Let Time Teach You: A Case Report of a Double Diagnosis of 17P Duplication and Ehlers-Danlos Syndrome.

Kyphoscoliotic Ehlers-Danlos syndrome and 17p13.3 microduplication share multiple clinical features such as muscle hypotonia, cleft palate, and growth impairment. This paper describes a patient who was first diagnosed with the duplication and a decade later also with FKBP14-kEDS. The latter was initially overlooked due to the pathogenic significance attributed to the duplication and to the fact that, at the time of the first diagnosis, this specific form of kEDS had yet to be discovered. The patient's progressive kyphoscoliosis and severe joint laxity were the clinical features that prompted the patient's physiatrist to reassess the genetic work-up. This extreme latency caused inaccurate management in the patient's follow-up program, which ultimately may have resulted in preventable clinical complications. This report underlines the importance of remaining up-to-date with patient status, reviewing old cases, and relying on specialist advice to reach a correct diagnosis.

Effect of primary lesions in cytoskeleton proteins on red cell membrane stability in patients with hereditary spherocytosis.

We investigated by targeted next generation sequencing the genetic bases of hereditary spherocytosis in 25 patients and compared the molecular results with the biochemical lesion of RBC membrane obtained by SDS-PAGE analysis. The HS diagnosis was based on available guidelines for diagnosis of congenital hemolytic anemia, and patients were selected because of atypical clinical presentation or intra-family variability, or because presented discrepancies between laboratory investigation and biochemical findings. In all patients but 5 we identified pathogenic variants in SPTA1, SPTB, ANK1, SLC4A1, EPB42 genes able to justify the clinical phenotype. Interestingly, a correspondence between the biochemical lesion and the molecular defect was identified in only 11/25 cases, mostly with band 3 deficiency due to SLC4A1 mutations. Most of the mutations in SPTB and ANK1 gene didn't hesitate in abnormalities of RBC membrane protein; conversely, in two cases the molecular lesion didn't correspond to the biochemical defect, suggesting that a mutation in a specific cytoskeleton protein may result in a more complex RBC membrane damage or suffering. Finally, in two cases the HS diagnosis was maintained despite absence of both protein defect and molecular lesion, basing on clinical and family history, and on presence of clear laboratory markers of HS. The study revealed complex relationships between the primary molecular lesion and the final effect in the RBC membrane cytoskeleton, and further underlines the concept that there is not a unique approach to the diagnosis of HS.

VPS13C-associated Parkinson's disease: Two novel cases and review of the literature.

VPS13C is a protein-coding gene involved in the regulation of mitochondrial function through the endolysosomal pathway in neurons. Homozygous and compound heterozygous VPS13C mutations are etiologically associated with early-onset Parkinson's disease (PD). Moreover, recent studies linked biallelic VPS13C mutations with the development of dementia with Lewy bodies (DLB). Neuropathological studies on two mutated subjects showed diffuse Lewy body disease. In this article, we report the clinical and genetic findings of two subjects affected by early-onset PD carrying three novel VPS13C mutations (i.e., one homozygous and one compound heterozygous), and review the previous literature on the genetic and clinical findings of VPS13C-mutated patients, contributing to the knowledge of this rare genetic alpha-synucleinopathy.

Ehlers-Danlos syndrome caused by the c.934C>T, p. Arg312Cys mutation in COL1A1 gene: an Italian family without cardiovascular events.

Classic Ehlers-Danlos syndrome (cEDS) is characterized by skin hyperelasticity, joint hypermobility, increased tendency to bruise, and abnormal scarring. Mutations in type V collagen, a regulator of type I collagen fibrillogenesis, underlie this type of EDS. In this article we report a genetic and clinical analysis of an Italian family that carried missense mutation c.934 C>T (p.R312C) in the COL1A1 gene. Literature review showed an association between this missense mutation and vascular complications. Genetic screening conducted on Italian family members, revealed that vascular events are absent. In conclusion, genetic and clinical data confirm the extreme heterogeneity of EDS. Nevertheless, vascular events could be a risk factor and periodical clinical evaluation could be relevant.

Beyond 35 years of Parkinson's disease: a comprehensive clinical and instrumental assessment.

BACKGROUND: We sought to characterize the clinical, neuropsychological, electrophysiological, and neuroimaging features of Parkinson's disease (PD) after over 35 years since the onset of motor symptoms. METHODS: Five consecutively consenting PD patients treated with subthalamic nucleus deep brain stimulation (STN-DBS) were recruited in a cross-sectional study of motor (Unified PD Rating Scale section-III), non-motor (Non-Motor Symptoms Scale), autonomic (Scale for Outcome in PD-Autonomic), and neuropsychological features associated with the very advanced phase of PD. In addition, patients underwent neurophysiological (autonomic tests and nerve conduction studies) and neuroimaging (brain MRI, 123I-FP-CIT SPECT, and 123I-MIBG myocardial scintigraphy) studies, as well as a genetic analysis of 34 genes and single nucleotide polymorphisms associated with PD. RESULTS: There was a sustained motor response to L-dopa (range 14.4-35.6%), STN-DBS (23.3-38.4%), and L-dopa plus STN-DBS (37.8-63.0%). There were mild-to-moderate non-motor symptoms (range 19-83 on a scale of 0 to 360) and autonomic dysfunction (8-28 on a scale of 0-69). Two patients were demented, one had mild cognitive impairment, and two were cognitively preserved. Three patients had a sensory-axonal peripheral neuropathy and two a moderate-to-severe autonomic neuropathy. All cases showed a complete nigro-striatal dopaminergic denervation and a severe cardiovascular noradrenergic denervation. The brain MRI revealed only moderate frontal atrophy. The genetic tests were unremarkable. CONCLUSIONS: Even after more than 35 years of disease, L-dopa  and STN-DBS remain effective on PD cardinal symptoms. Although axial, autonomic, and neuropsychological features may become key determinants of disability, some patients maintain a satisfactory quality of life, without significant motor and non-motor impairment.

Mitochondrial dysfunction in Parkinsonian mesenchymal stem cells impairs differentiation.

Sporadic cases account for 90-95% of all patients with Parkinson's Disease (PD). Atypical Parkinsonism comprises approximately 20% of all patients with parkinsonism. Progressive Supranuclear Palsy (PSP) belongs to the atypical parkinsonian diseases and is histopathologically classified as a tauopathy. Here, we report that mesenchymal stem cells (MSCs) derived from the bone marrow of patients with PSP exhibit mitochondrial dysfunction in the form of decreased membrane potential and inhibited NADH-dependent respiration. Furthermore, mitochondrial dysfunction in PSP-MSCs led to a significant increase in mitochondrial ROS generation and oxidative stress, which resulted in decrease of major cellular antioxidant GSH. Additionally, higher basal rate of mitochondrial degradation and lower levels of biogenesis were found in PSP-MSCs, together leading to a reduction in mitochondrial mass. This phenotype was biologically relevant to MSC stemness properties, as it heavily impaired their differentiation into adipocytes, which mostly rely on mitochondrial metabolism for their bioenergetic demand. The defect in adipogenic differentiation was detected as a significant impairment of intracellular lipid droplet formation in PSP-MSCs. This result was corroborated at the transcriptional level by a significant reduction of PPARγ and FABP4 expression, two key genes involved in the adipogenic molecular network. Our findings in PSP-MSCs provide new insights into the etiology of 'idiopathic' parkinsonism, and confirm that mitochondrial dysfunction is important to the development of parkinsonism, independent of the type of the cell.

RETRACTED: Ehlers-Danlos syndrome caused by the c.934C>T, p. Arg312Cys mutation in COL1A1 gene: an Italian family without cardiovascular events.

The article entitled "Ehlers-Danlos syndrome caused by the c.934C>T, p. Arg312Cys mutation in COL1A1 gene: an Italian family without cardiovascular events" has been retracted because the description and characterization of the disease in a family may have been previously published. Upon publication of this article we were notified by an author of a study appearing in 2016 in another journal claiming that characteristics and symptoms of the family described closely matched their study, and that the two studies describe the same family. Whereas constituent family members appearing in both articles were not identical (differing by one member), symptoms and diagnoses of each family proband appeared to be consistent in both studies, leading to the editors' conclusion that it is likely that the same family was being described in two separate articles.The corresponding author of the article in Dermatology Online Journal was informed of this incident, and responded with the assertion that they were unaware of the study published in 2016, and provided no additional information. They further requested that their article be retracted. In light of the available information and author's request, the editors of Dermatology Online Journal have retracted this article.The original article was published on July15, 2018 and corrected on September 15, 2018.The original article was published on July15, 2018 and corrected on September 15, 2018.

A New COL3A1 Mutation in Ehlers-Danlos Syndrome Vascular Type With Different Phenotypes in the Same Family.

Vascular Ehlers-Danlos syndrome (vEDS) is a rare and severe connective tissue disorder caused by mutations in the collagen type III alpha I chain ( COL3A1) gene. We describe a pathogenetic heterozygous COL3A1 mutation c.3140 G>A, p. Gly1047Asp, identified using next-generation sequencing, in a 40-year-old Italian female. The genetic test performed on her relatives, which present different clinical phenotypes, confirmed that they carry the same mutation in heterozygous state. This finding confirms that mutations causing vEDS have an incomplete penetrance.

Survival and dementia in GBA-associated Parkinson's disease: The mutation matters.

OBJECTIVE: The objective of this work was to investigate survival, dementia, and genotype-phenotype correlations in patients with Parkinson's disease (PD) with and without mutations on the glucocerebrosidase gene (GBA). METHODS: We included 2,764 unrelated consecutive PD patients: 123 GBA carriers (67 mild-p.N370S and 56 severe mainly p.L444P) and 2,641 noncarriers. Brain perfusion and dopamine transporter imaging was analyzed, including dementia with Lewy Bodies (DLB) as an additional control group. RESULTS: Multivariable analysis adjusted by sex, age at onset, and disease duration attributed to GBA carriers a greater risk for dementia (hazard ratio [HR] = 3.16; p < 0.001) and death (HR = 1.85; p = 0.002) than noncarriers. When dementia was introduced in the model as a time-dependent covariate, the mortality risk remained greater in carriers (HR = 1.65; p = 0.016), suggesting that other clinical features are likely to contribute to reduced survival. At last examination, GBA carriers had worse motor symptoms, particularly nondopaminergic features. Carriers of severe mutations had greater risk for dementia compared to mild mutations (p < 0.001), but similar mortality risk. Consistent with clinical data, GBA carriers showed reduced posterior parietal and occipital cortical synaptic activity and nigrostriatal function than PD noncarriers. Neuroimaging features of carriers of mild mutations overlapped with PD noncarriers, whereas carriers of severe mutations were closer to DLB. INTERPRETATION: Survival is reduced in GBA carriers compared to noncarriers; this seems to be partially independent from the increased risk for early dementia. The risk for dementia is strongly modulated by type of mutation. In the clinical continuum between PD and DLB, patients with GBA mutations seem to localize midway, with carriers of severe mutations closer to DLB than to idiopathic PD. Ann Neurol 2016;80:662-673.