Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Three siblings who suffered from progressive mental retardation, seizures, and rigidity showed degeneration of the cerebral cortex. This was manifested by severe to complete neuronal loss with astrogliosis and microgliosis. In one child a brain biopsy was performed at the age of 3 months. The only lesion found was large disorganized perinuclear mitochondria in the neurones. The possibility that the cerebral poliodystrophy is due to an inherited mitochondrial disorder is discussed.
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PMID:Progressive cerebral poliodystrophy--Alpers' disease. Disorganized giant neuronal mitochondria on electron microscopy. 464 49

We report the clinical, biochemical, and molecular genetic findings in a family with an unusual mitochondrial disease phenotype harboring a novel mtDNA tRNA glutamic acid mutation at position 14709. The proband and his sister presented with congenital myopathy and mental retardation and subsequently developed cerebellar ataxia. Other family members had either adult-onset diabetes mellitus with muscle weakness or adult-onset diabetes mellitus alone. Ragged-red and cytochrome c oxidase (COX)-negative fibers were present in muscle biopsies. Biochemical studies of muscle mitochondria showed reduced complex I and IV activities. The mtDNA mutation was heteroplasmic in blood and muscle in all matrilineal relatives analyzed. Primary myoblast, but not fibroblast, cultures containing high proportions of mutant mtDNA exhibited impaired mitochondrial translation. These observations indicate that mtDNA tRNA point mutations should be considered in the differential diagnosis of congenital myopathy. In addition they illustrate the diversity of phenotypes associated with this mutation in the same family and further highlight the association between mtDNA mutations and diabetes mellitus.
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PMID:Congenital encephalomyopathy and adult-onset myopathy and diabetes mellitus: different phenotypic associations of a new heteroplasmic mtDNA tRNA glutamic acid mutation. 772 55

Fourteen patients (10 boys, 4 girls) aged from 4 months to 14 years old were diagnosed with mitochondrial disease based on the clinical manifestations together with abnormal muscle mitochondrial morphologies. Their clinical diagnoses included Leigh syndrome, three; Menkes' syndrome, three; Kearns-Sayre syndrome, two; myoclonic epilepsy with ragged fibres, one; and infant-onset progressive myoclonic epilepsy, one; fatal infantile mitochondrial myopathy, one; fatty acid oxidation defect, two; and myopathy with cardiopathy, one. Organs involved other than muscles included central nervous system, ten; heart, six; eye, two; liver, two; and kidney, two. Clinical manifestations varied to include hypotonia, seizures, myoclonus, mental retardation, nystagmus, ataxia, ptosis, ophthalmoplegia, retinal degeneration, muscle atrophy, spasticity etc. Nine had an abnormal rise in lactate after glucose loading. Ragged-red fibres were found in four patients. Abnormal mitochondrial morphology included abnormal accumulation, abnormal cristae pattern of tubular, concentric, or parallel form, some contained osmiophilic inclusion bodies. One patient of Leigh syndrome had had brain necropsy which showed intramyelin splitting of myelinated axons.
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PMID:Clinical manifestation of mitochondrial diseases in children. 821 54

Mitochondrial encephalomyopathy is a hereditary syndrome showing impairment of muscle and the central nervous system. In this disorder, the following three syndromes have been identified on the basis of characteristic symptoms: Kearns-Sayre syndrome (KSS), mitochondrial encephalomyopathy with lactic acidosis, and stroke-like episodes (MELAS), and myotonic epilepsy with ragged-red fibers (MERRF). In this report, we describe a case of mitochondrial encephalomyopathy with renal disease. A 25-year-old man was referred to our hospital in May, 1992 for evaluation of long-standing proteinuria. He had a small stature, exotropia and no pretibial edema. No mental retardation was observed. Urinary protein excretion was 2.0 g/day and urine sugar was negative. Laboratory examination revealed a serum urea nitrogen 19 mg/dl, and a creatinine value of 1.5 mg/dl. Creatinine clearance was 45.8 ml/min. His serum and spinal fluid lactate value were elevated. Biopsied muscle showed an absence of ragged-red fibers, and the presence of an A-to-G point mutation at nucleotide pari 3243 in the mitochondrial tRNA(Leu(UUR)) in peripheral blood leucocytes. He was thought to have MELAS. On the renal biopsy specimens, light microscopic examinations showed minor glomerular abnormalities with two glomerular collapses and tubulo-interstitial damage. Electron microscopic examinations showed partial thickening of the glomerular basement membrane. We report here this rare case of MELAS with renal disease, and also review seventeen cases of mitochondrial encephalopathy associated with renal disease. The existence of a relationship between mitochondrial disorder and renal damage remains obscure.
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PMID:[A case of mitochondrial encephalomyopathy (MELAS)]. 871 14

The Mohr-Tranebjaerg syndrome (MTS), a neurodegenerative syndrome characterized by progressive sensorineural hearing loss, dystonia, mental retardation and blindness, is a mitochondrial disease caused by mutations in the deafness/dystonia peptide 1 (DDP1) gene. DDP1 shows similarity to the yeast proteins Tim9, Tim10 and Tim12, components of the mitochondrial import machinery for carrier proteins. Here, we show that DDP1 belongs to a large family of evolutionarily conserved proteins. We report the identification, chromosomal localization and expressional analysis of six human family members which represent further candidate genes for neurodegenerative diseases.
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PMID:The mitochondrial TIM22 preprotein translocase is highly conserved throughout the eukaryotic kingdom. 1061 80

A variety of endocrine and metabolic defects, including hypothalamopituitary hypofunction and diabetes mellitus, has been reported in association with mitochondrial disorders. We describe two sisters affected by mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS) syndrome in whom DNA analysis showed an A-->G transition at the 3243rd nucleotide position on the transfer RNALeu(UUR) gene with 65% and 45% of mutant-type mitochondrial DNA present in the blood cells of the younger and the older sister, respectively. The younger sister had severe involvement of the central nervous system with mental retardation, epilepsia partialis continua, and strokelike episodes. Endocrine investigations showed an extensive neuroendocrine dysfunction with growth hormone deficiency, hypothalamopituitary hypothyroidism, prepubertal gonadotropin levels, and absence of any secondary sexual characteristics at the age of 12 6/12 years. The neurologically normal older sister was affected by diabetes mellitus and had normal hypothalamopituitary function. Our report confirms that the endocrine system can be affected differently by the same mitochondrial DNA mutation, depending on the heteroplasmia phenomenon. A complete endocrine evaluation must be performed in patients affected by mitochondrial disease and the existence of a mitochondrial disorder should be taken into account in patients with endocrine abnormalities, even if neuromuscular signs are lacking.
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PMID:Endocrine disorders in two sisters affected by MELAS syndrome. 1110 10

The vast majority of mitochondrial proteins are encoded as precursors by the nuclear genome. A major aspect of mitochondrial biogenesis is therefore the transfer of nuclear-encoded, cytosplasmically synthesized precursor proteins across and into the mitochondrial membranes. During the past years the use of simple model organisms such as the yeasts S. cerevisiae and N. crassa has helped considerably to identify and unravel the structure and function of a substantial number of components involved in targeting of nuclear-encoded preproteins to mitochondria. Several pathways and a number of components were characterized that are involved in guiding mitochondrial preproteins to their specific sites of function. In particular, import of nuclear-encoded precursor proteins into and across the mitochondrial inner membrane is mediated by two distinct translocases, the TIM23 complex and the TIM22 complex. Both TIM complexes cooperate with the general preprotein translocase of the outer membrane, TOM complex. The TIM complexes differ in the their substrate specificity. While the TIM23 complex mediates import of preproteins with a positively charged matrix targeting signal, the TIM22 complex facilitates the insertion of a class of hydrophobic proteins with internal targeting signals into the inner membrane. Most recently the rapid progress of research has allowed elucidation of a new mitochondrial disease on the molecular level. This rare X-linked progressive neurodegenerative disorder, named Mohr-Tranebjaerg (MT syndrome), is caused by mutations in the DDP1 gene and includes sensorineural deafness, blindness, mental retardation and a complex movement disorder. The analysis of the novel pathomechanism is based on the homology of the affected DDP1 protein to a family of conserved yeast components acting along the TIM22 pathway. This contribution briefly summarizes the current knowledge of the pathways of protein import and proposes a mechanism to explain how defective import leads to neurodegeneration.
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PMID:Import of proteins into mitochondria: a novel pathomechanism for progressive neurodegeneration. 1140 38

MEHMO (Mental retardation, Epileptic seizures, Hypogenitalism, Microcephaly and Obesity) is an X-linked disorder characterised by mental retardation, epileptic seizures, hypogenitalism, microcephaly and obesity. It was recently assigned to the locus Xp21.1-p22.13. We describe a child with MEHMO and lactic acidosis whose muscle biopsy revealed markedly reduced activities of complexes 1,3 and 4 of the mitochondrial electron transport chain. Histological staining showed mitochondrial proliferation and lipid storage. Electron microscopy revealed abnormal and enlarged mitochondria with concentric cristae and electron dense bodies. This is the first identification of MEHMO as a mitochondrial disorder and one of the very few X-linked mitochondrial syndromes.
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PMID:MEHMO (Mental retardation, Epileptic seizures, Hypogenitalism, Microcephaly, Obesity): a new X-linked mitochondrial disorder. 1203 29

The Mohr-Tranebjaerg syndrome (MTS) is a rare neurodegenerative disorder characterized by early-onset deafness, dystonia and further neurological abnormalities such as cortical blindness, spasticity, dementia and mental retardation. Causative mutations were identified within the deafness-dystonia peptide (DDP1/TIMM8a) gene on the X-chromosome. The DDP1 protein is located in the intermembrane space of human mitochondria. Here, it acts in a complex together with its partner protein Tim13 in a chaperone-like manner to facilitate the import of nuclear-encoded precursor proteins into the mitochondrial inner membrane. Thus, MTS is a novel type of mitochondrial disorder. To obtain more insight into the pathophysiology of this neurodegenerative disorder, we performed for the first time a comprehensive clinical and functional characterization of a patient suffering from MTS. This patient exhibited a typical combination of deafness, dystonia and visual loss. Sequence analysis of the patient's DDP1 gene revealed a G to C transversion at nucleotide position 38 of the first exon. The mutation affects the ATG start codon, thereby changing methionine to isoleucine (M1I), and leads to a complete absence of the DDP1 protein. In addition, the partner protein Tim13 was found to be significantly reduced, suggesting that Tim13 requires the presence of DDP1 for its stabilization. The assessment of mitochondrial functions showed the enzyme activities of the mitochondrial energy-generating systems to be normal in the muscle biopsy. Structural abnormalities or aggregations of mitochondria were absent. Electron microscopy revealed only a mild neurogenic atrophy. Neurophysiological investigations showed cochlear dysfunction and disturbance of visual pathways. PET and MRI studies revealed a multifocal pattern of neurodegeneration with hypometabolic areas predominantly located over the right striatum and parietal cortex and marked atrophy of the occipital lobes. Although the visual loss is caused predominantly by neurodegeneration of the visual cortex, degeneration of the retina and the optic nerve contributes to the visual impairment. The pathological changes in basal ganglia and sensory cortex demonstrate the disintegration of subcortico-cortical circuits and correlate well with the clinical presentation of multifocal dystonia. The data presented here showed that, in contrast to most of the known mitochondrial disorders, MTS appears not to be associated with a functional defect of the energy generation system of the mitochondria. Whereas the specific mitochondrial dysfunction leading to neuronal loss in MTS remains to be clarified, the electrophysiological and neuroimaging findings allowed the multifocal manifestation of neurodegenerative lesions in MTS to be characterized specifically.
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PMID:Clinical and molecular findings in a patient with a novel mutation in the deafness-dystonia peptide (DDP1) gene. 1280 99

We describe a 20-year-old 46,XY woman, with clinical findings of Fraser syndrome and three mitochondrial DNA (mtDNA) mutations of Leber hereditary optic neuropathy. The patient had microphthalmia, blindness, widely spaced nipples, bifid ureter, syndactyly of the toes, and mental retardation. Sonography showed the presence of a uterus and intra-abdominal gonads. The proband was screened for mtDNA mutations because of chronic gastrointestinal pseudo-obstruction, urinary tract dysmotility, seizures, mental retardation and persistent macrocytosis, as well as the intermittent elevation of methylmalonic acid. Analysis of point mutations by multiplex polymerase chain reaction and allele-specific oligonucleotide dot-blot hybridization revealed three homoplasmic mtDNA mutations, T14484C, T4216C, and T3394C. This represents a unique case with sex reversal, Fraser-like syndrome, and mitochondrial disease.
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PMID:Mitochondrial DNA mutations in a patient with sex reversal and clinical features consistent with Fraser syndrome. 1569 63


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