Sindu Krishna

Fatal infantile cardioencephalomyopathy with COX deficiency and mutations in SCO2, a COX assembly gene.

Mammalian cytochrome c oxidase (COX) catalyses the transfer of reducing equivalents from cytochrome c to molecular oxygen and pumps protons across the inner mitochondrial membrane. Mitochondrial DNA (mtDNA) encodes three COX subunits (I–III) and nuclear DNA (nDNA) encodes ten. In addition, ancillary proteins are required for the correct assembly and function of COX (refs 2, 3, 4, 5, 6). Although pathogenic mutations in mtDNA-encoded COX subunits have been described, no mutations in the nDNA-encoded subunits have been uncovered in any mendelian-inherited COX deficiency disorder. In yeast, two related COX assembly genes, SCO1 and SCO2 (for synthesis of cytochrome c oxidase), enable subunits I and II to be incorporated into the holoprotein. Here we have identified mutations in the human homologue, SCO2, in three unrelated infants with a newly recognized fatal cardioencephalomyopathy and COX deficiency. Immunohistochemical studies implied that the enzymatic deficiency, which was most severe in cardiac and skeletal muscle, was due to the loss of mtDNA-encoded COX subunits. The clinical phenotype caused by mutations in human SCO2 differs from that caused by mutations in SURF1, the only other known COX assembly gene associated with a human disease, Leigh syndrome.

Maternally inherited hearing loss in a large kindred with a novel T7511C mutation in the mitochondrial DNA tRNASer(UCN) gene

Article abstract Thirty-six of 43 maternally related members of a large African American family experienced hearing loss. A muscle biopsy specimen from the proband showed cytochrome c oxidase (COX)-deficient fibers but no ragged-red fibers; biochemical analysis showed marked reduction of COX activity. A novel T7511C point mutation in the tRNASer(UCN) gene was present in almost homoplasmic levels (>95%) in the blood of 18 of 20 family members, and was also found in lower abundance in the other two. Single-fiber PCR showed that the mutational load was greater in COX-deficient muscle fibers. The tRNASer(UCN) gene may be a “hot spot” for mutations associated with maternally transmitted hearing loss.

A nonsense mutation (G15059A) in the cytochrome b gene in a patient with exercise intolerance and myoglobinuria

We describe a new mitochondrial DNA mutation in the cytochrome b gene in a patient presenting with progressive exercise intolerance and myoglobinuria associated with complex III deficiency in muscle. The point mutation results in the replacement of a glycine at amino acid position 190 with a stop codon. This change predicts premature termination of translation, leading to a truncated protein missing 244 amino acids at the C‐terminus of cytochrome b. The mutation fulfills all the accepted criteria for pathogenicity, suggesting that this is the primary cause of the myopathy in the patient. Ann Neurol 1999;45:127–130

Cockayne Syndrome in Adults: Review With Clinical and Pathologic Study of a New Case

Cockayne syndrome and xeroderma pigmentosum—Cockayne syndrome complex are rare autosomal recessive disorders with poorly understood biology. They are characterized by profound postnatal brain and somatic growth failure and by degeneration of multiple tissues resulting in cachexia, dementia, and premature aging. They result in premature death, usually in childhood, exceptionally in adults. This study compares the clinical course and pathology of a man with Cockayne syndrome group A who died at age 31½ years with 15 adequately documented other adults with Cockayne syndrome and 5 with xeroderma pigmentosum—Cockayne syndrome complex. Slowing of head and somatic growth was apparent before age 2 years, mental retardation and slowly progressive spasticity at 4 years, ataxia and hearing loss at 9 years, visual impairment at 14 years, typical Cockayne facies at 17 years, and cachexia and dementia in his twenties, with a retained outgoing personality. He experienced several transient right and left hemipareses and two episodes of status epilepticus following falls. Neuropathology disclosed profound microencephaly, bilateral old subdural hematomas, white-matter atrophy, tigroid leukodystrophy with string vessels, oligodendrocyte proliferation, bizarre reactive astrocytes, multifocal dystrophic calcification that was most marked in the basal ganglia, advanced atherosclerosis, mixed demyelinating and axonal neuropathy, and neurogenic muscular atrophy. Cellular degeneration of the organ of Corti, spiral and vestibular ganglia, and all chambers of the eye was severe. Rarely, and for unexplained reasons, in some patients with Cockayne syndrome the course is slower than usual, resulting in survival into adulthood. The profound dwarfing, failure of brain growth, cachexia, selectivity of tissue degeneration, and poor correlation between genotypes and phenotypes are not understood. Deficient repair of DNA can increase vulnerability to oxidative stress and play a role in the premature aging, but why patients with mutations in xeroderma pigmentosum genes present with the Cockayne syndrome phenotype is still not known. (J Child Neurol 2006;21:991—1006; DOI 10.2310/7010.2006.00088).

Maternally inherited cardiomyopathy: an atypical presentation of the mtDNA 12S rRNA gene A1555G mutation.

We thank Dr. Eduardo Bonilla for critical comments. This work was partially supported by National Institute of Child Health and Human Development program project PO1 HD32062, Telethon-Italy grant 844-1996 (to C.C.), Italian Ministry of Health grant 97/02/G/009 (to F.M.S.), and by grants from the Muscular Dystrophy Association. M.H. is supported by National Institutes of Health grant 1RO1 HL59657 and by the Columbia-Presbyterian Medical Center Irving Scholar program.

Missense mutation in the mtDNA cytochrome b gene in a patient with myopathy

A patient with progressive exercise intolerance, proximal weakness, and complex III deficiency in skeletal muscle had a missense mutation in the cytochrome b gene of mitochondrial DNA (G15762A). The mutation, which leads to the substitution of a highly conserved amino acid (G339E), was heteroplasmic (85%) in the patients muscle and was not present in 100 individuals of different ethnic backgrounds. These data strongly suggest that this molecular defect is the primary cause of the myopathy.

The G13513A Mutation in the ND5 Gene of Mitochondrial DNA as a Common Cause of MELAS or Leigh Syndrome: Evidence From 12 Cases

BACKGROUND The number of molecular causes of MELAS (a syndrome consisting of mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes) and Leigh syndrome (LS) has steadily increased. Among these, mutations in the ND5 gene (OMIM 516005) of mitochondrial DNA are important, and the A13513A change has emerged as a hotspot. OBJECTIVE To describe the clinical features, muscle pathological and biochemical characteristics, and molecular study findings of 12 patients harboring the G13513A mutation in the ND5 gene of mitochondrial DNA compared with 14 previously described patients with the same mutation. DESIGN Clinical examinations and morphological, biochemical, and molecular analyses. SETTING Tertiary care university hospital and molecular diagnostic laboratory. PATIENTS Three patients had the typical syndrome features of MELAS; the other 9 had typical clinical and radiological features of LS. RESULTS Family history suggested maternal inheritance in a few cases; morphological studies of muscle samples rarely showed typical ragged-red fibers and more often exhibited strongly succinate dehydrogenase-reactive blood vessels. Biochemically, complex I deficiency was inconsistent and generally mild. The mutation load was relatively high in the muscle and blood specimens. CONCLUSION The G13513A mutation is a common cause of MELAS and LS, even in the absence of obvious maternal inheritance, pathological findings in muscle, or severe complex I deficiency.

Identical Mitochondrial DNA Deletion in a Woman with Ocular Myopathy and in Her Son with Pearson Syndrome

Single deletions of mitochondrial DNA (mtDNA) are associated with three major clinical conditions: Kearns-Sayre syndrome, a multisystem disorder; Pearson syndrome (PS), a disorder of the hematopoietic system; and progressive external ophthalmoplegia (PEO), primarily affecting the ocular muscles. Typically, single mtDNA deletions are sporadic events, since the mothers, siblings, and offspring of affected individuals are unaffected. We studied a woman who presented with PEO, ptosis, and weakness of pharyngeal, facial, neck, and limb muscles. She had two unaffected children, but another of her children, an infant son, had sideroblastic anemia, was diagnosed with PS, and died at age 1 year. Morphological analysis of a muscle biopsy sample from the mother showed cytochrome c oxidase-negative ragged-red fibers-a typical pattern in patients with mtDNA deletions. Southern blot analysis using multiple restriction endonucleases and probed with multiple mtDNA fragments showed that both the mother and her infant son harbored an identical 5,355-bp single deletion in mtDNA, without flanking direct repeats. The deletion was the only abnormal species of mtDNA identified in both patients, and there was no evidence for duplications. We conclude that, although the vast majority of single large-scale deletions in mtDNA are sporadic, in rare cases, single deletions can be transmitted through the germline.

Mitochondrial myopathy and complex III deficiency in a patient with a new stop-codon mutation (G339X) in the cytochrome b gene

A 19-year-old woman complained of life-long exercise intolerance and had chronic lactic acidosis. Neurological examination was normal, but muscle biopsy showed cytochrome c oxidase-positive fibers and marked complex III deficiency. Sequence analysis showed a novel stop-codon mutation (G15761A) in the mitochondrial DNA (mtDNA)-encoded cytochrome b gene, resulting in loss of the last 41 amino acids of the protein. By PCR/restriction fragment-length polymorphism (RFLP) analysis, the G15761A mutation was very abundant (73%) in the patients muscle, barely detectable (less than 1%) in her urine, and absent in her blood; it was also absent in muscle, urine and blood from the patients mother. This mutation fulfills all accepted criteria for pathogenicity.

A5814G Mutation in Mitochondrial DNA Can Cause Mitochondrial Myopathy and Cardiomyopathy

We describe a 5-year-old child with hypertrophic cardiomyopathy, mitochondrial myopathy, and lactic acidosis. Mitochondrial DNA analysis showed a heteroplasmic A5814G point mutation in the tRNACys gene. The mutational load was extremely high (>95%) in muscle, fibroblasts, and blood. This report expands the clinical heterogeneity of the A5814G mutation, which should be considered in the differential diagnosis of hypertrophic cardiomyopathy in childhood. (J Child Neurol 2001;16:531-533).