Gene/Protein Disease Symptom Drug Enzyme Compound
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Blepharophimosis syndrome (BPES) is an autosomal dominant disorder of craniofacial development, the features of which are small palpebral fissures (blepharophimosis), drooping eyelids (ptosis) and a skin fold arising from the lower eyelid (epicanthus inversus). The chromosomal localization and identity of the BPES locus is not known with certainty. In the current paper, DNA samples from three individuals with a clinical history of BPES, two with interstitial deletions (cases 1 and 2) and one with a balanced translocation (case 3) all involving chromosome 3q23, were analyzed. Allele loss studies using short tandem repeat markers in cases 1 and 2 suggested that the region between the markers D3S1292 and D3S1306 was deleted in both cases. Subsequently, the derived chromosomes resulting from the translocation in case 3 were segregated in interspecific somatic cell hybrids. Analysis of the resultant hybrids showed that D3S1615 was retained in the derived chromosome 3, whereas D3S1316 was retained in the derived chromosome 4. In neither case was the marker present in the reciprocal hybrid. These results indicate that the BPES critical region lies in the D3S1615-D3S1316 interval.
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PMID:Definition of the blepharophimosis, ptosis, epicanthus inversus syndrome critical region at chromosome 3q23 based on the analysis of chromosomal anomalies. 763 59

A high frequency of spontaneous chromosomal breakage, endomitosis, endoreduplication and hypersensitivity toward both the alkylating agent Trenimon and the radiomimetric drug bleomycin was observed in phytohemagglutinin-stimulated peripheral lymphocytes from a girl with craniosynostosis, microcephaly, ptosis, bird-like facies, and moderate mental retardation. We also observed abnormal chromosomal spiralization and some aspects of abnormal cellular division. Several fruitless attempts were made to establish a cell line. The parents were consanguineous, supporting the existence of a new, rare, autosomal, recessive condition in man. The mutation might involve a gene involved in DNA repair and/or regulation of the mitotic cycle.
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PMID:Chromosomal breakage, endomitosis, endoreduplication, and hypersensitivity toward radiomimetric and alkylating agents: a possible new autosomal recessive mutation in a girl with craniosynostosis and microcephaly. 769 75

The mode of inheritance of Kearns-Sayre syndrome (KSS) and chronic progressive external ophthalmoplegia (CPEO) have not yet been established, since most cases are sporadic. We studied skeletal muscle pathology and mitochondrial DNA (mtDNA) in a sporadic KSS patient (proband) and examined mitochondrial function of the muscle in his asymptomatic family members. The proband was a 56-year-old male with bilateral ptosis, external ophthalmoplegia, retinal degeneration and cardiac conduction disturbance. Biopsied deltoid muscle showed 9.7% of ragged red fibers without cytochrome oxidase (COX) activity and abnormal mitochondria on electron microscopy. Analysis of muscle mtDNA revealed a 4,977 bp deletion between nt. 8,483 and 13,459. None of the family members had symptoms similar to those of the proband. However, an aerobic exercise test of 15W for 15 minutes with an ergometer induced a marked increase in serum lactate levels in the proband's mother. Histology of her biopsied deltoid muscle showed 0.3% of ragged red fibers without COX activity and morphologically abnormal mitochondria. These findings indicate that the abnormal mitochondria of the proband were transmitted from his asymptomatic mother. This also suggests that some of the sporadic KSS/CPEO cases are inherited one.
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PMID:[A case of Kearns-Sayre syndrome whose asymptomatic mother had abnormal mitochondria in skeletal muscle]. 778 Dec 38

Molecular genetic analysis of five cases of 3p- syndrome (del(3)(qter-->p25:)) was performed to investigate the relationship between the molecular pathology and clinical phenotype. Fluorescence in situ hybridization studies and analysis of polymorphic DNA markers from chromosome 3p25-p26 demonstrated that all four informative cases had distal deletions. However, the extent of the deletion was variable: in two patients with the most extensive deletions the deletion breakpoint mapped between RAF1 and D3S1250, in one patient the deletion breakpoint was between D3S1250 and D3S601, and in two patients the deletion commenced telomeric to D3S601 (and telomeric to D3S1317 in one of these). All five patients displayed the classical features of 3p- syndrome (mental retardation, growth retardation, microcephaly, ptosis and micrognathia) demonstrating that loss of sequences centromeric to D3S1317 is not required for expression of the characteristic 3p- syndrome phenotype. The three patients with the most extensive deletions had cardiac septal defects suggesting that a gene involved in normal cardiac development is contained in the interval D3S1250 and D3S18. The PMCA2 gene is contained within this region and deletion of this gene may cause congenital heart defects. At least three patients were deleted for the von Hippel-Lindau (VHL) disease gene although none had yet developed evidence of VHL disease. We conclude that molecular analysis of 3p- syndrome patients enhances the management of affected patients by identifying those at risk for VHL disease, and can be used to elucidate the critical regions for the 3p- syndrome phenotype.
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PMID:Molecular genetic analysis of the 3p- syndrome. 795 Dec 34

We have investigated a 15 year old girl with progressive external ophthalmoplegia, including bilateral ptosis and retinal rod and cone cell dysfunction with atypical retinal pigmentation, complicated by cerebellar ataxia, partial cardiac conduction block, and diabetes mellitus. In infancy she had a severe crisis of bone marrow depression, and as a child she suffered from hypersensitivity to light, increasing fatigue, and vertigo, signs that were initially though to be psychosomatic. Histological examination showed mitochondrial myopathy, and subsequent mitochondrial DNA (mtDNA) analysis showed a deletion of approximately 5500 base pairs in 35 to 40% of her muscle mtDNA. We therefore conclude that this patient has developed the Kearns-Sayre syndrome after a Pearson syndrome-like crisis in her first year of life.
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PMID:Juvenile Kearns-Sayre syndrome initially misdiagnosed as a psychosomatic disorder. 815 37

We report a case of chronic progressive external ophthalmoplegia with pituitary hypothyroidism. This patient had complained of hearing-loss at the age of fourteen and loss of body weight at fifteen. She was examined by otorhinolaryngologists at large hospitals yearly over a period of 5-6 years, but hearing-loss remained unknown. As her ophthalmoplegia progressed (as is evident from family photographs from the age of sixteen onward), with hindsight it should have been recognized. When examined on October 11, 1991, she complained of ptosis, speech disturbance and dysphagia at the age of thirty-four. Neurological examination revealed limitation of ocular movement, bilateral ophthalmoplegia, facial muscle atrophy, and weak gag reflex. She showed muscle atrophy in her neck including both sternocleidomastoid, major and minor rhomboid, girdle and distal parts of upper and lower extremities. Muscle biopsy of her biceps demonstrated ragged-red fibers, cytochrome c oxidase (CCO) deficient fibers and deletion of mitochondrial DNA. A plain CT scan revealed bilateral periventricular lucency, and a brain MR image showed a normal sized pituitary gland but diffuse high-signal intensities in the both periventricular white matter with proton density weighted and T2-weighted axial MR image. And also her electroencephalogram showed diffuse 7 Hz slow waves in all areas and increased slow waves by hyperventilation, and all waves from I to V of the auditory brain stem response disappeared. The effect of TRH on serum TSH secretion was not evident in this patient. This case was ascertained to be chronic progressive external ophthalmoplegia with pituitary hypothyroid function.
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PMID:[A case of chronic progressive external ophthalmoplegia with pituitary hypothyroidism]. 821 98

Recent discoveries in mitochondrial clinical genetics have revealed that a broad spectrum of clinical phenotypes are associated with mutations in mitochondrial DNA. Diseases caused by mutations in mitochondrial DNA are by nature quantitative. Myoclonic epilepsy and ragged-red fiber disease are caused by a mutation in the transfer RNA gene lysine. Although everyone in a maternal lineage will harbor the same mutation, the nature and severity of the symptoms vary markedly among individuals. This variability correlates with the inherited percentage of mutations in the individual's mitochondrial DNA and the individual's age. Age-related expression of mitochondrial disease has also been demonstrated for mitochondrial DNA deletions. Although deletions that retain both origins of replication result in late-onset disease because of the progressive enrichment of the deleted mitochondrial DNA, a 10.4-kb deletion that lacks the light-strand replication origin and maintains a stable mutant percentage in both tissues and cultured cells has been discovered. This deletion is associated with adult-onset diabetes and deafness, but not with ophthalmoplegia, ptosis, or mitochondrial myopathy. Biochemically, it causes a generalized defect in mitochondrial protein synthesis and oxidative phosphorylation. The age-related decline in oxidative phosphorylation could reflect the accumulation of somatic mitochondrial DNA mutations. Inhibition of oxidative phosphorylation stimulates this accumulation. The general paradigm for mitochondrial DNA diseases may be that inherited mutations inhibit the electron transport chain. This damages the mitochondrial DNA, further reducing oxidative phosphorylation. Ultimately, oxidative phosphorylation drops below the expression threshold of cells and tissues, and clinical symptoms appear.
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PMID:Mitochondrial DNA mutations in epilepsy and neurological disease. 829 23

We report a family of mitochondrial myopathy which appeared to be interited as an autosomal dominant trait. The proband is a 58-year-old Japanese male, who presented with bilateral ptosis, chronic progressive ophthalmopletia, dysphagia, and atrophy of proximal muscles in the upper extremities. There was no cataract or retinal degeneration. Serum creatine kinase (CK) and lactic acid levels were normal. Cardiac evaluations were normal. Muscle biopsy revealed 7% of ragged red fibers. Cytochrome c oxidase activity in the muscle was decreased to 50% of the control value. PCR analysis of muscle mitochondrial DNA revealed 3 large-scale deletions in the non-D-loop regions, ranging in size from 4.2 kb to 5.2 kb. His father, three siblings, and the two children had symptoms similar to the proband. We have reviewed forty-five individuals from six families, including our family, who had mitochondrial myopathy with autosomal dominant inheritance. Frequent manifestations include chronic progressive ophtalmoplegia (91.2%), ptosis (95.6%), hearing loss (72.7%), dysphagia (60.0%), limb weakness (74.1%), and respiratory muscle weakness (75.0%). Interestingly, there is no individual with retinal degeneration or cardiac involvement. Serum CK and lactic acid levels may be elevated. CT of the head is normal. Muscle biopsy shows ragged red fibers and the frequency of cytochrome c oxidase-negative fibers ranges from 0 to 38%. Multiple large-scale deletions of mitochondrial DNA, ranging in size from 4.2 to 8.3 kb, are found in the muscle, all of which are located in the non-D-loop region of the mitochondrial DNA. The multiplicity of deletions may be one to the characteristic features of this form of mitochondrial myopathy.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Mitochondrial myopathy with autosomal dominant inheritance--report of a family and review of the literature]. 831 87

We describe a 15-year-old boy with full-blown mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and chronic progressive external ophthalmoplegia (CPEO). He presented with visual disturbance, hearing impairment, continuous partial epilepsy on the right aspect of the face, and right hemiparesis since the age of 13. Four months later, he experienced another strokelike episode with continuous partial epilepsy on the left hand. Serial computed tomographic scans revealed bilateral parieto-occipital hypodense lesions with gyral enhancement and an additional low-density lesion in the right frontal area 4 months later, respectively. Results of laboratory examinations disclosed lactic acidosis and mitochondrial myopathy with many ragged-red fibers. To identify the defective gene in mitochondrial DNA, a simple molecular test was performed by using restriction endonuclease Apa I. A transition from A to G was found at nucleotide position 3243 of the tRNA(Leu) gene. Interestingly, the patient also had marked external ophthalmoplegia and ptosis commonly found in patients with CPEO. Therefore, we suggest that ophthalmoplegia also occurs in the MELAS syndrome.
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PMID:Ophthalmologic manifestations in MELAS syndrome. 836 52

Autosomal dominant progressive external ophthalmoplegia (adPEO) is a disorder characterized by ptosis, progressive weakness of the external eye muscles, and general muscle weakness. The patients have multiple deletions of mtDNA on Southern blots or in PCR analysis of muscle DNA and a mild deficiency of one or more respiratory-chain enzymes carrying mtDNA-encoded subunits. The pattern of inheritance indicates a nuclear gene defect predisposing to secondary mtDNA deletions. Recently, in one Finnish family, we assigned an adPEO locus to chromosome 10q 23.3-24.3 but also excluded linkage to this same locus in two Italian adPEO families with a phenotype closely resembling the Finnish one. We applied a random mapping approach to informative non-10q-linked Italian families to assign the second locus for adPEO and found strong evidence for linkage on chromosome 3p 14.1-21.2 in three Italian families, with a maximum two-point lod score of 4.62 at a recombination fraction of .0. However, in three additional families, linkage to the same chromosomal region was clearly absent, indicating further genetic complexity of the adPEO trait.
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PMID:An autosomal locus predisposing to multiple deletions of mtDNA on chromosome 3p. 864 40


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