Gert Van Goethem - Academia.edu (original) (raw)

Papers by Gert Van Goethem

Research paper thumbnail of 3 generation pedigree with paternal transmission of the 22q11.2 deletion syndrome: Intrafamilial phenotypic variability

European journal of medical genetics, Jan 3, 2015

In this case report, we present a paternal transmission of a classic 3 Mb 22q11.2 deletion syndro... more In this case report, we present a paternal transmission of a classic 3 Mb 22q11.2 deletion syndrome (22q11.2 DS) in a 3 generation family. In this family a young girl, her father, her uncle and her grandfather were diagnosed with this disorder. All carriers showed phenotypic expression, there were no unaffected siblings in the second or third generation. Presenting symptoms in the patient in first generation (grandfather) were psoriatic arthritis, thrombocytopenia and a right aortic arch. There was no intellectual disability. The second generation uncle was known with a severe intellectual disability, mild facial characteristics, a septal defect and a clubfoot, whereas the second generation father had a tetralogy of Fallot, no intellectual disability and minimal facial characteristics. The third generation daughter had a moderate intellectual disability, hypernasal speech, triphalangeal thumb, severe speech and language development delay, pronounced facial characteristics and a diag...

Research paper thumbnail of Twinkle and POLG defects enhance age-dependent accumulation of mutations in the control region of mtDNA

Nucleic Acids Research, 2004

Autosomal dominant and/or recessive progressive external ophthalmoplegia (ad/arPEO) is associated... more Autosomal dominant and/or recessive progressive external ophthalmoplegia (ad/arPEO) is associated with mtDNA mutagenesis. It can be caused by mutations in three nuclear genes, encoding the adenine nucleotide translocator 1, the mitochondrial helicase Twinkle or DNA polymerase g (POLG). How mutations in these genes result in progressive accumulation of multiple mtDNA deletions in postmitotic tissues is still unclear. A recent hypothesis suggested that mtDNA replication in®delity could promote slipped mispairing, thereby stimulating deletion formation. This hypothesis predicts that mtDNA of ad/arPEO patients will contain frequent mutations throughout; in fact, our analysis of muscle from ad/arPEO patients revealed an agedependent, enhanced accumulation of point mutations in addition to deletions, but speci®cally in the mtDNA control region. Both deleted and nondeleted mtDNA molecules showed increased point mutation levels, as did mtDNAs of patients with a single mtDNA deletion, suggesting that point mutations do not cause multiple deletions. Deletion breakpoint analysis showed frequent breakpoints around homopolymeric runs, which could be a signature of replication stalling. Therefore, we propose replication stalling as the principal cause of deletion formation.

Research paper thumbnail of Recessive POLG mutations presenting with sensory and ataxic neuropathy in compound heterozygote patients with progressive external ophthalmoplegia

Neuromuscular Disorders, 2003

Autosomal recessive progressive external ophthalmoplegia is a mitochondrial disease characterized... more Autosomal recessive progressive external ophthalmoplegia is a mitochondrial disease characterized by accumulation of multiple largescale deletions of mitochondrial DNA. We previously reported missense mutations in POLG, the gene encoding the mitochondrial DNA polymerase gamma in two nuclear families compatible with autosomal recessive progressive external ophthalmoplegia. Here, we report a novel POLG missense mutation (R627W) in a sporadic patient and we provide genetic support that all these POLG mutations are actually causal and recessive. The novel patient presented with sensory ataxic neuropathy and has the clinical triad of sensory ataxic neuropathy, dysarthria and ophthalmoparesis (SANDO). This is the first finding of a genetic cause of Sensory Ataxic Neuropathy, Dysarthria and Ophthalmoparesis and it implies that this disorder may actually be a variant of autosomal recessive progressive external ophthalmoplegia. Sensory neuropathy is the initial feature in Belgian compound heterozygote autosomal recessive progressive external ophthalmoplegia patients, all carrying the POLG A467T mutation, which occurs at a frequency of 0.6% in the Belgian population. q

Research paper thumbnail of P79 What modifies the clinical presentation of the common homozygous p.A467T POLG mutation?

Neuromuscular Disorders, 2010

Research paper thumbnail of A novel Twinkle gene mutation in autosomal dominant progressive external ophthalmoplegia

Neuromuscular Disorders, 2003

Autosomal dominant progressive external ophthalmoplegia is a common neurological presentation of ... more Autosomal dominant progressive external ophthalmoplegia is a common neurological presentation of mitochondrial disease and is characterised by multiple deletions of mitochondrial DNA in muscle. We describe a family with autosomal dominant progressive external ophthalmoplegia caused by a novel heterozygous A to C transversion at nucleotide 956 of the Twinkle gene. The deltoid muscle biopsy of the index case revealed sparse respiratory deficient cells. Multiple mitochondrial DNA deletions were clearly evident in the index case by both long-range and real-time polymerase chain reaction assays but not by Southern blotting, highlighting the diagnostic difficulties associated with characterising patients with multiple mitochondrial DNA deletions. q

Research paper thumbnail of Progressive External Ophthalmoplegia Characterized by Multiple Deletions of Mitochondrial DNA: Unraveling the Pathogenesis of Human Mitochondrial DNA Instability and the Initiation of a Genetic Classification

NeuroMolecular Medicine, 2003

Over the last decade, many sporadic and familial cases have been reported with multiple deletions... more Over the last decade, many sporadic and familial cases have been reported with multiple deletions of mitochondrial DNA (mtDNA) in postmitotic tissues. Most patients suffer from progressive external ophthalmoplegia (PEO) and may have a nuclear gene defect that predisposes to the accumulation of mtDNA deletions. Recently, positional cloning has led to the discovery of mutations in four such nuclear genes. Some mutations are dominant and others recessive. In all autosomal mutations, defective mtDNA replication and/or repair are probably responsible for the generation of secondary mtDNA deletions. There are also data suggestive of a prominent pathogenic role for disturbed nucleotide metabolism. We here present a tentative genotype-phenotype correlation. Since clinical presentations are heterogeneous and overlap with different previously described clinical syndromes, we advocate the use of a genetic, instead of a clinical, classification of disorders with multiple mtDNA deletions.

Research paper thumbnail of POLG mutations in neurodegenerative disorders with ataxia but no muscle involvement

Neurology, 2004

Objective: To identify POLG mutations in patients with sensory ataxia and CNS features. Methods: ... more Objective: To identify POLG mutations in patients with sensory ataxia and CNS features. Methods: The authors characterized clinical, laboratory, and molecular genetic features in eight patients from five European families. The authors conducted sequencing of coding exons of POLG, C10orf2 (Twinkle), and ANT1 and analyzed muscle mitochondrial DNA (mtDNA), including Southern blot analysis and long-range PCR. Results: Ataxia occurred in combination with various CNS features, including myoclonus, epilepsy, cognitive decline, nystagmus, dysarthria, thalamic and cerebellar white matter lesions on MRI, and neuronal loss in discrete gray nuclei on autopsy. Gastrointestinal dysmotility, weight loss, cardiomyopathy, and valproate-induced hepatotoxicity occurred less frequently. Two patients died without preceding signs of progressive external ophthalmoplegia. In muscle, typical findings of mitochondrial disease, such as ragged red fibers and Southern blot mtDNA abnormalities, were absent. POLG mutations were present in eight patients, including two isolated cases, and one Finnish and two unrelated Belgian families contained in total six patients. All POLG mutations were recessive, occurring in a homozygous state in seven patients and in a compound heterozygous state in one patient. The novel W748S mutation was identified in five patients from three unrelated families. Conclusions: The clinical spectrum of recessive POLG mutations is expanded by sensory ataxic neuropathy, combined with variable features of involvement of CNS and other organs. Progressive external ophthalmoplegia, myopathy, ragged red fibers, and Southern blot abnormalities of muscle mitochondrial DNA also are not mandatory features associated with POLG mutations.

Research paper thumbnail of Patient homozygous for a recessive POLG mutation presents with features of MERRF

Neurology, 2003

Both dominant and recessive missense mutations were recently reported in the gene encoding the mi... more Both dominant and recessive missense mutations were recently reported in the gene encoding the mitochondrial DNA polymerase gamma (POLG) in patients with progressive external ophthalmoplegia (PEO). The authors report on a patient homozygous for a recessive missense mutation in POLG who presented with a multisystem disorder without PEO. The most prominent features were myoclonus, seizure, and sensory ataxic neuropathy, so the clinical picture overlapped with the syndrome of myoclonus, epilepsy, and ragged red fibers (MERRF).

Research paper thumbnail of Neurodegenerative parkinsonism and progressive external ophthalmoplegia with a Twinkle mutation

Research paper thumbnail of Polymerase gamma deficiency (POLG): Clinical course in a child with a two stage evolution from infantile myocerebrohepatopathy spectrum to an Alpers syndrome and neuropathological findings of Leigh’s encephalopathy

European Journal of Paediatric Neurology, 2012

Description of the clinical course in a child compound heterozygous for POLG1 mutations, neuropat... more Description of the clinical course in a child compound heterozygous for POLG1 mutations, neuropathology findings and results of dietary treatment based on fasting avoidance and long chain triglycerides (LCT) restriction. At 3(1/2) months of age the patient presented with severe hypoglycemia, hyperlactatemia, moderate ketosis and hepatic failure. Fasting hypoglycemia occurred 8 h after meals. The hypoglycemia did not respond to glucagon. She was supplemented with IV glucose and/or frequent feedings, but developed liver insufficiency which was reversed by long-chain triglyceride (LCT) restriction. Alpha-foeto-protein (AFP) levels were elevated and returned to low values after dietary treatment. Liver biopsy displayed cirrhosis, bile ductular proliferation, steatosis, isolated complex IV defect in part of the liver mitochondria, and mitochondrial DNA depletion (27% of control values). Two heterozygous mutations (p. [Ala467Thr] + p. [Gly848Ser]) were found in the POLG1 gene. At 3 years of age she progressively developed refractory mixed type seizures including a focal component and psychomotor regression which fulfilled the criteria of Alpers syndrome (AS) although the initial presentation was compatible with infantile myocerebrohepatopathy spectrum (MCHS). She died at 5 years of age of respiratory insufficiency. Neuropathologic investigation revealed lesions in the right striatal area and the inferior colliculi typical for Leigh's encephalopathy. The present patient showed an evolution from infantile MCHS to AS, and dietary treatment seemed to slow the progression of liver failure. In spite of the late clinical features of AS, it extends the neuropathological spectrum of AS and polymerase gamma deficiency (POLG) to Leigh syndrome lesions.

Research paper thumbnail of Abundance of the POLG disease mutations in Europe, Australia, New Zealand, and the United States explained by single ancient European founders

European Journal of Human Genetics, 2007

We reported previously that the DNA polymerase c (POLG) W748S mutation, a common cause of mitocho... more We reported previously that the DNA polymerase c (POLG) W748S mutation, a common cause of mitochondrial recessive ataxia syndrome (MIRAS), has a common ancient founder for all the disease chromosomes in Finland, Norway, United Kingdom, and Belgium. Here, we present results showing that the same ancestral chromosome underlies MIRAS and Alpers syndrome in Australia and New Zealand. Furthermore, we show that a second common POLG mutation, A467T, also shows common European ancestry: patients from Australia, New Zealand, and the United States share a common haplotype with the previously reported European patients. These data of ancestral haplotypes indicate that the POLG locus is quite stable and that the recessive W748S and A467T mutations, and probably also G848S, have occurred once in history. They have effectively spread to populations of European descent with carrier frequencies up to 1% in several populations. Our data predict that these mutations are common causes of ataxia and Alpers disease in the Western world.

Research paper thumbnail of Novel POLG mutations in progressive external ophthalmoplegia mimicking mitochondrial neurogastrointestinal encephalomyopathy

European Journal of Human Genetics, 2003

Autosomal recessive progressive external ophthalmoplegia (PEO) is one clinical disorder associate... more Autosomal recessive progressive external ophthalmoplegia (PEO) is one clinical disorder associated with multiple mitochondrial DNA deletions and can be caused by missense mutations in POLG, the gene encoding the mitochondrial DNA polymerase gamma. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is another autosomal recessive disorder associated with PEO and multiple deletions of mitochondrial DNA in skeletal muscle. In several patients this disorder is caused by loss of function mutations in the gene encoding thymidine phosphorylase (TP). We report a recessive family with features of MNGIE but no leukoencephalopathy in which two patients carry three missense mutations in POLG, of which two are novel mutations (N846S and P587L). The third mutation was previously reported as a recessive POLG mutation (T251I). This finding indicates the need for POLG sequencing in patients with features of MNGIE without TP mutations.

Research paper thumbnail of What is influencing the phenotype of the common homozygous polymerase-  mutation p.Ala467Thr?

Research paper thumbnail of Mitochondrial mosaics in the liver of 3 infants with mtDNA defects

BMC Clinical Pathology, 2009

In muscle cytochrome oxidase (COX) negative fibers (mitochondrial mosaics) have often been visual... more In muscle cytochrome oxidase (COX) negative fibers (mitochondrial mosaics) have often been visualized.

Research paper thumbnail of 3 generation pedigree with paternal transmission of the 22q11.2 deletion syndrome: Intrafamilial phenotypic variability

European journal of medical genetics, Jan 3, 2015

In this case report, we present a paternal transmission of a classic 3 Mb 22q11.2 deletion syndro... more In this case report, we present a paternal transmission of a classic 3 Mb 22q11.2 deletion syndrome (22q11.2 DS) in a 3 generation family. In this family a young girl, her father, her uncle and her grandfather were diagnosed with this disorder. All carriers showed phenotypic expression, there were no unaffected siblings in the second or third generation. Presenting symptoms in the patient in first generation (grandfather) were psoriatic arthritis, thrombocytopenia and a right aortic arch. There was no intellectual disability. The second generation uncle was known with a severe intellectual disability, mild facial characteristics, a septal defect and a clubfoot, whereas the second generation father had a tetralogy of Fallot, no intellectual disability and minimal facial characteristics. The third generation daughter had a moderate intellectual disability, hypernasal speech, triphalangeal thumb, severe speech and language development delay, pronounced facial characteristics and a diag...

Research paper thumbnail of Twinkle and POLG defects enhance age-dependent accumulation of mutations in the control region of mtDNA

Nucleic Acids Research, 2004

Autosomal dominant and/or recessive progressive external ophthalmoplegia (ad/arPEO) is associated... more Autosomal dominant and/or recessive progressive external ophthalmoplegia (ad/arPEO) is associated with mtDNA mutagenesis. It can be caused by mutations in three nuclear genes, encoding the adenine nucleotide translocator 1, the mitochondrial helicase Twinkle or DNA polymerase g (POLG). How mutations in these genes result in progressive accumulation of multiple mtDNA deletions in postmitotic tissues is still unclear. A recent hypothesis suggested that mtDNA replication in®delity could promote slipped mispairing, thereby stimulating deletion formation. This hypothesis predicts that mtDNA of ad/arPEO patients will contain frequent mutations throughout; in fact, our analysis of muscle from ad/arPEO patients revealed an agedependent, enhanced accumulation of point mutations in addition to deletions, but speci®cally in the mtDNA control region. Both deleted and nondeleted mtDNA molecules showed increased point mutation levels, as did mtDNAs of patients with a single mtDNA deletion, suggesting that point mutations do not cause multiple deletions. Deletion breakpoint analysis showed frequent breakpoints around homopolymeric runs, which could be a signature of replication stalling. Therefore, we propose replication stalling as the principal cause of deletion formation.

Research paper thumbnail of Recessive POLG mutations presenting with sensory and ataxic neuropathy in compound heterozygote patients with progressive external ophthalmoplegia

Neuromuscular Disorders, 2003

Autosomal recessive progressive external ophthalmoplegia is a mitochondrial disease characterized... more Autosomal recessive progressive external ophthalmoplegia is a mitochondrial disease characterized by accumulation of multiple largescale deletions of mitochondrial DNA. We previously reported missense mutations in POLG, the gene encoding the mitochondrial DNA polymerase gamma in two nuclear families compatible with autosomal recessive progressive external ophthalmoplegia. Here, we report a novel POLG missense mutation (R627W) in a sporadic patient and we provide genetic support that all these POLG mutations are actually causal and recessive. The novel patient presented with sensory ataxic neuropathy and has the clinical triad of sensory ataxic neuropathy, dysarthria and ophthalmoparesis (SANDO). This is the first finding of a genetic cause of Sensory Ataxic Neuropathy, Dysarthria and Ophthalmoparesis and it implies that this disorder may actually be a variant of autosomal recessive progressive external ophthalmoplegia. Sensory neuropathy is the initial feature in Belgian compound heterozygote autosomal recessive progressive external ophthalmoplegia patients, all carrying the POLG A467T mutation, which occurs at a frequency of 0.6% in the Belgian population. q

Research paper thumbnail of P79 What modifies the clinical presentation of the common homozygous p.A467T POLG mutation?

Neuromuscular Disorders, 2010

Research paper thumbnail of A novel Twinkle gene mutation in autosomal dominant progressive external ophthalmoplegia

Neuromuscular Disorders, 2003

Autosomal dominant progressive external ophthalmoplegia is a common neurological presentation of ... more Autosomal dominant progressive external ophthalmoplegia is a common neurological presentation of mitochondrial disease and is characterised by multiple deletions of mitochondrial DNA in muscle. We describe a family with autosomal dominant progressive external ophthalmoplegia caused by a novel heterozygous A to C transversion at nucleotide 956 of the Twinkle gene. The deltoid muscle biopsy of the index case revealed sparse respiratory deficient cells. Multiple mitochondrial DNA deletions were clearly evident in the index case by both long-range and real-time polymerase chain reaction assays but not by Southern blotting, highlighting the diagnostic difficulties associated with characterising patients with multiple mitochondrial DNA deletions. q

Research paper thumbnail of Progressive External Ophthalmoplegia Characterized by Multiple Deletions of Mitochondrial DNA: Unraveling the Pathogenesis of Human Mitochondrial DNA Instability and the Initiation of a Genetic Classification

NeuroMolecular Medicine, 2003

Over the last decade, many sporadic and familial cases have been reported with multiple deletions... more Over the last decade, many sporadic and familial cases have been reported with multiple deletions of mitochondrial DNA (mtDNA) in postmitotic tissues. Most patients suffer from progressive external ophthalmoplegia (PEO) and may have a nuclear gene defect that predisposes to the accumulation of mtDNA deletions. Recently, positional cloning has led to the discovery of mutations in four such nuclear genes. Some mutations are dominant and others recessive. In all autosomal mutations, defective mtDNA replication and/or repair are probably responsible for the generation of secondary mtDNA deletions. There are also data suggestive of a prominent pathogenic role for disturbed nucleotide metabolism. We here present a tentative genotype-phenotype correlation. Since clinical presentations are heterogeneous and overlap with different previously described clinical syndromes, we advocate the use of a genetic, instead of a clinical, classification of disorders with multiple mtDNA deletions.

Research paper thumbnail of POLG mutations in neurodegenerative disorders with ataxia but no muscle involvement

Neurology, 2004

Objective: To identify POLG mutations in patients with sensory ataxia and CNS features. Methods: ... more Objective: To identify POLG mutations in patients with sensory ataxia and CNS features. Methods: The authors characterized clinical, laboratory, and molecular genetic features in eight patients from five European families. The authors conducted sequencing of coding exons of POLG, C10orf2 (Twinkle), and ANT1 and analyzed muscle mitochondrial DNA (mtDNA), including Southern blot analysis and long-range PCR. Results: Ataxia occurred in combination with various CNS features, including myoclonus, epilepsy, cognitive decline, nystagmus, dysarthria, thalamic and cerebellar white matter lesions on MRI, and neuronal loss in discrete gray nuclei on autopsy. Gastrointestinal dysmotility, weight loss, cardiomyopathy, and valproate-induced hepatotoxicity occurred less frequently. Two patients died without preceding signs of progressive external ophthalmoplegia. In muscle, typical findings of mitochondrial disease, such as ragged red fibers and Southern blot mtDNA abnormalities, were absent. POLG mutations were present in eight patients, including two isolated cases, and one Finnish and two unrelated Belgian families contained in total six patients. All POLG mutations were recessive, occurring in a homozygous state in seven patients and in a compound heterozygous state in one patient. The novel W748S mutation was identified in five patients from three unrelated families. Conclusions: The clinical spectrum of recessive POLG mutations is expanded by sensory ataxic neuropathy, combined with variable features of involvement of CNS and other organs. Progressive external ophthalmoplegia, myopathy, ragged red fibers, and Southern blot abnormalities of muscle mitochondrial DNA also are not mandatory features associated with POLG mutations.

Research paper thumbnail of Patient homozygous for a recessive POLG mutation presents with features of MERRF

Neurology, 2003

Both dominant and recessive missense mutations were recently reported in the gene encoding the mi... more Both dominant and recessive missense mutations were recently reported in the gene encoding the mitochondrial DNA polymerase gamma (POLG) in patients with progressive external ophthalmoplegia (PEO). The authors report on a patient homozygous for a recessive missense mutation in POLG who presented with a multisystem disorder without PEO. The most prominent features were myoclonus, seizure, and sensory ataxic neuropathy, so the clinical picture overlapped with the syndrome of myoclonus, epilepsy, and ragged red fibers (MERRF).

Research paper thumbnail of Neurodegenerative parkinsonism and progressive external ophthalmoplegia with a Twinkle mutation

Research paper thumbnail of Polymerase gamma deficiency (POLG): Clinical course in a child with a two stage evolution from infantile myocerebrohepatopathy spectrum to an Alpers syndrome and neuropathological findings of Leigh’s encephalopathy

European Journal of Paediatric Neurology, 2012

Description of the clinical course in a child compound heterozygous for POLG1 mutations, neuropat... more Description of the clinical course in a child compound heterozygous for POLG1 mutations, neuropathology findings and results of dietary treatment based on fasting avoidance and long chain triglycerides (LCT) restriction. At 3(1/2) months of age the patient presented with severe hypoglycemia, hyperlactatemia, moderate ketosis and hepatic failure. Fasting hypoglycemia occurred 8 h after meals. The hypoglycemia did not respond to glucagon. She was supplemented with IV glucose and/or frequent feedings, but developed liver insufficiency which was reversed by long-chain triglyceride (LCT) restriction. Alpha-foeto-protein (AFP) levels were elevated and returned to low values after dietary treatment. Liver biopsy displayed cirrhosis, bile ductular proliferation, steatosis, isolated complex IV defect in part of the liver mitochondria, and mitochondrial DNA depletion (27% of control values). Two heterozygous mutations (p. [Ala467Thr] + p. [Gly848Ser]) were found in the POLG1 gene. At 3 years of age she progressively developed refractory mixed type seizures including a focal component and psychomotor regression which fulfilled the criteria of Alpers syndrome (AS) although the initial presentation was compatible with infantile myocerebrohepatopathy spectrum (MCHS). She died at 5 years of age of respiratory insufficiency. Neuropathologic investigation revealed lesions in the right striatal area and the inferior colliculi typical for Leigh's encephalopathy. The present patient showed an evolution from infantile MCHS to AS, and dietary treatment seemed to slow the progression of liver failure. In spite of the late clinical features of AS, it extends the neuropathological spectrum of AS and polymerase gamma deficiency (POLG) to Leigh syndrome lesions.

Research paper thumbnail of Abundance of the POLG disease mutations in Europe, Australia, New Zealand, and the United States explained by single ancient European founders

European Journal of Human Genetics, 2007

We reported previously that the DNA polymerase c (POLG) W748S mutation, a common cause of mitocho... more We reported previously that the DNA polymerase c (POLG) W748S mutation, a common cause of mitochondrial recessive ataxia syndrome (MIRAS), has a common ancient founder for all the disease chromosomes in Finland, Norway, United Kingdom, and Belgium. Here, we present results showing that the same ancestral chromosome underlies MIRAS and Alpers syndrome in Australia and New Zealand. Furthermore, we show that a second common POLG mutation, A467T, also shows common European ancestry: patients from Australia, New Zealand, and the United States share a common haplotype with the previously reported European patients. These data of ancestral haplotypes indicate that the POLG locus is quite stable and that the recessive W748S and A467T mutations, and probably also G848S, have occurred once in history. They have effectively spread to populations of European descent with carrier frequencies up to 1% in several populations. Our data predict that these mutations are common causes of ataxia and Alpers disease in the Western world.

Research paper thumbnail of Novel POLG mutations in progressive external ophthalmoplegia mimicking mitochondrial neurogastrointestinal encephalomyopathy

European Journal of Human Genetics, 2003

Autosomal recessive progressive external ophthalmoplegia (PEO) is one clinical disorder associate... more Autosomal recessive progressive external ophthalmoplegia (PEO) is one clinical disorder associated with multiple mitochondrial DNA deletions and can be caused by missense mutations in POLG, the gene encoding the mitochondrial DNA polymerase gamma. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is another autosomal recessive disorder associated with PEO and multiple deletions of mitochondrial DNA in skeletal muscle. In several patients this disorder is caused by loss of function mutations in the gene encoding thymidine phosphorylase (TP). We report a recessive family with features of MNGIE but no leukoencephalopathy in which two patients carry three missense mutations in POLG, of which two are novel mutations (N846S and P587L). The third mutation was previously reported as a recessive POLG mutation (T251I). This finding indicates the need for POLG sequencing in patients with features of MNGIE without TP mutations.

Research paper thumbnail of What is influencing the phenotype of the common homozygous polymerase-  mutation p.Ala467Thr?

Research paper thumbnail of Mitochondrial mosaics in the liver of 3 infants with mtDNA defects

BMC Clinical Pathology, 2009

In muscle cytochrome oxidase (COX) negative fibers (mitochondrial mosaics) have often been visual... more In muscle cytochrome oxidase (COX) negative fibers (mitochondrial mosaics) have often been visualized.