Truncating ARL6IP1 variant as the genetic cause of fatal complicated hereditary spastic paraplegia.

BACKGROUND: Mutations in ARL6IP1, which encodes a tetraspan membrane protein localized to the endoplasmic reticulum (ER), have been recently described in a large family with a complicated form of hereditary spastic paraplegia (HSP). CASE PRESENTATION: We sought to expand the HSP phenotype associated with ARL6IP1 variants by examining a Saudi kindred with a clinically more severe presentation, which resulted in spontaneous neonatal death of both affected siblings. Clinical features encompassed not only spastic paraplegia but also developmental delay, microcephaly, cerebral atrophy, periventricular leukoencephalopathy, hypotonia, seizures, spasticity, jejunal stricture, gastrointestinal reflux, neuropathy, dysmorphism and respiratory distress. We performed clinical assessment and radiological studies of this family, in addition to homozygosity mapping and whole exome sequencing (WES) to identify the disease-associated variant. Homozygosity mapping localized the causative gene to a region on chromosome 16 harboring ARL6IP1. WES of the index case identified the homoallelic nonsense variant, c.112C > T in ARL6IP1 that segregated with the phenotype and was predicted to result in loss of the protein. Allelic expression analysis of the parents demonstrated downward pressure on the mutant allele, suggestive of nonsense-mediated decay. CONCLUSIONS: Our report shows that the phenotype associated with ARL6IP1 variants may be broader and more acute than so far reported and identifies fatal HSP as the severe end of the phenotypic spectrum of ARL6IP1 variants.

Impact of the International Nosocomial Infection Control Consortium (INICC)'s multidimensional approach on rates of ventilator-associated pneumonia in intensive care units in 22 hospitals of 14 cities of the Kingdom of Saudi Arabia.

BACKGROUND: To analyze the impact of the International Nosocomial Infection Control Consortium (INICC) Multidimensional Approach (IMA) and use of INICC Surveillance Online System (ISOS) on ventilator-associated pneumonia (VAP) rates in Saudi Arabia from September 2013 to February 2017. METHODS: A multicenter, prospective, before-after surveillance study on 14,961 patients in 37 intensive care units (ICUs) of 22 hospitals. During baseline, we performed outcome surveillance of VAP applying the definitions of the CDC/NHSN. During intervention, we implemented the IMA and the ISOS, which included: (1) a bundle of infection prevention practice interventions, (2) education, (3) outcome surveillance, (4) process surveillance, (5) feedback on VAP rates and consequences and (6) performance feedback of process surveillance. Bivariate and multivariate regression analyses were performed using generalized linear mixed models to estimate the effect of intervention. RESULTS: The baseline rate of 7.84 VAPs per 1000 mechanical-ventilator (MV)-days-with 20,927 MV-days and 164 VAPs-, was reduced to 4.74 VAPs per 1000 MV-days-with 118,929 MV-days and 771 VAPs-, accounting for a 39% rate reduction (IDR 0.61; 95% CI 0.5-0.7; P 0.001). CONCLUSIONS: Implementing the IMA was associated with significant reductions in VAP rates in ICUs of Saudi Arabia.

Prospective multicentre study in intensive care units in five cities from the Kingdom of Saudi Arabia: Impact of the International Nosocomial Infection Control Consortium (INICC) multidimensional approach on rates of central line-associated bloodstream infection.

OBJECTIVE: To analyse the impact of the International Nosocomial Infection Control Consortium (INICC) Multidimensional Approach (IMA) and INICC Surveillance Online System (ISOS) on central line-associated bloodstream infection (CLABSI) rates in five intensive care units (ICUs) from October 2013 to September 2015. DESIGN: Prospective, before-after surveillance study of 3769 patients hospitalised in four adult ICUs and one paediatric ICU in five hospitals in five cities. During baseline, we performed outcome and process surveillance of CLABSI applying CDC/NHSN definitions. During intervention, we implemented IMA and ISOS, which included: (1) a bundle of infection prevention practice interventions; (2) education; (3) outcome surveillance; (4) process surveillance; (5) feedback on CLABSI rates and consequences; and (6) performance feedback of process surveillance. Bivariate and multivariate regression analyses were performed. RESULTS: During baseline, 4468 central line (CL) days and 31 CLABSIs were recorded, accounting for 6.9 CLABSIs per 1000 CL-days. During intervention, 12,027 CL-days and 37 CLABSIs were recorded, accounting for 3.1 CLABSIs per 1000 CL-days. The CLABSI rate was reduced by 56% (incidence-density rate, 0.44; 95% confidence interval, 0.28-0.72; P = 0.001). CONCLUSIONS: Implementing IMA through ISOS was associated with a significant reduction in the CLABSI rate in the ICUs of Saudi Arabia.

Novel mutations in TGM1 and ABCA12 cause autosomal recessive congenital ichthyosis in five Saudi families.

BACKGROUND: Autosomal recessive congenital ichthyosis (ARCI) is a rare disorder of keratinization. Infants (10-15%) born with this condition are encapsulated in hyperkeratotic membrane covering the entire body and are called "collodion babies." So far, mutations in nine different genes have been identified as causative and implicated in the pathogenesis of the clinically and genetically heterogeneous group of ARCI disorders. Among these, TGM1 is the gene most commonly mutated in ARCI. METHODS: We identified 11 patients from five consanguineous but unrelated families affected by ARCI. These patients manifested thick adherent polygonal large scales all over the body. All six patients with TGM1 mutations were born with collodion membrane and had ectropion and eclabium, while none of the patients with ABCA12 mutations had these features. Molecular investigations were performed using the combined approach of homozygosity mapping and Sanger sequencing. RESULTS: Here we report two novel mutations c.397_398insAGTATGAGTA (p.Tyr136Ter); c.977-978delCT (p.Ser326Cysfs*8) in TGM1 in three different, unrelated Saudi families and one novel mutation c.6900C>A (p.Phe2300Leu) and one reported mutation c.3470C>T (p.Ser1157Leu) in the ABCA12 gene in two unrelated Saudi families with ARCI. CONCLUSIONS: The identification of these homozygous variants using combined approaches of homozygosity mapping with direct sequencing are the disease causing mutations in these families. Furthermore, these findings are essential for the genetic diagnostic and prognostic workup with ARCI in Saudi patients.

Infantile-onset ascending hereditary spastic paraplegia with bulbar involvement due to the novel ALS2 mutation c.2761C>T.

Recessive mutations in the alsin gene cause three clinically distinct motor neuron diseases: juvenile amyotrophic lateral sclerosis (ALS2), juvenile primary lateral sclerosis (JPLS) and infantile-onset ascending hereditary spastic paraplegia (IAHSP). A total of 23 different ALS2 mutations have been described for the three disorders so far. Most of these mutations result in a frameshift leading to a premature truncation of the alsin protein. We report the novel ALS2 truncating mutation c.2761C>T; p.R921X detected by homozygosity mapping and sequencing in two infants affected by IAHSP with bulbar involvement. The mutation c.2761C>T resides in the pleckstrin domain, a characteristic segment of guanine nucleotide exchange factors of the Rho GTPase family, which is involved in the overall neuronal development or maintenance. This study highlights the importance of using homozygosity mapping combined with candidate gene analysis to identify the underlying genetic defect as in this Saudi consanguineous family.

A novel splice site mutation in ERLIN2 causes hereditary spastic paraplegia in a Saudi family.

Hereditary Spastic Paraplegias (HSP) encompass a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by insidiously progressive weakness and spasticity of the lower extremities. We describe a consanguineous Saudi family segregating a complicated form of HSP in an autosomal recessive pattern. The two affected siblings had early onset, cognitive, speech and motor involvement with spasticity of the lower extremities. Their upper extremities were mildly hypertonic. An intronic splice acceptor site mutation in ERLIN2 was found to be responsible for causing this disorder found in this family. ERLIN2 is a mediator of endoplasmic reticulum degradation pathway (ERAD) which helps to remove the aberrant proteins. Our results, in concurrence with previous studies suggest that alteration in ERLIN2 is one of the causes of complicated HSP, thereby increasing the spectrum of known mutations in SPG18.