Research advances in the pathogenesis and treatment of neurodegeneration with brain iron accumulation / 中国当代儿科杂志

Neurodegeneration with brain iron accumulation (NBIA) is a group of rare neurogenetic degenerative diseases caused by genetic mutations and characterized by iron deposition in the central nervous system, especially in the basal ganglia, with an overall incidence rate of 2/1 000 000-3/1 000 000. Major clinical manifestations are extrapyramidal symptoms. This disease is presently classified into 14 different subtypes based on different pathogenic genes, and its pathogenesis and treatment remain unclear. This article summarizes the research advances in the pathogenesis and treatment of NBIA, so as to help pediatricians understand this disease and provide a reference for subsequent research on treatment.

Hemichorea-Hemiballism Syndrome Caused by Nonketotic Hyperglycemia in a Newly Diagnosed Diabetes Mellitus Type 2 Patient with Euglycemia at Presentation

@#INTRODUCTION: Nonketotic hyperglycemia among type 2 diabetic patients have recently been documented to cause the rare movement disorder called Hemichorea-hemiballism syndrome which is a hyperkinetic movement disorder presenting as a continuous, non-patterned, involuntary movements caused by a basal ganglia dysfunction. METHODS: A 76-year-old male with a known history of hypertension and no history of stroke and diabetes presented with a 10-day history of increasingly persistent involuntary movements of the right extremities. On admission, the patient was conscious with stable vital signs and unremarkable neurologic findings except for the involuntary flailing movements of the right extremities. Diagnostic testing revealed first documentation of hyperglycemia with brain MRI changes on T1 hyperintensity signals on the basal ganglia and T2/FLAIR weighted imaging showing mixed hypointense and hyperintense signals which is a classical MRI finding in patients with HC-HB syndrome caused by nonketotic hyperglycemia. The patient was treated for diabetes and was maintained on anti-dopaminergic medications for the uncontrollable involuntary movements. After five months, resolution of the hemiballism-hemichorea syndrome was noted after appropriate treatment. CONCLUSION: This case report highlights hemichoreahemiballism syndrome in a newly diagnosed type 2 diabetic patient who had normal glucose levels at presentation. The prompt recognition and correction of uncontrolled newly diagnosed diabetes and administration of anti-dopamine agents lead to a rapid improvement of symptoms, less neurologic sequelae and an overall favorable prognosis.

Extrapiramidalismo por antieméticos / Extrapyramidal Side Effects of Antiemetics / Reações extrapiramidais causadas por antieméticos

Resumen: Los antieméticos son usados frecuentemente por diversas áreas de la medicina, aunque existe una tendencia a subestimar sus efectos adversos neurológicos. El objetivo del presente estudio de revisión fue revisar la literatura sobre la fisiología, farmacología, factores predisponentes, clínica y manejo del extrapiramidalismo por antieméticos. Se realizó una búsqueda en la literatura de artículos de revistas científicas, libros y trabajos de grado. Se utilizaron los buscadores Medline, LILACS, PubMed, EMBASE, Current contents y Google Scholar con las siguientes palabras claves: deshidratación, gastroenteritis, vómitos, antieméticos, distonía, dopamina, hipertermia, citocromo, meto-clopramida y domperidona. Se obtuvieron 252 artículos, de los cuales 50 fueron considerados aptos para la revisión. A partir del análisis, se concluyó que el uso de antieméticos es de uso frecuente por medicina general y especialidades como anestesiología y pediatría, por lo cual un conocimiento sobre los efectos extrapiramidales permitirá un diagnóstico y manejo temprano.

Abstract: Antiemetics are frequently used by various areas of medicine, although there is a tendency to underestimate their neurological adverse effects. This paper aims to review the literature on the physiology, pharmacology, predisposing factors, clinical picture, and management of the extrapyramidal side effects of antiemetics. Scientific journal articles, books, and dissertations were searched. The search engines Medline, LILACS, PubMed, EMBASE, Current Contents, and Google Scholar were used with the following keywords: dehydration, gastroenteritis, vomit, antiemetics, dystonia, dopamine, hyperthermia, cytochrome, metoclopramide, and domperidone. Two hundred and fifty-two articles were obtained, 50 of which were considered suitable for review. From the analysis, it was concluded that antiemetics are often used by general medicine and specialties such as anesthesiology and pediatrics; therefore, knowledge of the extrapyramidal effects will allow early diagnosis and treatment.

Resumo: Os antieméticos são frequentemente usados por diversas áreas da medicina, embora possamos constatar uma tendência a subestimar seus efeitos adversos neurológicos. O objetivo do presente estudo é revisar a literatura sobre a fisiologia, a farmacologia, os fatores predisponentes, a clínica e o tratamento de reações extrapiramidais causadas por antieméticos. Foi realizada uma busca na literatura por artigos de revistas científicas, livros e monografias. Os mecanismos de busca Medline, LILACS, PubMed, EMBASE, Current contents e Google Scholar foram utilizados com as seguintes palavras-chave: desidratação, gastroenterite, vómito, antieméticos, distonia, dopamina, hipertermia, citocromo, metoclopramida e domperidona. Foram encontrados 252 artigos, dos quais 50 foram considerados aptos para a revisão. A partir da análise, concluiu-se que os antieméticos são frequentemente utilizados pela medicina geral e especialidades, como anestesiologia e pediatria, portanto, o conhecimento dos efeitos extrapiramidais possibilitará um diagnóstico e tratamento precoces.

Paroxysmal crying and motor regression for more than two months in an infant / 中国当代儿科杂志

The patient was a male who was found to be abnormal at the age of 4.5 months. He presented with irritability, motor regression and opisthotonus. Brain MRI revealed bilateral abnormality in the lentiform nucleus, thalamus, deutocerebrum and cerebellar hemispheres. Novel compound heterozygous mutations of SLC19A3 gene, c.950G>A(p.G317E) and c.962C>T(p.A321V), were found in the patient. Further study showed that c.950G>A was inherited from his father and c.962C>T came from his mother. Using bioinformatics software analysis, both of the mutations were found to be harmful. His symptoms were improved remarkably after biotin, thiamine and "cocktail" therapy. One month later a brain MRI revealed that the lesions in basal ganglia and cerebellar hemispheres were improved. The patient was definitely diagnosed with biotin-thiamine responsive basal ganglia disease (BTBGD). BTBGD is a treatable autosomal recessive disease and early administration of biotin and thiamine may lead to clinical improvement.

A Novel Mutation Associated with Familial Idiopathic Basal Ganglia Calcification and Analysis of the Genotype-Phenotype Association in Chinese Patients / 中华医学杂志(英文版)

<p><b>Background</b>Idiopathic basal ganglia calcification (IBGC) is a genetic disorder characterized by bilateral basal ganglia calcification and neural degeneration. In this study, we reported a new SLC2OA2 mutation of IBGC and reviewed relevant literature to explore the association between phenotypes and genotypes in Chinese IBGC patients.</p><p><b>Methods</b>Clinical information of the proband and her relatives were collected comprehensively. Blood samples of both the patient and her father were obtained, and genetic screening related to IBGC was performed using second generation sequencing with their consent. Findings were confirmed by Sanger sequencing. Polyphen-2 was used to predict the potential association between mutations and disease. Then, we retrieved literatures of Chinese IBGC patients and explored the association between phenotype and genotype.</p><p><b>Results</b>A novel mutation was identified through genetic testing, and it is suggested to be a damage mutation predicted by Polyphen-2. Through literature review, we found that SLC20A2 mutation is the most common cause for IBGC in China. Its hot spot regions are mainly on the 1 and 8 exons; the second common one is PDGFB where the hot spot covered a length of 220-230 bp localized on the 2 exon; moreover, Chinese IBGC patients featured early-onset, more severe movement disorder and relatively mild cognitive impairment compared with those in other countries.</p><p><b>Conclusions</b>There is significant heterogeneity both in phenotype and genotype in Chinese IBGC patients. Further research of pathogenic mechanism of IBGC is required to eventually develop precise treatment for individuals who suffered this disease.</p>

A diagnostic approach for neurodegeneration with brain iron accumulation: clinical features, genetics and brain imaging / Uma orientação diagnóstica para neurodegeneração com acúmulo cerebral de ferro: aspectos clínicos, genéticos e de neuroimagem

ABSTRACT Neurodegeneration with brain iron accumulation (NBIA) represents a heterogeneous and complex group of inherited neurodegenerative diseases, characterized by excessive iron accumulation, particularly in the basal ganglia. Common clinical features of NBIA include movement disorders, particularly parkinsonism and dystonia, cognitive dysfunction, pyramidal signs, and retinal abnormalities. The forms of NBIA described to date include pantothenase kinase-associated neurodegeneration (PKAN), phospholipase A2 associated neurodegeneration (PLAN), neuroferritinopathy, aceruloplasminemia, beta-propeller protein-associated neurodegeneration (BPAN), Kufor-Rakeb syndrome, mitochondrial membrane protein-associated neurodegeneration (MPAN), fatty acid hydroxylase-associated neurodegeneration (FAHN), coenzyme A synthase protein-associated neurodegeneration (CoPAN) and Woodhouse-Sakati syndrome. This review is a diagnostic approach for NBIA cases, from clinical features and brain imaging findings to the genetic etiology.

RESUMO A neurodegeneração com acúmulo cerebral de ferro (sigla em inglês NBIA) representa um grupo heterogêneo e complexo de doenças neurodegenerativas hereditárias, caracterizada pelo acúmulo cerebral de ferro, especialmente nos núcleos da base. O quadro clínico das NBIAs em geral inclui distúrbios do movimento, particularmente parkinsonismo e distonia, disfunção cognitiva, sinais piramidais e anormalidades da retina. As formas de NBIA descritas até o momento incluem neurodegeneração associada a pantothenase kinase (PKAN), neurodegeneração associada a phospholipase A2 (PLAN), neuroferritinopatia, aceruloplasminemia, neurodegeneração associada a beta-propeller protein (BPAN), síndrome de Kufor-Rakeb, neurodegeneração associada a mitochondrial membrane protein (MPAN), neurodegeneração associada a “fatty acid hydroxylase” (FAHN), neurodegeneração associada a coenzyme A synthase protein (CoPAN) e síndrome de Woodhouse-Sakati. Esta revisão é uma orientação para o diagnóstico das NBIAs, partindo das características clínicas e achados de neuroimagem, até a etiologia genética.

Síndrome do QT longo adquirido em paciente portadora de doença de Fahr / Acquired long QT syndrome in a patient with Fahr's disease

A síndrome do QT longo é uma doença caracterizada por um atraso na repolarização ventricular, que se manifesta como síncope cardíaca até morte súbita. Alguns distúrbios hidroeletrolíticos podem corresponder à forma adquirida da síndrome, como a hipocalcemia. A hipocalcemia pode ocorrer em função do hipoparatireoidismo, que, em um quadro crônico, pode determinar calcificação em núcleos da base no sistema nervoso central, caracterizando a doença de Fahr. Paciente ISC, sexo feminino, 71 anos, referiu episódio de perda súbita da consciência associado a movimentos tônico-clônicos e relaxamento esfincteriano.Os achados do exame físico foram hipotensão arterial (80x60mmHg) e bradipsiquismo. Foi realizado eletrocardiograma, que mostrou alargamento do segmento QT, corrigido em 0,57'' pela fórmula de Bazett. Na história pregressa, referiu tiroidectomia parcial à direita há 20 anos, hipotireoidismo e hipertensão arterial. Fazia uso de quatro anti-hipertensivos e de um tireoestimulante. A análise da tomografia de crânio mostrou densos componentes calcificados nas regiões dos gânglios da base. A ultrassonografia de tireoide mostrou lobotomização à direita. O diagnóstico de hipoparatireoidismo foi suspeitado pelos sintomas de fadiga, sonolência, e sinais de Chvostek e Trousseau positivos, e confirmado por exames que demonstraram hipocalcemia significativa, hiperfosfatemia e níveis reduzidos de hormônio paratireóideo. Por se tratar de um quadro insidioso, o diagnóstico de hipoparatireoidismo é pouco elucidado apenas pela clínica. Neste caso, o alargamento do QT foi imprescindível para esclarecer e tratar sua etiologia. Além disso, a doença de Fahr, apesar de rara, deve ser considerada diante de um paciente com hipoparatireoidismo e história clínica compatível

Long QT syndrome is a disease characterized by a delay in ventricular repolarization that is manifested as cardiac syncope or even as sudden death. Some water and electrolyte disturbances can reflect the acquired form of the syndrome, such as hypocalcemia. Hypocalcemia can arise because of hypoparathyroidism, which in a chronic setting can determine basal ganglia calcification in the central nervous system, featuring Fahr's disease. ISC, female, 71, reported an episode of sudden loss of consciousness associated with tonic-clonic movements, and sphincter relaxation. Physical examination findings were hypotension (80x60mm Hg) and bradypsychism. The electrocardiogram (ECG) showed QT interval prolongation, corrected for 0.57'' by Bazett's formula. In her previous history she reported right partial thyroidectomy 20 years ago, hypothyroidism and high blood pressure. She made use of four anti-hypertensive drugs and one thyroid stimulating hormone. CT scan analysis showed dense calcified componentes in the regions of basal ganglia. Thyroid ultrasound showed right lobotomization. The diagnosis of hypoparathyroidism was suspected due to symptoms of fatigue, sleepiness, and positive signs of Chvostek and Trousseau, and confirmed by tests that showed significant hypocalcemia, hyperphosphatemia and low levels of parathyroid hormone (PTH) Because of its insidious picture, the diagnosis of hypoparathyroidism is only slightly elucidated by the clinical exam. In this case, QT prolongation was essential to clarify and treat its etiology. Furthermore, Fahr's disease, although rare, should be considered in a patient with hypoparathyroidism and consistent clinical history.

Widespread intracranial calcifications in a patient with hypoparathyroidism

No abstract available.

Clinical and genetic characteristics of patients with dentatorubro-pallidoluysian atrophy / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To explore the clinical and genetic characteristics of patients with dentatorubro-pallidoluysian atrophy (DRPLA).</p><p><b>METHODS</b>DNA analysis for DRPLA gene was performed in two patients. Clinical features and genetic testing of Chinese DRPLA patients reported in the literature were reviewed in terms of initial symptoms, CAG repeat and age of onset.</p><p><b>RESULTS</b>Both families were confirmed by genetic analysis. In family 1, the number of CAG repeat in the proband, his brother and his mother was determined respectively as 8/65, 8/53 and 8/18. In family 2, the number of CAG repeat was respectively 13/63, 13/18, 18/52 and 13/13 in the proband, his brother, his father and his mother. The size of the expanded CAG repeats has inversely correlated with the age at onset (P<0.05, r=- 0.555). The age at onset of epilepsy was 10 and that for the onset of ataxia is forty years in initial symptom.</p><p><b>CONCLUSION</b>The clinical characteristics of DRPLA include epilepsy, ataxia and cognitive impairment. The initial symptoms are epilepsy in adolescence and ataxia in adults. The size of expanded CAG repeats inversely correlates with the age at onset. The initial symptoms are different with different age of onset. It is difficult to diagnose DRPLA at an early stage.</p>

Clinical features of familial idiopathic basal ganglia calcification caused by a novel mutation in the SLC20A2 gene / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To describe clinical and genetic feature in a Chinese family with familial idiopathic basal ganglia calcification 3 (IBGC-3) caused by a novel mutation in the SLC20A2 gene.</p><p><b>METHODS</b>Clinical data was collected from a family with familial IBGC-3. All of the family members underwent cerebral CT. Potential mutation of the SLC20A2 gene were screened in the proband, 5 symptomatic patients, 5 asymptomatic family members, and 100 healthy Chinese controls. Exon 8 of the SLC20A2 gene was cloned into plasmid and sequenced.</p><p><b>RESULTS</b>There were 6 symptomatic patients (3 males and 3 females) in an autosomal dominant pedigree. The patients manifested as juvenile-onset paroxysmal kinesigenic dyskinesia, in addition to pyramidal signs in proband. 5 patients alive had calcification in bilateral basal ganglia and subcortical areas. One asymptomatic member also had calcification in the brain; and 2 cases of asymptomatic young members had bilateral globus pallidus calcification. A novel c.1086delC mutation in SLC20A2 gene has been identified in proband and 7 family members with intracranial calcification. The deletion mutation was not found in 2 family members without intracranial calcification and healthy controls members. There is no clear relationship between clinical symptoms and the severity of calcification in cerebral CT.</p><p><b>CONCLUSION</b>Familial idiopathic basal ganglia calcification caused by the SLC20A2 gene mutation can manifest as juvenile onset paroxysmal kinesigenic dyskinesia. Further study should be done to validate the unrelated relationships between the severity of calcification in IBGC 3 cranial CT and clinical symptoms.</p>

Dysfunctions of the stomatognathic system and vocal aspects in Fahr disease: case report / Disfunções do sistema estomatognático e aspectos vocais na doença de Fahr: relato de caso

The aim of this study is to report the case of a patient with Fahr's Disease in order to describe the main stomatognathic and vocal changes that can be found in individuals with this disease. In order to establish the diagnosis, an assessment of the conditions of orofacial motor system and speech production, as well the efficiency of swallowing, was realized. Based on these assessments, there were difficulties in coordinating and sustaining muscle during speech and presence of oropharyngeal dysphagia. Speech disorders found in Fahr's disease manifest themselves in complex and cover various aspects of phonological knowledge and the diseases that affect the basal ganglia have similar frames of speech-language disorders of the stomatognathic system, being able to present a picture of dysarthria.

O objetivo deste estudo consiste em relatar o caso de uma paciente com Doença de Fahr buscando descrever as principais alterações estomatognáticas e vocais que podem ser encontradas em indivíduos com essa doença. A fim de estabelecer o diagnóstico fonoaudiológico, foi realizada avaliação das condições motoras orofaciais e produção da fala, além de eficiência da deglutição. Com base nessas avaliações, observaram-se dificuldades na coordenação e na sustentação muscular durante a fala e presença de disfagia orofaríngea. Os achados fonoaudiológicos na Doença de Fahr manifestam-se de forma complexa, incluindo disfagias e disartria e as doenças que acometem os núcleos da base apresentam quadros semelhantes de alterações fonoaudiológicas do sistema estomatognático, podendo apresentar quadro de disartria.

Calcificações nos núcleos da base após hipoparatireoidismo secundário: relato de caso / Cerebral calcifications due to secondary hypoparathyroidism: case report

JUSTIFICATIVA E OBJETIVOS: As calcificações dos gânglios da base ocorrem em diversas situações clínicas e podem se apresentar de modo variado. Desde formas assintomáticas e incidentalmente encontradas em exames de imagem; até formas convulsivas graves ou manifestações clínicas de parkinsonismo.O objetivo deste estudo foi relatar um caso de hipocalcemia com repercussões neurológicas 10 anos após hipoparatireoidismo secundário devido à tireoidectomia por carcinoma folicular. RELATO DO CASO: Paciente do sexo feminino, 23 anos, submetida à tireoidectomia aos 9 anos de idade devido a carcinoma folicular, tendo posteriormente recebido dose de I131 e desde então em uso de puran T4. Após aproximadamente 10 anos da cirurgia,iniciou episódios de crises convulsivas tônico-clônicas, além de parestesias e episódios de tetania. Hipoparatireoidismo com manifestações neurológicas, diagnosticado longo tempo após a cirurgia de tireoide é considerado uma raridade. A paciente procurou atendimento médico facultativo com quadro sugestivo de crise convulsiva e tetania. Solicitado exames laboratoriais e tomografia computadorizada (TC) de crânio que demonstrou áreas de calcificações cerebrais nos núcleos caudados, lenticulares e tálamo. Tratada com cálcio e Vitamina D apresentando melhora clínica importante. CONCLUSÃO: O tratamento do hipoparatireoidismo com cálcio e vitamina D, restabelecendo a calcemia, propiciou a estabilizaçãodo quadro neurológico.

BACKGROUND AND OBJECTIVES: Calcifications of the basal ganglia occur in various clinical situations and can present variably. Even asymptomatic forms which are incidentally found on imaging studies until severe seizures or clinical manifestations of parkinsonism are described. To report a case of hypocalcemia with neurological repercussions ten years after secondary hypoparathyroidism due to thyroidectomy for follicular carcinoma. CASE REPORT: The diagnosis of hypoparathyroidism with neurological findings occurring years after thyroid surgery is considered to be rare. The authors describe one case of hypoparathyroidismassociated to brain calcifications diagnosed ten yearsafter thyroidectomy due to follicular thyroid carcinoma. Thepatient was admitted to Emergency Service presenting with seizures,without a previous diagnosis of hypoparathyroidism. Thediagnosis was suspected adding the biochemical analysis and thecerebral computed tomography, which showed cerebral calcificationsin basal ganglia. The patient was treated with calcium andvitamin D with improvement of clinical status. CONCLUSION: The treatment of hypoparathyroidism withcalcium and vitamin D, restoring the calcium levels, brought thestabilization of the neurological symptoms.

Gitelman's syndrome presenting with hypocalcaemia, basal ganglia calcification and periodic paralysis

Gitelman's syndrome (GS), also referred to as familial hypokalaemia-hypomagnesaemia syndrome, is an autosomal recessive renal tubular disorder characterised by hypokalaemic metabolic alkalosis, hypomagnesaemia and hypocalciuria. It is caused by a defect of the thiazide-sensitive sodium chloride co-transporter at the distal tubule. This condition was previously confused with Bartter syndrome. Documentation of hypocalciuria helps to differentiate GS from Bartter syndrome. We report a 44-year-old woman who presented with a history of seizure disorder and periodic paralysis. On investigation, she was found to have hypokalaemic metabolic alkalosis, hypomagnesaemia, hypocalciuria, hypoparathyroidism, hypocalcaemia and basal ganglia calcification, consistent with GS. The atypical features in our case, namely basal ganglia calcification and hypocalcaemia, prompted the writing of this case report.

Pseudohypoparathyroidism type-II with striopallidodentate calcification with positive anti glutamic acid decarboxylase antibody and seizures

Pseudohypoparathyroidism [PHP] is disorder characterized by biological insensitivity of parathyroid hormone [PTH] at tissue level. There are several sub types of PHP have been described with identical features of increased resistance to PTH by kidney and bone with resultant biochemical features of increased level of PTH, hypocalcemia and hyperphosphatemia. We describe unique case of subtype of Pseudohypoparathyroidism [PHP] type II complicated by massive intracranial calcification of Striopallidentate [SPD] system resulting in seizure activity. This case is quite unique and worthwhile to report linking PHP type II and intra cranial calcification

Basal ganglia involvement in herpes simplex encephalitis.

Herpes simplex encephalitis (HSE) is a leading cause of sporadic, nonepidemic viral encephalitis in children and adults. We report a very rare case of HSE with involvement of bilateral thalamus, putamen, upper pons and midbrain, with development of extrapyramidal symptoms which responded to corticosteroid therapy. A 15-mth-old female baby admitted with complaint of fever for 5 days and generalised tonic clonic seizure 10 hours before admission. On clinical examination patient was drowsy, temperature was 39.4 oC and vitals were stable with signs of increased intracranial tension. There were no signs of meningeal irritation. Patient gradually become unconscious in the next few hours and pupils were constricted bilaterally with development of atonia in all four limbs and neck muscles. Doll’s eye phenomenon was absent.

Spectrum of purpura fulminans.

Purpura Fulminans is a severe disorder of acute onset with high morbidity and mortality. It is characterized by DIC with thrombocytopenia, hyofibrinogenemia, hypothrombinemia and anemia. It most often occurs in young with sudden appearance of symmetrical, tender, ecchymotic skin lesions usually involving the lower extremities. An infectious and noninfectious etiology has been proposed. Early recognition and early therapy with appropriate antibiotics and heparin is known to limit both morbidity and mortality. This article reports 5 cases of Purpura Fulminans treated at our centre with review of etiology, pathogenesis, clinical features and treatment.