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Elevated serum prolactin concentrations occur in inherited disorders of biogenic amine metabolism because dopamine deficiency leads to insufficient inhibition of prolactin secretion. This work from the International Working Group on Neurotransmitter Related Disorders (iNTD) presents the results of the first standardized study on levodopa-refractory hyperprolactinemia (LRHP; >1000 mU/L) and pituitary magnetic resonance imaging (MRI) abnormalities in patients with inherited disorders of biogenic amine metabolism. Twenty-six individuals had LRHP or abnormal pituitary findings on MRI. Tetrahydrobiopterin deficiencies were the most common diagnoses (n = 22). The median age at diagnosis of LRHP was 16 years (range: 2.5-30, 1st-3rd quartiles: 12.25-17 years). Twelve individuals (nine females) had symptoms attributed to hyperprolactinemia: menstruation-related abnormalities (n = 7), pubertal delay or arrest (n = 5), galactorrhea (n = 3), and decreased sexual functions (n = 2). MRI of the pituitary gland was obtained in 21 individuals; six had heterogeneity/hyperplasia of the gland, five had adenoma, and 10 had normal findings. Eleven individuals were treated with the dopamine agonist cabergoline, ameliorating the hyperprolactinemia-related symptoms in all those assessed. Routine monitoring of these symptoms together with prolactin concentrations, especially after the first decade of life, should be taken into consideration during follow-up evaluations. The potential of slow-release levodopa formulations and low-dose dopamine agonists as part of first-line therapy in the prevention and treatment of hyperprolactinemia should be investigated further in animal studies and human trials. This work adds hyperprolactinemia-related findings to the current knowledge of the phenotypic spectrum of inherited disorders of biogenic amine metabolism.
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Cafe-au-lait macules are the most distinctive clinical finding in neurofibromatosis type I. The aim of this prospective study of Greek children diagnosed with neurofibromatosis type I was to describe the dermatological phenotype and to analyse the characteristics of cafe-au-lait macules and their association with genotype. Pigment intensity and melatonin content of cafe-au-lait macules were measured with a narrowband spectrophotometer. A total of 63 children aged 6 months to 16 years old were studied. Mean melanin content varied, both among patients, and within each patient (p < 0.001). Females had a higher number of cafe-au-lait macules than did males (p = 0.025), and the melanin content of cafe-au-lait macules was lower in females than males (p < 0.001). Patients with protein-truncating variants in the neurofibromatosis type I gene had higher melanin content of cafe-au-lait macules than other types of genetic variants t (55) = 2.196, p = 0.032. Plexiform neurofibromas were also detected in the majority of patients with protein- truncating variants, while juvenile xanthogranulomas were detected equally in patients with protein-truncating and non-protein-truncating variants. In conclusion, cafe-au-lait macules with high melatonin content are associated with patients carrying non-protein-truncating variants. Therefore, measurement of cafe-au-lait macule pigment intensity might provide useful information for initial assessment of patients with neurofibromatosis type I and the severity of their future phenotype.
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Melatonina , Neurofibromatose 1 , Masculino , Feminino , Humanos , Neurofibromatose 1/diagnóstico , Neurofibromatose 1/genética , Melaninas , Estudos Prospectivos , Grécia , Manchas Café com Leite/diagnóstico , Manchas Café com Leite/genética , GenótipoRESUMO
BACKGROUND AND OBJECTIVE: The objective of this study was to better delineate the genetic landscape and key clinical characteristics of complex, early-onset, monogenic hyperkinetic movement disorders. METHODS: Patients were recruited from 14 international centers. Participating clinicians completed standardized proformas capturing demographic, clinical, and genetic data. Two pediatric movement disorder experts reviewed available video footage, classifying hyperkinetic movements according to published criteria. RESULTS: One hundred forty patients with pathogenic variants in 17 different genes (ADCY5, ATP1A3, DDC, DHPR, FOXG1, GCH1, GNAO1, KMT2B, MICU1, NKX2.1, PDE10A, PTPS, SGCE, SLC2A1, SLC6A3, SPR, and TH) were identified. In the majority, hyperkinetic movements were generalized (77%), with most patients (69%) manifesting combined motor semiologies. Parkinsonism-dystonia was characteristic of primary neurotransmitter disorders (DDC, DHPR, PTPS, SLC6A3, SPR, TH); chorea predominated in ADCY5-, ATP1A3-, FOXG1-, NKX2.1-, SLC2A1-, GNAO1-, and PDE10A-related disorders; and stereotypies were a prominent feature in FOXG1- and GNAO1-related disease. Those with generalized hyperkinetic movements had an earlier disease onset than those with focal/segmental distribution (2.5 ± 0.3 vs. 4.7 ± 0.7 years; P = 0.007). Patients with developmental delay also presented with hyperkinetic movements earlier than those with normal neurodevelopment (1.5 ± 2.9 vs. 4.7 ± 3.8 years; P < 0.001). Effective disease-specific therapies included dopaminergic agents for neurotransmitters disorders, ketogenic diet for glucose transporter deficiency, and deep brain stimulation for SGCE-, KMT2B-, and GNAO1-related hyperkinesia. CONCLUSIONS: This study highlights the complex phenotypes observed in children with genetic hyperkinetic movement disorders that can lead to diagnostic difficulty. We provide a comprehensive analysis of motor semiology to guide physicians in the genetic investigation of these patients, to facilitate early diagnosis, precision medicine treatments, and genetic counseling. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Coreia , Distonia , Distúrbios Distônicos , Transtornos dos Movimentos , Criança , Humanos , Hipercinese , Transtornos dos Movimentos/genética , Transtornos dos Movimentos/diagnóstico , Distúrbios Distônicos/genética , Coreia/diagnóstico , Coreia/genética , Proteínas do Tecido Nervoso , Fatores de Transcrição Forkhead , Diester Fosfórico Hidrolases , ATPase Trocadora de Sódio-Potássio , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/genéticaAssuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adolescente , Anticorpos Biespecíficos/efeitos adversos , Anticorpos Biespecíficos/uso terapêutico , Antineoplásicos/efeitos adversos , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológicoRESUMO
OBJECTIVE: To describe the frequency, motor phenotype, clinical patterns and functional consequences of dystonia in patients with cerebral palsy (CP) in the setting of periventricular leukomalacia. METHODS: Retrospective analysis of a cohort of 31 patients with CP and periventricular leukomalacia. Gross Motor Function Classification System (GMFCS) and Manual Ability Classification System (MACS) were used to classify functional ability. Spasticity was rated using the Modified Ashworth Scale. Presence of dystonia was assessed by reviewing video recordings, and its severity by using the Burke-Fahn-Marsden Dystonia Rating Scale. RESULTS: All patients showed evidence of dystonia involving upper and/or lower limbs, neck, trunk, mouth and eyes in order of frequency. In 29% of patients dystonia involved only the limbs and in 71% it was multifocal. Dystonia severity ranged from slight to severe. Severity and distribution of dystonia did not correlate with gender, age, weeks of gestation or duration of neonatal unit stay. GMFCS and MACS correlated with dystonia but not with spasticity. CONCLUSIONS: Severity of dystonia, but not spasticity is associated with the severity of motor functional disability in CP patients with periventricular leukomalacia and demonstrates the key role of dystonia in the motor function of these patients.
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Paralisia Cerebral/complicações , Distonia/etiologia , Leucomalácia Periventricular/complicações , Atividades Cotidianas , Paralisia Cerebral/fisiopatologia , Criança , Pré-Escolar , Estudos de Coortes , Humanos , Leucomalácia Periventricular/fisiopatologia , Masculino , Destreza Motora/fisiologia , Estudos Retrospectivos , Índice de Gravidade de DoençaRESUMO
The neurological phenotype of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) and short-chain enoyl-CoA hydratase (SCEH) defects is expanding and natural history studies are necessary to improve clinical management. From 42 patients with Leigh syndrome studied by massive parallel sequencing, we identified five patients with SCEH and HIBCH deficiency. Fourteen additional patients were recruited through collaborations with other centres. In total, we analysed the neurological features and mutation spectrum in 19 new SCEH/HIBCH patients. For natural history studies and phenotype to genotype associations we also included 70 previously reported patients. The 19 newly identified cases presented with Leigh syndrome (SCEH, n = 11; HIBCH, n = 6) and paroxysmal dystonia (SCEH, n = 2). Basal ganglia lesions (18 patients) were associated with small cysts in the putamen/pallidum in half of the cases, a characteristic hallmark for diagnosis. Eighteen pathogenic variants were identified, 11 were novel. Among all 89 cases, we observed a longer survival in HIBCH compared to SCEH patients, and in HIBCH patients carrying homozygous mutations on the protein surface compared to those with variants inside/near the catalytic region. The SCEH p.(Ala173Val) change was associated with a milder form of paroxysmal dystonia triggered by increased energy demands. In a child harbouring SCEH p.(Ala173Val) and the novel p.(Leu123Phe) change, an 83.6% reduction of the protein was observed in fibroblasts. The SCEH and HIBCH defects in the catabolic valine pathway were a frequent cause of Leigh syndrome in our cohort. We identified phenotype and genotype associations that may help predict outcome and improve clinical management.
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Anormalidades Múltiplas/genética , Erros Inatos do Metabolismo dos Aminoácidos/genética , Distonia/genética , Enoil-CoA Hidratase/genética , Doença de Leigh/genética , Tioléster Hidrolases/deficiência , Valina/metabolismo , Encéfalo/diagnóstico por imagem , Pré-Escolar , Distonia/diagnóstico , Enoil-CoA Hidratase/deficiência , Feminino , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Internacionalidade , Doença de Leigh/diagnóstico , Doença de Leigh/metabolismo , Imageamento por Ressonância Magnética , Masculino , Redes e Vias Metabólicas/genética , Mutação , Fenótipo , Taxa de Sobrevida , Tioléster Hidrolases/genéticaRESUMO
An open debate in antiangiogenic therapies is about their consequence on tumor invasiveness and metastasis, which is undoubtedly relevant for patients currently treated with antiangiogenics, such as renal cell carcinoma patients. To address, this we developed an extensive series of 27 patient biopsy-derived orthotopic xenograft models (Ren-PDOX) that represent inter-patient heterogeneity. In specific tumors, antiangiogenics produced increased invasiveness and metastatic dissemination, while in others aggressiveness remained unchanged. Mechanistically, species-discriminative RNA sequencing identified a tumor cell-specific differential expression profile associated with tumor progression and aggressivity in TCGA RCC patients. Gene filtering using an invasion-annotated patient series pinpointed two candidate genes, of which ALDH1A3 differentiated the pro-invasive subtype of Ren-PDOXs. Validation in an independent series of 15 antiangiogenic-treated patients confirmed that pre-treatment ALDH1A3 can significantly discriminate patients with pro-aggressive response upon treatment. Overall, results confirm that effects of antiangiogenic drugs on tumor invasion and metastasis are heterogeneous and may profoundly affect the natural progression of tumors and promote malignancy. Furthermore, we identify a specific molecular biomarker that could be used to select patients that better benefit from treatment.
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Inibidores da Angiogênese/efeitos adversos , Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , Modelos Biológicos , Invasividade Neoplásica/patologia , Metástase Neoplásica/patologia , Animais , Linhagem Celular Tumoral , Humanos , Masculino , Camundongos , Camundongos Nus , Medicina de Precisão , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
OBJECTIVE: To define the risks and consequences of cardiac abnormalities in ATP1A3-related syndromes. METHODS: Patients meeting clinical diagnostic criteria for rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) with ATP1A3 genetic analysis and at least 1 cardiac assessment were included. We evaluated the cardiac phenotype in an Atp1a3 knock-in mouse (Mashl+/-) to determine the sequence of events in seizure-related cardiac death. RESULTS: Ninety-eight patients with AHC, 9 with RDP, and 3 with CAPOS (63 female, mean age 17 years) were included. Resting ECG abnormalities were found in 52 of 87 (60%) with AHC, 2 of 3 (67%) with CAPOS, and 6 of 9 (67%) with RDP. Serial ECGs showed dynamic changes in 10 of 18 patients with AHC. The first Holter ECG was abnormal in 24 of 65 (37%) cases with AHC and RDP with either repolarization or conduction abnormalities. Echocardiography was normal. Cardiac intervention was required in 3 of 98 (≈3%) patients with AHC. In the mouse model, resting ECGs showed intracardiac conduction delay; during induced seizures, heart block or complete sinus arrest led to death. CONCLUSIONS: We found increased prevalence of ECG dynamic abnormalities in all ATP1A3-related syndromes, with a risk of life-threatening cardiac rhythm abnormalities equivalent to that in established cardiac channelopathies (≈3%). Sudden cardiac death due to conduction abnormality emerged as a seizure-related outcome in murine Atp1a3-related disease. ATP1A3-related syndromes are cardiac diseases and neurologic diseases. We provide guidance to identify patients potentially at higher risk of sudden cardiac death who may benefit from insertion of a pacemaker or implantable cardioverter-defibrillator.
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Ataxia Cerebelar/genética , Deformidades Congênitas do Pé/genética , Perda Auditiva Neurossensorial/genética , Hemiplegia/genética , Mutação/genética , Atrofia Óptica/genética , Reflexo Anormal/genética , ATPase Trocadora de Sódio-Potássio/genética , Adolescente , Adulto , Ataxia Cerebelar/metabolismo , Ataxia Cerebelar/terapia , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Deformidades Congênitas do Pé/metabolismo , Deformidades Congênitas do Pé/terapia , Perda Auditiva Neurossensorial/metabolismo , Perda Auditiva Neurossensorial/terapia , Hemiplegia/diagnóstico , Hemiplegia/terapia , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Atrofia Óptica/metabolismo , Atrofia Óptica/terapia , Fenótipo , Convulsões/terapia , Adulto JovemRESUMO
Given the complexity of neurocutaneous syndromes, a multidisciplinary approach has been advocated in order to provide optimum care. Subjects and Methods: Retrospective analysis of a cohort of 157 patients during a 3-year period, seen at a newly developed neurocutaneous clinic in a pediatric tertiary care hospital in Athens (Greece); and systematic chart review of the patients diagnosed with neurofibromatosis type 1 during this time period. Results: The most frequent neurocutaneous syndromes were neurofibromatosis type 1 (NF1) in 89 patients and tuberous sclerosis complex in 17. In 20.38% of patients a neurocutaneous syndrome was not confirmed. Approximately 2/3 of the NF1 patients underwent genetic analysis, and for 76.67% of them, a pathogenic mutation on the NF1 gene was revealed. Eighty-one patients manifested with generalized NF1 and eight with mosaic NF1. Dermatological manifestations included café-au-lait macules in all patients, followed by axillary and/or inguinal freckling (n = 57), external plexiform neurofibromas (n = 17), and cutaneous and subcutaneous neurofibromas (n = 11). Approximately half of patients had learning disabilities and attention deficit hyperactivity disorder, followed by mental retardation (n = 9), autistic spectrum disorders (n = 4), headaches (n = 3) and seizures (n = 2). Neuroimaging showed characteristic areas of hyperintensity on T2-weighted images in 74.07% of patients and optic pathway glioma in 19.75%. Two patients developed malignant peripheral sheath nerve tumor. Conclusions: Neurocutaneous syndromes are clinically heterogeneous and the surveillance of potential clinical complications is challenging. The availability of genetic diagnosis and novel imaging methods in this group of disorders is likely to further expand their clinical spectrum. Guidelines for assessment and management will need to be modified based on new available data.
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Neurofibromatose 1/fisiopatologia , Equipe de Assistência ao Paciente , Esclerose Tuberosa/fisiopatologia , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/complicações , Transtorno do Espectro Autista/complicações , Manchas Café com Leite/complicações , Criança , Pré-Escolar , Estudos de Coortes , Dermatologistas , Feminino , Genes da Neurofibromatose 1 , Testes Genéticos , Genética Médica , Grécia , Humanos , Lactente , Deficiência Intelectual/complicações , Deficiências da Aprendizagem/complicações , Masculino , Mosaicismo , Síndromes Neurocutâneas/genética , Síndromes Neurocutâneas/fisiopatologia , Síndromes Neurocutâneas/terapia , Neurofibroma Plexiforme/complicações , Neurofibromatose 1/complicações , Neurofibromatose 1/genética , Neurofibromatose 1/terapia , Neurologistas , Neuropsicologia , Oncologistas , Oftalmologistas , Cirurgiões Ortopédicos , Ambulatório Hospitalar , Pediatras , Radiologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/fisiopatologia , Neoplasias Cutâneas/terapia , Esclerose Tuberosa/complicações , Esclerose Tuberosa/genética , Esclerose Tuberosa/terapiaRESUMO
One of the main consequences of inhibition of neovessel growth and vessel pruning produced by angiogenesis inhibitors is increased intratumor hypoxia. Growing evidence indicates that tumor cells escape from this hypoxic environment to better nourished locations, presenting hypoxia as a positive stimulus for invasion. In particular, anti-VEGF/R therapies produce hypoxia-induced invasion and metastasis in a spontaneous mouse model of pancreatic neuroendocrine cancer (PanNET), RIP1-Tag2. Here, a novel vascular-targeting agent targeting semaphorin 4D (Sema4D) demonstrated impaired tumor growth and extended survival in the RIP1-Tag2 model. Surprisingly, although there was no induction of intratumor hypoxia by anti-Sema4D therapy, the increase in local invasion and distant metastases was comparable with the one produced by VEGFR inhibition. Mechanistically, the antitumor effect was due to an alteration in vascular function by modification of pericyte coverage involving platelet-derived growth factor B. On the other hand, the aggressive phenotype involved a macrophage-derived Sema4D signaling engagement, which induced their recruitment to the tumor invasive fronts and secretion of stromal cell-derived factor 1 (SDF1) that triggered tumor cell invasive behavior via CXCR4. A comprehensive clinical validation of the targets in different stages of PanNETs demonstrated the implication of both Sema4D and CXCR4 in tumor progression. Taken together, we demonstrate beneficial antitumor and prosurvival effects of anti-Sema4D antibody but also unravel a novel mechanism of tumor aggressivity. This mechanism implicates recruitment of Sema4D-positive macrophages to invasive fronts and their secretion of proinvasive molecules that ultimately induce local tumor invasion and distant metastasis in PanNETs. SIGNIFICANCE: An anti-semaphorin-4D vascular targeting agent demonstrates antitumor and prosurvival effects but also unravels a novel promalignant effect involving macrophage-derived SDF1 that promotes tumor invasion and metastasis, both in animal models and patients.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/20/5328/F1.large.jpg.See related commentary by Tamagnone and Franzolin, p. 5146.
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Neoplasias , Semaforinas , Animais , Antígenos CD , Humanos , Camundongos , Transdução de SinaisRESUMO
Tuberous Sclerosis Complex (TSC) is a rare neurocutaneous syndrome inherited by an autosomal dominant manner. The disorder is commonly manifested by the presence of multiple benign tumors located in numerous tissues, including the brain, heart, skin and kidneys. Seizures, autism, developmental and behavioral delay, as well as non-neurological phenotypic findings, are suggestive of TSC. The identification of one pathogenic mutation in either the TSC1 or TSC2 genes is considered to be an independent diagnostic criterion. In our study, seventeen Greek patients, 2yo on average, were analyzed for the presence of pathogenic germline mutations in the aforementioned loci by Next-Generation Sequencing. A TSC1/2 gene panel was designed for the molecular diagnosis of the disease. Patients underwent initial diagnosis based on their clinical symptoms, most frequently involving the presence of skin lesions and/or epilepsy. Only one case was familial. Sixteen different genetic alterations were identified in TSC1 and TSC2 genes in fifteen patients, giving a 88% detection rate by employing NGS technology. Overall, most pathogenic mutations (11/15) identified were located in the TSC2 gene with exon 41 being the most frequent. With respect to genotype-phenotype association, no patient TSC1 (+) developed SEGA or renal cysts. No significant differences were observed between different types of TSC2 mutations and any clinical feature. Sequencing also revealed 18 different SNPs across the TSC1 and 20 across the TSC2 genes. This is the first registry of the genetic profile of TSC patients in Greece using a custom-made gene panel as molecular diagnostic tool.
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Sistema de Registros , Esclerose Tuberosa/genética , Proteínas Supressoras de Tumor/genética , Criança , Pré-Escolar , Éxons , Feminino , Grécia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Mutação , Fenótipo , Proteína 1 do Complexo Esclerose Tuberosa , Proteína 2 do Complexo Esclerose TuberosaRESUMO
Assessment of upper limb function, kinematic analysis, and dystonia in patients with spastic diplegia cerebral palsy and periventricular leukomalacia. Seven children with spastic diplegia cerebral palsy and 8 controls underwent upper limb kinematics. Movement duration, average and maximum linear velocity, index of curvature, index of dystonia, and target accuracy and stability were analyzed. In the patients with spastic diplegia, Gross Motor Function and Manual Ability Classification Systems were determined, and spasticity and dystonia were rated using the Modified Ashworth and the Burke-Fahn-Marsden Dystonia scales respectively. Children with spastic diplegia demonstrated a tendency toward higher index of dystonia reflecting overflow, higher index of curvature, lower velocities, and poor target accuracy and stability. All patients showed clinical evidence of dystonia in the upper limbs. Dystonia scores correlated with the Manual Ability Classification System (r = 0.86, P = .01) and with the index of dystonia (r = 0.82, P = .02). Children with spastic diplegia cerebral palsy present dystonia in the upper limbs. This is functionally relevant and can be measured with kinematic analysis.
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Paralisia Cerebral/complicações , Paralisia Cerebral/fisiopatologia , Leucomalácia Periventricular/complicações , Leucomalácia Periventricular/fisiopatologia , Movimento , Extremidade Superior/fisiopatologia , Adolescente , Fenômenos Biomecânicos , Paralisia Cerebral/diagnóstico por imagem , Criança , Avaliação da Deficiência , Feminino , Humanos , Leucomalácia Periventricular/diagnóstico por imagem , Masculino , Movimento/fisiologiaRESUMO
Dystrophinopathies are allelic X-linked myopathies caused by large deletions/duplications or small lesions along the DMD gene. An unexpected dynamic trinucleotide (GAA) expansion, ranging from â¼59 to 82 pure GAA repeats, within the DMD intron 62, was revealed to segregate through three family generations. From the pedigree, two female patients were referred for DMD investigation due to chronic myopathy and a muscle biopsy compatible with dystrophinopathy. As the size of the GAA repeat is limited to 11-33 within the general population our findings may provide a novel insight towards a Trinucleotide Repeat Expansion. Whether this TNR has an impact on the reported phenotype remains to be resolved.
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Distrofina/genética , Repetições de Trinucleotídeos/genética , Adolescente , Adulto , Sequência de Bases , Criança , Metilação de DNA/genética , Distrofina/química , Feminino , Humanos , Masculino , Distrofia Muscular de Duchenne/genética , LinhagemRESUMO
Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous group of neurodegenerative disorders mainly characterized by progressive spasticity of the lower limbs. Adult case series dominate the literature, and there have been only a few studies in children. The purpose of this study is to describe our experience with pediatric HSP in Greece. We report the clinical and genetic findings in our patients and aim to offer insights into the diagnostic difficulties of childhood-onset disease. A series of 15 Greek children affected by pure HSP underwent extensive diagnostic investigations. Molecular analysis included whole exome sequencing (WES) or consecutive screening of candidate genes ATL1, SPAST, REEP1, and CYP7B1. WES performed in three cases yielded previously reported mutations in ATL1 and CYP7B1, and a variant c.397C>T of unknown significance in SPG7. Candidate gene screening performed in the remaining patients identified previously reported mutations in ATL1 (2), SPAST (2), and REEP1 (1), and two novel mutations, c.1636G>A and c.1413+3_6delAAGT, in SPAST. In six cases, the mutations were inherited from their parents, while in three cases, the mutations were apparently de novo. Our data confirm the genetic heterogeneity of childhood-onset pure HSP, with SPG4/SPAST and SPG3A/ATL1 being the most frequent forms. De novo occurrence of HSP does not seem to be uncommon. Candidate gene studies guided by diagnostic algorithms and WES seem both to be reasonable genetic testing strategies.
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Adenosina Trifosfatases/genética , Proteínas de Ligação ao GTP/genética , Predisposição Genética para Doença/genética , Proteínas de Membrana/genética , Mutação/genética , Paraplegia Espástica Hereditária/diagnóstico , Paraplegia Espástica Hereditária/genética , Adolescente , Criança , Pré-Escolar , Análise Mutacional de DNA , Avaliação da Deficiência , Progressão da Doença , Feminino , Grécia , Humanos , Masculino , Índice de Gravidade de Doença , EspastinaRESUMO
BACKGROUND: Only a few studies have been conducted with the objective of creating norms of the Alberta Infant Motor Scale (AIMS) for the assessment of gross motor development of preterm infants. The AIMS performance of preterm infants has been compared with that of the Canadian norms of full-term infants, but not with that of full-term infants of the same nationality. Moreover, the possible impact of prematurity-related morbidity factors on AIMS performance is unknown. OBJECTIVES: The aims of this study were: (1) to evaluate AIMS trajectory in a large population of Greek preterm infants and create norms, (2) to compare it with the AIMS trajectory of Greek full-term infants, and (3) to examine the possible influence of neonatal morbidity on AIMS scores in the preterm sample. DESIGN: This was a cross-sectional study. METHODS: Mean AIMS scores were compared, per month (1-19), between 403 preterm infants (≤32 weeks of age, corrected for prematurity) and 1,038 full-term infants. In preterm infants, the association of AIMS scores with respiratory distress syndrome (RDS), intraventricular hemorrhage (IVH) of grade ≤III, bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), and sepsis was assessed by hierarchical regression analysis. RESULTS: Alberta Infant Motor Scale scores were significantly lower in preterm infants than in full-term infants. Mean AIMS scores in preterm infants were significantly associated with RDS (b=-1.93; 95% CI=-2.70, -1.16), IVH (b=-0.97; 95% CI=-1.69, -0.25), and ROP (b=-1.12; 95% CI=-1.99, -0.24) but not with BPD or sepsis in hierarchical regression analysis. CONCLUSIONS: Alberta Infant Motor Scale norms were created for Greek preterm infants. This study confirms that AIMS trajectories of preterm infants are below those of full-term infants of the same nationality. The influence of morbidity factors, including RDS, IVH, and ROP, should be taken into account when administering the AIMS in preterm infants.
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Desenvolvimento Infantil/fisiologia , Recém-Nascido Prematuro/fisiologia , Destreza Motora/fisiologia , Nascimento Prematuro/fisiopatologia , Nascimento a Termo , Displasia Broncopulmonar/complicações , Displasia Broncopulmonar/fisiopatologia , Estudos Transversais , Feminino , Grécia , Humanos , Lactente , Hemorragias Intracranianas/complicações , Hemorragias Intracranianas/fisiopatologia , Masculino , Valores de Referência , Síndrome do Desconforto Respiratório do Recém-Nascido/complicações , Síndrome do Desconforto Respiratório do Recém-Nascido/fisiopatologia , Retinopatia da Prematuridade/complicações , Retinopatia da Prematuridade/fisiopatologia , Sepse/complicações , Sepse/fisiopatologiaRESUMO
Alternating hemiplegia of childhood (AHC) is a rare neurodevelopmental disorder featuring attacks of hemiplegia and other paroxysmal and non-paroxysmal manifestations leading to progressive neurological impairment. De novo mutations in ATP1A3 have been identified in up to 80% of patients. AHC is also associated with rare mutations in other genes involved in episodic neurological disorders. We sought to find mutations in ATP1A3, CACNA1A, ATP1A2, SCN1A and SLC2A1 in a cohort of ten unrelated patients from Spain and Greece. All patients fulfilled AHC diagnostic criteria. All five genes were amplified by PCR and Sanger sequenced. Copy number variation (CNV) analysis of SLC2A1 and CACNA1A was performed using two different approaches. We identified three previously described heterozygous missense ATP1A3 mutations (p.Asp801Asn, p.Glu815Lys and p.Gly947Arg) in five patients. No disease-causing mutations were found in the remaining genes. All mutations occurred de novo; carriers presented on average earlier than non-carriers. Intellectual disability was more severe with the p.Glu815Lys variant. A p.Gly947Arg carrier harbored a maternally-inherited CACNA1A p.Ala454Thr variant. Of note, three of our patients exhibited remarkable clinical responses to the ketogenic diet. We confirmed ATP1A3 mutations in half of our patients. Further AHC genetic studies will need to investigate large rearrangements in ATP1A3 or consider greater genetic heterogeneity than previously suspected.