Peroxisome mosaics.
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ATPases Associated with Diverse Cellular Activitie↗
Biomedical subjects
Hanna Mandel
Publications and source records attributed to Hanna Mandel.
Resolution of the molecular defect in a patient with peroxisomal mosaicism in the liver.
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Adolescent↗
Phenotypic variability (heterogeneity) of peroxisomal disorders.
Peroxisomes perform a multitude of biosynthetic and catabolic functions, many of which are related to lipid metabolism. Peroxisomal disorders result either from deficiency of a single peroxisomal enzyme or protein, or from a defect in the complex mechanism of peroxisomal biogenesis, resulting in deficiency of several or multiple peroxisomal functions. These can be assessed by a battery of biochemical assays, enabling a biochemical phenotype to be defined that is specific and diagnostic for each of the peroxisomal disorders. Some peroxisomal disorders have unique and specific clinical phenotypes, which may be diagnostic. Others share patterns of clinical abnormalities (particularly neurological dysfunction, craniofacial dysmorphism, skeletal defects, sensory deafness, retinopathy) consistent with defined clinical phenotypes, but with considerable overlap and heterogeneity. To a certain extent, the clinical features of a particular disorder reflect the accumulation or deficiency of specific metabolites. Thus, the same clinical phenotypes may be caused by both single enzyme defects and PBDs. Furthermore, the same defect may present with different clinical phenotypes. In general, the severity of the clinical phenotype correlates with the degree of biochemical dysfunction. The clinical heterogeneity of peroxisomal disorders constitutes a diagnostic challenge demanding a high index of suspicion on the clinician's part.
Chondrodysplasia Punctata, Rhizomelic↗
Nonsyndromic paucity of interlobular bile ducts: report of 10 patients.
OBJECTIVES: Only a few reports of nonsyndromic paucity of interlobular bile ducts (NS-PILBD) have been published. The authors' aim was to outline the clinical and laboratory profile of patients with NS-PILBD diagnosed at a tertiary referral center. METHODS: The authors reviewed all the reports of pediatric liver biopsies performed between 1991 and 2000 at their institution. Upon diagnosis of NS-PILBD, patients' records were examined for clinical, laboratory, and histologic data, and liver biopsy specimens were re-evaluated. RESULTS: Three hundred biopsies were performed in children during the study period, of which 64 were in infants younger than 1 year. NS-PILBD was diagnosed in 10 of 64 (16%) biopsy specimens. Mean age at presentation was 10 days (range, 1 day-6 weeks), and mean follow-up was 4.5 years (range, 1-9 years). An underlying condition was identified in 70% of children with NS-PILBD: namely congenital cytomegalovirus (n = 2), progressive familial intrahepatic cholestasis (PFIC, n = 2), mitochondrial DNA depletion (n = 1), Niemann-Pick type C (n = 1), and arthrogryposis multiplex congenita, renal dysfunction, and cholestasis (ARC syndrome; n = 1). All children presented with jaundice. Four children had initially acholic stools. At their last follow-up visit, failure to thrive was present in five children, and cholestasis in six children. Mortality was noted only in children with metabolic diseases (n = 2). CONCLUSIONS: In the study, NS-PILBD was common in young children undergoing liver biopsy. Although NS-PILBD is nonspecific, a wide survey for inborn errors of metabolism should be included in the diagnostic work-up of NS-PILBD. In the authors' center, the association of certain metabolic diseases with NS-PILBD carries a grave prognosis.
Arthrogryposis↗
C7 complement deficiency in an Israeli Arab village.
Deficiencies of terminal complement components, particularly the latter ones, are often detected because of increased susceptibility to Neisserial infections. Herein we document the first report of C7 deficiency among a highly inbred Arab population living in the lower Galilee region of Israel. Both biochemical and molecular analysis were performed on samples from infected survivors and parents of children who succumbed to Neisserial infections in a 4-year period. Only the index case who suffered recurrent infections and a sibling who had not suffered an infection during the outbreak were found to be C7-deficient. The mutation was found to be the one previously described to be prevalent among Israeli Jews of Moroccan ancestry (mutation G1135C). The implications of this finding are discussed in the context of family pedigree, the protective effect of complement deficiency, and the clinical outcome.
Adolescent↗
Depletion of the other genome-mitochondrial DNA depletion syndromes in humans.
We present the current knowledge on the genetic and phenotypic aspects of mitochondrial DNA depletion syndromes. The human mitochondrial DNA encodes 13 of the 82 structural proteins of the mitochondrial electron transport chain. The replication and maintenance of the mtDNA require a large number of nuclear encoded enzymes and balanced nucleotide pools. Mitochondrial nucleotide synthesis is of major importance because of the constant need for nucleotides for mtDNA maintenance even in quiescent cells. As de novo enzymes are not present in the mitochondria, synthesis is accomplished via the salvage pathway. Defective mtDNA synthesis and maintenance manifest by multiple deletions or by depletion of the mitochondrial genome. Patients with multiple deletions typically present with progressive external ophthalmoplegia, ptosis and, exercise intolerance after the first decade of life. mtDNA depletion is usually an infantile disease characterized by severe muscle weakness, hepatic failure, or renal tubulopathy with fatal outcome. Linkage analysis in families with multiple mtDNA deletions reveal mutations in proteins that participate in mtDNA replication, the mitochondrial DNA polymerase gene, and the Twinkle gene, a putative mitochondrial helicase and in factors which play a role in mitochondrial nucleotide metabolism, the adenine nucleotide translocator, and the thymidine phosphorylase gene. We have recently identified mutations in an additional two essential proteins in the nucleotide salvage pathway, the mitochondrial deoxyribonucleoside kinases. The phenotype was distinctive for each gene, with hepatic failure and encephalopathy associated with mutations in the deoxyguanosine kinase gene and isolated devastating myopathy as the sole manifestation of thymidine kinase 2 deficiency. The tissue selectivity of these disorders and especially the exclusive muscle involvement in thymidine kinase 2 mutations is puzzling. The normal sequence of the remaining mtDNA copies in spite of a serious mitochondrial nucleotide imbalance is also unexpected. We propose several tissue-specific protective mechanisms and a time window, likely encompassing fetal life and even early infancy, during which nuclear nucleotide synthesis provides mitochondrial needs in all organs. We also speculate on future genes to be discovered in other phenotypes of mtDNA depletion.
Animals↗
A novel mutation in the deoxyguanosine kinase gene causing depletion of mitochondrial DNA.
Recently, a homozygous single-nucleotide deletion in exon 2 of the deoxyguanosine kinase gene (DGUOK) was identified as the disease-causing mutation in 3 apparently unrelated Israeli-Druze families with depleted hepatocerebral mitochondrial DNA. We have discovered a novel homozygous nonsense mutation in exon 3 of DGUOK (313C-->T) from a patient born to nonconsanguineous German parents. This finding shows that mutations in DGUOK causing mitochondrial DNA depletion are not confined to a single ethnic group.
Amino Acid Sequence↗