CADASIL in Arabs: clinical and genetic findings

<p>Abstract</p> <p>Background</p> <p>Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is increasingly recognized as an inherited arterial disease leading to a step-wise decline and eventually to dementia. CADASIL is caused by mutations in <it>NOTCH3 </it>epidermal growth factor-like repeat that maps to chromosome 19. CADASIL cases have been identified in most countries of Western and Central Europe, the Americas, Japan, Australia, the Caribbean, South America, Tanzania, Turkey, South Africa and Southeast Asia, but not in Arabs.</p> <p>Methods</p> <p>We studied three families from Saudi Arabia (Family A), Kuwait (Family B) and Yemen (Family C) with 19 individuals affected by CADASIL.</p> <p>Results</p> <p>The mean age of onset was 31 ± 6 and the clinical presentation included stroke in 68%, subcortical dementia in 17% and asymptomatic leukoariosis detected by MRI in 15%. Migraine and depression were frequently associated, 38% and 68% respectively. The mean age of death was 56 ± 11. All <it>NOTCH3 </it>exons were screened for mutations, which revealed the presence of previously reported mutations c.406C>T (p.Arg110>Cys) in two families (family A&B) and c.475C>T (p.Arg133>Cys) mutation in family C.</p> <p>Conclusion</p> <p>CADASIL occurs in Arabs, with clinical phenotype and genotype similar to that in other ethnic groups.</p

Clinical and Molecular Characterization of Ataxia with Oculomotor Apraxia Patients In Saudi Arabia

<p>Abstract</p> <p>Background</p> <p>Autosomal recessive ataxias represent a group of clinically overlapping disorders. These include ataxia with oculomotor apraxia type1 (AOA1), ataxia with oculomotor apraxia type 2 (AOA2) and ataxia-telangiectasia-like disease (ATLD). Patients are mainly characterized by cerebellar ataxia and oculomotor apraxia. Although these forms are not quite distinctive phenotypically, different genes have been linked to these disorders. Mutations in the <it>APTX </it>gene were reported in AOA1 patients, mutations in <it>SETX </it>gene were reported in patients with AOA2 and mutations in <it>MRE11 </it>were identified in ATLD patients. In the present study we describe in detail the clinical features and results of genetic analysis of 9 patients from 4 Saudi families with ataxia and oculomotor apraxia.</p> <p>Methods</p> <p>This study was conducted in the period between 2005-2010 to clinically and molecularly characterize patients with AOA phenotype. Comprehensive sequencing of all coding exons of previously reported genes related to this disorder (<it>APTX</it>, <it>SETX </it>and <it>MRE11</it>).</p> <p>Results</p> <p>A novel nonsense truncating mutation c.6859 C > T, R2287X in <it>SETX </it>gene was identified in patients from one family with AOA2. The previously reported missense mutation W210C in <it>MRE11 </it>gene was identified in two families with autosomal recessive ataxia and oculomotor apraxia.</p> <p>Conclusion</p> <p>Mutations in <it>APTX </it>, <it>SETX </it>and <it>MRE11 </it>are common in patients with autosomal recessive ataxia and oculomotor apraxia. The results of the comprehensive screening of these genes in 4 Saudi families identified mutations in <it>SETX </it>and <it>MRE11 </it>genes but failed to identify mutations in <it>APTX </it>gene.</p

Novel sequence variants detected in this study.

<p>Key: Heterozygous, Het; Homozygous, Homo; Familial, FM; Sporadic, SP; Not available, n.a.</p><p>* Frequency: No. of control carriers/ total No. of controls.</p><p>Novel sequence variants detected in this study.</p

Genetic characterization of <i>PARKIN</i> (p.G409R) and <i>PINK1</i> (p.E195Q) variants and their predicted functional impact.

<p>(A) Pedigree of FM 49 with LOPD. (B) Part of the sequencing chromatogram of <i>PINK1</i> exon 6 showing homozygous c.1225G>A mutation (corresponding to p.G409R substitution) in 49-a and 49-b but not in WT. (C) Part of the sequencing chromatogram of <i>PARKIN</i> exon 5 showing heterozygous c.583G>C variant (corresponding to p.E195Q substitution) in SP-7. (D) Ribbon presentation of PINK1^WT and PINK1^mut structural models. The secondary structures are colored as follows: β-strands (magenta), α-helices (cyan), coils (light pink). (E) PINK1^WT. (F) PINK1^mut. The spatial distance between the P+1 binding motif (cyan) and helix G (blue), measured in Angstrom (Å), is increased in PINK1^mut compared to PINK1^WT. A close-up view of the activation loop (aa 384–417) containing the P+1 binding motif and the helix G is represented [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0135950#pone.0135950.ref027" target="_blank">27</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0135950#pone.0135950.ref028" target="_blank">28</a>]. (G and H) p.E195Q has a very subtle impact on the protein conformation. Ribbon presentation of PARKIN^WT and PARKIN^mut structural models. The UPD, is shown in (yellow) or (cyan) in PARKIN^WT and PARKIN^mut, respectively. (G) Positions of the missing β-strand and α-helix are indicated by the asterisk and the hash symbols, respectively. (H) Superimposition of PARKIN^WT and PARKIN^mut showing parts of the protein (indicated by a hash symbol) that had lost the β-strand structure and adopted a random coil instead. Age at onset: AAO. Years: y. WT: wild-type.</p

Embracing Monogenic Parkinson's Disease: The MJFF Global Genetic PD Cohort

BACKGROUND: As gene-targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial-ready cohorts is limited. OBJECTIVE: The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants; (2) provide harmonized and quality-controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD. METHODS: We conducted a worldwide, systematic online survey to collect individual-level data on individuals with PD-linked variants in SNCA, LRRK2 VPS35, PRKN, PINK1, DJ-1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype-phenotype relationships were analyzed. RESULTS: We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35 429 PRKN, 75 PINK1, 13 DJ-1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34\%) were indicated as not previously published. CONCLUSIONS: Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD-linked variants; (2) provide harmonized and quality-controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene-targeted clinical trials. 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society