To study clinical response to treatment with enzyme replacement therapy (ERT) and substrate reduction therapy (SRT) in a cohort of Gaucher disease.
Retrospective data of 8 patients of Gaucher disease ...was compiled. The treatment included all three currently available enzyme replacement therapies as well as substrate reduction therapy with Eliglustat. The relevant blood investigations were done in follow-up visits. The assessment of the effects of long-term treatment over varying periods up to 13 y was done with various issues related to the course of therapy documented.
Improvement in hematological parameters was seen in all patients. Reduction of spleen size occurred in 7 of 8 patients (87.5%). One patient had 2 successful pregnancies while on therapy. A distinct patient with type 3 Gaucher disease developed complication in the form of Gaucheroma within the spleen.
Awareness about the disease and the efficacy of the therapies amongst pediatricians will help in early diagnosis and better outcomes. The available therapies have changed the outcome of the patients and improved the quality of life in patients with Gaucher disease. The data of Indian patients is important at this juncture when under Rare Disease Policy, government funding has become available for ERT for Gaucher disease patients in India.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background & objectives: Haemophilia is a debilitating bleeding disorder with significant comorbidities affecting the quality of life. In India, the management of these individuals is still limited ...to on-demand institutional treatment with coagulant factors. In this study, we highlighted the problems faced by these patients in the COVID-19 period due to nationwide lockdown.
Methods: A retrospective study was done to ascertain the trend in the number of patients with haemophilia A and B visiting the hospital, those succumbing to haemophilic complications and indications for factor requirement in the pre-COVID (October 2019-March 2020) and during the COVID-19 period (April-September 2020). Representative cases with unusual complications were described along with significant challenges faced in providing standard care of treatment to these individuals due to the COVID-19 pandemic.
Results: A total of 818 and 162 individuals with haemophilia A and B, respectively, were registered with the department. The overall number of patient visits to the hospital significantly reduced from an average of 6.9 outpatient department (OPD) visits per patient in the pre-COVID-19 period to an average of 3.9 OPD visits per patient and admissions reduced to 50 per cent during the COVID-19 period. This led to a reduction in utilization of factors VIII and IX except VIIa for haemophilia with inhibitors. There was no factor utilization for elective surgeries during the COVID-19 period. A total of eight patients succumbed to haemophilia-related complications during the COVID-19 period due to delay in reaching the hospital. The challenges faced in the management of three cases with musculoskeletal bleeds, one case with scrotal haematoma and one with haemothorax during the COVID-19 period were also highlighted.
Interpretation & conclusions: COVID-19 pandemic has unveiled the need for on-demand home treatment with coagulant factors and has also brought to light the existing need for primary prophylaxis, especially for younger individuals with haemophilia.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Peroxisome biogenesis disorders (PBDs) are a group of autosomal recessive disorders caused due to impaired peroxisome assembly affecting the formation of functional peroxisomes. PBDs are caused by a ...mutation in PEX gene family resulting in disease manifestation with extreme variability ranging from the onset of profound neurologic symptoms in newborns to progressive degenerative disease in adults. Disease causing variations in PEX7 is known to cause severe rhizomelic chondrodysplasia punctata type 1 and PBD 9B, an allelic disorder resulting in a milder phenotype, often indistinguishable from that of classic Refsum disease. This case report highlights the variability of PEX7 related phenotypes and suggests that other than RCDP1 and late onset phenotype similar to Refsum disease, some cases present with cataract and neurodevelopmetal abnormalities during childhood without chondrodysplasia or rhizomelia. This report also underlines the importance of considering PBD 9B in children presenting with neurodevelopmental abnormalities especially if they have congenital cataract.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
We describe two unrelated Indian boys with Mental retardation with language impairment with or without autistic features (OMIM#613670). Novel pathogenic variants c. 593_599 delins AGAAG and c.1556T>C ...in FOXP1 were identified in Patients 1 and 2, respectively by exome sequencing. The patients shared the cardinal features of significant language impairment, prominent forehead, downslanted palpebral fissures, frontal upsweep of hair, and behavioral abnormalities. Camptodactyly (with pterygia in Patient 2) was an additional feature noted in our study. The phenotype was consistent with previous reports of patients with monogenic defects in FOXP1. The facial features overlap with Sotos syndrome. However, presence of frontal upsweep of hair is a good pointer toward FOXP1 related syndromic intellectual disability.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background: Cytogenetic microarray (CMA) has brought a revolution in the field of cytogenetics by improving resolution by 500 times that of traditional karyotyping. Analysis and interpretation of ...whole genome copy number variations (CNVs) is quite a challenging task for clinicians. Some software packages and databases are available which are based on algorithm. However, there is no clear rule to decide the pathogenicity.
Objective: To formulate a step-wise approach to evaluate the interpretation of a CNV and to help the clinicians to interpret the CNV reported by a laboratory with help of four representative cases of different phenotypes.
Methods and Material: CMA was done using AffymetrixCytoscan 750K array in four cases from different families. Analysis was done based on the proposed approach.
Results: The prediction of the effect of these CNVs depends on multiple factors and can change over time as the databases are expanded. CMA in four cases from different families revealed, a rare co-occurrence of 22q13.3 duplication and 22q13.3 deletion in a proband, a deletion along with mosaicism on 10q21.2 and 10p15.3, respectively, in the second case. Third case resulted in one variant of unknown significance of 1.2 Kb deletion on 10q11.22 and the fourth case showed a benign CNV. All CNVs were analyzed based on the proposed approach and helped in subsequent management and counselling of the families. The results indicate the effectiveness of a principled, feature-based, statistical framework for uncharacterized CNV interpretation, which future studies can expand upon to construct more reliable classifiers.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Compaction of chromosomes is essential for accurate segregation of the genome during mitosis. In vertebrates, two condensin complexes ensure timely chromosome condensation, sister chromatid ...disentanglement, and maintenance of mitotic chromosome structure. Here, we report that biallelic mutations in NCAPD2, NCAPH, or NCAPD3, encoding subunits of these complexes, cause microcephaly. In addition, hypomorphic Ncaph2 mice have significantly reduced brain size, with frequent anaphase chromatin bridge formation observed in apical neural progenitors during neurogenesis. Such DNA bridges also arise in condensin-deficient patient cells, where they are the consequence of failed sister chromatid disentanglement during chromosome compaction. This results in chromosome segregation errors, leading to micronucleus formation and increased aneuploidy in daughter cells. These findings establish "condensinopathies" as microcephalic disorders, with decatenation failure as an additional disease mechanism for microcephaly, implicating mitotic chromosome condensation as a key process ensuring mammalian cerebral cortex size.
We report the third case of FADS due to biallelic DOK7 variants, which further strengthens the association of DOK7 with this lethal phenotype and lack of genotype phenotype correlation.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
FAR1
(MIM *616107) is required for the reduction of fatty acyl CoAs to fatty alcohols which is important for plasmalogen biosynthesis. Recently, heterozygous
de novo
variants in
FAR1
have been ...associated with cataracts, spastic paraparesis, and speech delay (MIM# 619338). Three different heterozygous
de novo
variants, all located in the same codon, causing substitution of arginine at position 480 into cysteine, histidine, or leucine, were reported in patients in the latter disorder.
Here, authors have identified a novel substitution in the same Arg480 position into serine. The authors also provide
in silico
docking analysis of the mutant protein.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
FIG4 related leukoencephalopathy has recently been considered as an expanded spectrum of FIG4 related disorders characterized by upper and lower motor neuron involvement, dystonia, intellectual ...disability, bulbar symptoms with cerebellar atrophy. We report a 7‐year‐old girl who presented with classic clinical features of FIG4 related leukoencephalopathy and neuroimaging showed characteristic T2 olivary nuclei hyperintensities in addition to bilateral parietal lobe and thalamic hyperintensities and mild cerebellar atrophy. Trio exome sequencing with Sanger confirmation revealed a novel variant c.504C>G in the FIG4 gene. Phase contrast microscopy of skin fibroblast cultures detect enlarged vacuoles in 50% of patient's fibroblasts as opposed to 18.6% vacuolation in cultured control fibroblasts (p < 0.00001), a feature characteristic of fibroblasts with deleterious variants of FIG4. In addition, we have reviewed and compared the phenotypic features of published cases of FIG4 related leukoencephalopathy from literature. This case adds to the delineation of FIG4 related leukoencephalopathy phenotype. The radiological finding of T2 inferior olivary nuclei hyperintensities appear to be characteristic for the phenotype or at least for the cases due to variants in and around the 168th codon and active effort should be made to detect the same as it can add to the genotype phenotype spectrum.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
10.
Renpenning syndrome in an Indian patient Masih, Suzena; Moirangthem, Amita; Phadke, Shubha R.
American journal of medical genetics. Part A,
February 2020, 2020-02-00, 20200201, Volume:
182, Issue:
2
Journal Article
Peer reviewed
Renpenning syndrome is one of the well‐characterized causes of X‐linked intellectual disability and is associated with microcephaly and various visceral malformations. Face is considered ...characteristic but the dysmorphism is subtle. Here we report an Indian adult with a very lean habitus, progressive atrophy of the upper back muscles, microcephaly, loss of cervical lordosis, and upper thoracic scoliosis. Using whole‐exome sequencing, a hemizygous deletion was identified in PQBP1 that leads to a frameshift and premature termination of translation. The loss of normal curvatures of cervical and upper thoracic spine due to muscular atrophy is a characteristic feature, though it may be age dependent.
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