Autosomal-recessive early-onset parkinsonism is clinically and genetically heterogeneous. The genetic causes of approximately 50% of autosomal-recessive early-onset forms of Parkinson disease (PD) remain to be elucidated. Homozygozity mapping and exome sequencing in 62 isolated individuals with early-onset parkinsonism and confirmed consanguinity followed by data mining in the exomes of 1,348 PD-affected individuals identified, in three isolated subjects, homozygous or compound heterozygous truncating mutations in vacuolar protein sorting 13C (VPS13C). VPS13C mutations are associated with a distinct form of early-onset parkinsonism characterized by rapid and severe disease progression and early cognitive decline; the pathological features were striking and reminiscent of diffuse Lewy body disease. In cell models, VPS13C partly localized to the outer membrane of mitochondria. Silencing of VPS13C was associated with lower mitochondrial membrane potential, mitochondrial fragmentation, increased respiration rates, exacerbated PINK1/Parkin-dependent mitophagy, and transcriptional upregulation of PARK2 in response to mitochondrial damage. This work suggests that loss of function of VPS13C is a cause of autosomal-recessive early-onset parkinsonism with a distinctive phenotype of rapid and severe progression.
Triggering receptor expressed on myeloid cells 2 (TREM2) homozygous mutations cause Nasu-Hakola disease, an early-onset recessive form of dementia preceded by bone cysts and fractures. The same type of mutations has recently been shown to cause frontotemporal dementia (FTD) without the presence of any bone phenotype. Here, we further confirm the association of TREM2 mutations with FTD-like phenotypes by reporting the first compound heterozygous mutation in a Turkish family.
This is the first time a FBXO7 mutation has been identified that causes a phenotype compatible with typical idiopathic PD and presents with some of its common nonmotor features, such as rapid eye movement sleep behavior disorder, depression, and anxiety.
Ataxia-telangiectasia (A-T) is an autosomal recessive inherited disease characterized by progressive childhood-onset cerebellar ataxia, oculomotor apraxia, choreoathetosis and telangiectasias of the conjunctivae. Further symptoms may be immunodeficiency and frequent infections, and an increased risk of malignancy. As well as this classic manifestation, several other non-classic forms exist, including milder or incomplete A-T phenotypes caused by homozygous or compound heterozygous mutations in the ATM gene. Recently, ATM mutations have been found in 13 Canadian Mennonites with early-onset, isolated, predominantly cervical dystonia, in a French family with generalized dystonia and in an Indian family with dopa-responsive cervical dystonia. In this article, we will describe a Turkish family with three affected sibs. Their phenotypes range from pure cervical dystonia associated with hand tremor to truncal and more generalized dystonic postures. Exome sequencing has revealed the potentially pathogenic compound heterozygous variants p.V2716A and p.G301VfsX19 in the ATM gene. The variants segregated perfectly with the phenotypes within the family. Both mutations detected in ATM have been shown to be pathogenic, and the α-fetoprotein, a marker of ataxia telangiectasia, was found to be increased. This report supports recent literature showing that ATM mutations are not exclusively associated with A-T but may also cause a more, even intra-familial variable phenotype in particular in association with dystonia.
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