Gene/Protein Disease Symptom Drug Enzyme Compound
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A 7-year-old boy presented with bilateral ptosis and atypical retinitis pigmentosa. Before age two, he had had an Fe-refractory anemia, with neutropenia and thrombopenia. Just prior to the ophthalmic examination, the patient developed lactate acidosis, muscular hypotonia, ataxia and increased protein in the spinal fluid. Pancytopenia, pancreas dysfunction and growth retardation are the main features of Pearson's syndrome, most children not surviving beyond age three. The cause of Pearson's syndrome in our patient turned out to be a 5 kb deletion in the mitochondrial DNA. Similar deletions have been described in the Kearns-Sayre syndrome. It seems that children who survive the initial phase of Pearson's syndrome, may develop Kearns-Sayre syndrome.
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PMID:Kearns-Sayre's syndrome developing in a boy who survived pearson's syndrome caused by mitochondrial DNA deletion. 130 30

Waardenburg syndrome is a recognizable disorder characterized by autosomal dominant inheritance of pigmentary abnormalities of the eyes, hair, and skin sometimes associated with congenital hearing impairment. At least two different types of Waardenburg syndrome have been described. The different types of Waardenburg syndrome are differentiated as follows: type I, with dystopia canthorum; type II, without dystopia canthorum; and type III, without dystopia, with unilateral eyelid ptosis and skeletal abnormalities. Results of pooled linkage analysis done by a consortium of investigators suggests that Waardenburg syndrome type I is genetically heterogeneous, meaning that there is probably more than one genotype that can be associated with the findings typical of the syndrome. A mutated gene that can cause Waardenburg syndrome type I has been discovered. Either a single base pair substitution or an 18 base pair deletion in exon 2 has been found in affected individuals but is not found in unaffected members. Most likely, the mutated gene causes a perturbation in DNA binding of a paired domain, in turn having an effect on the regulation of other genes so the development and spatial orientation of cells and structures derived from the neural crest are affected. Forty years after Waardenburg syndrome was first described, a mutant gene has been found that is known to cause the syndrome. The process of discovery that has transpired in the time from syndrome description to gene identification has been one of steady progress and interdisciplinary cooperation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Finding the gene(s) for Waardenburg syndrome(s). 140 97

Two sisters in the first year of life presented with a proximal tubulopathy of unknown etiology. They subsequently developed a pluritissular disorder including diabetes mellitus, skin abnormalities, mitochondrial myopathy with ragged-red fibers, and cerebellar ataxia. Their mother had ptosis, ophthalmoplegia, and muscle weakness. Analysis of the mitochondrial respiratory chain showed a complex III deficiency in both skeletal muscle and lymphocytes of the second girl. Southern blot analysis provided evidence for a heteroplasmic partial duplication of the mtDNA (26 kb), involving one full-length and one partly deleted mitochondrial genome and with one single abnormal junction between the genes for ATPase 6 and cytochrome b. Using PCR amplification of lymphocyte DNA, we were able to detect minute amounts of duplicated molecules in the mother, which provided evidence for maternal inheritance of the partial duplication. While maternal transmission of point mutations have been reported in Leber disease, retinitis pigmentosa, and MERRF disease, this observation is, to our knowledge, the first example of a maternally inherited duplication of the mitochondrial genome in man.
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PMID:Maternally inherited duplication of the mitochondrial genome in a syndrome of proximal tubulopathy, diabetes mellitus, and cerebellar ataxia. 153 Nov 67

Spinocerebellar ataxial 1 (SCA1) is the locus name of autosomal dominant olivopontocerebellar atrophy (OPCA), and is assigned to the short arm of chromosome 6. The tight linkage between SCA1 and D6S89 has recently been reported. In order to examine possible locus heterogeneity, we studied linkage for D6S89 to disease loci in 16 pedigrees of dominant OPCA. D6S89 polymorphism was analysed with PCR amplification of genomic DNA by using specific oligonucleotide primers. Lod scores were computed by LIPED program with the correction of age-dependent penetrance. Homogeneity test was performed by using HOMOG program. Fifteen out of 16 pedigrees were informative to D6S89. Among them, 7 pedigrees showed positive and 8 pedigrees showed negative lod scores throughout all recombination fractions. Homogeneity testing disclosed that approximately 55% of pedigrees are linked to D6S89, and others were not linked. Our results provide evidences that dominant OPCA in Japan are genetically heterogenous. At now, it has been still unknown whether there are any clinico-pathological differences among OPCA genotypes. Based on the alpha-constant from homogeneity testing, we divided our pedigrees into linked-pedigree (SCA1) and nonlinked-pedigrees (nonSCA1). Then, clinical features were compared between these two groups. Hyperactive DTR was more common in SCA1 than nonSCA1 group. On the other hand, hypoactive DTR was more significantly dominated in nonSCA1 than SCA1. Slow saccade and Babinski sign were common in both groups. Although not statistically significant, nystagmus, exteral ophthalmoparesis, mydriasis, ptosis, facio-lingual twitching, and limb spasticity were more frequently observed in SCA1 than nonSCA1. These results indicate that there are possible correlation between disease genotype and phenotype.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Linkage study of hereditary olivopontocerebellar atrophy: genetic evidence for locus heterogeneity in Japanese cases]. 162 32

A 52-year-old woman with chronic progressive external ophthalmoplegia (CPEO) with familial hypercholesterolemia (FH) was reported. Her mother died from heart disease, and her elder sister has hypercholesterolemia with swelling of Achilles tendons. She had slowly progressive external ophthalmoplegia, bilateral ptosis, swelling of Achilles tendons since twenties. At 40 years of age, she was pointed out hypercholesterolemia. Physical examination was within normal limits except for bilateral swelling of Achilles tendons. Neurological findings showed bilateral ptosis, disturbance of eye movements, mild proximal muscle weakness and dysesthesia in bilateral hands. Routine laboratory findings were within normal limits except for high serum cholesterol level (512 mg/dl). In the biopsied muscle, there was mild variation in fiber size with several ragged-red fibers and focal cytochrome c oxidase defective fibers. Biochemical analysis of the biopsied muscle revealed normal values in the mitochondrial fraction. Southern blot analysis of the mitochondrial DNA (mtDNA) of the muscle disclosed mixed population of mtDNA, consisting of the normal one and partially deleted (4.9-kilobase). Southern blot analysis of the leukocytes from the patient against the cDNA of LDL receptor was normal at least using the restriction enzyme of BglII, XbaI, EcoRI, PvuII and BamHI. This case has CPEO with deleted mtDNA associated with familial hypercholesterolemia, which is caused to nuclear DNA abnormalities, and is thought to be an important case for us to study the relationship between deleted mtDNA and abnormal nuclear DNA in CPEO.
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PMID:[A case of chronic progressive external ophthalmoplegia associated with familial hypercholesterolemia]. 162 35

A 9-year-old girl and an 11-year-old boy had ptosis, progressive external ophthalmoplegia, pigmentary retinopathy, and sensorineural hearing loss. The girl had diabetes mellitus and the boy had hypoparathyroidism. Both children also developed recurrent vomiting and cerebral infarcts with lactic acidosis. Muscle biopsy specimens showed ragged-red fibers and Southern analysis demonstrated a distinct heteroplasmic deletion of muscle mitochondrial DNA in each patient but no evidence of the point mutation in the transfer RNALeu(UUR) gene recently identified in mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). These 2 children had combined features of Kearns-Sayre syndrome and MELAS, suggesting that mitochondrial DNA deletions occasionally can have pleomorphic clinical expression.
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PMID:Deletion of mitochondrial DNA in patients with combined features of Kearns-Sayre and MELAS syndromes. 189 71

The fuel preference of human muscle mitochondria has been given. Substrates which are oxidized with low velocity cannot be used to detect defects in oxidative phosphorylation. After general anaesthesia, the oxygen uptake with the different substrates is much lower than after local analgesia. The latter was therefore used in the subsequent study. In 15 out of 18 patients with ocular myopathy, defects in oxidative phosphorylation could be detected in isolated muscle mitochondria prepared from freshly biopsied tissue. Measurement of the activity of segments of the respiratory chain in homogenate from frozen muscle showed no, or minor defects. In two of these patients showing exercise intolerance, decreased oxidation of NAD(+)-linked substrates and apparently normal mitochondrial DNA, further study revealed deficiency of pyruvate dehydrogenase in a girl with ptosis and a high Km of complex I for NADH in a man. Both patients responded to vitamin therapy.
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PMID:Oxidative phosphorylation in human muscle in patients with ocular myopathy and after general anaesthesia. 211 84

Renal tubular acidosis and tetany were the 1st manifestations of Kearns-Sayre syndrome in a 5-year-old child. Subsequently, he developed progressive external ophthalmoplegia, ptosis, retinopathy, heart block, and endocrinopathy. There was a 7.5-kb deletion of mitochondrial DNA documented in muscle, kidney, skin fibroblasts, and leukocytes, providing evidence for a multisystem mitochondrial cytopathy.
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PMID:Kearns-Sayre syndrome presenting as renal tubular acidosis. 223 34

A 37-year-old man suffered from photosensitivity and urinary casts with serological findings of positive anti-DNA antibody, LE cells and false positive VD reaction in September of 1979. He developed general fatigue, dyspnea and diplopia with ptosis of bilateral eyelids in November of 1979, which were improved by the anti-cholinesterase drugs. In January of 1980, he had an attack of unconsciousness and his chest X-ray film showed several tumorous shadows in the anterior mediastinum and middle and lower lung fields. Treating him with chemotherapy of VEMP, the pulmonary shadows disappeared. However, he developed severe muscle weakness with an elevated CPK (430 mU/ml) and a myogenic EMG pattern along with an increased anti-acetylcholine receptor antibody (243 n Mol/l), dysphagia and eyelid-ptosis. He died in September of 1985 and his autopsy disclosed a malignant thymoma of mixed type in the anterior mediastinum and an atrophy and fibrosis with infiltration of inflammatory cells in the striated muscles.
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PMID:[An autopsy case of a patient with myasthenia gravis who showed various symptoms of collagen diseases and complicated with malignant thymoma]. 281 7

Mitochondrial myopathy, encephalopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome is one of the mitochondrial encephalomyopathies that has distinct clinical features including stroke-like episodes with migraine-like headache, nausea, vomiting, encephalopathy and lactic acidosis. We report a 27-year-old woman who presented with partial seizure, stroke-like episodes including hemiparesis, hemianopia and hemihypethesia, sensorineural hearing loss, migraine-like headache, and lactic acidosis. Brain computed tomographic scan showed encephalomalacia in the right parieto-occipital area and recent hypodensity in the left temporoparieto-occipital area with cortical atrophy. Muscle biopsy revealed ragged-red fibers and paracrystaline inclusions in the mitochondria. Genetic study revealed an A to G point mutation at nucleotide position (np) 3243 of mitochondrial DNA. External ophthalmoplegia and ptosis were also found during two exaggerated episodes in this patient. Therefore, the overlapping syndrome of chronic progressive external ophthalmoplegia in the MELAS syndrome is considered in this case. Furthermore, we also found carnitine deficiency in this patient and she was responsive well to steroid therapy. Muscle biopsy also revealed excessive lipid droplets deposits. Therefore, the carnitine deficiency may occur in MELAS syndrome with the A to G point mutation at np 3243. We recommend the steroid or carnitine supplement therapy be applied to the MELAS syndrome with carnitine deficiency.
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PMID:CPEO and carnitine deficiency overlapping in MELAS syndrome. 748 81


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