Distal hereditary motor neuronopathy of the Jerash type is caused by a novel SIGMAR1 c.500A>T missense mutation.

BACKGROUND: Distal hereditary motor neuronopathies (dHMN) are a group of genetic disorders characterised by motor neuron degeneration leading to muscle weakness that are caused by mutations in various genes. HMNJ is a distinct form of the disease that has been identified in patients from the Jerash region of Jordan. Our aim was to identify and characterise the genetic cause of HMNJ. METHODS: We used whole exome and Sanger sequencing to identify a novel genetic variant associated with the disease and then carried out immunoblot, immunofluorescence and apoptosis assays to extract functional data and clarify the effect of this novel SIGMAR1 mutation. Physical and neurological examinations were performed on selected patients and unaffected individuals in order to re-evaluate clinical status of patients 20 years after the initial description of HMNJ as well as to evaluate new and previously undescribed patients with HMNJ. RESULTS: A homozygous missense mutation (c.500A>T, N167I) in exon 4 of the SIGMAR1 gene was identified, cosegregating with HMNJ in the 27 patients from 7 previously described consanguineous families and 3 newly ascertained patients. The mutant SIGMAR1 exhibits reduced expression, altered subcellular distribution and elevates cell death when expressed. CONCLUSION: In conclusion, the homozygous SIGMAR1 c.500A>T mutation causes dHMN of the Jerash type, possibly due to a significant drop of protein levels. This finding is in agreement with other SIGMAR1 mutations that have been associated with autosomal recessive dHMN with pyramidal signs; thus, our findings further support that SIGMAR1 be added to the dHMN genes diagnostic panel.

Significance of the parkin and PINK1 gene in Jordanian families with incidences of young-onset and juvenile parkinsonism.

BACKGROUND: Parkinson's disease is a progressive neurodegenerative disorder, where most cases are sporadic with a late onset. In rare incidences familial forms of early-onset parkinsonism occur, and when recessively inherited, cases are often explained by mutations in either the parkin (PARK2) or PINK1 (PARK6) gene or on exceptional occasions the DJ-1 (PARK7) or ATP13A2 (PARK9) gene. Recessively inherited deletions/duplications and point mutations in the parkin gene are the most common cause of early-onset parkinsonism known so far, but in an increasing number of studies, genetic variations in the serine/threonine kinase domain of the PINK1 gene are found to explain early-onset parkinsonism. METHODS: In this study all families were from a population with a high incidence of consanguinity. We investigated 11 consanguineous families comprising 17 affected with recessively inherited young-onset parkinsonism for mutations both in the parkin and PINK1 gene. Exons and flanking regions were sequenced, and segregation patterns of genetic variation were assessed in members of the respective families. An exon dosage analysis was performed for all exons in both genes. RESULTS: In the parkin gene, a three generation family was identified with an exon 4 deletion segregating with disease. Both affected were homozygous for the deletion that segregated on a haplotype that spanned the gene in a haplotype segregation analysis that was performed using additional markers. Exon dosage analysis confirmed the recessive pattern of inheritance with heterozygous deletions segregating in healthy family members. In the PINK1 gene we identified two novel putative pathogenic substitutions, P416R and S419P, located in a conserved motif of the serine/threonine kinase domain. Both substitutions segregated with disease in agreement with a recessive pattern of inheritance within respective families and both were present as homozygous in two affected each. We also discuss common polymorphisms in the two genes found to be co-segregating within families. CONCLUSION: Our results further extend on the involvement of PINK1 mutations in recessive early-onset parkinsonism with clinical features similar to carriers of parkin mutations.

Multiple sclerosis in Jordan: A clinical and epidemiological study.

OBJECTIVES: To characterize the clinical, demographic and epidemiological features of multiple sclerosis (MS) in Jordan. METHODS: Data for consecutive Jordanian patients, fulfilling the McDonald criteria for clinically definite and clinically probable MS, during the time period 2004-2005 were collected and analyzed in the three major referral centers for MS in Jordan. RESULTS: We identified a total of 224 patients (165 females, 87%; 59 males, 13%). The mean (+/-SD) age of onset was 29.3 (+/-9.6) years, and mean (+/-SD) duration of illness was 3.9 (+/-9.3) years. The prevalence of MS in the city of Amman was 39/100,000. The prevalence of MS in Irbid, north Jordan, was 38/100,000. The most frequent presentation was weakness (30.8%), followed by optic neuritis (20.1%), sensory impairment (19.6%), and ataxia (14.3%). A relapsing remitting pattern was identified in 90.2% of patients, the rest being primary and secondary progressive, and one patient had a progressive relapsing course. Family history of MS was found in 9.4% of the cases. About 60% of the patients were using interferon beta. The degree of physical disability was determined using the Expanded Disability Status Scale (EDSS). Younger age of onset, shorter duration of illness, a relapsing remitting pattern, and use of interferon were identified as statistically significant predictors of less disability. CONCLUSION: Jordan is a medium-high risk country for MS, with prevalence higher than what has previously been reported, possibly representing an increase in incidence. Clinical and demographic characteristics are similar to most reports worldwide.