1,721,071 research outputs found
Genetic bases and experimental models for the study of inherited metabolic diseases
Full text linkInherited metabolic diseases are genetic disorders caused by the alteration of a specific metabolic reaction. We focused on the study of the genetic bases of two main types of metabolic disorders, mitochondrial diseases and urea cycle defects. In this work, we report the characterization of novel genes that are potentially involved in mitochondrial respiratory chain defects: we identified three novel COX-assembly genes required for Cytochrome c Oxidase (COX) biogenesis and two novel genes involved in coenzyme Q biosynthesis.These genes represent new candidates to be screened in patients with isolated COX defect or primary coenzyme Q deficiency, without mutations in other known genes. We then studied a family affected by coenzyme Q deficiency and found a homozygous mutation in the COQ2 gene, this is the first report of a mutation in a ubiquinone biosynthetic gene. Moreover, we developed a C.elegans model of COX defect in order to study the pathogenesis of this disease. Finally, we performed a mutational screening in a cohort of patients affected by argininosuccininc aciduria and developed a functional complementation assay using S.cerevisiae strain to prove the pathogenesis of the novel mutations; we also established some genotype-phenotype correlations
Regression of gadolinium-enhanced lesions in patients affected by neurofibromatosis type 1
No full textNeurofibromatosis type I is a genetic condition with an autosomal dominant transmission characterized by neurocutaneous involvement and a predisposition to tumor development. Central nervous system manifestations include benign areas of dysmyelination and possibly hazardous glial tumors whose clinical management may result challenging. Here, we report on three patients diagnosed with Neurofibromatosis type I whose brain MRI follow-up showed the presence of gadolinium-enhancing lesions which spontaneously regressed. In none of the three cases, the lesions showed any clinical correlate and eventually presented a striking reduction in size while gadolinium enhancement disappeared despite no specific therapy administration during the follow-up. Although their nature remains undetermined, these lesions presented a benign evolution. However, they might be misdiagnosed as potentially life-threatening tumors. Hitherto, a similar behavior has been described only in scattered cases and we believe these findings may be of particular interest for the clinical management of patients affected by neurofibromatosis type
Yeast complementation is sufficiently sensitive to detect the residual activity of ASL alleles associated with mild forms of argininosuccinic aciduria
No full textDemonstration that functional complementaiton in yeast can detect residual activity in hypomorphic ASL alleles and provide phenotype-genotype correlations for this disorder
Primary Coenzyme Q10 Deficiency
Full text linkCLINICAL CHARACTERISTICS:
Primary coenzyme Q10 (CoQ10) deficiency is usually associated with multisystem involvement, including neurologic manifestations such as fatal neonatal encephalopathy with hypotonia; a late-onset slowly progressive multiple-system atrophy-like phenotype (neurodegeneration with autonomic failure and various combinations of parkinsonism and cerebellar ataxia, and pyramidal dysfunction); and dystonia, spasticity, seizures, and intellectual disability. Steroid-resistant nephrotic syndrome (SRNS), the hallmark renal manifestation, is often the initial manifestation either as isolated renal involvement that progresses to end-stage renal disease (ESRD), or associated with encephalopathy (seizures, stroke-like episodes, severe neurologic impairment) resulting in early death. Hypertrophic cardiomyopathy (HCM), retinopathy or optic atrophy, and sensorineural hearing loss can also be seen.
DIAGNOSIS/TESTING:
The diagnosis of primary CoQ10 deficiency in a proband is established by identification of biallelic pathogenic variants in one of the nine genes encoding proteins directly involved in the synthesis of coenzyme Q10 or by detection of reduced levels of CoQ10 (ubiquinone) in skeletal muscle or reduced activities of complex I+III and II+III of the mitochondrial respiratory chain on frozen muscle homogenates.
MANAGEMENT:
Treatment of manifestations: In individuals with primary CoQ10 deficiency early treatment with high-dose oral CoQ10 supplementation (ranging from 5 to 50 mg/kg/day) can limit disease progression and reverse some manifestations; however, established severe neurologic and/or renal damage cannot be reversed. ACE inhibitors may be used in combination with CoQ10 supplementation in persons with proteinuria; renal transplantation is an option for those with ESRD. Treatment of hypertrophic cardiomyopathy, retinopathy, and sensorineural hearing loss is per usual practice. Prevention of primary manifestations: Supplementation with high-dose oral CoQ10 can prevent progression of the renal disease and onset of neurologic manifestations. Surveillance: Periodic neurologic evaluation, urine analysis (for proteinuria) and renal function tests, ophthalmologic evaluation, and audiometry. Evaluation of relatives at risk: Presymptomatic diagnosis for the purpose of early treatment with CoQ10 supplementation is warranted for relatives at risk.
GENETIC COUNSELING:
Primary coenzyme Q10 deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic diagnosis are possible if the pathogenic variants in a family are known
Clinical syndromes associated with Coenzyme Q10 deficiency.
Full text linkPrimary Coenzyme Q deficiencies represent a group of rare conditions caused by mutations in one of the genes required in its biosynthetic pathway at the enzymatic or regulatory level. The associated clinical manifestations are highly heterogeneous and mainly affect central and peripheral nervous system, kidney, skeletal muscle and heart. Genotype-phenotype correlations are difficult to establish, mainly because of the reduced number of patients and the large variety of symptoms. In addition, mutations in the same COQ gene can cause different clinical pictures. Here, we present an updated and comprehensive review of the clinical manifestations associated with each of the pathogenic variants causing primary CoQ deficiencies
Neurofibromatosis type 1 in two siblings due to Maternal Germline Mosaicism.
No full textNeurofibromatosis type 1 is caused by loss of function mutations of the NF1 gene, which are de novo in 50% of cases. Although this gene shows one of the highest mutation rates in the human genome, germline mosaicism is very rare in this condition. We describe the molecular analysis of a family in which Neurofibromatosis type 1 occurred in two out of four siblings born to unaffected parents. Molecular analysis of the NF1 gene identified in both patients the same splicing mutation c.1392+1G>A, which was absent in parental lymphocytes. Microsatellite analysis showed that the two affected siblings shared the same maternal allele, however a specific PCR-RFLP assay excluded the presence of the NF1 splicing mutation in multiple maternal tissues. Our molecular and clinical findings are consistent with a germline mosaicism for the NF1 splicing mutation. This is the first case of maternal germline mosaicism for a NF1 mutation characterized so far at the molecular level. Our data confirm that germline mosaicism is rare in Neurofibromatosis 1, but it has important implications for genetic counseling
OPA1 and Its Clinical Implications
No full textAutosomal dominant optic atrophy (ADOA) or Kjer disease (MIM #165500) is a primary inherited nonsyndromic
optic neuropathy that results in loss of retinal ganglion cells, leading to the clinical appearance of optic atrophy.
It is caused by mutations in optic atrophy 1 (OPA1), a dynamin-related protein of the inner mitochondrial
membrane. Recent evidence supports a role for OPA1 in the regulation of the process of cristae remodelling during
apoptosis, by which the complete release of mitochondrial stores of cytochrome c is achieved, supporting a
role for apoptosis in the pathogenesis of ADOA. Here we review the basic clinical features of ADOA, the biology of
OPA1and its role in the regulation of mitochondrial shape changes during apoptosis
Molecular Genetics of Argininosuccinic Aciduria
No full textArgininosuccinic aciduria is an autosomal recessive disorder of the urea cycle caused by mutations in argininosuccinate
lyase (ASL). Two main clinical phenotypes are reported: an acute neonatal form characterised by severe hyperammonaemia and coma, and a subacute, late-onset form which may present with relatively milder neurological
symptoms.
More than 120 ASL mutations have been reported so far: the majority are missense, but virtually all types of point mutations are found. Large rearrangements are rare and standard genomic deoxyribonucleic acid (DNA) analysis has a high diagnostic yield. Genotype–phenotype correlations have been difficult to establish as standard biochemical techniques are not sufficiently sensitive to measure residual activity, and other factors such as intragenic complementation, overexpression of nonfunctional ASL transcripts and environmental factors may modulate the phenotype.
Clinical manifestations result from the block in the urea cycle and also from impairment of nitric oxide biosynthesis, and the therapy is aimed at restoring these two functions
Coenzyme Q deficiency in muscle
Full text linkPURPOSE OF REVIEW:
Coenzyme Q (CoQ) is a vital component of the mitochondrial respiratory chain. A number of patients with CoQ deficiency presented with different clinical phenotypes, often affecting skeletal muscle, and responded well to CoQ supplementation. We discuss recent advances in this field with special attention to muscle involvement.
RECENT FINDINGS:
The identification of genetic defects causing CoQ deficiency has allowed to distinguish primary forms, due to mutations in biosynthetic genes, from secondary defects caused either by mutations in genes unrelated to CoQ biosynthesis or by nongenetic factors. To date, none of the patients with genetically proven primary deficiency presented with an exclusively (or prominently) myopathic phenotype. Most patients with myopathy were found to harbor other genetic defects (mutations in electron-transferring-flavoprotein dehydrogenase or mitochondrial DNA). The majority of patients with CoQ deficiency still lack a genetic diagnosis. The pathogenesis of CoQ deficiency cannot be attributed solely to the bioenergetic defect, suggesting that other roles of CoQ, including its antioxidant properties or its role in pyrimidine metabolism, may also play crucial roles.
SUMMARY:
Early recognition of CoQ deficiency is essential to institute appropriate and timely treatment, thus avoiding irreversible tissue damage
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