Haigusjuht: haruldane suhkruhaigus MODY 2

Maturity-onset diabetes of the young (MODY) – noorte küpsuseas algav diabeet – on autosoom-dominant selt päritav mono geense etioloogiaga insuliinisõltumatu diabeedi vorm, mida iseloomustab haiguse algus enne 25. eluaastat, stabiilne kergekujuline hüperglükeemia ja isuliini sõltumatu diabeedi esinemine vähemalt ühel esimese astme sugulasel. Eesti Arst 2006; 85 (1): 46–4

Kawasaki haigus Eestis aastatel 2002–2007

Kawasaki haigus (KH) on tundmatu etioloogiaga vaskuliit, mis esineb peamiselt alla 5aastastel lastel. Haiguse diagnoosimise aluseks on tüüpiline kliiniline pilt koos lisasümptomite ning südame pärgarterite kahjustusega. Artiklis käsitletakse KH epidemioloogilisi aspekte, diagnostikat ja raviküsimusi ning tuuakse ära Eestis aastatel 2002–2007 Tallinna Lastehaiglas ja TÜ Kliinikumi lastekliinikus diagnoositud haigusjuhtude analüüs. Eesti Arst 2009; 88(Lisa4):46−5

Natural history of epilepsy in argininosuccinic aciduria provides new insights into pathophysiology: A retrospective international study

OBJECTIVE: Argininosuccinate lyase (ASL) is integral to the urea cycle, which enables nitrogen wasting and biosynthesis of arginine, a precursor of nitric oxide. Inherited ASL deficiency causes argininosuccinic aciduria, the second most common urea cycle defect and an inherited model of systemic nitric oxide deficiency. Patients present with developmental delay, epilepsy, and movement disorder. Here we aim to characterize epilepsy, a common and neurodebilitating comorbidity in argininosuccinic aciduria. METHODS: We conducted a retrospective study in seven tertiary metabolic centers in the UK, Italy, and Canada from 2020 to 2022, to assess the phenotype of epilepsy in argininosuccinic aciduria and correlate it with clinical, biochemical, radiological, and electroencephalographic data. RESULTS: Thirty-seven patients, 1-31 years of age, were included. Twenty-two patients (60%) presented with epilepsy. The median age at epilepsy onset was 24 months. Generalized tonic-clonic and focal seizures were most common in early-onset patients, whereas atypical absences were predominant in late-onset patients. Seventeen patients (77%) required antiseizure medications and six (27%) had pharmacoresistant epilepsy. Patients with epilepsy presented with a severe neurodebilitating disease with higher rates of speech delay (p = .04) and autism spectrum disorders (p = .01) and more frequent arginine supplementation (p = .01) compared to patients without epilepsy. Neonatal seizures were not associated with a higher risk of developing epilepsy. Biomarkers of ureagenesis did not differ between epileptic and non-epileptic patients. Epilepsy onset in early infancy (p = .05) and electroencephalographic background asymmetry (p = .0007) were significant predictors of partially controlled or refractory epilepsy. SIGNIFICANCE: Epilepsy in argininosuccinic aciduria is frequent, polymorphic, and associated with more frequent neurodevelopmental comorbidities. We identified prognostic factors for pharmacoresistance in epilepsy. This study does not support defective ureagenesis as prominent in the pathophysiology of epilepsy but suggests a role of central dopamine deficiency. A role of arginine in epileptogenesis was not supported and warrants further studies to assess the potential arginine neurotoxicity in argininosuccinic aciduria

Multiple Sulfatase Deficiency (MSD): Review of the Literature and Case Reports of Two Siblings with Dental Caries and Trauma

Multiple sulfatase deficiency (MSD) (MIM # 272200) is an extraordinarily rare inborn error of metabolism (IEM). The phenotypic spectrum is largely heterogeneous and attributed to the combined effects of deficiencies in the nine sulfatases currently known to be related to human diseases. Systemic sequelae of MSD are vast and multisystemic, primarily encompassing developmental delay and neurological, cardiopulmonary, dermatological, gastroenterological, and skeletal manifestations. The dental phenotype is scarcely described in the literature due to a paucity of cases. Dental treatment under local and general anaesthesia mandates an integrated multidisciplinary approach to safeguard systemic health and optimise outcomes. This paper presents two siblings with multiple sulfatase deficiency who presented to the Paediatric Dental Department at Great Ormond Street Hospital, requiring comprehensive care under general anaesthesia for dental caries and trauma

Fenüülketonuuria Eesti ravijuhend

Eesti Arst 2012; 91(1):46–5

Üle-eestiline vastsündinute laiendatud sõeltestimine tandemmass-spektromeetria meetodil ravitavate kaasasündinud ainevahetushaiguste suhtes

Ainevahetushaigused (av-haigused) on rühm pärilikke haigusi, mille korral ensüümidefekti tõttu pidurdub organismis teatud metaboliitide lammutamine, ülesehitus või transport. Selle tagajärjel võivad häiruda kehas mitmed elutähtsad funktsioonid, põhjustades ägedat või kroonilist elundipuudulikkust, eluohtlikke seisundeid ja enneaegset surma. Haigused avalduvad eri vanuses – vastsündinueast täiskasvanueani – ning esmased sümptomid on sageli mittespetsiifilised. See muudab nende haiguste õigeaegse diagnoosimise ja ravi keeruliseks. Alates 1. jaanuarist 2014 alustati Eestis katseprojekti vastsündinute laiendatud sõeltestimiseks tandemmass-spektromeetria meetodil, mille raames lisandub kahele juba skriinitavale haigusele, milleks on fenüülketonuuria ja kaasasündinud hüpotüreoos, veel 18 uut ravitavat av-haigust. Katseuuringu eesmärk on uue laborimeetodi juurutamine ja sellega teatud ravitavate ainevahetushaiguste võimalikult varane diagnoosimine ning ravi alustamine haiguste kaugprognoosi parandamiseks.Eesti Arst 2014; 93(4):218–22

Natural history of epilepsy in argininosuccinic aciduria provides new insights into pathophysiology: A retrospective international study.

Funder: NIHR Great Ormond Street Hospital Biomedical Research Centre; Id: http://dx.doi.org/10.13039/501100019256OBJECTIVE: Argininosuccinate lyase (ASL) is integral to the urea cycle, which enables nitrogen wasting and biosynthesis of arginine, a precursor of nitric oxide. Inherited ASL deficiency causes argininosuccinic aciduria, the second most common urea cycle defect and an inherited model of systemic nitric oxide deficiency. Patients present with developmental delay, epilepsy, and movement disorder. Here we aim to characterize epilepsy, a common and neurodebilitating comorbidity in argininosuccinic aciduria. METHODS: We conducted a retrospective study in seven tertiary metabolic centers in the UK, Italy, and Canada from 2020 to 2022, to assess the phenotype of epilepsy in argininosuccinic aciduria and correlate it with clinical, biochemical, radiological, and electroencephalographic data. RESULTS: Thirty-seven patients, 1-31 years of age, were included. Twenty-two patients (60%) presented with epilepsy. The median age at epilepsy onset was 24 months. Generalized tonic-clonic and focal seizures were most common in early-onset patients, whereas atypical absences were predominant in late-onset patients. Seventeen patients (77%) required antiseizure medications and six (27%) had pharmacoresistant epilepsy. Patients with epilepsy presented with a severe neurodebilitating disease with higher rates of speech delay (p = .04) and autism spectrum disorders (p = .01) and more frequent arginine supplementation (p = .01) compared to patients without epilepsy. Neonatal seizures were not associated with a higher risk of developing epilepsy. Biomarkers of ureagenesis did not differ between epileptic and non-epileptic patients. Epilepsy onset in early infancy (p = .05) and electroencephalographic background asymmetry (p = .0007) were significant predictors of partially controlled or refractory epilepsy. SIGNIFICANCE: Epilepsy in argininosuccinic aciduria is frequent, polymorphic, and associated with more frequent neurodevelopmental comorbidities. We identified prognostic factors for pharmacoresistance in epilepsy. This study does not support defective ureagenesis as prominent in the pathophysiology of epilepsy but suggests a role of central dopamine deficiency. A role of arginine in epileptogenesis was not supported and warrants further studies to assess the potential arginine neurotoxicity in argininosuccinic aciduria

An LC–MS/MS-Based Method for the Quantification of Pyridox(am)ine 5′-Phosphate Oxidase Activity in Dried Blood Spots from Patients with Epilepsy

We report the development of a rapid, simple, and robust LC–MS/MS-based enzyme assay using dried blood spots (DBS) for the diagnosis of pyridox­(am)­ine 5′-phosphate oxidase (PNPO) deficiency (OMIM 610090). PNPO deficiency leads to potentially fatal early infantile epileptic encephalopathy, severe developmental delay, and other features of neurological dysfunction. However, upon prompt treatment with high doses of vitamin B₆, affected patients can have a normal developmental outcome. Prognosis of these patients is therefore reliant upon a rapid diagnosis. PNPO activity was quantified by measuring pyridoxal 5′-phosphate (PLP) concentrations in a DBS before and after a 30 min incubation with pyridoxine 5′-phosphate (PNP). Samples from 18 PNPO deficient patients (1 day–25 years), 13 children with other seizure disorders receiving B₆ supplementation (1 month–16 years), and 37 child hospital controls (5 days–15 years) were analyzed. DBS from the PNPO-deficient samples showed enzyme activity levels lower than all samples from these two other groups as well as seven adult controls; no false positives or negatives were identified. The method was fully validated and is suitable for translation into the clinical diagnostic arena

The incidence of movement disorder increases with age and contrasts with subtle and limited neuroimaging abnormalities in argininosuccinic aciduria.

Publication status: PublishedFunder: NIHR Great Ormond Street Hospital Biomedical Research Centre; doi: http://dx.doi.org/10.13039/501100019256Funder: Moderna Therapeutics; doi: http://dx.doi.org/10.13039/100019533Argininosuccinate lyase (ASL) is integral to the urea cycle detoxifying neurotoxic ammonia and the nitric oxide (NO) biosynthesis cycle. Inherited ASL deficiency causes argininosuccinic aciduria (ASA), a rare disease with hyperammonemia and NO deficiency. Patients present with developmental delay, epilepsy and movement disorder, associated with NO-mediated downregulation of central catecholamine biosynthesis. A neurodegenerative phenotype has been proposed in ASA. To better characterise this neurodegenerative phenotype in ASA, we conducted a retrospective study in six paediatric and adult metabolic centres in the UK in 2022. We identified 60 patients and specifically looked for neurodegeneration-related symptoms: movement disorder such as ataxia, tremor and dystonia, hypotonia/fatigue and abnormal behaviour. We analysed neuroimaging with diffusion tensor imaging (DTI) magnetic resonance imaging (MRI) in an individual with ASA with movement disorders. We assessed conventional and DTI MRI alongside single photon emission computer tomography (SPECT) with dopamine analogue radionuclide 123 I-ioflupane, in Asl-deficient mice treated by hASL mRNA with normalised ureagenesis. Movement disorders in ASA appear in the second and third decades of life, becoming more prevalent with ageing and independent from the age of onset of hyperammonemia. Neuroimaging can show abnormal DTI features affecting both grey and white matter, preferentially basal ganglia. ASA mouse model with normalised ureagenesis did not recapitulate these DTI findings and showed normal 123 I-ioflupane SPECT and cerebral dopamine metabolomics. Altogether these findings support the pathophysiology of a late-onset movement disorder with cell-autonomous functional central catecholamine dysregulation but without or limited neurodegeneration of dopaminergic neurons, making these symptoms amenable to targeted therapy