Genetic landscape of pediatric acute liver failure of indeterminate origin.

BACKGROUND AIMS Pediatric acute liver failure (PALF) is a life-threatening condition. In Europe, main causes are viral infections (12-16%) and inherited metabolic diseases (14-28%). Yet, in up to 50% of cases the underlying etiology remains elusive, challenging clinical management, including liver transplantation. We systematically studied indeterminate PALF cases referred for genetic evaluation by whole-exome sequencing (WES), and analyzed phenotypic and biochemical markers, and the diagnostic yield of WES in this condition. METHODS With this international, multicenter observational study, patients (0-18 y) with indeterminate PALF were analyzed by WES. Data on the clinical and biochemical phenotype were retrieved and systematically analyzed. RESULTS In total, 260 indeterminate PALF patients from 19 countries were recruited between 2011 and 2022, of whom 59 had recurrent PALF (RALF). WES established a genetic diagnosis in 37% of cases (97/260). Diagnostic yield was highest in children with PALF in the first year of life (46%), and in children with RALF (64%). Thirty-six distinct disease genes were identified. Defects in NBAS (n=20), MPV17 (n=8) and DGUOK (n=7) were the most frequent findings. When categorizing, most frequent were mitochondrial diseases (45%), disorders of vesicular trafficking (28%) and cytosolic aminoacyl-tRNA synthetase deficiencies (10%). One-third of patients had a fatal outcome. Fifty-six patients received liver transplants. CONCLUSION This study elucidates a large contribution of genetic causes in PALF of indeterminate origin with an increasing spectrum of disease entities. The high proportion of diagnosed cases and potential treatment implications argue for exome or in future rapid genome sequencing in PALF diagnostics

Auditory Discrimination—A Missing Piece of Speech and Language Development: A Study on 6–9-Year-Old Children with Auditory Processing Disorder

Auditory discrimination, the hearing ability crucial for speech and language development, allowing one to perceive changes in volume, duration and frequency of sounds, was assessed for 366 participants with normal peripheral hearing: 220 participants with auditory processing disorders (APD) and 146 typically developing (TD) children, all aged 6–9 years. Discrimination of speech was tested with nonsense words using the phoneme discrimination test (PDT), while pure tones—with the frequency pattern test (FPT). The obtained results were statistically analyzed and correlated. The median of the FPT results obtained by participants with APD was more than twice lower than those of TD (20% vs. 50%; p p p < 0.05), indicating that the significant FPT deficit strongly suggests APD. The process of auditory discrimination development does not complete with the acquisition of phonemes but continues during school age. Physiological phonemes discrimination is not yet equalized among 9-year-olds. Nonsense word tests allow for reliable testing of phoneme discrimination. APD children require testing with PDT and FPT because both test results allow for developing individual therapeutic programs

Balance control of children and adolescents suffering from vertigo symptoms: in what way posturography is helpful in clinical evaluation of vestibular system pathology?

The aim of the study was to determine balance parameters in a group of young patients with vertigo symptoms and to verify posturography helpfulness in clinical evaluation of vestibular system pathology. Methods: 77 children and adolescents of age 3–18 suffering from vertigo episodes participated in the study (46 girls, 31 boys). They underwent audiology objective tests and balance test on stable surface. Calculated balance parameters were analyzed in reference to: eyes opened and closed, age influence, sway comparison in anterior-posterior and medial-lateral, differences between subgroups with and without vestibular deficits. Discriminant analysis was performed to assess classification ability to impaired group in two cases: only balance parameters and both audiology and balance parameters. Results: Patients with vertigo symptoms generally keep their balance properly on stable surface. Balance parameters do not depend on presence of vestibular system pathology. Values increased in eyes closed conditions. Left/Right and Anterior/Posterior differences were not statistically significant. The negative correlation between age and some balance parameters is present, stronger in the case of eyes opened and weaker or absent in vestibular impaired group. Also, correlations between axes were found, higher in impaired group in comparison with not impaired one. Conclusions: Discrimination based on balance parameters is poor not comparable to one built on combined: audiology and balance parameters, so typical balance parameters’ analysis is not so useful in clinical practice when the reason of vertigo episodes should be assessed, but verify compensation process and measure with objective numbers the progress of recovering, the actual functional patient’s status

Normative values of screening adaptive frequency discrimination test and adaptive gap detection test included

Introduction. Understanding the sounds of our environment, including speech sounds and music, depends on efficient operation of central auditory system. Auditory discrimination and temporal processing are key parts of auditory processing. There is a need to develop and standardize clinical procedures that will enable efficient and reliable assessment of these auditory functions. Aim. Assessment of clinical usefulness of screening adaptive frequency discrimination test (aDLF) and adaptive gap detection test (aGDT) and development of normative values for these tests. Material and method. Adaptive test of frequency discrimination (aDLF) and adaptive gap detection test (aGDT) were performed on the study group including 311 children with normal hearing, aged 8-12 years, divided into age groups. The hearing tests were performed by means of tests included on APD-Medical platform. The tests are based on the principles of signal detection theory and make use of adaptive procedures. Results. It was demonstrated that age significantly affects the results of aDLF and a GDT tests. The younger participants (aged  8) achieved poorer results than older children (aged 10-12). Reference values for auditory processing tests were set at 75 percentile level. Conclusions. Determining normative values will allow to use the disagnostic-therapeutic APD-Medical platform for screening purposes in primary school children.Wprowadzenie. Rozumienie dźwięków otoczenia, w tym również dźwięków mowy i muzyki, uzależnione jest od sprawnego działania ośrodkowego układu słuchowego. W procesie tym niezwykle ważne są mechanizmy dyskryminacji słuchowej i aspektów przetwarzania czasowego dźwięków. Istnieje potrzeba opracowania i wystandaryzowania procedur klinicznych, umożliwiających skuteczną i wiarygodną ocenę tych funkcji słuchowych. Cel pracy. Ocena przydatności klinicznej i opracowanie wartości referencyjnych dla przesiewowych adaptacyjnych testów dyskryminacji częstotliwości dźwięku (aDLF) oraz rozdzielczości czasowej układu słuchowego (aGDT). Materiał i metoda. Badania aDLF i aGDT przeprowadzono w grupie 311 zdrowych, z prawidłowym słuchem dzieci w wieku od 8 do 12 lat, podzielonych na grupy wiekowe. Testy te zawarte są na platformie APD-Medical, wykorzystują procedury adaptacyjne oraz oparte są na zasadach teorii detekcji sygnału. Wyniki. Wykazano, że wiek w istotny sposób wpływa na wyniki uzyskane w testach dyskryminacji słuchowej i rozdzielczości czasowej. Dzieci najmłodsze (8 lat) osiągnęły istotnie słabsze wyniki, niż dzieci starsze (10-12 lat). Wartości referencyjne dla obu testów wyznaczono na poziomie 75 percentyla. Wnioski. Ustalenie wartości normatywnych pozwoli na wykorzystanie platformy diagnostyczno-terapeutycznej APD-Medical dla celów badań przesiewowych u dzieci szkół podstawowych

Postlingual hearing loss as a mitochondrial 3243A>G mutation phenotype.

BACKGROUND: The prevalence of isolated hearing loss (HL) associated with the m.3243A>G mutation is unknown. The aim of this study was to assess the frequency and heteroplasmy level of the m.3243A>G mutation in a large group of Polish patients with postlingual bilateral sensorineural HL of unidentified cause. METHODOLOGY/PRINCIPAL FINDINGS: A molecular search was undertaken in the archival blood DNA of 1482 unrelated patients with isolated HL that had begun at ages between 5 and 40 years. Maternal relatives of the probands were subsequently investigated and all carriers underwent audiological tests. The m.3243A>G mutation was found in 16 of 1482 probands (an incidence of 1.08%) and 18 family members. Of these 34 individuals, hearing impairment was detected in 29 patients and the mean onset of HL was at 26 years. Some 42% of the identified m.3243A>G carriers did not develop multisystem symptomatology over the following 10 years. Mean heteroplasmy level of m.3243A>G was lowest in blood at a level of 14% and highest in urine at 58%. These values were independent of the manifested clinical severity of the disease. CONCLUSIONS: A single m.3243A>G carrier can usually be found among each 100 individuals who have postlingual hearing loss of unknown cause. Urine samples are best for detecting the m.3243A>G mutation and diagnosing mitochondrially inherited hearing loss

Neuropathological characteristics of the brain in two patients with SLC19A3 mutations related to the biotin-thiamine-responsive basal ganglia disease

Biotin-thiamine-responsive basal ganglia disease is a severe form of a rare neurogenetic disorder caused by pathogenic molecular variants in the thiamine transporter gene. Nowadays, a potentially effective treatment is known, therefore the early diagnosis is mandatory. The aim of the paper was to assess the contribution of neuropathological and magnetic resonance imaging (MRI) studies to a proper diagnosis. We present the brain study of two Polish patients with SLC19A3 mutations, including (1) an infant with an intriguing “walnut” appearance of the brain autopsied many years before the discovery of the SLC19A3 defect, and (2) a one-year-old patient with clinical features of Leigh syndrome. In patient 2, biotin/thiamine responsiveness was not tested at the time of diagnosis and causal treatment started with one-year delay. The central nervous system lesions found in the patients displayed almost clearly a specific pattern for SLC19A3 defect, as previously proposed in diagnostic criteria. Our study presents a detailed description of neuropathological and MRI findings of both patients. We confirm that the autopsy and/or MRI of the brain is sufficient to qualify a patient with an unknown neuropathological disorder directly for SLC19A3 mutations testing and a prompt trial of specific treatment

Latest audiograms of the three patients shown in <b>Figs. 1</b> and <b>2</b>.

<p>Patients 15 and 29 have become cochlear implant users. The HL threshold of patient 28 has still not changed.</p