RESUMO
Objective: To investigate the clinical pathology and gene mutation characteristics of patients with glycogen storage disease type â £ (GSD â £). Methods: The clinical data, liver histopathology and ultrastructural morphology, and gene sequencing results of 5 GSD â £ cases diagnosed in the Children's Hospital Affiliated to Shanghai Jiaotong University School of Medicine and the Children's Hospital of Fudan University from January 2015 to February 2022 were collected and analyzed retrospectively. Results: Among the 5 cases, 3 were male and 2 were female, ranging in age from 4 months to 1 year and 9 months. The clinical manifestations included fever, hepatosplenomegaly, liver insufficiency, growth retardation and hypotonia. Four cases had liver biopsy showing ground-glass-like changes in hepatocytes with intracytoplasmic inclusion bodies and varying degrees of fibrosis. Liver electron microscopy in 2 cases showed that the level of glycogen increased to varying degrees, and the cytoplasm was filled with low electron density substances. Genetic testing revealed that 3 cases had compound heterozygous variants in GBE1 gene; 1 case had a single pathogenic variant in GBE1 gene; and 1 case was deceased with no genetic testing, but each parent was tested for a heterozygous variant in the GBE1 gene. A total of 9 GBE1 gene mutations were detected, 3 of which were reported mutations and 6 novel mutations. One case died of liver cirrhosis, and 1 case underwent autologous liver transplantation. After transplantation, the liver function basically returned to normal, and the growth and development improved; the other 3 cases were managed through diet control and symptomatic treatment. Conclusions: CSD â £ is an extremely rare inherited metabolic disease caused by GBE1 gene mutation, often presenting with hepatic and neuromuscular disorders, with heterogeneous clinical manifestations. The diagnosis mainly depends on histopathology and a pedigree gene analysis.
Assuntos
Doença de Depósito de Glicogênio Tipo IV , Lactente , Criança , Humanos , Masculino , Feminino , Doença de Depósito de Glicogênio Tipo IV/genética , Doença de Depósito de Glicogênio Tipo IV/diagnóstico , Doença de Depósito de Glicogênio Tipo IV/patologia , Estudos Retrospectivos , China , Mutação , Testes Genéticos/métodosRESUMO
Glycogen storage disease type IV (GSD IV) is caused by mutations in the glycogen branching enzyme 1 (GBE1) gene and is characterized by accumulation of polyglucosan bodies in liver, muscle and other tissues. We report three cases with neuromuscular forms of GSD IV, none of whom had polyglucosan bodies on muscle biopsy. The first case had no neonatal problems and presented with delayed walking. The other cases presented at birth: one with arthrogryposis, hypotonia, and respiratory distress, the other with talipes and feeding problems. All developed a similar pattern of axial weakness, proximal upper limb weakness and scapular winging, and much milder proximal lower limb weakness. Our cases expand the phenotypic spectrum of neuromuscular GSD IV, highlight that congenital myopathy and limb girdle weakness can be caused by mutations in GBE1, and emphasize that GSD IV should be considered even in the absence of characteristic polyglucosan bodies on muscle biopsy.
Assuntos
Artrogripose , Doença de Depósito de Glicogênio Tipo IV , Recém-Nascido , Humanos , Doença de Depósito de Glicogênio Tipo IV/diagnóstico , Doença de Depósito de Glicogênio Tipo IV/genética , Hipotonia Muscular , GlucanosRESUMO
Glycogen storage disease type IV (GSD IV, Andersen disease) is a rare autosomal recessive condition. The childhood neuromuscular subtype of GSD IV is characterised by a progressive skeletal myopathy with cardiomyopathy also reported in some individuals. We report a case of a 19-year-old man who presented with severe non-ischaemic dilated cardiomyopathy (NIDCM) necessitating heart transplantation, with biopsy showing aggregations of polyglucosan bodies in cardiac myocytes. He had no signs or symptoms of muscle weakness, liver dysfunction or neurologic involvement. A homozygous GBE1 c.607C>A (p.His203Asn) variant was identified. Our case is unusual in that our patient presented with an isolated NIDCM in the absence of other clinical manifestations of GSD IV. This case highlights the importance of considering storage disorders in young adults presenting with isolated NIDCM of unknown aetiology. It also emphasises the potential synergy between histopathological evaluation and genomic testing in enhancing diagnostic certainty.
Assuntos
Cardiomiopatia Dilatada/cirurgia , Doença de Depósito de Glicogênio Tipo IV/diagnóstico , Transplante de Coração , Adulto , Cardiomiopatia Dilatada/etiologia , Dispneia , Doença de Depósito de Glicogênio Tipo IV/complicações , Humanos , Masculino , Adulto JovemRESUMO
The fatal infantile neuromuscular type is the most severe form of glycogen storage disease type IV (GSD IV). We report a case of a 22-day-old female neonate born at 34 weeks gestation with polyhyramnios, fetal hydrops, and severe hypotonia. Placental examination revealed numerous periodic acid schiff-positive diastase-resistant polyglucosan bodies in the cytoplasm of extravillous trophoblast predominantly in the placental basal plate. Muscle biopsy and autopsy findings supported a diagnosis of neuromuscular-type glycogen storage disease type IV with extensive involvement of skeletal muscle, heart, and liver. The diagnosis was confirmed by molecular genetic testing. We could only find 1 prior report in the English literature that describes placental pathological changes. Our findings suggest that placental examination can be a useful adjunct for early diagnosis, as placentas are often received for pathological examination shortly after birth and usually before a diagnostic muscle biopsy can be performed. Pathologists need to be aware of characteristic placental features.
Assuntos
Glucanos/metabolismo , Doença de Depósito de Glicogênio Tipo IV/diagnóstico , Placenta/patologia , Trofoblastos/patologia , Biomarcadores/metabolismo , Evolução Fatal , Feminino , Doença de Depósito de Glicogênio Tipo IV/metabolismo , Doença de Depósito de Glicogênio Tipo IV/patologia , Humanos , Recém-Nascido , Placenta/metabolismo , Gravidez , Trofoblastos/metabolismoAssuntos
Doença de Depósito de Glicogênio Tipo IV/diagnóstico , Doença de Depósito de Glicogênio Tipo IV/enzimologia , Hexosaminidases/sangue , Biópsia , Carbono-Carbono Ligases/deficiência , Carbono-Carbono Ligases/genética , Consanguinidade , Análise Mutacional de DNA , Feminino , Genes Recessivos/genética , Alemanha , Doença de Depósito de Glicogênio Tipo IV/genética , Doença de Depósito de Glicogênio Tipo IV/patologia , Humanos , Recém-Nascido , Macrófagos/patologia , Músculo Esquelético/patologia , Miofibrilas/patologia , Turquia/etnologia , Distúrbios Congênitos do Ciclo da Ureia/diagnóstico , Distúrbios Congênitos do Ciclo da Ureia/enzimologia , Distúrbios Congênitos do Ciclo da Ureia/genéticaRESUMO
Glycogen storage disease type IV is an autosomal recessive disorder of carbohydrates caused by deficiency of amylo-1-4-glycanoglycosyltransferase, which leads to accumulation of amylopectin-like polysaccharides in tissues including liver, heart and neuromuscular system. More than 40 different mutations in the glycogen branching enzyme gene (GBE1) have been described. In this study, we report a 2-year-old boy who presented with developmental delay and muscle weakness. He subsequently was diagnosed with glycogen storage disease type IV based on a liver biopsy histology and electron microscopy. Glycogen branching enzyme activity was in the low range. Genetic analysis demonstrated a novel heterozygous variant (c.760A>G; p.Thr254Ala) in exon 6 of the GBE1 gene, which is believed to be pathogenic. This variant was inherited from the patient's mother who was asymptomatic with normal glycogen branching enzyme activity. Whole-exome sequencing failed to reveal additional variations in the GBE1 gene.
Assuntos
Variação Genética , Sistema da Enzima Desramificadora do Glicogênio/genética , Doença de Depósito de Glicogênio Tipo IV/genética , Biópsia , Pré-Escolar , Éxons , Predisposição Genética para Doença , Sistema da Enzima Desramificadora do Glicogênio/deficiência , Doença de Depósito de Glicogênio Tipo IV/diagnóstico , Doença de Depósito de Glicogênio Tipo IV/enzimologia , Hereditariedade , Heterozigoto , Humanos , Fígado/enzimologia , Fígado/ultraestrutura , Masculino , Microscopia Eletrônica , Técnicas de Diagnóstico Molecular , Linhagem , FenótipoRESUMO
Glycogen branching enzyme deficiency/Andersen disease can manifest with a spectrum of clinical phenotypes, making the diagnosis difficult. An 11-year-old Pakistani boy presented with a history of progressive weakness and delayed milestones. Echocardiography showed features of dilated cardiomyopathy. He was suspected to have congenital myopathy and was evaluated further. Muscle biopsy showed subsarcolemmal accumulation of basophilic material, which stained positively with Periodic acid-Schiff reagent (diastase-resistant). Ultrastructural examination revealed accumulation of structurally abnormal forms of filamentous glycogen, confirming the diagnosis as Andersen disease. As histopathological and immunohistochemical evaluation of muscle biopsies is not always diagnostic, ultrastructural examination may serve as a valuable adjunct in difficult cases.
Assuntos
Doença de Depósito de Glicogênio Tipo IV/diagnóstico , Músculo Esquelético/ultraestrutura , Biópsia , Cardiomiopatia Dilatada/etiologia , Criança , Doença de Depósito de Glicogênio Tipo IV/complicações , Humanos , Imuno-Histoquímica , Masculino , Microscopia Eletrônica de TransmissãoRESUMO
A total of 11 types of glycogen storage disorders have been recognized with variable clinical presentations. Type IV, also known as Andersen disease, represents a rare subtype that can induce severe clinical findings early in life. We report on a patient with early fetal onset of symptoms with severe neuromuscular findings at birth. The pregnancy was further complicated by polyhydramnios and depressed fetal movement. At birth severe hypotonia was noticed requiring active resuscitation and then mechanical ventilation. His lack of expected course for hypoxic ischemic encephalopathy prompted genetic testing, including a muscle biopsy, which confirmed the diagnosis of glycogen storage disease IV (GSD IV). Mutation analysis of the glycogen branching enzyme 1 gene demonstrated a previously unrecognized mutation. We review recent information on early presentation of GSD IV with particular interest in the presentation of the neonatal lethal neuromuscular form of this rare disorder.
Assuntos
Enzima Ramificadora de 1,4-alfa-Glucana/genética , Doença de Depósito de Glicogênio Tipo IV/diagnóstico , Doenças Neuromusculares/diagnóstico , Complicações na Gravidez/diagnóstico , Análise Mutacional de DNA , Feminino , Testes Genéticos , Doença de Depósito de Glicogênio Tipo IV/genética , Humanos , Recém-Nascido , Mutação , Doenças Neuromusculares/genética , Gravidez , Complicações na Gravidez/genéticaRESUMO
Liver involvement in genetic and metabolic disorders may result in intrahepatic accumulation of specific precursors or byproducts, which have distinctive features on light microscopy. The "polyglucosan disorders" are diseases in which polyglucosan (abnormal glycogen with decreased branching) is formed and deposited in various tissues because of decreased or absent glycogen branching enzyme activity. These disorders include Lafora disease (myoclonus epilepsy) and type IV glycogen storage disease. Polyglucosan deposits in both conditions result in ground-glass hepatocellular inclusions resembling those seen in chronic hepatitis B virus infection. In the present report, we describe a case of the rare, adulthood form of glycogen branching enzyme deficiency, adult polyglucosan body disease (APBD), in which abnormal serum liver tests prompted a liver biopsy. The pathologic findings of periportal ground-glass hepatocellular inclusions, mild chronic portal inflammation, and periportal fibrosis are not well described in APBD, but resemble the chronic changes that have been reported in Lafora disease. The differential diagnosis of ground-glass hepatocytes and the genetic basis of APBD are discussed.
Assuntos
Enzima Ramificadora de 1,4-alfa-Glucana/genética , Glucanos/metabolismo , Doença de Depósito de Glicogênio Tipo IV/diagnóstico , Hepatite/genética , Hepatócitos/patologia , Corpos de Inclusão/patologia , Cirrose Hepática/genética , Enzima Ramificadora de 1,4-alfa-Glucana/deficiência , Biópsia , Doença Crônica , Diagnóstico Diferencial , Doença de Depósito de Glicogênio Tipo IV/complicações , Doença de Depósito de Glicogênio Tipo IV/enzimologia , Doença de Depósito de Glicogênio Tipo IV/genética , Doença de Depósito de Glicogênio Tipo IV/patologia , Hepatite/enzimologia , Hepatite/patologia , Hepatócitos/metabolismo , Humanos , Corpos de Inclusão/metabolismo , Cirrose Hepática/enzimologia , Cirrose Hepática/patologia , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos TestesRESUMO
We report a recent case of the severe congenital variant of glycogen storage disease type IV with prolonged survival. The patient was found to be a compound heterozygote for two novel mutations, a missense mutation in exon 5 (p.H188P, c.563A>C) and a severe mutation in intron 5 (c.691+2T>C). We propose that the genotype and the quality of medical care may account for the severe but non-lethal phenotype.
Assuntos
Enzima Ramificadora de 1,4-alfa-Glucana/genética , Doença de Depósito de Glicogênio Tipo IV/genética , Mutação de Sentido Incorreto/genética , Doenças Neuromusculares/genética , Biópsia , Feminino , Genótipo , Doença de Depósito de Glicogênio Tipo IV/diagnóstico , Humanos , Lactente , Músculo Esquelético/patologia , Doenças Neuromusculares/diagnósticoRESUMO
Glycogen storage disease type IV (GSD IV, or Andersen disease) is an autosomal recessive disorder due to the deficiency of 1,4-alpha-glucan branching enzyme (or glycogen branching enzyme, GBE1), resulting in an accumulation of amylopectin-like polysaccharide in muscle, liver, heart and central and peripheral nervous system. Typically, the presentation is in childhood with liver involvement up to cirrhosis. The neuromuscular form varies in onset (congenital, perinatal, juvenile and adult) and in severity. Congenital cases are rare, and fewer than 20 cases have been described and genetically determined so far. This form is characterized by polyhydramnios, neonatal hypotonia, and neuronal involvement; hepatopathy is uncommon, and the babies usually die between 4 weeks and 4 months of age. We report the case of an infant who presented severe hypotonia, dilatative cardiomyopathy, mild hepatopathy, and brain lateral ventricle haemorrhage, features consistent with the congenital form of GSD IV. He died at one month of life of cardiorespiratory failure. Muscle biopsy and heart and liver autoptic specimens showed many vacuoles filled with PAS-positive diastase-resistant materials. Electron-microscopic analysis showed mainly polyglucosan accumulations in all the tissues examined. Postmortem examination showed the presence of vacuolated neurons containing this abnormal polysaccharide. GBE1 biochemical activity was virtually absent in muscle and fibroblasts, and totally lacking in liver and heart as well as glycogen synthase activity. GBE1 gene sequence analysis revealed a novel homozygous nonsense mutation, p.E152X, in exon 4, correlating with the lack of enzyme activity and with the severe neonatal involvement. Our findings contribute to increasing the spectrum of mutation associated with congenital GSD IV.
Assuntos
Códon sem Sentido , Sistema da Enzima Desramificadora do Glicogênio/deficiência , Sistema da Enzima Desramificadora do Glicogênio/genética , Doença de Depósito de Glicogênio Tipo IV/diagnóstico , Doença de Depósito de Glicogênio Tipo IV/genética , Sequência de Bases , Encéfalo/enzimologia , Encéfalo/patologia , Análise Mutacional de DNA , Evolução Fatal , Doença de Depósito de Glicogênio Tipo IV/enzimologia , Homozigoto , Humanos , Recém-Nascido , Fígado/enzimologia , Fígado/patologia , Masculino , Microscopia Eletrônica de Transmissão , Músculo Esquelético/patologia , Miocárdio/enzimologia , Miocárdio/patologiaRESUMO
We report a 13-year-old boy with multisystem involvement secondary to accumulation of amylopectin-like material. He was born to consanguineous parents at full term without any complications and his maternal perinatal history was uneventful. His parents were cousins. He had normal growth and development except for his weight. His sister died from an unexplained cardiomyopathy at the age of 8 years. Our patient's initial symptom was severe heart failure. Since he also had a complaint of muscle weakness, electromyography was performed which showed muscle involvement. The diagnosis was suggested by tissue biopsy of skeletal muscle showing intracellular, basophilic, diastase-resistant, periodic acid-Schiff-positive inclusion bodies and was confirmed by the presence of a completed branching enzyme deficiency. Similar intracytoplasmic inclusion-like bodies were also found in liver biopsy, but very few in number compared with the skeletal muscle. The patient died from an intercurrent infection. Postmortem endomyocardial biopsy revealed the same intracytoplasmic inclusions as described above affecting almost all myocardial cells. Ultrastructural examination of liver biopsy was nondiagnostic; however, myocardium showed prominent, large, intracytoplasmic deposits. Glycogen branching enzyme gene sequence was normal, and thus classical branching enzyme deficiency was excluded. Our patient represents the first molecular study performed on a patient in whom there was multiple system involvement secondary to accumulation of amylopectin-like material. We suggest that this is an as yet undefined and different phenotype of glycogen storage disease associated with multisystemic involvement.
Assuntos
Enzima Ramificadora de 1,4-alfa-Glucana/deficiência , Amilopectina/biossíntese , Doença de Depósito de Glicogênio Tipo IV/complicações , Corpos de Inclusão/enzimologia , Fígado/enzimologia , Músculo Esquelético/enzimologia , Miocárdio/enzimologia , Enzima Ramificadora de 1,4-alfa-Glucana/genética , Adolescente , Autopsia , Biópsia , Eletromiografia , Evolução Fatal , Genótipo , Doença de Depósito de Glicogênio Tipo IV/diagnóstico , Doença de Depósito de Glicogênio Tipo IV/enzimologia , Doença de Depósito de Glicogênio Tipo IV/genética , Doença de Depósito de Glicogênio Tipo IV/patologia , Insuficiência Cardíaca/enzimologia , Insuficiência Cardíaca/etiologia , Humanos , Corpos de Inclusão/patologia , Fígado/patologia , Masculino , Debilidade Muscular/enzimologia , Debilidade Muscular/etiologia , Músculo Esquelético/patologia , Miocárdio/patologia , Fenótipo , Regulação para CimaRESUMO
BACKGROUND: Lafora disease (LD; progressive myoclonus epilepsy type 2; EPM2) is an autosomal recessive disorder caused by mutations in the EPM2A and EPM2B genes. LD is characterized by the presence of strongly PAS-positive intracellular inclusions (Lafora bodies) in several tissues. Glycogen storage disease type IV (GSD-IV; Andersen disease) is an autosomal recessive disorder characterized by cirrhosis leading to severe liver failure. GSD-IV has been associated with mutations in the glycogen branching enzyme gene (GBE). Histopathologic changes of the liver in both diseases show an identical appearance, although cirrhosis has never been described in patients with LD. We report a LD family in which the proband presented severe liver failure at onset of the disease. METHODS: Clinical histories, physical and neurologic examination, laboratory tests, EEGs, MRI of the brain, and liver or axillary skin biopsies were performed in the two affected siblings. The diagnosis was confirmed by molecular genetic analysis of the EPM2A, EPM2B, and GBE genes and loci. RESULTS: During the first decade of life, abnormalities in liver function tests were detected in the two affected siblings. The proband's liver dysfunction was severe enough to require liver transplantation. Subsequently, both sibs developed LD. Mutation analysis of EPM2A revealed a homozygous Arg241stop mutation in both patients. CONCLUSIONS: This is the first description of severe hepatic dysfunction as the initial clinical manifestation of LD. The phenotypic differences between the two affected siblings suggest that modifier genes must condition clinical expression of the disease outside the CNS.
Assuntos
Doença de Lafora/diagnóstico , Falência Hepática/etiologia , Proteínas Tirosina Fosfatases/genética , Enzima Ramificadora de 1,4-alfa-Glucana/genética , Biópsia , Encéfalo/patologia , Proteínas de Transporte/genética , Criança , Códon sem Sentido , Diagnóstico Diferencial , Progressão da Doença , Nanismo/etiologia , Eletroencefalografia , Éxons/genética , Doença de Depósito de Glicogênio Tipo IV/diagnóstico , Humanos , Lactente , Doença de Lafora/complicações , Doença de Lafora/genética , Fígado/patologia , Cirrose Hepática/etiologia , Falência Hepática/cirurgia , Transplante de Fígado , Imageamento por Ressonância Magnética , Masculino , Repetições de Microssatélites , Mutação de Sentido Incorreto , Linhagem , Reação do Ácido Periódico de Schiff , Fenótipo , Mutação Puntual , Polimorfismo Conformacional de Fita Simples , Proteínas Tirosina Fosfatases não Receptoras , Pele/patologia , Espanha , Ubiquitina-Proteína LigasesRESUMO
We report two patients with polyglycosan body disease manifesting in adulthood. Clinical, electrophysiological, and histopathological characteristics of their disorders are summarized, and diagnostic classification is discussed.
Assuntos
Enzima Ramificadora de 1,4-alfa-Glucana/deficiência , Sistema da Enzima Desramificadora do Glicogênio/deficiência , Doença de Depósito de Glicogênio Tipo III/genética , Doença de Depósito de Glicogênio Tipo IV/genética , Miosite de Corpos de Inclusão/genética , Enzima Ramificadora de 1,4-alfa-Glucana/genética , Idoso , Biópsia , Diagnóstico Diferencial , Feminino , Sistema da Enzima Desramificadora do Glicogênio/genética , Doença de Depósito de Glicogênio Tipo III/diagnóstico , Doença de Depósito de Glicogênio Tipo III/patologia , Doença de Depósito de Glicogênio Tipo IV/diagnóstico , Doença de Depósito de Glicogênio Tipo IV/patologia , Humanos , Masculino , Músculo Esquelético/patologia , Miosite de Corpos de Inclusão/diagnóstico , Miosite de Corpos de Inclusão/patologia , Vacúolos/patologiaRESUMO
A 62-year-old man developed progressive gait instability, bladder dysfunction, proximal weakness, distal sensory loss, and mild cognitive impairment over 6 years. Neurologic examination revealed upper and lower motor neuron dysfunction in the lower extremities, with distal sensory loss. Electrodiagnostic studies, magnetic resonance imaging of the brain, and sural nerve biopsy were consistent with adult polyglucosan body disease. Biochemical and genetic analyses demonstrated reduced glycogen brancher enzyme levels associated with a heterozygous point mutation (Tyr329Ser or Y329S) in the glycogen brancher enzyme gene on chromosome 3. Mutational heterozygosity in the glycogen brancher enzyme gene has not been previously reported as a cause for this rare disease. A review of the clinical presentation, pathogenesis, etiology, and diagnosis of this disease is presented.
Assuntos
Enzima Ramificadora de 1,4-alfa-Glucana/deficiência , Encéfalo/patologia , Glucanos/metabolismo , Doença de Depósito de Glicogênio Tipo IV/diagnóstico , Doença de Depósito de Glicogênio Tipo IV/enzimologia , Corpos de Inclusão , Enzima Ramificadora de 1,4-alfa-Glucana/genética , Idoso , Sequência de Bases , Cromossomos Humanos Par 3 , Diagnóstico Diferencial , Doença de Depósito de Glicogênio Tipo IV/complicações , Doença de Depósito de Glicogênio Tipo IV/patologia , Heterozigoto , Humanos , Judeus , Imageamento por Ressonância Magnética , Masculino , Dados de Sequência Molecular , Mutação PuntualRESUMO
Andersen syndrome includes a clinical triad with periodic paralysis, cardiac arrhythmia and dysmorphic features most often mild but relevant. It is a potassium channelopathy due to mutation of KCJN2 gene coding for Kir 2.1 protein. We report a familial case with mutation R218W of Kir 2.1 and discuss the main phenotypic and genetic aspects of Andersen syndrome. Muscle manifestations are essentially a periodic paralysis most often of hypokaliemic type. Muscle biopsy reveals tubular aggregates but can be normal as it is shown in the same patient in our kindred. Our proband complained of paralytic attacks since childhood and at adult age she demonstrated a mild permanent deficit of pelvic girdle muscles as it has been described in other types of periodic paralysis after a long duration course. Cardiac manifestations may include in a variable manner a long QT syndrome, premature ventricular contractions, complex ventricular ectopy, polymorphic or bidirectional ventricular tachycardia. Imipramine had a positive effect on arrhythmia in our case. Dysmorphic features are often mild and have to be cautiously looked for as a clue to the diagnosis of Andersen syndrome. They can be easily overlooked if not systematically looked for. Clinical expressivity is variable including in the same family. In our observation, the daughter showed a complete triad, early expressed, which allowed the diagnosis. Her father was late diagnosed on ventricular dysrhytmia but without muscle manifestations and dysmorphic features. Since KCJN2 gene mutation identification, locus heterogeneity of Andersen syndrome was shown. Andersen syndrome kindreds without mutations in KCNJ2 were clinically indistinguishable from KCNJ2-associated subjects. KCNJ2 gene encodes the inward rectifier K+ channel Kir2.1 which plays an important role in maintaining membrane potential and during the terminal phase of cardiac action potential repolarization. Several studies showed a dominant negative effect of the mutation on Kir 2.1 channel function.
Assuntos
Arritmias Cardíacas/fisiopatologia , Doença de Depósito de Glicogênio Tipo IV/fisiopatologia , Paralisia/fisiopatologia , Adolescente , Eletrocardiografia , Ossos Faciais/anormalidades , Feminino , Doença de Depósito de Glicogênio Tipo IV/diagnóstico , Doença de Depósito de Glicogênio Tipo IV/genética , Humanos , Masculino , Potenciais da Membrana/fisiologia , Pessoa de Meia-Idade , Canais de Potássio/genéticaRESUMO
Glycogenosis type IV is an autosomal recessive disease, exceptionally diagnosed at birth: only very few reports of the fatal perinatal neuromuscular form have been described. We report on two sibling male newborns who died at 10 and 4 weeks of age with clinical signs of a systemic storage disease. Prenatal history included polyhydramnios, reduced fetal movements and fetal hydrops, and Caesarean section was performed at 36 weeks of gestational age because of fetal distress. At birth, both babies showed severe hypotonia, hyporeflexia and no spontaneous breathing activity. They never showed active movements, sucking and swallowing and were respirator-dependent until death. A muscle biopsy revealed, in both patients, the presence of PAS-positive and partially diastase-resistant cytoplasmic inclusions containing granular and filamentous amylopectin-like material. This suggested that the stored material consisted of abnormal glycogen. At autopsy, ultrastructural examination of cardiac and skeletal muscle, liver, kidney and brain showed PAS-positive diastase-resistant eosinophilic cytoplasmic inclusions. Determination of branching enzyme activity, in cultured fibroblasts from the second patient, showed markedly reduced enzyme activity, confirming diagnosis of glycogenosis type IV. Our patients showed the full spectrum of both prenatal signs (hydrops, polyhydramnios) and postnatal signs (hypotonia, hyporeflexia, absence of active movements, cardiomegaly), which have been reported previously. They suffered from a very severe form of glycogenosis type IV with clinical and histological involvement of many tissues and organs. Diagnosis was accomplished on the second baby and required several biochemical and histological studies, in order to rule out both neuromuscular disorders and the most common storage diseases with neonatal onset. In our experience, the correct interpretation of the histological findings was essential in the search for the diagnosis.
Assuntos
Doença de Depósito de Glicogênio Tipo IV/diagnóstico , Doença de Depósito de Glicogênio Tipo IV/genética , Idade de Início , Autopsia , Sistema Nervoso Central/metabolismo , Citoplasma/metabolismo , Saúde da Família , Evolução Fatal , Genes Recessivos , Glicogênio/sangue , Doença de Depósito de Glicogênio Tipo IV/metabolismo , Humanos , Lactente , Recém-Nascido , Masculino , Músculo Esquelético/patologia , Distribuição TecidualRESUMO
We report of an infant with neonatal glycogen storage disease type IV (GSD IV) who was examined for severe hypotonia and cardiomyopathy. On the muscle biopsy there were many fibers with diastase-resistant polyglucosan bodies. Glycogen branching enzyme (GBE1) activity in the muscle was markedly reduced. The infant had a homozygous single nucleotide deletion in the open reading frame of GBE1 gene.
Assuntos
Doença de Depósito de Glicogênio Tipo IV/diagnóstico , Enzima Ramificadora de 1,4-alfa-Glucana/análise , Enzima Ramificadora de 1,4-alfa-Glucana/deficiência , Enzima Ramificadora de 1,4-alfa-Glucana/genética , Cardiomiopatias/complicações , Cardiomiopatias/diagnóstico , Creatina Quinase/sangue , Análise Mutacional de DNA , Progressão da Doença , Evolução Fatal , Feminino , Glucanos/análise , Doença de Depósito de Glicogênio Tipo IV/complicações , Doença de Depósito de Glicogênio Tipo IV/genética , Humanos , Corpos de Inclusão/ultraestrutura , Recém-Nascido , Músculo Esquelético/química , Músculo Esquelético/enzimologia , Músculo Esquelético/patologia , Mutação , Poli-Hidrâmnios/complicações , Poli-Hidrâmnios/diagnóstico por imagem , Gravidez , Deleção de Sequência , UltrassonografiaRESUMO
McArdle disease, one of the most common metabolic causes of exercise intolerance and recurrent myoglobinuria, is due to biochemical defects of the muscle isoform of glycogen phosphorylase. The gene for myophosphorylase (PGYM) is on chromosome 11, and 33 distinct mutations have been identified in patients from all over the world. In Caucasians, a nonsense mutation in exon 1 (R49X) is common enough to warrant screening of genomic DNA from blood before considering muscle biopsy. Other mutations are prevalent in different ethnic groups or are "private". Mutations are spread throughout the gene and there is no clear genotype:phenotype correlation. High-protein diet and aerobic exercise are beneficial, and gene therapy appears promising.
Assuntos
Doença de Depósito de Glicogênio Tipo IV/diagnóstico , Doença de Depósito de Glicogênio Tipo IV/genética , Adolescente , Animais , Códon sem Sentido , Modelos Animais de Doenças , Éxons , Feminino , Terapia Genética , Genótipo , Glicogênio Fosforilase Muscular/química , Glicogênio Fosforilase Muscular/genética , Humanos , Lactente , Recém-Nascido , Masculino , Modelos Genéticos , Mutação , Fenótipo , Isoformas de ProteínasRESUMO
We describe a 46 year old patient with adult polyglucosan body disease (APBD). She presented clinically with late onset pyramidal tetraparesis, sensory motor polyneuropathy and micturition difficulties. Magnetic resonance imaging of the brain revealed extensive leucencephalopathy and diffuse atrophy. The diagnosis based on the demonstration of polyglucosan bodies in the sural nerve biopsy. In search of a possible metabolic defect, we evaluated glycogen metabolism in this patient and her clinically unaffected daughters. Branching enzyme activity in the patients leukocytes was between 20-30% of the lower limit of normal range, whereas their children displayed values of 80%, suggesting a possible autosomal recessive mode of transmission. Branching enzyme deficiency in APBD with predominantly attack of the central and peripheral nervous system was so far described in 3 Jewish patients.