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- Wiessner, M., et al.
(författare)
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Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia
- 2021
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 144:5, s. 1422-1434
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Tidskriftsartikel (refereegranskat)abstract
- Human 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) is a putative iron-containing non-heme oxygenase of unknown specificity and biological significance. We report 25 families containing 34 individuals with neurological disease associated with biallelic HPDL variants. Phenotypes ranged from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spasticity and global developmental delays, sometimes complicated by episodes of neurological and respiratory decompensation. Variants included bona fide pathogenic truncating changes, although most were missense substitutions. Functionality of variants could not be determined directly as the enzymatic specificity of HPDL is unknown; however, when HPDL missense substitutions were introduced into 4-hydroxyphenylpyruvate dioxygenase (HPPD, an HPDL orthologue), they impaired the ability of HPPD to convert 4-hydroxyphenylpyruvate into homogentisate. Moreover, three additional sets of experiments provided evidence for a role of HPDL in the nervous system and further supported its link to neurological disease: (i) HPDL was expressed in the nervous system and expression increased during neural differentiation; (ii) knockdown of zebrafish hpdl led to abnormal motor behaviour, replicating aspects of the human disease; and (iii) HPDL localized to mitochondria, consistent with mitochondrial disease that is often associated with neurological manifestations. Our findings suggest that biallelic HPDL variants cause a syndrome varying from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spastic tetraplegia associated with global developmental delays. © 2021 The Author(s).
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- Geijer, Fredrik, et al.
(författare)
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Minimizing Contrast Medium Doses to Diagnose Pulmonary Embolism with 80-kVp Multidetector Computed Tomography in Azotemic Patients.
- 2009
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Ingår i: Acta radiologica (Stockholm, Sweden : 1987). - : SAGE Publications. - 1600-0455 .- 0284-1851. ; 50, s. 181-193
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Tidskriftsartikel (refereegranskat)abstract
- Background: In diagnosing acute pulmonary embolism (PE) in azotemic patients, scintigraphy and magnetic resonance imaging are frequently inconclusive or not available in many hospitals. Computed tomography is readily available, but relatively high doses (30-50 g I) of potentially nephrotoxic iodine contrast media (CM) are used. Purpose: To report on the diagnostic quality and possible contrast-induced nephropathy (CIN) after substantially reduced CM doses to diagnose PE in azotemic patients using 80-peak kilovoltage (kVp) 16-row multidetector computed tomography (MDCT) combined with CM doses tailored to body weight, fixed injection duration adapted to scan time, automatic bolus tracking, and saline chaser. Material and Methods: Patients with estimated glomerular filtration rate (eGFR) <50 ml/min were scheduled to undergo 80-kVp MDCT using 200 mg I/kg, and those with eGFR >/=50 ml/min, 120-kVp MDCT with 320 mg I/kg. Both protocols used an 80-kg maximum dose weight and a fixed 15-s injection time. Pulmonary artery density and contrast-to-noise ratio were measured assuming 70 Hounsfield units (HU) for a fresh clot. CIN was defined as a plasma creatinine rise >44.2 micromol/l from baseline. Results: 89/148 patients (63/68 females) underwent 80-/120-kVp protocols, respectively, with 95% of the examinations being subjectively excellent or adequate. Mean values in the 80-/120-kVp cohorts regarding age were 82/65 years, body weight 66/78 kg, effective mAs 277/117, CM dose 13/23 g I, pulmonary artery density 359/345 HU, image noise (1 standard deviation) 24/21 HU, contrast-to-noise ratio 13/13, and dose-length product 173/258 mGy.cm. Only 1/65 and 2/119 patients in the 80- and 120-kVp cohorts, respectively, with negative CT and no anticoagulation suffered non-fatal thromboembolism during 3-month follow-up. No patient developed CIN. Conclusion: 80-kVp 16-row MDCT with optimization of injection parameters may be performed with preserved diagnostic quality, using markedly reduced CM doses compared with common routine practice, which should be to the benefit of patients at risk of CIN.
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