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1.
Phenotypic spectrum and genetic analysis in the fatal cases of Schaaf-Yang syndrome: Two case reports and literature review.
Chen, X, Ma, X, Zou, C
Medicine. 2020;(29):e20574
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Abstract
RATIONALE Schaaf-Yang syndrome, a rare imprinted hereditary disease caused by MAGEL2 variants, manifests as developmental delay/intellectual disability, neonatal hypotonia, feeding difficulties, contractures, and autism spectrum disorder. PATIENT CONCERNS Patient 1 and 2 were infant girls presenting facial dysmorphisms, contractures of interphalangeal joints, neonatal hypotonia, feeding difficulties, congenital heart diseases, and respiratory complications. Besides, Patient 2 presented with delayed psychomotor development. DIAGNOSIS Whole-exome sequencing was performed and heterozygous mutations of the MAGEL2 gene were detected in the patients. They were diagnosed as Schaaf-Yang syndrome. INTERVENTIONS The patients received supportive treatment including mechanical ventilation, parenteral nutrition and gastric tube feeding. OUTCOMES Whole-exome sequencing revealed de novo heterozygous c.1996dupC pathogenic mutations in the MAGEL2 gene in the 2 patients. They died due to respiratory failure at the age of 20 days and 98 days, respectively. LESSONS Our results indicate that MAGEL2 variants can cause congenital heart disease and fatal respiratory complications, broadening the phenotypic spectrum and adding to the fatal cases of Schaaf-Yang syndrome. We highly suggest that the MAGEL2 gene should be added to gene-panels or gene-filters in next-generation sequencing-based diagnostics, which is of great significance for early diagnosis and early intervention of Schaaf-Yang syndrome patients.
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Sudden cardiac death in a patient with LGI1 antibody-associated encephalitis.
Rizzi, R, Fisicaro, F, Zangrandi, A, Ghidoni, E, Baiardi, S, Ragazzi, M, Parchi, P
Seizure. 2019;:148-150
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Antibody-LGI 1 autoimmune encephalitis manifesting as rapidly progressive dementia and hyponatremia: a case report and literature review.
Li, X, Yuan, J, Liu, L, Hu, W
BMC neurology. 2019;(1):19
Abstract
BACKGROUND Anti leucine-rich glioma inactivated 1 (LGI1) encephalitis is a rare autoimmune encephalitis (AE), characterized by acute or subacute cognitive impairment, faciobrachial dystonic seizures, psychiatric disturbances and hyponatremia. Antibody-LGI 1 autoimmune encephalitis (anti-LGI1 AE) has increasingly been recognized as a primary autoimmune disorder with favorable prognosis and response to treatment. CASE PRESENTATION Herein, we reported a male patient presenting as rapidly progressive dementia and hyponatremia. He had antibodies targeting LGI1 both in the cerebrospinal fluid and serum, which demonstrated the diagnosis of typical anti-LGI1 AE. The scores of Mini-Mental State Examination and Montreal Cognitive Assessment were 19/30 and 15/30, respectively. Cranial magnetic resonance images indicated hyperintensities in bilateral hippocampus. The findings of brain arterial spin labeling and Fluorine-18-fluorodeoxyglucose positron emission tomography showed no abnormal perfusion/metabolism. After the combined treatment of intravenous immunoglobulin and glucocorticoid, the patient's clinical symptoms improved obviously. CONCLUSIONS This case raises the awareness that a rapid progressive dementia with predominant memory deficits could be induced by immunoreactions against LGI1. The better recognition will be great importance for the early diagnosis, essential treatment, even a better prognosis.
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R106C TFG variant causes infantile neuroaxonal dystrophy "plus" syndrome.
Catania, A, Battini, R, Pippucci, T, Pasquariello, R, Chiapparini, ML, Seri, M, Garavaglia, B, Zorzi, G, Nardocci, N, Ghezzi, D, et al
Neurogenetics. 2018;(3):179-187
Abstract
TFG (tropomyosin-receptor kinase fused gene) encodes an essential protein in the regulation of vesicular trafficking between endoplasmic reticulum and Golgi apparatus. The homozygous variant c.316C > T within TFG has been previously associated with a complicated hereditary spastic paraplegia (HSP) phenotype in two unrelated Indian families. Here, we describe the first Italian family with two affected siblings harboring the same variant, who in childhood were classified as infantile neuroaxonal dystrophy (INAD) based on clinical and neuropathological findings. Twenty years after the first diagnosis, exome sequencing was instrumental to identify the genetic cause of this disorder and clinical follow-up of patients allowed us to reconstruct the natural history of this clinical entity. Investigations on patient's fibroblasts demonstrate the presence of altered mitochondrial network and inner membrane potential, associated with metabolic impairment. Our study highlights phenotypic heterogeneity characterizing individuals carrying the same pathogenic variant in TFG and provides an insight on tight connection linking mitochondrial efficiency and neuronal health to vesicular trafficking.
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SOFT syndrome caused by compound heterozygous mutations of POC1A and its skeletal manifestation.
Ko, JM, Jung, S, Seo, J, Shin, CH, Cheong, HI, Choi, M, Kim, OH, Cho, TJ
Journal of human genetics. 2016;(6):561-4
Abstract
SOFT syndrome (MIM614813) is an extremely rare primordial dwarfism characterized by short stature, onychodysplasia, facial dysmorphism and hypotrichosis, which is caused by biallelic mutations in the POC1A gene. Only 19 patients with mutation-confirmed SOFT syndrome have been reported to date, all of whom carried homozygous variants that were strongly associated with consanguineous marriages. We report an 8.5-year-old boy with SOFT syndrome showing primordial dwarfism, no effect of growth-hormone therapy and skeletal dysplasia. This is the first report of compound heterozygous variants in POC1A, one previously reported and the other novel. A characteristic skeletal manifestation is reported.
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MKS1 mutations cause Joubert syndrome with agenesis of the corpus callosum.
Bader, I, Decker, E, Mayr, JA, Lunzer, V, Koch, J, Boltshauser, E, Sperl, W, Pietsch, P, Ertl-Wagner, B, Bolz, H, et al
European journal of medical genetics. 2016;(8):386-91
Abstract
Joubert syndrome (JS) is a clinically and genetically heterogeneous ciliopathy characterized by episodic hyperpnea and apnea, hypotonia, ataxia, cognitive impairment and ocular motor apraxia. The "molar tooth sign" is pathognomonic of this condition. Mutations in the MKS1 gene are a major cause of Meckel-Gruber syndrome (MKS), the most common form of syndromic neural tube defects, frequently resulting in perinatal lethality. We present the phenotype and genotype of a child with severe JS and agenesis of the corpus callosum (ACC). In our patient, a next generation sequencing (NGS) approach revealed the following two variants of the MKS1 gene: first, a novel missense variant [ c.240G > T (p.Trp80Cys)], which affects a residue that is evolutionarily highly conserved in mammals and ciliates; second, a 29 bp deletion in intron 15 [c.1408-35_1408-7del29], a founder mutation, which in a homozygous state constitutes the major cause of MKS in Finland. We review the MKS1-variants in all of the eleven JS patients reported to date and compare these patients to our case. To our knowledge, this is the first patient with Joubert syndrome and agenesis of the corpus callosum where a potentially causal genotype is provided.
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Screening LGI1 in a cohort of 26 lateral temporal lobe epilepsy patients with auditory aura from Turkey detects a novel de novo mutation.
Kesim, YF, Uzun, GA, Yucesan, E, Tuncer, FN, Ozdemir, O, Bebek, N, Ozbek, U, Iseri, SA, Baykan, B
Epilepsy research. 2016;:73-8
Abstract
Autosomal dominant lateral temporal lobe epilepsy (ADLTE) is an autosomal dominant epileptic syndrome characterized by focal seizures with auditory or aphasic symptoms. The same phenotype is also observed in a sporadic form of lateral temporal lobe epilepsy (LTLE), namely idiopathic partial epilepsy with auditory features (IPEAF). Heterozygous mutations in LGI1 account for up to 50% of ADLTE families and only rarely observed in IPEAF cases. In this study, we analysed a cohort of 26 individuals with LTLE diagnosed according to the following criteria: focal epilepsy with auditory aura and absence of cerebral lesions on brain MRI. All patients underwent clinical, neuroradiological and electroencephalography examinations and afterwards they were screened for mutations in LGI1 gene. The single LGI1 mutation identified in this study is a novel missense variant (NM_005097.2: c.1013T>C; p.Phe338Ser) observed de novo in a sporadic patient. This is the first study involving clinical analysis of a LTLE cohort from Turkey and genetic contribution of LGI1 to ADLTE phenotype. Identification of rare LGI1 gene mutations in sporadic cases supports diagnosis as ADTLE and draws attention to potential familial clustering of ADTLE in suggestive generations, which is especially important for genetic counselling.
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8.
Autoantibody-mediated encephalitis: Not just paraneoplastic, not just limbic, and not untreatable.
Jammoul, A, Li, Y, Rae-Grant, A
Cleveland Clinic journal of medicine. 2016;(1):43-53
Abstract
Autoantibody-mediated encephalitis is a heterogeneous group of recently identified disorders, all caused by autoimmunity directed against components of the central nervous system. Despite severe and even prolonged neurologic deficits, dramatic improvements may occur with aggressive treatment.
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9.
Effect of rituximab in patients with leucine-rich, glioma-inactivated 1 antibody-associated encephalopathy.
Irani, SR, Gelfand, JM, Bettcher, BM, Singhal, NS, Geschwind, MD
JAMA neurology. 2014;(7):896-900
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Abstract
IMPORTANCE This observational study describes the efficacy and safety of rituximab in 5 patients with voltage-gated potassium channel (VGKC)-complex/leucine-rich, glioma-inactivated 1 (LGI1) antibody-associated encephalopathy. Rituximab is a monoclonal antibody that targets CD20 and is used to treat other neurologic and nonneurologic diseases. OBSERVATIONS This case series reports sequential seizure frequencies, modified Rankin Scale scores, and VGKC-complex antibody titers in 5 adult patients (median age, 65 years; range, 48-73 years) treated with rituximab. Median time from symptom onset to rituximab initiation was 414 days (range, 312-851 days). One patient showed a rapid clinical improvement after treatment with rituximab alone and experienced a rituximab-responsive clinical relapse. Another showed possible improvement on neuropsychometric memory indexes after rituximab therapy. In contrast, all patients showed robust responses to treatment with glucocorticoids, intravenous immunoglobulins, and/or plasma exchange at some point in their illness. Treatment with glucocorticoids-less so with intravenous immunoglobulins and plasma exchange-was associated with the most marked reductions in VGKC-complex antibodies. The only patient who did not receive glucocorticoids showed the poorest clinical and serologic responses. CONCLUSIONS AND RELEVANCE Rituximab was well tolerated in this predominantly older adult patient population and may be an effective option for some patients with LGI1 antibody-associated encephalopathy. Glucocorticoid therapy appears particularly efficacious. Earlier rituximab administration and randomized trials are required to formally assess efficacy.
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10.
Imerslund-Gräsbeck syndrome in a 25-month-old Italian girl caused by a homozygous mutation in AMN.
De Filippo, G, Rendina, D, Rocco, V, Esposito, T, Gianfrancesco, F, Strazzullo, P
Italian journal of pediatrics. 2013;:58
Abstract
Imerslund-Gräsbeck syndrome is a rare autosomal recessive disorder, characterized by vitamin B12 deficiency due to selective malabsorption of the vitamin and usually results in megaloblastic anemia appearing in childhood. It is responsive to parenteral vitamin B12 therapy.The estimated prevalence (calculated based on Scandinavian data) is less than 6:1,000,000. However, many cases may be misdiagnosed.When there is reasonable evidence to suspect that a patient suffers from IGS, a new and straightforward approach to diagnosis is mutational analysis of the appropriate genes. We report for the first time the case of a girl of Italian ancestry with IGS genetically confirmed by the detection of a homozygous missense mutation in the AMN gene (c.208-2 A > G).