Tuan Vu

Mitochondrial neurogastrointestinal encephalomyopathy: an autosomal recessive disorder due to thymidine phosphorylase mutations.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder defined clinically by severe gastrointestinal dysmotility; cachexia; ptosis, ophthalmoparesis, or both; peripheral neuropathy; leukoencephalopathy; and mitochondrial abnormalities. The disease is caused by mutations in the thymidine phosphorylase (TP) gene. TP protein catalyzes phosphorolysis of thymidine to thymine and deoxyribose 1‐phosphate. We identified 21 probands (35 patients) who fulfilled our clinical criteria for MNGIE. MNGIE has clinically homogeneous features but varies in age at onset and rate of progression. Gastrointestinal dysmotility is the most prominent manifestation, with recurrent diarrhea, borborygmi, and intestinal pseudo‐obstruction. Patients usually die in early adulthood (mean, 37.6 years; range, 26–58 years). Cerebral leukodystrophy is characteristic. Mitochondrial DNA (mtDNA) has depletion, multiple deletions, or both. We have identified 16 TP mutations. Homozygous or compound heterozygous mutations were present in all patients tested. Leukocyte TP activity was reduced drastically in all patients tested, 0.009 ± 0.021 μmol/hr/mg (mean ± SD; n = 16), compared with controls, 0.67 ± 0.21 μmol/hr/mg (n = 19). MNGIE is a recognizable clinical syndrome caused by mutations in thymidine phosphorylase. Severe reduction of TP activity in leukocytes is diagnostic. Altered mitochondrial nucleoside and nucleotide pools may impair mtDNA replication, repair, or both. Ann Neurol 2000;47:792–800

Mitochondrial involvement in Alzheimer’s disease

The causes of most neurodegenerative diseases, including sporadic Alzheimers disease (AD), remain enigmatic. There is, however, increasing evidence implicating mitochondrial dysfunction resulting from deafferentiation of disconnected neural circuits in the pathogenesis of energy deficit in AD. The patterns of reduced expression of both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) encoded genes is consistent with a physiological down-regulation of the mitochondrial respiratory chain in response to reduced neuronal activity. On the other hand, the role(s) of somatic cell or maternally inherited mtDNA mutations in the pathogenesis of mitochondrial dysfunction in AD are still controversial.

Mitochondrial DNA depletion Mutations in thymidine kinase gene with myopathy and SMA

Background: The mitochondrial DNA (mtDNA) depletion syndrome (MDS) is an autosomal recessive disorder of early childhood characterized by decreased mtDNA copy number in affected tissues. Recently, MDS has been linked to mutations in two genes involved in deoxyribonucleotide (dNTP) metabolism: thymidine kinase 2 (TK2) and deoxy-guanosine kinase (dGK). Mutations in TK2 have been associated with the myopathic form of MDS, and mutations in dGK with the hepatoencephalopathic form. Objectives: To further characterize the frequency and clinical spectrum of these mutations, the authors screened 20 patients with myopathic MDS. Results: No patient had dGK gene mutations, but four patients from two families had TK2 mutations. Two siblings were compound heterozygous for a previously reported H90N mutation and a novel T77M mutation. The other siblings harbored a homozygous I22M mutation, and one of them had evidence of lower motor neuron disease. The pathogenicity of these mutations was confirmed by reduced TK2 activity in muscle (28% to 37% of controls). Conclusions: These results show that the clinical expression of TK2 mutations is not limited to myopathy and that the myopathic form of MDS is genetically heterogeneous.

Mitochondrial DNA depletion and dGK gene mutations

Mitochondrial DNA depletion syndrome is a clinically heterogeneous group of disorders characterized by a reduction in mitochondrial DNA copy number. The recent discovery of mutations in the deoxyguanosine kinase (dGK) gene in patients with the hepatocerebral form of mitochondrial DNA depletion syndrome prompted us to screen 21 patients to determine the frequency of dGK mutations, further characterize the clinical spectrum, and correlate genotypes with phenotypes. We detected mutations in three patients (14%). One patient had a homozygous GATT duplication (nucleotides 763–766), and another had a homozygous GT deletion (nucleotides 609–610); both mutations lead to truncated proteins. The third patient was a compound heterozygote for two missense mutations (R142K and E227K) that affect critical residues of the protein. These mutations were associated with variable phenotypes, and their low frequencies suggests that dGK is not the only gene responsible for mitochondrial DNA depletion in liver. The patient with the missense mutations had isolated liver failure and responded well to liver transplantation, which may be a therapeutic option in selected cases.

Clinical manifestations of mitochondria1 DNA depletion

Objective We studied five new patients with mitochondrial DNA (mtDNA) depletion to better define the clinical spectrum of this disorder. Background mtDNA depletion has been associated with myopathy or hepatopathy, or both, in infants and young children. Involvement of the CNS and peripheral nervous system has not been clearly established. Methods We reviewed the clinical course and performed morphologic, biochemical, and genetic analyses of muscle samples from five patients. Results Age at onset ranged from 3 months to 5 years, and one patient survived until age 10% years. Two patients had laboratory and clinical features reminiscent of dystrophinopathy, two had evidence of brain involvement, and two had peripheral neuropathy. Muscle biopsy specimens in all patients showed abundant ragged-red fibers. Biochemistry showed cytochrome c oxidase deficiency in all patients tested and decreased activities of other respiratory chain complexes in some. Conclusions Inheritance appeared to be autosomal recessive, suggesting that mutations in nuclear DNA are responsible for mtDNA depletion. mtDNA depletion should be considered in children with mitochondria1 disorders of uncertain etiology, and criteria for diagnosis are proposed.

Navajo Neurohepatopathy Is Caused by a Mutation in the MPV17 Gene

Navajo neurohepatopathy (NNH) is an autosomal recessive disease that is prevalent among Navajo children in the southwestern United States. The major clinical features are hepatopathy, peripheral neuropathy, corneal anesthesia and scarring, acral mutilation, cerebral leukoencephalopathy, failure to thrive, and recurrent metabolic acidosis with intercurrent infections. Infantile, childhood, and classic forms of NNH have been described. Mitochondrial DNA (mtDNA) depletion was detected in the livers of two patients, suggesting a primary defect in mtDNA maintenance. Homozygosity mapping of two families with NNH suggested linkage to chromosome 2p24. This locus includes the MPV17 gene, which, when mutated, causes a hepatocerebral form of mtDNA depletion. Sequencing of the MPV17 gene in six patients with NNH from five families revealed the homozygous R50Q mutation described elsewhere. Identification of a single missense mutation in patients with NNH confirms that the disease is probably due to a founder effect and extends the phenotypic spectrum associated with MPV17 mutations.

X-Linked Dominant Scapuloperoneal Myopathy Is Due to a Mutation in the Gene Encoding Four-and-a-Half-LIM Protein 1

Scapuloperoneal (SP) syndrome encompasses heterogeneous neuromuscular disorders characterized by weakness in the shoulder-girdle and peroneal muscles. In a large Italian-American pedigree with dominant SP myopathy (SPM) previously linked to chromosome 12q, we have mapped the disease to Xq26, and, in all of the affected individuals, we identified a missense change (c.365G-->C) in the FHL1 gene encoding four-and-a-half-LIM protein 1 (FHL1). The mutation substitutes a serine for a conserved trypophan at amino acid 122 in the second LIM domain of the protein. Western blot analyses of muscle extracts revealed FHL1 loss that paralleled disease severity. FHL1 and an isoform, FHL1C, are highly expressed in skeletal muscle and may contribute to stability of sarcomeres and sarcolemma, myofibrillary assembly, and transcriptional regulation. This is the first report, to our knowledge, of X-linked dominant SP myopathy and the first human mutation in FHL1.

MNGIE NEUROPATHY: FIVE CASES MIMICKING CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY

We report five patients with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) who had demyelinating peripheral neuropathy. The MNGIE neuropathy had clinical and electrodiagnostic features typical of acquired, rather than inherited, etiologies. In fact, three patients were actually treated for chronic inflammatory demyelinating polyneuropathy (CIDP). We discuss findings that may help distinguish patients with MNGIE from those with CIDP. Muscle Nerve 29: 364–368, 2004

Mitochondrial myopathy simulating spinal muscular atrophy

A patient with a severe progressive neuromuscular disorder resembling spinal muscular atrophy is reported. The initial muscle biopsy was consistent with a denervating process. DNA analysis did not reveal deletions in exons 7 and 8 of the survival motor neuron gene. Histology, histochemistry, and biochemistry of a second muscle biopsy suggested mitochondrial myopathy accompanying the denervating features. Immunohistochemistry using anti-DNA antibodies revealed only nuclear staining in skeletal muscle, suggesting mitochondrial DNA depletion. In patients with clinical features of spinal muscular atrophy and no deletions in the survival motor neuron gene, mitochondrial DNA depletion should be considered.

Mitochondrial DNA depletion in a patient with long survival

We studied a 29-year-old woman with myopathy since childhood with evidence of mitochondrial DNA (mtDNA) depletion. Muscle biopsy sample showed cytochrome c oxidase (COX)-negative fibers. Biochemistry showed COX deficiency. Southern blot analysis showed 76% depletion of mtDNA as compared with controls. This patients clinical course suggests that long survival is possible in some patients with mtDNA depletion.