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1.
Hum Mutat ; 2018 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-30372562

RESUMO

The Sjögren-Larsson syndrome (SLS) is a rare autosomal recessive disorder caused by pathogenic variants in the ALDH3A2 gene, which codes for fatty aldehyde dehydrogenase (FALDH). FALDH prevents the accumulation of toxic fatty aldehydes by converting them into fatty acids. Pathogenic ALDH3A2 variants cause symptoms such as ichthyosis, spasticity, intellectual disability, and a wide range of less common clinical features. Interpreting patient-to-patient variability is often complicated by inconsistent reporting and negatively impacts on establishing robust criteria to measure the success of SLS treatments. Thus, with this study, patient-centered literature data was merged into a concise genotype-based, open-access database (www.LOVD.nl/ALDH3A2). One hundred and seventy eight individuals with 90 unique SLS-causing variants were included with phenotypic data being available for more than 90%. While the three lead symptoms did occur in almost all cases, more heterogeneity was observed for other frequent clinical manifestations of SLS. However, a stringent genotype-phenotype correlation analysis was hampered by the considerable variability in reporting phenotypic features. Consequently, we compiled a set of recommendations of how to generate comprehensive SLS patient descriptions in the future. This will be of benefit on multiple levels, for example, in clinical diagnosis, basic research, and the development of novel treatment options for SLS.

2.
Genet Med ; 2018 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-30214072

RESUMO

PURPOSE: To investigate immune tolerance induction with transient low-dose methotrexate (TLD-MTX) initiated with recombinant human acid α-glucosidase (rhGAA), in treatment-naïve cross-reactive immunologic material (CRIM)-positive infantile-onset Pompe disease (IOPD) patients. METHODS: Newly diagnosed IOPD patients received subcutaneous or oral 0.4 mg/kg TLD-MTX for 3 cycles (3 doses/cycle) with the first 3 rhGAA infusions. Anti-rhGAA IgG titers, classified as high-sustained (HSAT; ≥51,200, ≥2 times after 6 months), sustained intermediate (SIT; ≥12,800 and <51,200 within 12 months), or low (LT; ≤6400 within 12 months), were compared with those of 37 CRIM-positive IOPD historic comparators receiving rhGAA alone. RESULTS: Fourteen IOPD TLD-MTX recipients at the median age of 3.8 months (range, 0.7-13.5 months) had a median last titer of 150 (range, 0-51,200) at median rhGAA duration ~83 weeks (range, 36-122 weeks). One IOPD patient (7.1%) developed titers in the SIT range and one patient (7.1%) developed titers in the HSAT range. Twelve of the 14 patients (85.7%) that received TLD-MTX remained LT, versus 5/37 HSAT (peak 51,200-409,600), 7/37 SIT (12,800-51,000), and 23/37 LT (200-12,800) among comparators. CONCLUSION: Results of TLD-MTX coinitiated with rhGAA are encouraging and merit a larger longitudinal study.

3.
Mol Genet Metab ; 125(3): 217-227, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30146451

RESUMO

BACKGROUND: Phenylketonuria (PKU) is caused by a deficiency in phenylalanine hydroxylase enzyme activity that leads to phenylalanine (Phe) accumulation in the blood and brain. Elevated blood Phe levels are associated with complications in adults, including neurological, psychiatric, and cognitive issues. Even with nutrition and pharmacological management, the majority of adults with PKU do not maintain blood Phe levels at or below guideline recommended levels. Pegvaliase, PEGylated recombinant Anabaena variabilis phenylalanine ammonia lyase (PAL), converts Phe to trans-cinnamic acid and ammonia, and is an investigational enzyme substitution therapy to lower blood Phe in adults with PKU. METHODS: Pegvaliase was administered using an induction, titration, and maintenance dosing regimen in adults with PKU naïve to pegvaliase treatment. Doses were gradually increased until blood Phe ≤ 600 µmol/L was achieved. The maintenance dose was the dose at which participants achieved and sustained blood Phe ≤ 600 µmol/L for at least 4 weeks without dose modification. Analyses were performed for participants who achieved (Group A, n = 11) and did not achieve (Group B, n = 13) maintenance dose during the first 24 weeks of study treatment. RESULTS: Baseline mean blood Phe for Group A and Group B were 1135 µmol/L and 1198 µmol/L, respectively. Mean blood Phe ≤ 600 µmol/L was achieved for Group A by Week 11 (mean blood Phe of 508 ±â€¯483 µmol/L) and for Group B by Week 48 (mean blood Phe of 557 ±â€¯389 µmol/L). The most common adverse events involved hypersensitivity reactions, which were mostly mild to moderate in severity and decreased over time. One participant in Group B had four acute systemic hypersensitivity events of anaphylaxis consistent with clinical National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network criteria; all events were non-IgE mediated and resolved without sequelae, with pegvaliase dosing discontinued after the fourth event. The incidence and titers of anti-drug antibodies were generally lower in Group A compared to Group B. CONCLUSIONS: Pegvaliase administered with an induction, titration, and maintenance dosing regimen demonstrated substantial efficacy at reducing blood Phe in both Group A and Group B by Week 48, with a manageable safety profile in most participants. Blood Phe reduction due to pegvaliase appears to be related to dose, treatment duration, and individual immune response; given additional time on treatment and dose titration, later Phe responders (Group B) achieved benefit similar to early Phe responders (Group A), with similar long-term safety profiles.

4.
Genet Med ; 20(10): 1274-1283, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29419819

RESUMO

PURPOSE: Peroxisome biogenesis disorders-Zellweger spectrum disorders (PBD-ZSD) are metabolic diseases with multisystem manifestations. Individuals with PBD-ZSD exhibit impaired peroxisomal biochemical functions and have abnormal levels of peroxisomal metabolites, but the broader metabolic impact of peroxisomal dysfunction and the utility of metabolomic methods is unknown. METHODS: We studied 19 individuals with clinically and molecularly characterized PBD-ZSD. We performed both quantitative peroxisomal biochemical diagnostic studies in parallel with untargeted small molecule metabolomic profiling in plasma samples with detection of >650 named compounds. RESULTS: The cohort represented intermediate to mild PBD-ZSD subjects with peroxisomal biochemical alterations on targeted analysis. Untargeted metabolomic profiling of these samples revealed elevations in pipecolic acid and long-chain lysophosphatidylcholines, as well as an unanticipated reduction in multiple sphingomyelin species. These sphingomyelin reductions observed were consistent across the PBD-ZSD samples and were rare in a population of >1,000 clinical samples. Interestingly, the pattern or "PBD-ZSD metabolome" was more pronounced in younger subjects suggesting studies earlier in life reveal larger biochemical changes. CONCLUSION: Untargeted metabolomics is effective in detecting mild to intermediate cases of PBD-ZSD. Surprisingly, dramatic reductions in plasma sphingomyelin are a consistent feature of the PBD-ZSD metabolome. The use of metabolomics in PBD-ZSD can provide insight into novel biomarkers of disease.

5.
Eur J Med Genet ; 61(3): 139-144, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29183715

RESUMO

Sjögren-Larsson syndrome (SLS) is a rare autosomal recessive disorder characterized by ichthyosis, spasticity and intellectual disability. The disease is caused by mutations in the ALDH3A2 gene that encodes fatty aldehyde dehydrogenase. We describe 7 Iranian SLS patients from 5 unrelated consanguineous families. Sequencing of ALDH3A2 identified 4 novel mutations, including a 26-bp deletion (c.25_50del), small in-frame deletion (c.370_372del; p.G124del), a termination (p.Q35Ter) and a missense mutation (p.Lys211Glu). Bacterial expression of the p.Lys211Glu and p.G124del mutations showed little or no detectable enzyme activity. Three of the patients exhibited an unusual neuro-regressive clinical course associated with seizures, which may reflect the presence of unidentified genetic or environmental modifiers in this consanguineous population. This cohort represents the largest group of Iranian patients with molecularly confirmed SLS and expands the mutational and clinical spectrum of this disease.


Assuntos
Aldeído Oxirredutases/genética , Mutação , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/patologia , Índice de Gravidade de Doença , Síndrome de Sjogren-Larsson/complicações , Adulto , Sequência de Aminoácidos , Criança , Pré-Escolar , Consanguinidade , Feminino , Humanos , Lactente , Irã (Geográfico) , Masculino , Linhagem , Fenótipo , Alinhamento de Sequência , Deleção de Sequência
6.
Am J Med Genet A ; 173(9): 2428-2434, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28816422

RESUMO

Congenital disorders of glycosylation (CDGs) are a group of genetic diseases caused by mutations in genes that are necessary for the addition of oligosaccharides to acceptor proteins or lipids. An early step in this process requires dolichol kinase (DK) to catalyze the formation of dolichyl phosphate, which acts as a membrane anchor for initial attachment of sugar residues that are subsequently built up to oligosaccharides and transferred to acceptor proteins and lipids for further processing. Biallelic mutations in DOLK, the gene for DK, result in human in a CDG with variable symptoms, ranging from nonsyndromic dilated cardiomypopathy to severe multiorgan involvement. We report two female siblings with novel compound heterozygous mutations in DOLK: c.951C>A (p.Tyr317Ter) and c.1558A>G (p.Thr520Ala). Both patients presented in the neonatal period with severe ichthyosis, unusual distal digital constrictions and dilated cardiomyopathy which resulted in death. Histology of the skin showed lipid droplet accumulation in the stratum corneum and keratinocytes, which suggests defective epidermal lipid metabolism. These patients represent an earlier and more severe form of DOLK-CDG (CDG-1m) with a striking presentation at birth that expands the known phenotypic spectrum.


Assuntos
Cardiomiopatia Dilatada/genética , Defeitos Congênitos da Glicosilação/genética , Fosfotransferases (Aceptor do Grupo Álcool)/deficiência , Cardiomiopatia Dilatada/complicações , Cardiomiopatia Dilatada/fisiopatologia , Defeitos Congênitos da Glicosilação/fisiopatologia , Feminino , Humanos , Ictiose/complicações , Ictiose/genética , Ictiose/fisiopatologia , Lactente , Recém-Nascido , Metabolismo dos Lipídeos/genética , Mutação , Fenótipo , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Irmãos
7.
J Child Neurol ; 32(1): 100-103, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-28257279

RESUMO

Intrathecal baclofen therapy is widely accepted as a treatment option for patients with severe spasticity. The current treatment of spasticity in patients with Sjögren-Larsson syndrome is largely symptomatic, given that no effective causal therapy treatments are available. We report the outcome of 2 patients with Sjögren-Larsson syndrome who had pump implantation for intrathecal baclofen. We observed a positive response, with a decrease of spasticity, reflecting in the Modified Ashworth Scale, and parents and caregivers observed a functional improvement in both patients. One patient experienced skin irritation 15 months after surgery, necessitating pump repositioning. No infection occurred. Our report shows that intrathecal baclofen therapy can have a positive therapeutic effect on spasticity in patients with Sjögren-Larsson syndrome, and therefore may be a promising addition to current treatments.


Assuntos
Baclofeno/administração & dosagem , Relaxantes Musculares Centrais/administração & dosagem , Espasticidade Muscular/tratamento farmacológico , Síndrome de Sjogren-Larsson/diagnóstico por imagem , Baclofeno/efeitos adversos , Pré-Escolar , Feminino , Humanos , Bombas de Infusão Implantáveis , Injeções Espinhais , Masculino , Relaxantes Musculares Centrais/efeitos adversos , Espasticidade Muscular/etiologia , Espasticidade Muscular/fisiopatologia , Síndrome de Sjogren-Larsson/complicações , Síndrome de Sjogren-Larsson/fisiopatologia , Resultado do Tratamento , Adulto Jovem
8.
Expert Opin Orphan Drugs ; 4(4): 395-406, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27547594

RESUMO

INTRODUCTION: Sjögren-Larsson syndrome (SLS) is a rare neurocutaneous disease characterized by ichthyosis, spasticity, intellectual disability and a distinctive retinopathy. It is caused by inactivating mutations in ALDH3A2, which codes for fatty aldehyde dehydrogenase (FALDH) and results in abnormal metabolism of long-chain aliphatic aldehydes and alcohols. The potential disease mechanisms leading to symptoms include 1) accumulation of toxic fatty aldehydes that form covalent adducts with lipids and membrane proteins; 2) physical disruption of multi-lamellar membranes in skin and brain; 3) abnormal activation of the JNK cell signaling pathway; and 4) defective farnesol metabolism resulting in abnormal PPAR-α dependent gene expression. Currently, no effective pathogenesis-based therapy is available. AREAS COVERED: The clinical, pathologic and genetic features of SLS are summarized. The biochemical abnormalities caused by deficient activity of FALDH are reviewed in the context of proposed pathogenic mechanisms and potential therapeutic interventions. EXPERT OPINION: The most promising pharmacologic approach to SLS involves blocking the formation of potentially harmful fatty aldehyde adducts using aldehyde scavenging drugs, currently in phase 2 clinical trials. Other approaches needing further investigation include: 1) ALDH-specific activator drugs and PPAR-α agonists to increase mutant FALDH activity; 2) inhibitors of the JNK phosphorylation cascade; 3) antioxidants to decrease aldehyde load; 4) dietary lipid modification; and 5) gene therapy.

10.
Mol Genet Metab ; 117(3): 313-21, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26750748

RESUMO

Peroxisome biogenesis disorders in the Zellweger spectrum (PBD-ZSD) are a heterogeneous group of genetic disorders caused by mutations in PEX genes responsible for normal peroxisome assembly and functions. As a result of impaired peroxisomal activities, individuals with PBD-ZSD can manifest a complex spectrum of clinical phenotypes that typically result in shortened life spans. The extreme variability in disease manifestation ranging from onset of profound neurologic symptoms in newborns to progressive degenerative disease in adults presents practical challenges in disease diagnosis and medical management. Recent advances in biochemical methods for newborn screening and genetic testing have provided unprecedented opportunities for identifying patients at the earliest possible time and defining the molecular bases for their diseases. Here, we provide an overview of current clinical approaches for the diagnosis of PBD-ZSD and provide broad guidelines for the treatment of disease in its wide variety of forms. Although we anticipate future progress in the development of more effective targeted interventions, the current guidelines are meant to provide a starting point for the management of these complex conditions in the context of personalized health care.


Assuntos
Mutação , Transtornos Peroxissômicos/diagnóstico , Transtornos Peroxissômicos/terapia , Síndrome de Zellweger/diagnóstico , Síndrome de Zellweger/terapia , Adulto , Testes Genéticos , Perda Auditiva Neurossensorial/etiologia , Perda Auditiva Neurossensorial/fisiopatologia , Humanos , Proteínas de Membrana/genética , Endopeptidase Neutra Reguladora de Fosfato PHEX/genética , Peroxissomos/genética , Fenótipo , Guias de Prática Clínica como Assunto , Medicina de Precisão , Distrofias Retinianas/etiologia , Distrofias Retinianas/fisiopatologia
11.
Mol Genet Metab ; 117(1): 33-7, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26643206

RESUMO

Patients with Zellweger Spectrum Disorders (ZSDs) have impaired peroxisome biogenesis and severe, multisystem disease. Although the neurologic symptoms of ZSD tend to be the most prominent, patients also have hepatic, renal and adrenal impairment. Little is known about bone health in patients with ZSD, particularly those with mild or moderate presentation. We investigated 13 ZSD patients who had strikingly abnormal bone mineral density for age. DXA scans showed mean lumbar and femoral neck Z-scores of -3.2. There were no major differences between ambulatory and nonambulatory patients, and no biochemical abnormalities consistent with rickets or vitamin D deficiency were seen. Cyclic bisphosphonate therapy in one ZSD patient was successfully used to increase in bone mineral density. Although the etiology of bone disease in this condition is unknown, we speculate that altered signaling through the PPARγ pathway or deficient plasmalogens in patients with ZSD disrupts osteogenesis, resulting in poor bone formation and poor mineralization. Further investigation into the pathogenic mechanisms of bone disease in ZSD and the role of peroxisomal metabolism in osteogenesis may yield insights into the pathology of bone disease and suggest novel treatment options.


Assuntos
Densidade Óssea/fisiologia , PPAR gama/metabolismo , Síndrome de Zellweger/fisiopatologia , ATPases Associadas a Diversas Atividades Celulares , Absorciometria de Fóton , Adolescente , Densidade Óssea/efeitos dos fármacos , Densidade Óssea/genética , Conservadores da Densidade Óssea/uso terapêutico , Criança , Pré-Escolar , Feminino , Colo do Fêmur , Humanos , Lactente , Região Lombossacral , Masculino , Proteínas de Membrana/genética , Osteogênese , Peroxissomos/metabolismo , Vitamina D/sangue , Síndrome de Zellweger/genética
13.
Mol Genet Metab ; 114(4): 501-515, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25655951

RESUMO

Leukodystrophies (LD) and genetic leukoencephalopathies (gLE) are disorders that result in white matter abnormalities in the central nervous system (CNS). Magnetic resonance (MR) imaging (MRI) has dramatically improved and systematized the diagnosis of LDs and gLEs, and in combination with specific clinical features, such as Addison's disease in Adrenoleukodystrophy or hypodontia in Pol-III related or 4H leukodystrophy, can often resolve a case with a minimum of testing. The diagnostic odyssey for the majority LD and gLE patients, however, remains extensive--many patients will wait nearly a decade for a definitive diagnosis and at least half will remain unresolved. The combination of MRI, careful clinical evaluation and next generation genetic sequencing holds promise for both expediting the diagnostic process and dramatically reducing the number of unresolved cases. Here we present a workflow detailing the Global Leukodystrophy Initiative (GLIA) consensus recommendations for an approach to clinical diagnosis, including salient clinical features suggesting a specific diagnosis, neuroimaging features and molecular genetic testing. We also discuss recommendations on the use of broad-spectrum next-generation sequencing in instances of ambiguous MRI or clinical findings. We conclude with a proposal for systematic trials of genome-wide agnostic testing as a first line diagnostic in LDs and gLEs given the increasing number of genes associated with these disorders.


Assuntos
Doenças Desmielinizantes/diagnóstico , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/diagnóstico , Doenças por Armazenamento dos Lisossomos/diagnóstico , Adrenoleucodistrofia/diagnóstico , Anodontia/diagnóstico , Humanos , Imagem por Ressonância Magnética
14.
SAGE Open Med Case Rep ; 2: 2050313X14546348, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-27489649

RESUMO

INTRODUCTION: Ornithine transcarbamylase deficiency is the most common inherited disorder of the urea cycle, has a variable phenotype, and is caused by mutations in the OTC gene. We report three cases of ornithine transcarbamylase deficiency to illustrate the late-onset presentation of this disorder and provide strategies for diagnosis and treatment. The patients were maternal first cousins, presenting with hyperammonemia and obtundation. Urea cycle disorder was not initially suspected in the first patient, delaying diagnosis. RESULTS: Sequencing of the OTC gene showed a novel missense mutation, c.563G > C (p.G188A). Numerous family members were found to carry this mutation, which shows a trend toward later onset. Each urea cycle disorder has its own unique pattern of biochemical abnormalities, which differ from non-metabolic causes of critical illness. CONCLUSION: Regardless of age, clinical suspicion of a urea cycle disorder is important in encephalopathic patients to ensure quick diagnosis and definitive treatment of the underlying inborn error of metabolism.

15.
Biochim Biophys Acta ; 1841(3): 377-89, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24036493

RESUMO

Normal fatty aldehyde and alcohol metabolism is essential for epidermal differentiation and function. Long-chain aldehydes are produced by catabolism of several lipids including fatty alcohols, sphingolipids, ether glycerolipids, isoprenoid alcohols and certain aliphatic lipids that undergo α- or ω-oxidation. The fatty aldehyde generated by these pathways is chiefly metabolized to fatty acid by fatty aldehyde dehydrogenase (FALDH, alternately known as ALDH3A2), which also functions to oxidize fatty alcohols as a component of the fatty alcohol:NAD oxidoreductase (FAO) enzyme complex. Genetic deficiency of FALDH/FAO in patients with Sjögren-Larsson syndrome (SLS) results in accumulation of fatty aldehydes, fatty alcohols and related lipids (ether glycerolipids, wax esters) in cultured keratinocytes. These biochemical changes are associated with abnormalities in formation of lamellar bodies in the stratum granulosum and impaired delivery of their precursor membranes to the stratum corneum (SC). The defective extracellular SC membranes are responsible for a leaky epidermal water barrier and ichthyosis. Although lamellar bodies appear to be the pathogenic target for abnormal fatty aldehyde/alcohol metabolism in SLS, the precise biochemical mechanisms are yet to be elucidated. Nevertheless, studies in SLS highlight the critical importance of FALDH and normal fatty aldehyde/alcohol metabolism for epidermal function. This article is part of a Special Issue entitled The Important Role of Lipids in the Epidermis and their Role in the Formation and Maintenance of the Cutaneous Barrier. Guest Editors: Kenneth R. Feingold and Peter Elias.


Assuntos
Aldeído Oxirredutases/metabolismo , Aldeídos/metabolismo , Epiderme/metabolismo , Ácidos Graxos/metabolismo , Álcoois Graxos/metabolismo , Metabolismo dos Lipídeos , Síndrome de Sjogren-Larsson/metabolismo , Aldeído Oxirredutases/genética , Animais , Epiderme/patologia , Ácidos Graxos/genética , Humanos , Oxirredução , Síndrome de Sjogren-Larsson/genética , Síndrome de Sjogren-Larsson/patologia
16.
Science ; 341(6148): 1233158, 2013 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-23845948

RESUMO

Metachromatic leukodystrophy (MLD) is an inherited lysosomal storage disease caused by arylsulfatase A (ARSA) deficiency. Patients with MLD exhibit progressive motor and cognitive impairment and die within a few years of symptom onset. We used a lentiviral vector to transfer a functional ARSA gene into hematopoietic stem cells (HSCs) from three presymptomatic patients who showed genetic, biochemical, and neurophysiological evidence of late infantile MLD. After reinfusion of the gene-corrected HSCs, the patients showed extensive and stable ARSA gene replacement, which led to high enzyme expression throughout hematopoietic lineages and in cerebrospinal fluid. Analyses of vector integrations revealed no evidence of aberrant clonal behavior. The disease did not manifest or progress in the three patients 7 to 21 months beyond the predicted age of symptom onset. These findings indicate that extensive genetic engineering of human hematopoiesis can be achieved with lentiviral vectors and that this approach may offer therapeutic benefit for MLD patients.


Assuntos
Cerebrosídeo Sulfatase/genética , Terapia Genética/métodos , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/metabolismo , Leucodistrofia Metacromática/terapia , Encéfalo/patologia , Dano ao DNA , Seguimentos , Engenharia Genética , Vetores Genéticos/toxicidade , Humanos , Lentivirus , Leucodistrofia Metacromática/patologia , Imagem por Ressonância Magnética , Transdução Genética , Resultado do Tratamento , Integração Viral
17.
Dermatol Ther ; 26(1): 39-45, 2013 Jan-Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23384019

RESUMO

Although ichthyoses are noted for their skin features, like many dermatologic conditions, patients are often impacted in ways beyond the skin. Much has been described in recent years regarding quality of life and skin disorders. This is certainly the case for ichthyosis. For neonates or others with diffuse involvement of their skin, nutritional needs are often exceeding normal requirements. These can often result in growth abnormalities. Lastly, with specific subtypes of ichthyosis, compromise of tissues around the eyes and ears can be of concern to some patients. Certainly, some forms of ichthyosis are routinely complicated by such findings. It is important for practitioners caring for individuals with ichthyosis to have these issues in mind.


Assuntos
Otopatias/etiologia , Anormalidades do Olho/etiologia , Oftalmopatias/etiologia , Ictiose/complicações , Qualidade de Vida/psicologia , Raquitismo/etiologia , Otopatias/psicologia , Anormalidades do Olho/psicologia , Oftalmopatias/psicologia , Crescimento e Desenvolvimento/fisiologia , Humanos , Ictiose/psicologia , Recém-Nascido , Raquitismo/psicologia , Índice de Gravidade de Doença
18.
J Child Neurol ; 28(10): 1259-65, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23034980

RESUMO

Sjögren-Larsson syndrome is an inherited disorder of lipid metabolism caused by mutations in the ALDH3A2 gene that codes for fatty aldehyde dehydrogenase, which results in accumulation of fatty aldehydes and alcohols and is characterized by ichthyosis, intellectual disability, and spastic diplegia/quadriplegia. The authors describe 2 unrelated Honduran patients who carried the same novel homozygous nonsense mutation (c.1309A>T, p.K437X) and ALDH3A2 DNA haplotype, but widely differed in disease severity. One patient exhibited spastic quadriplegia with unusual neuroregression, whereas the other patient had the usual static form of spastic diplegia with neurodevelopmental disabilities. Biochemical analyses showed a similar profound deficiency of fatty aldehyde dehydrogenase activity and impaired fatty alcohol metabolism in both patients' cultured fibroblasts. These results indicate that variation in the neurologic phenotype of Sjögren-Larsson syndrome is not strictly determined by the ALDH3A2 mutation or the biochemical defect as expressed in cultured fibroblasts, but by unidentified epigenetic/environmental factors, gene modifiers, or other mechanisms.


Assuntos
Aldeído Oxirredutases/genética , Mutação , Fenótipo , Síndrome de Sjogren-Larsson/genética , Aldeído Oxirredutases/metabolismo , Pré-Escolar , Feminino , Fibroblastos/metabolismo , Humanos , Ictiose/genética , Ictiose/metabolismo , Metabolismo dos Lipídeos/genética , Masculino , Índice de Gravidade de Doença , Síndrome de Sjogren-Larsson/metabolismo
19.
Semin Neurol ; 32(1): 75-84, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22422210

RESUMO

The combination of neurologic disease and ichthyosis defines a heterogeneous group of rare inherited disorders that present in infancy through early adulthood. Although affected patients share the cutaneous feature of ichthyosis, there is variability in the nature and severity of neurologic disease. Impaired cognition, spasticity, sensorineural deafness, visual impairment, and/or seizures are the primary neurologic findings. Most of these disorders are caused by genetic defects in lipid metabolism, glycoprotein synthesis, or intracellular vesicle trafficking. The clinical features of some of the neuro-ichthyoses are distinct enough to allow their clinical recognition, but confirmatory biochemical or genetic tests are necessary for accurate diagnosis. Treatment of the ichthyosis is largely symptomatic, and except for Refsum's disease, there are no effective pathogenesis-based therapies for the neurologic disease.


Assuntos
Ictiose/diagnóstico , Ictiose/genética , Mutação/genética , Pele/fisiopatologia , Humanos , Lactente , Recém-Nascido , Metabolismo dos Lipídeos , Pele/metabolismo , Síndrome
20.
J Child Neurol ; 27(12): 1589-92, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22378672

RESUMO

Zellweger syndrome (cerebrohepatorenal syndrome) is very rare and is the most severe form of peroxisomal biogenesis disorders. These can be caused by mutations in any of the currently known Peroxin genes and typically present in the neonatal period with multiorgan involvement. Patients usually do not survive beyond 1 year of age. This article reports a case of Zellweger syndrome in a male Native American infant confirmed by clinical findings, imaging studies, and biochemical analysis. Genetic studies show a novel mutation (c.3030G>T, p. Glutamine1010Histidine) altering the last nucleotide of exon 19 in the Peroxin1 (PEX1) gene.


Assuntos
Encéfalo/anormalidades , Proteínas de Membrana/genética , Mutação/genética , Síndrome de Zellweger/genética , Síndrome de Zellweger/patologia , ATPases Associadas a Diversas Atividades Celulares , Éxons/genética , Humanos , Índios Norte-Americanos/genética , Lactente , Imagem por Ressonância Magnética , Masculino
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