Background: GTP cyclohydrolase I (GCH1) mutations are the commonest cause of Dopa-responsive dystonia (DRD). Clinical phenotypes can be broad, even within a single family. Methods: We present clinical, genetic and functional imaging data on a British kindred in which affected subjects display phenotypes ranging from DRD to Parkinson's disease (PD). Twelve family members were studied. Clinical examination, dopamine transporter (DAT) imaging, and molecular genetic analysis of GCH1 and the commonest known familial PD-related genes were performed. Results: We have identified a novel missense variant, c.5A > G, p.(Glu2Gly), within the GCH1 gene in affected family members displaying a range of phenotypes. Two affected subjects carrying this variant had abnormal DAT imaging. These two with abnormal DAT imaging had a PD phenotype, while the remaining three subjects with the novel GCH1 variant had normal DAT imaging and a DRD phenotype. Conclusions: We propose that this GCH1 variant is pathogenic in this family and these findings suggest that similar mechanisms involving abnormal GTP cyclohydolase I may underlie both PD and DRD. GCH1 genetic testing should be considered in patients with PD and a family history of DRD. © 2015 Published by Elsevier Ltd.

Background: GTP cyclohydrolase I (GCH1) mutations are the commonest cause of Dopa-responsive dystonia (DRD). Clinical phenotypes can be broad, even within a single family.Methods: We present clinical, genetic and functional imaging data on a British kindred in which affected subjects display phenotypes ranging from DRD to Parkinson's disease (PD). Twelve family members were studied. Clinical examination, dopamine transporter (DAT) imaging, and molecular genetic analysis of GCH1 and the commonest known familial PD-related genes were performed.Results: We have identified a novel missense variant, c.5A > G, p.(G1u2Gly), within the GCH1 gene in affected family members displaying a range of phenotypes. Two affected subjects carrying this variant had abnormal DAT imaging. These two with abnormal DAT imaging had a PD phenotype, while the remaining three subjects with the novel GCH1 variant had normal DAT imaging and a DRD phenotype.Conclusions: We propose that this GCH1 variant is pathogenic in this family and these findings suggest that similar mechanisms involving abnormal GTP cyclohydolase I may underlie both PD and DRD. GCHI genetic testing should be considered in patients with PD and a family history of DRD. (c) 2015 The Authors. Published by Elsevier Ltd.

Background: The combination of early-onset, progressive parkinsonism with pyramidal tract signs has been known as pallido-pyramidal or parkinsonian-pyramidal syndrome since the first description by Davison in 1954. Very recently, a locus was mapped in a single family with an overlapping phenotype, and an FBXO7 gene mutation was nominated as the likely disease cause. Methods: We performed clinical and genetic studies in two families with early-onset, progressive parkinsonism and pyramidal tract signs. Results: An FBXO7 homozygous truncating mutation (Arg498Stop) was found in an Italian family, while compound heterozygous mutations (a splice-site IVS7 + 1G/T mutation and a missense Thr22Met mutation) were present in a Dutch family. We also found evidence of expression of novel normal splice-variants of FBXO7. The phenotype associated with FBXO7 mutations consisted of early-onset, progressive parkinsonism and pyramidal tract signs, thereby matching clinically the pallido-pyramidal syndrome of Davison. The parkinsonism exhibits varying degrees of levodopa responsiveness in different patients. Conclusions: We conclusively show that recessive FBXO7 mutations cause progressive neurodegeneration with extrapyramidal and pyramidal system involvement, delineating a novel genetically defined entity that we propose to designate as PARK15. Understanding how FBXO7 mutations cause disease will shed further light on the molecular mechanisms of neurodegeneration, with potential implications also for more common forms of parkinsonism, such as Parkinson disease and multiple system atrophy.

Background: Mutations in the gene Leucine-Rich Repeat Kinase 2 (LRRK2) were recently identified as the cause of PARK8 linked autosomal dominant Parkinson's disease.Objective: To study recurrent LRRK2 mutations in a large sample of patients from Italy, including early (,50 years) and late onset familial and sporadic Parkinson's disease.Results: Among 629 probands, 13 (2.1%) were heterozygous carriers of the G2019S mutation.The mutation frequency was higher among familial (5.1%, 9/177) than among sporadic probands (0.9%, 4/452) (p,0.002), and highest among probands with one affected parent (8.7%, 6/ 69) (p,0.001).There was no difference in the frequency of the G2019S mutation in probands with early v late onset disease.Among 600 probands, one heterozygous R1441C but no R1441G or Y1699C mutations were detected.None of the four mutations was found in Italian controls.Haplotype analysis in families from five countries suggested that the G2019S mutation originated from a single ancient founder.The G2019S mutation was associated with the classical Parkinson's disease phenotype and a broad range of onset age (34 to 73 years).Conclusions: G2019S is the most common genetic determinant of Parkinson's disease identified so far.It is especially frequent among cases with familial Parkinson's disease of both early and late onset, but less common among sporadic cases.These findings have important implications for diagnosis and genetic counselling in Parkinson's disease.