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Inherited metabolic disorders (IMDs), previously considered as a paediatric sub-specialisation are more and more prevalent in adults, thanks to improved survival, and the expansion of diagnostic tools detecting attenuated-late onset forms in adulthood. Italy is one of the countries with the highest number of IMDs screened by dry blood spots in neonates, allowing them to receive early treatments and to reach adult age. Despite this, awareness of IMDs is still low by the adult medical community, with difficulties in transition and transfer of patients to adult services and unmet patient needs. In 2022, a collaboration between the adult metabolic working group of the Italian Society for the Study of Inherited Metabolic Disorders and Neonatal Screening (SIMMESN) and the European Reference Network for Hereditary Metabolic Disorders (MetabERN) was established to face problems linked to IMDs in adulthood. "The Statement of Udine" was developed to guide further steps towards improvements in inherited metabolic medicine in adults, referencing the experience from the UK. The aim of this paper is to present "The Statement of Udine" explaining its background and its possible applications.
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Arginine:glycine amidinotransferase (AGAT) deficiency is an ultrarare disorder of creatine metabolism, presenting with developmental delay, characteristic biochemical findings and muscle weakness. Most known cases have been identified and treated in early childhood. We describe a 27-year-old woman with learning difficulties and significant myopathy who was diagnosed through genetic investigation in adulthood. Treatment with creatine (10-15 g/day) led to a significant and rapid improvement of muscle strength. A literature review of the few reported adult cases confirms that progressive myopathy is a prominent feature that responds well to creatine supplementation. AGAT deficiency, a partially treatable condition, should be considered in the differential diagnosis of a genetic myopathy, particularly in people with developmental delay and progressive myopathy.
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Nutritional peripheral neuropathies are a global problem, heavily influenced by geopolitical, cultural and socioeconomic factors. Peripheral neuropathy occurs most frequently secondary to B-vitamin deficiencies, which is suspected to increase in years to come due to the popularity of vegan and vegetarian diets and increased use of bariatric surgery.This review will focus on the common B-vitamins for which a causal link to peripheral neuropathy is more established (vitamins B1, B2, B6, B9 and B12). We will review the historical human and animal data on which much of the clinical descriptions of vitamin deficiencies are based and summarise current available tools for accurately diagnosing a nutritional deficiency. We will also review recently described genetic diseases due to pathogenic variants in genes involved in B-vitamin metabolism that have helped to inform the phenotypes and potential causality of certain B-vitamins in peripheral neuropathy (B2 and B9).Endemic outbreaks of peripheral neuropathy over the last two centuries have been linked to food shortages and nutritional deficiency. These include outbreaks in Jamaican sugar plantation workers in the nineteenth century (Strachan's syndrome), World War two prisoners of war, Cuban endemic neuropathy and also Tanzanian endemic optic neuropathy, which remains a significant public health burden today. An improved understanding of lack of which vitamins cause peripheral neuropathy and how to identify specific deficiencies may lead to prevention of significant and irreversible disability in vulnerable populations.
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Deficiência de Vitaminas , Desnutrição , Doenças do Nervo Óptico , Doenças do Sistema Nervoso Periférico , Complexo Vitamínico B , Animais , Humanos , Doenças do Sistema Nervoso Periférico/etiologia , Doenças do Sistema Nervoso Periférico/complicações , Deficiência de Vitaminas/epidemiologia , Deficiência de Vitaminas/complicações , Deficiência de Vitaminas/diagnóstico , Desnutrição/complicações , Tiamina/uso terapêutico , Vitamina A/uso terapêuticoRESUMO
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.
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Acidúria Argininossuccínica , Epilepsia , Humanos , Acidúria Argininossuccínica/complicações , Acidúria Argininossuccínica/genética , Acidúria Argininossuccínica/metabolismo , Estudos Retrospectivos , Óxido Nítrico , Arginina/metabolismo , Arginina/uso terapêutico , Epilepsia/complicações , Epilepsia/epidemiologia , Epilepsia/tratamento farmacológico , Ureia , Convulsões/tratamento farmacológicoRESUMO
Long-chain fatty acid oxidation disorders (LC-FAODs) result in life-threatening energy metabolism deficiencies/energy source depletion. Triheptanoin is an odd-carbon, medium chain triglyceride (that is an anaplerotic substrate of calories and fatty acids) for treating pediatric and adult patients with LC-FAODs. Study CL202 (NCT02214160), an open-label extension study of study CL201 (NCT01886378), evaluated the long-term safety/efficacy of triheptanoin in patients with LC-FAODs (N = 94), including cohorts who were triheptanoin naïve (n = 33) or had received triheptanoin in study CL201 (n = 24) or in investigator-sponsored trials/expanded access programs (IST/EAPs; n = 37). Primary endpoint was the annualized rate of LC-FAOD major clinical events (MCEs; rhabdomyolysis, hypoglycemia, cardiomyopathy). Mean ± standard deviation (SD) triheptanoin treatment durations were 27.4 ± 19.9, 46.9 ± 13.6, and 49.6 ± 21.4 months for the triheptanoin-naïve, CL201 rollover, and IST/EAP cohorts, respectively. In the triheptanoin-naïve cohort, median (interquartile range [IQR]) MCE rate significantly decreased from 2.00 (0.67-3.33) events/patient/year pre-triheptanoin to 0.28 (0.00-1.43) events/patient/year with triheptanoin (p = 0.0343), a reduction of 86%. In the CL201 rollover cohort, mean ± SD MCE rate significantly decreased from 1.76 ± 1.64 events/patient/year pre-triheptanoin to 1.00 ± 1.00 events/patient/year with triheptanoin (p = 0.0347), a reduction of 43%. In the IST/EAP cohort, mean ± SD MCE rate was 1.40 ± 2.37 (median [IQR] 0.57 [0.00-1.67]) events/patient/year with triheptanoin. Safety data were consistent with previous observations. Treatment-related treatment-emergent adverse events (TEAEs) occurred in 68.1% of patients and were mostly mild/moderate in severity. Five patients had seven serious treatment-related TEAEs; all resolved. Our results confirm the long-term efficacy of triheptanoin for patients with LC-FAOD.
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Erros Inatos do Metabolismo Lipídico , Adulto , Criança , Humanos , Ácidos Graxos/metabolismo , Erros Inatos do Metabolismo Lipídico/metabolismo , Oxirredução , Triglicerídeos/uso terapêuticoRESUMO
The SARS-CoV-2 pandemic challenges healthcare systems worldwide. Within inherited metabolic disorders (IMDs) the vulnerable subgroup of intoxication-type IMDs such as organic acidurias (OA) and urea cycle disorders (UCD) show risk for infection-induced morbidity and mortality. This study (observation period February 2020 to December 2021) evaluates impact on medical health care as well as disease course and outcome of SARS-CoV-2 infections in patients with intoxication-type IMDs managed by participants of the European Registry and Network for intoxication type metabolic diseases Consortium (E-IMD). Survey's respondents managing 792 patients (n = 479 pediatric; n = 313 adult) with intoxication-type IMDs (n = 454 OA; n = 338 UCD) in 14 countries reported on 59 (OA: n = 36; UCD: n = 23), SARS-CoV-2 infections (7.4%). Medical services were increasingly requested (95%), mostly alleviated by remote technologies (86%). Problems with medical supply were scarce (5%). Regular follow-up visits were reduced in 41% (range 10%-50%). Most infected individuals (49/59; 83%) showed mild clinical symptoms, while 10 patients (17%; n = 6 OA including four transplanted MMA patients; n = 4 UCD) were hospitalized (metabolic decompensation in 30%). ICU treatment was not reported. Hospitalization rate did not differ for diagnosis or age group (p = 0.778). Survival rate was 100%. Full recovery was reported for 100% in outpatient care and 90% of hospitalized individuals. SARS-CoV-2 impacts health care of individuals with intoxication-type IMDs worldwide. Most infected individuals, however, showed mild symptoms and did not require hospitalization. SARS-CoV-2-induced metabolic decompensations were usually mild without increased risk for ICU treatment. Overall prognosis of infected individuals is very promising and IMD-specific or COVID-19-related complications have not been observed.
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COVID-19 , Doenças Metabólicas , Distúrbios Congênitos do Ciclo da Ureia , Adulto , Humanos , Criança , SARS-CoV-2 , Pandemias , Distúrbios Congênitos do Ciclo da Ureia/complicaçõesRESUMO
An increasing number of women with urea cycle disorders (UCDs) are reaching child-bearing age and becoming pregnant. Improved diagnostics and increased awareness of inherited metabolic diseases has also led to more previously undetected women being diagnosed with a UCD during or shortly after pregnancy. Pregnancy increases the risk of acute metabolic decompensation with hyperammonemia-which can occur in any trimester, and/or the postpartum period, and may lead to encephalopathy, psychosis, coma, and even death, if not diagnosed promptly and treated appropriately. There are also (theoretical) concerns that a maternal UCD, or its treatment, may cause potential risks for the unborn child. Currently evidence on management and outcome of pregnancies in UCDs is limited to case reports and there are no clear guidelines. In order to inform management and investigate outcomes of pregnancies in women with a UCD, we performed a retrospective review of published cases and analyzed data collected from an international online survey. We conclude that, although risk during the intra- and postpartum period exists, multidisciplinary management by an experienced team and a prospective plan usually result in successful pregnancy, labor, delivery, and postpartum period. No deaths were reported in mothers managed accordingly. With the exception of male neonates with Ornithine Transcarbamylase deficiency, the clinical outcome of children born to mothers with UCDs appears positive, although follow-up is limited. The outcome for women presenting with a first acute metabolic decompensation during pregnancy or postpartum is less favorable. Deaths were associated with diagnostic delay/late management of hyperammonemia in previously undiagnosed women.
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Argininosuccinate 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.
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Fabry disease (FD) is an X-linked lysosomal storage disorder with multi-system involvement including cerebrovascular disease. Patients with FD also have a high risk of ischaemic stroke and TIA. White matter hyperintensities are common, but their clinical impact on cognition remains uncertain. Previous studies have examined the neuropsychological profile of FD, but have been inconclusive in part due to methodological limitations including small sample sizes. We sought to address these limitations in a case-control study of 26 patients with Fabry disease with mild to moderate disease symptoms matched with 18 healthy controls for age and premorbid intellectual level. We obtained detailed neuropsychological data and MRI neuroimaging data on the severity of white matter changes. Mood was accounted for as a possible confounder. Our results showed significant compromise of executive functions and information processing speed for the FD group. Error analyses suggested that the compromise of executive functions could not be entirely accounted for by slowed information processing speed. We demonstrated significant correlations between cognitive decline and the overall volume of white matter hyperintensities in the FD group. Our results point to significant compromise of cognition in FD even without stroke or mood difficulties. This suggests that neuropsychological assessment and rehabilitation should be routinely offered to patients with FD.
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Isquemia Encefálica , Disfunção Cognitiva , Doença de Fabry , Acidente Vascular Cerebral , Substância Branca , Estudos de Casos e Controles , Disfunção Cognitiva/etiologia , Doença de Fabry/complicações , Doença de Fabry/psicologia , Humanos , Imageamento por Ressonância Magnética , Testes Neuropsicológicos , Acidente Vascular Cerebral/etiologia , Substância Branca/diagnóstico por imagemRESUMO
OBJECTIVES: To present the very long-term follow up of patients with cobalamin A (cblA) deficiency. METHODS: A retrospective case series of adult (>16 years) patients with molecular or enzymatic diagnosis of cblA deficiency. RESULTS: We included 23 patients (mean age: 27 ± 7.6 years; mean follow-up: 24.9 ± 7.6 years). Disease onset was mostly pediatric (78% < 1 year, median = 4 months) with acute neurologic deterioration (65%). Eight patients presented with chronic symptoms, and one had an adult-onset mild cblA deficiency. Most of the patients (61%) were initially classified as vitamin B12-unresponsive methylmalonic aciduria (MMA); in vitro B12 responsiveness was subsequently found in all the tested patients (n = 13). Initial management consisted of protein restriction (57%), B12 (17%), or both (26%). The main long-term problems were intellectual disability (39%) and renal failure (30%). However, 56.5% of the patients were living independently. Intellectual disability was equally distributed among the initial treatment groups, while renal failure (moderate and beginning at the age of 38 years) was present in only one out of seven patients initially treated with B12. CONCLUSIONS: We provide a detailed picture of the long-term outcome of a series of adult cblA patients, mostly diagnosed before the enzymatic and molecular era. We confirm that about 35% of the patients do not present acutely, underlining the importance of measuring MMA in any case of unexplained chronic renal failure, intellectual disability, or growth delay. In addition, we describe a patient with a milder adult-onset form. Early B12 supplementation seems to protect from severe renal insufficiency.
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Erros Inatos do Metabolismo dos Aminoácidos , Deficiência Intelectual , Falência Renal Crônica , Deficiência de Vitamina B 12 , Adulto , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Erros Inatos do Metabolismo dos Aminoácidos/terapia , Criança , Humanos , Ácido Metilmalônico , Estudos Retrospectivos , Vitamina B 12/uso terapêutico , Deficiência de Vitamina B 12/complicações , Deficiência de Vitamina B 12/diagnóstico , Deficiência de Vitamina B 12/tratamento farmacológico , Adulto JovemRESUMO
Sitosterolemia is a rare inherited condition in which plant sterols are stored and deposited in the tissues. Described in 1974 by Battacharyya and Connor, it is characterized by tendon and tuberous xanthomas and a propensity to premature coronary atherosclerosis. We present the first reported case of the disease being manifest in the periorbital region. A 44-year-old man presented with a six-month history of swelling below the left eyebrow overlying the orbital rim, but without displacement of the globe. Magnetic resonance imaging identified a soft tissue mass within the orbit, with subsequent biopsy confirming a xanthogranulomatous process consistent with the diagnosis of sitosterolemia. Management of sitosterolemia aims to reduce plasma plant sterol concentrations which subsequently lowers serum cholesterol reducing the xanthomas and atherosclerotic cardiovascular diseases. This report highlights a rare, under-recognised condition (and indeed the first reporting periocular disease), and the potential dangers if misdiagnosed as hypercholesterolemia.
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Hipercolesterolemia , Enteropatias , Erros Inatos do Metabolismo Lipídico , Fitosteróis , Adulto , Humanos , Erros Inatos do Metabolismo Lipídico/diagnóstico , Masculino , Fitosteróis/efeitos adversosRESUMO
Long-chain fatty acid oxidation disorders (LC-FAOD) are autosomal recessive conditions that impair conversion of long-chain fatty acids into energy, leading to significant clinical symptoms. Triheptanoin is a highly purified, 7-carbon chain triglyceride approved in the United States as a source of calories and fatty acids for treatment of pediatric and adult patients with molecularly confirmed LC-FAOD. CL202 is an open-label, long-term extension study evaluating triheptanoin (Dojolvi) safety and efficacy in patients with LC-FAOD. Patients rolled over from the CL201 triheptanoin clinical trial (rollover); were triheptanoin-naïve (naïve); or had participated in investigator-sponsored trials/expanded access programs (IST/other). Results focus on rollover and naïve groups, as pretreatment data allow comparison. Primary outcomes were annual rate and duration of major clinical events (MCEs; rhabdomyolysis, hypoglycemia, and cardiomyopathy events). Seventy-five patients were enrolled (24 rollover, 20 naïve, 31 IST/other). Mean study duration was 23.0 months for rollover, 15.7 months for naïve, and 34.7 months for IST/other. In the rollover group, mean annualized MCE rate decreased from 1.76 events/year pre-triheptanoin to 0.96 events/year with triheptanoin (P = .0319). Median MCE duration was reduced by 66%. In the naïve group, median annualized MCE rate decreased from 2.33 events/year pre-triheptanoin to 0.71 events/year with triheptanoin (P = .1072). Median MCE duration was reduced by 80%. The most common related adverse events (AEs) were diarrhea, abdominal pain/discomfort, and vomiting, most mild to moderate. Three patients had serious AEs (diverticulitis, ileus, rhabdomyolysis) possibly related to drug; all resolved. Two patients had AEs leading to death; neither drug related. Triheptanoin reduced rate and duration of MCEs. Safety was consistent with previous observations.
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Ácidos Graxos/metabolismo , Erros Inatos do Metabolismo Lipídico/tratamento farmacológico , Oxirredução/efeitos dos fármacos , Triglicerídeos/administração & dosagem , Adolescente , Adulto , Cardiomiopatias/metabolismo , Criança , Pré-Escolar , Feminino , Humanos , Hipoglicemia/metabolismo , Lactente , Erros Inatos do Metabolismo Lipídico/metabolismo , Masculino , Pessoa de Meia-Idade , Rabdomiólise/metabolismo , Reino Unido , Estados Unidos , Adulto JovemRESUMO
Previous studies have suggested that cognitive and psychosocial underfunctioning in early-treated adults with phenylketonuria (PKU) may be explained by suboptimal adherence to dietary treatments, however, these studies often employ small samples, with different outcome measures, definitions and cut-offs. Samples have also tended to comprise participants with a limited range of blood phenylalanine concentrations, and often individuals who may not have been treated early enough to avoid neurological damage. In this study, we explore the impact of lifetime dietary control, as indicated by blood phenylalanine concentrations in childhood, adolescence and adulthood, on long-term cognitive and psychosocial outcomes in a large sample of adults with PKU who were diagnosed by neonatal screening and commenced on dietary treatment within the first month of life. One hundred and fifty-four participants underwent cognitive testing, assessing attention, learning, working memory, language, executive functioning and processing speed. One hundred and forty-nine completed measures of psychosocial functioning, documenting educational, occupational, quality of life, emotional and social outcomes which were compared with a group of healthy controls. Many adults with PKU demonstrated cognitive impairments, most frequently affecting processing speed (23%), executive function (20%) and learning (12%). Cognitive outcomes were related to measures of historic metabolic control, but only processing speed was significantly related to phenylalanine concentration at the time of testing after controlling for historic levels. Adults with PKU did not, however, differ from controls in educational, occupational, quality of life or emotional outcomes, or on a measure of family functioning, and showed only minor differences in relationship style. These findings have implications for patient counselling and decisions regarding the management of PKU in adulthood.
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Cognição , Emoções , Fenilcetonúrias/psicologia , Adulto , Atenção , Estudos de Casos e Controles , Função Executiva , Feminino , Humanos , Inibição Psicológica , Testes de Linguagem , Masculino , Memória de Curto Prazo , Saúde Mental , Pessoa de Meia-Idade , Fenilalanina/sangue , Fenilcetonúrias/sangue , Fenilcetonúrias/dietoterapia , Qualidade de Vida , Reino Unido , Adulto JovemRESUMO
Cerebral white matter pathology is a common CNS manifestation of Fabry disease, visualized as white matter hyperintensities on MRI in 42-81% of patients. Diffusion tensor imaging (DTI) MRI is a sensitive technique to quantify microstructural damage within the white matter with potential value as a disease biomarker. We evaluated the pattern of DTI abnormalities in Fabry disease, and their correlations with cognitive impairment, mood, anxiety, disease severity and plasma lyso-Gb3 levels in 31 patients with genetically proven Fabry disease and 19 age-matched healthy control subjects. We obtained average values of fractional anisotropy and mean diffusivity within the white matter and performed voxelwise analysis with tract-based spatial statistics. Using a standardized neuropsychological test battery, we assessed processing speed, executive function, anxiety, depression and disease severity. The mean age (% male) was 44.1 (45%) for patients with Fabry disease and 37.4 (53%) for the healthy control group. In patients with Fabry disease, compared to healthy controls the mean average white matter fractional anisotropy was lower in [0.423 (standard deviation, SD 0.023) versus 0.446 (SD 0.016), P = 0.002] while mean average white matter mean diffusivity was higher (749 × 10-6 mm2/s (SD 32 × 10-6) versus 720 × 10-6 mm2/s (SD 21 × 10-6), P = 0.004]. Voxelwise statistics showed that the diffusion abnormalities for both fractional anisotropy and mean diffusivity were anatomically widespread. A lesion probability map showed that white matter hyperintensities also had a wide anatomical distribution with a predilection for the posterior centrum semiovale. However, diffusion abnormalities in Fabry disease were not restricted to lesional tissue; compared to healthy controls, the normal appearing white matter in patients with Fabry disease had reduced fractional anisotropy [0.422 (SD 0.022) versus 0.443 (SD 0.017) P = 0.003] and increased mean diffusivity [747 × 10-6 mm2/s (SD 26 × 10-6) versus 723 × 10-6 mm2/s (SD 22 × 10-6), P = 0.008]. Within patients, average white matter fractional anisotropy and white matter lesion volume showed statistically significant correlations with Digit Symbol Coding Test score (r = 0.558, P = 0.001; and r = -0.633, P ≤ 0.001, respectively). Average white matter fractional anisotropy correlated with the overall Mainz Severity Score Index (r = -0.661, P ≤ 0.001), while average white matter mean diffusivity showed a strong correlation with plasma lyso-Gb3 levels (r = 0.559, P = 0.001). Our findings using DTI confirm widespread areas of microstructural white matter disruption in Fabry disease, extending beyond white matter hyperintensities seen on conventional MRI. Moreover, diffusion measures show strong correlations with cognition (processing speed), clinical disease severity and a putative plasma biomarker of disease activity, making them promising quantitative biomarkers for monitoring Fabry disease severity and progression.
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Doença de Fabry/diagnóstico por imagem , Doença de Fabry/psicologia , Substância Branca/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Ansiedade/etiologia , Ansiedade/psicologia , Encéfalo/diagnóstico por imagem , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/psicologia , Depressão/etiologia , Depressão/psicologia , Imagem de Tensor de Difusão , Função Executiva , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos do Humor/etiologia , Transtornos do Humor/psicologia , Testes Neuropsicológicos , Triexosilceramidas/sangue , Adulto JovemRESUMO
Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in CHM in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.
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Análise Mutacional de DNA , Variação Genética/genética , Genoma Humano/genética , Doenças Retinianas/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Alelos , Sequência de Bases , Coroideremia/genética , Etnicidade/genética , Exoma/genética , Feminino , Genes Recessivos/genética , Humanos , Íntrons/genética , Masculino , Mutação , Doenças Raras/genéticaRESUMO
In this article, we report four new patients, from three kindreds, with pathogenic variants in RBCK1 and a multisystem disorder characterised by widespread polyglucosan storage. We describe the clinical presentation of progressive skeletal and cardiac myopathy, combined immunodeficiencies and auto-inflammation, illustrate in detail the histopathological findings in multiple tissue types, and report muscle MRI findings.
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Glucanos/metabolismo , Doença de Depósito de Glicogênio/genética , Doença de Depósito de Glicogênio/metabolismo , Fatores de Transcrição/genética , Ubiquitina-Proteína Ligases/genética , Criança , Pré-Escolar , Feminino , Humanos , Inflamação/patologia , Masculino , Músculo Esquelético/patologia , Doenças Musculares/patologia , Reinfecção/patologiaRESUMO
Hyperammonaemia is often encountered in acute neurology and can be the cause of acute or chronic neurological symptoms. Patients with hyperammonaemia may present with seizures or encephalopathy, or may be entirely asymptomatic. The underlying causes are diverse but often straightforward to diagnose, although sometimes require specialist investigations. Haemodialysis or haemo(dia)filtration is the first-line treatment for acute severe hyperammonaemia (of any cause) in an adult. Here we discuss our approach to adult patients with hyperammonaemia identified by a neurologist.
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Genetic and acquired disorders of white matter comprise a diverse group of conditions, with often overlapping clinical and radiological findings. Patients present with a variable combination of cognitive impairment, ataxia, spasticity or movement disorders, among others. There are many genetic causes, and the route to diagnosis involves comprehensive clinical assessment, radiological expertise, metabolic investigations and finally genetic studies. It is essential not to miss the treatable acquired causes. In this review, we present a practical approach to investigating patients with acquired and genetic disorders of white matter, based on the experience of a large international referral centre. We present a guide for clinicians, including pitfalls of testing, clinical pearls and where to seek advice.