were previously diagnosed: obstructive sleep apnea (OSA; 43%), sleep-related accident (7%), or other causes to suspect sleepiness. All underwent a full-night polysomnography (PSG) followed by MWT, five trials of 20 min each (MWT20). Of the 54 participants, 13 were treated for OSA and 28 had untreated OSA, 21 of them had severe OSA (Respiratory Disturbance Index > 30/h). Seventy-four percent of the participants had a BMI >30 kg/m2. Only 5 of the participants fell asleep in any of the MWT trials (one to five trials), which could not be predicted by severity of OSA, age, BMI, or variables derived from the previous night PSG. Of the 21 patients with severe untreated OSA, only 1 patient fell asleep during the MWT20. We conclude that motivation profoundly affects the MWT results, raising the question what should be considered normal or abnormal when sleepy results may cause penalty or other practical implications. In addition, we believe that these results suggest that for renewal of driving license purposes, the MWT20 is insufficient. We speculate that MWT40, with tighter cutoff threshold, would be a more effective tool.