Guilherme Riccioppo Rodrigues

Novel Pathogenic Mutations and Copy Number Variations in the VPS13A Gene in Patients With Chorea-Acanthocytosis

Chorea‐acanthocytosis (ChAc) is a rare autosomal recessive neurodegenerative disorder caused by loss of function mutations in the vacuolar protein sorting 13 homolog A (VPS13A) gene that encodes chorein. It is characterized by adult‐onset chorea, peripheral acanthocytes, and neuropsychiatric symptoms. In the present study, we performed a comprehensive mutation screen, including sequencing and copy number variation (CNV) analysis, of the VPS13A gene in ChAc patients. All 73 exons and flanking regions of VPS13A were sequenced in 35 patients diagnosed with ChAc. To detect CNVs, we also performed real‐time quantitative PCR and long‐range PCR analyses for the VPS13A gene on patients in whom only a single heterozygous mutation was detected. We identified 36 pathogenic mutations, 20 of which were previously unreported, including two novel CNVs. In addition, we investigated the expression of chorein in 16 patients by Western blotting of erythrocyte ghosts. This demonstrated the complete absence of chorein in patients with pathogenic mutations. This comprehensive screen provides an accurate and useful method for the molecular diagnosis of ChAc.

Shape alterations in the striatum in chorea-acanthocytosis

Chorea-acanthocytosis (ChAc) is an uncommon autosomal recessive disorder due to mutations of the VPS13A gene, which encodes for the membrane protein chorein. ChAc presents with progressive limb and orobuccal chorea, but there is often a marked dysexecutive syndrome. ChAc may first present with neuropsychiatric disturbance such as obsessive-compulsive disorder (OCD), suggesting a particular role for disruption to striatal structures involved in non-motor frontostriatal loops, such as the head of the caudate nucleus. Two previous studies have suggested a marked reduction in volume in the caudate nucleus and putamen, but did not examine morphometric change. We investigated morphometric change in 13 patients with genetically or biochemically confirmed ChAc and 26 age- and gender-matched controls. Subjects underwent magnetic resonance imaging and manual segmentation of the caudate nucleus and putamen, and shape analysis using a non-parametric spherical harmonic technique. Both structures showed significant and marked reductions in volume compared with controls, with reduction greatest in the caudate nucleus. Both structures showed significant shape differences, particularly in the head of the caudate nucleus. No significant correlation was shown between duration of illness and striatal volume or shape, suggesting that much structural change may have already taken place at the time of symptom onset. Our results suggest that striatal neuron loss may occur early in the disease process, and follows a dorsal-ventral gradient that may correlate with early neuropsychiatric and cognitive presentations of the disease.

Validity of the PHQ-2 for the screening of major depression in Parkinson's disease: Two questions and one important answer

Introduction: Depression is the most common psychiatric comorbidity in Parkinsons disease (PD), but is often under-diagnosed and under-recognized. Objectives: To evaluate and compare the psychometric qualities of the Patient Health Questionnaire (PHQ-2) and the depression item of the Unified Parkinsons Disease Rating Scale (UPDRS). Method: Cross-sectional study conducted at a movement disorders outpatient clinic. One hundred ten patients with a diagnosis of PD without dementia were evaluated. A neurologist administered the PHQ-2 and the UPDRS, and the diagnosis of major depression was performed using the structured clinical interview for DSM disorders – clinical version. Two self-rating scales (Zung Self-rating Depression Scale and 15-item Geriatric Depression Scale) were also used. Results: The prevalence of current depression in the sample was 25.5% (n = 28). The scores of the PHQ-2 discriminated between subjects with and without depression, with an area under the receiver operating characteristic curve of 0.90. The sensitivity and specificity for a cut-off score of three were 75% and 89%, respectively. The values for the depression item of the UPDRS were slightly lower. Conclusion: The PHQ-2 is a valid tool for screening depression in PD.

Huntington's disease-like 2 in Brazil--report of 4 patients.

Huntingtons disease‐like 2 (HDL2) is a neurodegenerative disorder found in people of African ancestry with clinical, radiological, and neuropathological manifestations similar to Huntingtons disease (HD). HDL2 is caused by a pathological expansion of CAG/CTG triplets in exon 2A of the JPH3 gene. We describe four cases of HDL2 from four unrelated families, and discuss their clinical findings. HDL2 should be considered in every patient with an HD‐like phenotype who tests negative for the HD mutation, even if African ancestry is not immediately apparent.

Validation and internal consistency of Patient Health Questionnaire-9 for major depression in Parkinson's disease

BACKGROUND depression is common in Parkinsons disease (PD), although frequently under-recognised. Among the scales used to investigate depressive features in PD, the Patient Health Questionnaire-9 (PHQ-9) has been largely used, but no specific cut-off scores for depression have been established thus far, which hinders the use of the PHQ-9 in clinical and research settings. OBJECTIVE we assessed the discriminant validity of the PHQ-9 in order to establish the best cut-off score for the diagnosis of major depression in PD patients. METHOD one hundred and ten patients with a diagnosis of PD without dementia were evaluated with the Structured Clinical Interview for DSM-IV (SCID), considered as the gold standard for the diagnosis of major depression. Eighty-four PD patients completed the PHQ-9, the 15-item Geriatric Depression Scale (GDS-15) and the Zung Self-rating Depression Scale (SDS). RESULTS the prevalence of current depression in the sample of PD patients was 25.5%. Maximal discrimination between depressed and non-depressed patients was reached with a cut-off score of 9 in the PHQ-9 (sensitivity of 100% and specificity of 83.1%). The internal consistency of the scale was 0.83 and, when used as a diagnostic instrument, the PHQ-9 had a sensitivity of 52.6% and specificity of 95.4%. The correlation coefficient between the PHQ-9 and the other two scales was 0.63. CONCLUSIONS the PHQ-9 is an adequate instrument for the screening-but not diagnosis-of depression in PD patients, with optimal sensitivity and specificity attained with a cut-off score of 9.

Chorea-acanthocytosis: report of two Brazilian cases.

Chorea‐acanthocytosis (ChAc) is a neurodegenerative disorder characterized by chorea, neuropsychiatric disturbances and acanthocytosis, caused by mutations of VPS13A. This gene produces the protein chorein which is absent in patients with ChAc on Western blot assay. We report the first two Brazilian patients with ChAc confirmed by chorein detection. Patient 1 is a 36‐year‐old man with chorea, epilepsy, myopathy, and suicidal ideation. Patient 2 is a 60‐year‐old woman with a 30 year history of psychiatric disturbances, epilepsy, choreic movements, and myopathy. Both patients had acanthocytosis, elevated creatine kinase (CK), and absence of chorein on Western blot analysis. The presence of chorea and neuropsychiatric disturbances associated with elevated CK levels, epilepsy, hyporeflexia, and acanthocytosis suggests the diagnosis of ChAc. Chorein assay of peripheral blood confirms the diagnosis.

Neurodevelopmental disorders associated with dosage imbalance of ZBTB20 correlate with the morbidity spectrum of ZBTB20 candidate target genes

Background Recently, a number of patients have been described with structural rearrangements at 3q13.31, delineating a novel microdeletion syndrome with common clinical features including developmental delay and other neurodevelopmental disorders (NDD). A smallest region of overlapping deletions (SRO) involved five RefSeq genes, including the transcription factor gene ZBTB20 and the dopamine receptor gene DRD3, considered as candidate genes for the syndrome. Methods and results We used array comparative genomic hybridization and next-generation mate-pair sequencing to identify key structural rearrangements involving ZBTB20 in two patients with NDD. In a patient with developmental delay, attention-deficit hyperactivity disorder, psychosis, Tourette’s syndrome and autistic traits, a de novo balanced t(3;18) translocation truncated ZBTB20. The other breakpoint did not disrupt any gene. In a second patient with developmental delay and autism, we detected the first microdeletion at 3q13.31, which truncated ZBTB20 but did not involve DRD3 or the other genes within the previously defined SRO. Zbtb20 directly represses 346 genes in the developing murine brain. Of the 342 human orthologous ZBTB20 candidate target genes, we found 68 associated with NDD. Using chromatin immunoprecipitation and quantitative PCR, we validated the in vivo binding of Zbtb20 in evolutionary conserved regions in six of these genes (Cntn4, Gad1, Nrxn1, Nrxn3, Scn2a, Snap25). Conclusions Our study links dosage imbalance of ZBTB20 to a range of neurodevelopmental, cognitive and psychiatric disorders, likely mediated by dysregulation of multiple ZBTB20 target genes, and provides new knowledge on the genetic background of the NDD seen in the 3q13.31 microdeletion syndrome.

Increased frequency of hippocampal sclerosis ILAE type 2 in patients with mesial temporal lobe epilepsy with normal episodic memory

Sir, We read with interest the study of Coras et al. (2014) reporting the absence of verbal anterograde episodic memory (AEM) impairment in patients with mesial temporal lobe epilepsy (MTLE) with a hippocampal sclerosis ILAE type 2 classification (HS ILAE 2, i.e. CA1 predominant cell loss). This finding may provide an anatomical basis for the dissociation of anterograde/long-term episodic memory seen in some disorders like accelerated long-term forgetting (Butler et al. , 2007), which has not been explained …

Clinical and genetic analysis of 29 Brazilian patients with Huntington's disease-like phenotype

Huntingtons disease (HD) is a neurodegenerative disorder characterized by chorea, behavioral disturbances and dementia, caused by a pathological expansion of the CAG trinucleotide in the HTT gene. Several patients have been recognized with the typical HD phenotype without the expected mutation. The objective of this study was to assess the occurrence of diseases such as Huntingtons disease-like 2 (HDL2), spinocerebellar ataxia (SCA) 1, SCA2, SCA3, SCA7, dentatorubral-pallidoluysian atrophy (DRPLA) and chorea-acanthocytosis (ChAc) among 29 Brazilian patients with a HD-like phenotype. In the group analyzed, we found 3 patients with HDL2 and 2 patients with ChAc. The diagnosis was not reached in 79.3% of the patients. HDL2 was the main cause of the HD-like phenotype in the group analyzed, and is attributable to the African ancestry of this population. However, the etiology of the disease remains undetermined in the majority of the HD negative patients with HD-like phenotype.

Validity of the Brazilian version of the freezing of gait questionnaire

OBJECTIVE To validate the freezing of gait questionnaire (FOG-Q) for a Brazilian population of Parkinsons disease (PD) patients. METHODS One hundred and seven patients with a diagnosis of PD were evaluated by shortened UPDRS motor scale (sUPDRm), Hoehn and Yahr (HY), Schwab and England scale (SE), Berg balance scale (BBS), falls efficacy scale international (FES-I), gait and balance scale (GABS), and the FOG-Q Brazilian version. RESULTS 47.7% of PD patients had FOG episodes; this group had worse scores on sUPDRSm, FOGQ, FES-I, BBS, GABS and FOG item of UPDRS when compared to the PD group without FOG. The internal consistency was 0.86, intra-rater 0.82 and inter-rater 0.78. The FOG-Q Brazilian version was significantly correlated with items related to gait and balance. The ROC curve was 0.94, the sensitivity was 0.90and specificity was 0.92. CONCLUSION Our study suggests that the FOG-Q Brazilian version is a reliable and valid instrument for assessing FOG in PD patients.