| 1. |
- Ali, Zafar, et al.
(författare)
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Homozygous GRID2 missense mutation predicts a shift in the D-serine binding domain of GluD2 in a case with generalized brain atrophy and unusual clinical features
- 2017
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Ingår i: BMC Medical Genetics. - : Springer Science and Business Media LLC. - 1471-2350. ; 18:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Spinocerebellar ataxias comprise a large and heterogeneous group of disorders that may present with isolated ataxia, or ataxia in combination with other neurologic or non-neurologic symptoms. Monoallelic or biallelic GRID2 mutations were recently reported in rare cases with cerebellar syndrome and variable degree of ataxia, ocular symptoms, hypotonia and developmental delay.CASE PRESENTATION: We report on a consanguineous family with autosomal recessive childhood onset of slowly progressive cerebellar ataxia and delayed psychomotor development in three siblings. MRI of an adult and affected family member revealed slightly widened cerebral and cerebellar sulci, suggesting generalized brain atrophy, and mild cerebellar atrophy. Using whole exome sequencing we identified a novel homozygous missense variant [c.2128C > T, p.(Arg710Trp)] in GRID2 that segregates with the disease. The missense variant is located in a conserved region encoding the extracellular serine-binding domain of the GluD2 protein and predicts a change in conformation of the protein.CONCLUSION: The widespread supratentorial brain abnormalities, absence of oculomotor symptoms, increased peripheral muscle tone and the novel missense mutation add to the clinical and genetic variability in GRID2 associated cerebellar syndrome. The neuroradiological findings in our family indicate a generalized neurodegenerative process to be taken into account in other families segregating complex clinical features and GRID2 mutations.
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| 2. |
- Ebrahimi-Fakhari, Darius, et al.
(författare)
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Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic paraplegia
- 2020
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Ingår i: Brain. - OXFORD ENGLAND : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 143:10, s. 2929-2944
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Tidskriftsartikel (refereegranskat)abstract
- Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to prototypical yet poorly understood forms of childhood-onset and complex hereditary spastic paraplegia: SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). Here, we report a detailed cross-sectional analysis of clinical, imaging and molecular data of 156 patients from 101 families. Enrolled patients were of diverse ethnic backgrounds and covered a wide age range (1.0-49.3 years). While the mean age at symptom onset was 0.8 +/- 0.6 years [standard deviation (SD), range 0.2-5.0], the mean age at diagnosis was 10.2 +/- 8.5 years (SD, range 0.1-46.3). We define a set of core features: early-onset developmental delay with delayed motor milestones and significant speech delay (50% non-verbal); intellectual disability in the moderate to severe range; mild hypotonia in infancy followed by spastic diplegia (mean age: 8.4 +/- 5.1 years, SD) and later tetraplegia (mean age: 16.1 +/- 9.8 years, SD); postnatal microcephaly (83%); foot deformities (69%); and epilepsy (66%) that is intractable in a subset. At last follow-up, 36% ambulated with assistance (mean age: 8.9 +/- 6.4 years, SD) and 54% were wheelchair-dependent (mean age: 13.4 +/- 9.8 years, SD). Episodes of stereotypic laughing, possibly consistent with a pseudobulbar affect, were found in 56% of patients. Key features on neuroimaging include a thin corpus callosum (90%), ventriculomegaly (65%) often with colpocephaly, and periventricular white-matter signal abnormalities (68%). Iron deposition and polymicrogyria were found in a subset of patients. AP4B1-associated SPG47 and AP4M1-associated SPG50 accounted for the majority of cases. About two-thirds of patients were born to consanguineous parents, and 82% carried homozygous variants. Over 70 unique variants were present, the majority of which are frameshift or nonsense mutations. To track disease progression across the age spectrum, we defined the relationship between disease severity as measured by several rating scales and disease duration. We found that the presence of epilepsy, which manifested before the age of 3 years in the majority of patients, was associated with worse motor outcomes. Exploring genotype-phenotype correlations, we found that disease severity and major phenotypes were equally distributed among the four subtypes, establishing that SPG47, SPG50, SPG51 and SPG52 share a common phenotype, an 'AP-4 deficiency syndrome'. By delineating the core clinical, imaging, and molecular features of AP-4-associated hereditary spastic paraplegia across the age spectrum our results will facilitate early diagnosis, enable counselling and anticipatory guidance of affected families and help define endpoints for future interventional trials.
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| 3. |
- Fatima, Ambrin, et al.
(författare)
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Monoallelic and bi-allelic variants in NCDN cause neurodevelopmental delay, intellectual disability, and epilepsy
- 2021
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Ingår i: American Journal of Human Genetics. - : Cell Press. - 0002-9297 .- 1537-6605. ; 108:4, s. 739-748
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Tidskriftsartikel (refereegranskat)abstract
- Neurochondrin (NCDN) is a cytoplasmatic neural protein of importance for neural growth, glutamate receptor (mGluR) signaling, and synaptic plasticity. Conditional loss of Ncdn in mice neural tissue causes depressive-like behaviors, impaired spatial learning, and epileptic seizures. We report on NCDN missense variants in six affected individuals with variable degrees of developmental delay, intellectual disability (ID), and seizures. Three siblings were found homozygous for a NCDN missense variant, whereas another three unrelated individuals carried different de novo missense variants in NCDN. We assayed the missense variants for their capability to rescue impaired neurite formation in human neuroblastoma (SH-SY5Y) cells depleted of NCDN. Overexpression of wild-type NCDN rescued the neurite-phenotype in contrast to expression of NCDN containing the variants of affected individuals. Two missense variants, associated with severe neurodevelopmental features and epilepsy, were unable to restore mGluR5-induced ERK phosphorylation. Electrophysiological analysis of SH-SY5Y cells depleted of NCDN exhibited altered membrane potential and impaired action potentials at repolarization, suggesting NCDN to be required for normal biophysical properties. Using available transcriptome data from human fetal cortex, we show that NCDN is highly expressed in maturing excitatory neurons. In combination, our data provide evidence that bi-allelic and de novo variants in NCDN cause a clinically variable form of neurodevelopmental delay and epilepsy, highlighting a critical role for NCDN in human brain development.
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| 4. |
- Jameel, Muhammad, et al.
(författare)
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A novel AP4M1 mutation in autosomal recessive cerebral palsy syndrome and clinical expansion of AP-4 deficiency
- 2014
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Ingår i: BMC Medical Genetics. - : Springer Science and Business Media LLC. - 1471-2350. ; 15, s. 133-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:Cerebral palsy (CP) is a heterogeneous neurodevelopmental disorder associated with intellectual disability in one-third of cases. Recent findings support Mendelian inheritance in subgroups of patients with the disease. The purpose of this study was to identify a novel genetic cause of paraplegic CP with intellectual disability in a consanguineous Pakistani family.METHODS:We performed whole-exome sequencing (WES) in two brothers with CP and intellectual disability. Analysis of AP4M1 mRNA was performed using quantitative real-time PCR on total RNA from cultured fibroblasts. The brothers were investigated clinically and by MRI.RESULTS:We identified a novel homozygous AP4M1 mutation c.194_195delAT, p.Y65Ffs*50 in the affected brothers. Quantitative RT-PCR analysis showed markedly reduced AP4M1 mRNA levels suggesting partial non-sense mediated mRNA decay. Several clinical and MRI features were consistent with AP-4 complex deficiency. However, in contrast to previously reported cases with AP4M1 mutations our patients show an aggressive behavior and a relatively late onset of disease.CONCLUSION:This study shows an AP4M1 mutation associated with aggressive behavior in addition to mild dysmorphic features, intellectual disability, spastic paraparesis and reduced head circumference. Our findings expand the clinical spectrum associated with AP-4 complex deficiency and the study illustrates the importance of MRI and WES in the diagnosis of patients with CP and intellectual disability.
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| 5. |
- Nonyane, Bareng As, et al.
(författare)
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Equity improvements in maternal and newborn care indicators : results from the Bardiya district of Nepal
- 2016
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Ingår i: Health Policy and Planning. - : Oxford University Press (OUP). - 0268-1080 .- 1460-2237. ; 31:4, s. 405-414
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Tidskriftsartikel (refereegranskat)abstract
- Community-based maternal and newborn care interventions have been shown to improve neonatal survival and other key health indicators. It is important to evaluate whether the improvement in health indicators is accompanied by a parallel increase in the equitable distribution of the intervention activities, and the uptake of healthy newborn care practices. We present an analysis of equity improvements after the implementation of a Community Based Newborn Care Package (CB-NCP) in the Bardiya district of Nepal. The package was implemented alongside other programs that were already in place within the district. We present changes in concentration indices (CIndices) as measures of changes in equity, as well as percentage changes in coverage, between baseline and endline. The CIndices were derived from wealth scores that were based on household assets, and they were compared using t-tests. We observed statistically significant improvements in equity for facility delivery [CIndex: -0.15 (-0.24, -0.06)], knowledge of at least three newborn danger signs [-0.026(-0.06, -0.003)], breastfeeding within 1 h [-0.05(-0.11, -0.0001)], at least one antenatal visit with a skilled provider [-0.25(-0.04, -0.01)], at least four antenatal visits from any provider [-0.15(-0.19, -0.10)] and birth preparedness [-0.09(-0.12, -0.06)]. The largest increases in practices were observed for facility delivery (50%), immediate drying (34%) and delayed bathing (29%). These results and those of similar studies are evidence that community-based interventions delivered by female community health volunteers can be instrumental in improving equity in levels of facility delivery and other newborn care behaviours. We recommend that equity be evaluated in other similar settings within Nepal in order to determine if similar results are observed.
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| 6. |
- Saadi, Saadia Maryam, et al.
(författare)
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Genetic Investigation of Consanguineous Pakistani Families Segregating Rare Spinocerebellar Disorders
- 2023
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Ingår i: Genes. - : MDPI AG. - 2073-4425. ; 14:7
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Tidskriftsartikel (refereegranskat)abstract
- Spinocerebellar disorders are a vast group of rare neurogenetic conditions, generally characterized by overlapping clinical symptoms including progressive cerebellar ataxia, spastic paraparesis, cognitive deficiencies, skeletal/muscular and ocular abnormalities. The objective of the present study is to identify the underlying genetic causes of the rare spinocerebellar disorders in the Pakistani population. Herein, nine consanguineous families presenting different spinocerebellar phenotypes have been investigated using whole exome sequencing. Sanger sequencing was performed for segregation analysis in all the available individuals of each family. The molecular analysis of these families identified six novel pathogenic/likely pathogenic variants; ZFYVE26: c.1093del, SACS: c.1201C>T, BICD2: c.2156A>T, ALS2: c.2171-3T>G, ALS2: c.3145T>A, and B4GALNT1: c.334_335dup, and three already reported pathogenic variants; FA2H: c.159_176del, APTX: c.689T>G, and SETX: c.5308_5311del. The clinical features of all patients in each family are concurrent with the already reported cases. Hence, the current study expands the mutation spectrum of rare spinocerebellar disorders and implies the usefulness of next-generation sequencing in combination with clinical investigation for better diagnosis of these overlapping phenotypes.
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| 7. |
- Zakaria, Muhammad, et al.
(författare)
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Primary microcephaly, primordial dwarfism, and brachydactyly in adult cases with biallelic skipping of RTTN exon 42
- 2019
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 40:7, s. 899-903
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Tidskriftsartikel (refereegranskat)abstract
- Biallelic and pathogenic variants in the RTTN gene, encoding the centrosomal protein Rotatin, are associated with variable degrees of neurodevelopmental abnormalities, microcephaly, and extracranial malformations. To date, no reported case has reached their third decade. Herein, we report on a consanguineous family with three adult members, age 43, 57, and 60 years respectively, with primary microcephaly, developmental delay, primordial dwarfism, and brachydactyly segregating a homozygous splice site variant NM_173630.3:c.5648–5T>A in RTTN. The variant RTTN allele results in a nonhypomorphic skipping of exon 42 and a frameshift [(NP_775901.3:p.Ala1883Glyfs*6)]. Brain MRI of one affected individual showed markedly reduced volume of cerebral lobes and enlarged sulci but without signs of neural migration defects. Our assessment of three adult cases with a biallelic RTTN variant shows that a predicted shortened Rotatin, lacking the C‐terminal end, are associated with stationary clinical features into the seventh decade. Furthermore, our report adds brachydactyly to the phenotypic spectrum in this pleiotropic entity.
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| 8. |
- Zulfiqar, Shumaila, et al.
(författare)
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Identification of a novel variant in GPR56/ADGRG1 gene through whole exome sequencing in a consanguineous Pakistani family
- 2021
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Ingår i: Journal of clinical neuroscience. - : Elsevier. - 0967-5868 .- 1532-2653. ; 94, s. 8-12
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Tidskriftsartikel (refereegranskat)abstract
- GPR56 gene is best known for its pivotal role in cerebral cortical development. Mutations in GPR56 give rise to cobblestone-like brain malformation, white matter changes and cerebellar dysplasia. This study aimed to identify causative variant in a consanguineous family having five individuals affected with developmental delay, mild to severe intellectual disability, speech impairment, strabismus and seizures. Whole exome sequencing was performed to identify mutation in affected individuals. Variants were filtered and further validated by Sanger sequencing and segregation analysis. A novel frameshift variant c.1601dupT leading to p.Ala535GlyfsTer17) was identified in GPR56 gene by whole exome sequencing and subsequent filtering. All five affected individuals were homozygous for the mutant allele while four asymptomatic individuals carried the variant in heterozygous state. Radiological findings of a representative patient presented features of GPR56-associated cobblestone like brain malformation. MRI findings suggested paucity of sulci, dilated ventricular system and brainstem atrophy. The microgyria were observed in a simplified gyral pattern (cobblestone). This single bp insertion, and the consequent frame-shift, results in the truncation of GPR56 protein. This could result in a malformed cortex giving the brain a cobblestone like shape. Our study identified a 7th novel frameshift variant from Pakistani population in GPR56 gene, thus broadening mutation spectrum.
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| 9. |
- Zulfiqar, Shumaila, et al.
(författare)
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Whole exome sequencing identifies novel variant underlying hereditary spastic paraplegia in consanguineous Pakistani families
- 2019
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Ingår i: Journal of clinical neuroscience. - : Elsevier BV. - 0967-5868 .- 1532-2653. ; 67, s. 19-23
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Tidskriftsartikel (refereegranskat)abstract
- Hereditary Spastic paraplegias (HSPs) are heterogeneous group of degenerative disorders characterized by progressive weakness and spasticity of the lower limbs, combined with additional neurological features. This study aimed to identify causative gene variants in two nonrelated consanguineous Pakistani families segregating HSP. Whole exome sequencing (WES) was performed on a total of five individuals from two families including four affected and one phenotypically normal individual. The variants were validated by Sanger sequencing and segregation analysis. In family A, a novel homozygous variant c.604G > A (p.Glu202Lys) was identified in the CYP2U1 gene with clinical symptoms of SPG56 in 3 siblings. Whereas, a previously reported variant c.5769delT (p.Ser1923Argfs*28) in the SPG11 gene was identified in family B manifesting clinical features of SPG11 in 3 affected individuals. Our combined findings add to the clinical and genetic variability associated with CYP2U1 and SPG11 variants highlighting the complexity of HSPs. These findings further emphasize the usefulness of WES as a powerful diagnostic tool.
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