Frontotemporal Dementia (FTD) is a common cause of Young Onset Dementia and has diverse clinical manifestations involving behavior, executive function, language and motor function, including parkinsonism. Up to 50% of FTD patients report a positive family history, supporting a strong genetic basis, particularly in cases with both FTD and amyotrophic lateral sclerosis (FTD-ALS). Mutations in three genes are associated with the majority of familial FTD (fFTD) cases - microtubule associated protein tau gene (MAPT), granulin precursor (GRN), and hexanucleotide repeat expansions in chromosome 9 open reading frame 72- SMCR8complex subunit (C9orf72) while mutations in other genes such as optineurin (OPTN) have rarely been reported. Mutations in OPTN have been reported mostly in familial and sporadic cases of ALS, or in rare cases of FTD-ALS, but not in association with pure or predominant FTD and/or parkinsonian phenotype. Here, we report for the first time, a family from the Philippines with four members harboring a novel frameshift insertion at OPTN (Chr 10:13166090 G>GA) p.Lys328GluTer11, three of whom presented with FTD-related phenotypes. Additionally, one sibling heterozygous for the frameshift insertion had a predominantly parkinsonian phenotype resembling corticobasal syndrome, but it remains to be determined if this phenotype is related to the frameshift insertion. Notably, none of the affected members showed any evidence of motor neuron disease or ALS at the time of writing, both clinically and on electrophysiological testing, expanding the phenotypic spectrum of OPTN mutations. Close follow-up of mutation carriers for the development of new clinical features and wider investigation of additional family members with further genetic analyses will be conducted to investigate the possibility of other genetic modifiers in this family which could explain phenotypic heterogeneity.
<b><i>Background:</i></b> Compared to Western populations, familial frontotemporal lobar degeneration (FTLD) is rare among Asians. Progranulin (GRN) gene mutation, which is a major cause of FTLD, is likewise rare. We present a family with FTLD from the Philippines with an autosomal dominant pattern of inheritance and GRN mutation and briefly review reports of GRN mutations in Asia. <b><i>Case Presentation:</i></b> The proband is 66 years old with progressive nonfluent aphasia (PNFA)-corticobasal syndrome . We assessed 3 generations of her pedigree and found 11 affected relatives with heterogenous phenotypes, usually behavioral variant frontotemporal dementia (FTD) and PNFA. Neuroimaging showed atrophy and hypometabolism consistent with FTD syndromes. White matter hyperintensities were seen in affected members even in the absence of vascular risk factors. A GRN mutation R110X was found in 6 members, 3 with symptoms and 3 were asymptomatic. Plasma GRN was low (<112 ng/mL) in all mutation carriers. No mutations were found in microtubule-associated protein tau, APP, PSEN1, and PSEN2 genes, and all were APOE3. <b><i>Conclusion:</i></b> This is the first Filipino family with autosomal dominant FTD documented with GRN mutation. Identifying families and cohorts would contribute to therapeutic developments in an area with FTD-GRN.
Females were more illiterate and unemployed compared to males, but higher number of males were unmarried. Tonic clonic seizures were more frequent in males. Specific epileptic syndromes as juvenile myoclonic epilepsy (JME), idiopathic generalized tonic clonic (IGTC) epilepsy, and temporal lobe epilepsy (TLE) were more frequent in females (p = .01, p = .02, p = .02) while juvenile absence epilepsy (JAE) was more common in males (p = .02) More males had an underlying secondary etiology (p = .001). The commonest drug used was valproate (51.2%) which was more utilized by males while more females were prescribed CBZ and levetiracetam. Conclusions Significant differences between both sexes were observed in certain social impacts in addition to seizure syndromes, etiology and drug utilization.
Background We report the clinical profiles and genetics of multiple family members from Samar, Philippines presenting with varying phenotypes of frontotemporal dementia. Literature studies report three gene mutations associated with a majority of fFTD cases, namely the microtubule associated protein tau gene (MAPT), and progranulin gene (PGRN), chromosome 9 open reading frame 72 (C9ORF72). These were all excluded in our case. Methods Clinical examination, Cranial MRI, and FDG‐PET were done. Genomic DNA was extracted from blood samples and analyzed via targeted exome sequencing. Result A frameshift mutation in the Optineurin (OPTN Chr 10:13166090 G>GA) was identified in multiple family members. This mutation is absent in public large international databases. Clinical and genetic studies show that frontotemporal dementia and motor neuron disease, in particular amyotrophic lateral sclerosis, are part of a disease spectrum with a common pathogenesis. However, there was no clinical or diagnostic evidence of motor neuron disease in family members with Optineurin mutations. A second mutation‐ missense mutation in the Colony‐Stimulating Factor‐1R V235G genes was seen in several family members. Colony‐Stimulating Factor‐1R gene mutations are associated with leukodystrophies when occurring singly. Clinical presentation and diagnostic tests did not support any of these findings. Conclusion At present, this is the only reported family with such combined mutations and genotype‐phenotype discordance. We are further investigating this family by conducting whole exome sequencing.
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