DOUBLE HOMOZYGOSITY FOR MUTATIONS OF
            <i>AGL</i>
            AND
            <i>SCN9A</i>
            MIMICKING NEUROHEPATOPATHY SYNDROME

Ebermann, Inga; Elsayed, Solaf M.; Abdel-Ghaffar, Tawhida Yassin; Nürnberg, Gudrun; Nürnberg, Peter; Elsobky, Ezzat; Bolz, Hanno J.

doi:10.1212/01.wnl.0000314731.65875.5c

Cited by 8 publications

(7 citation statements)

References 5 publications

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“…The three phenotypes led to a name change from NN to neurohepatopathy (NNH) [4] . Similar syndromes were later reported from Egypt [5] Morocco [6] and Iraq [7] . Familial sensory autonomic neuropathy with arthropathy is different from MPV17-NNH.…”

Section: Introductionsupporting

confidence: 86%

“…The phenotype of this syndrome has been reported from Egypt [5] , Morocco, [6] , and Iraq, [7] These parts of the world are known to have major metal pollutions [13] , [14] , [15] . The implication is that MPV17-NNH is not a unique syndrome limited to the Four Corners region of NM, USA but that it does occur in other areas of the world where similar mutations have been reported and heavy pollution with metals and other neurotoxins has been documented.…”

Section: Discussionmentioning

confidence: 98%

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MPV17-related hepatocerebral mitochondrial DNA depletion syndrome (MPV17-NNH) revisited

et al. 2016

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MPV17-related hepatocerebral mitochondrial DNA depletion syndrome (previously known as Navajo neurohepatopathy) was discovered in children in the Four Corner's region of New Mexico approximately 40 years ago. This disease is associated with a single missense mutation in exon 2 in the MPV17 gene. The syndrome has now been recognized world-wide. We find that huge quantities of neurotoxins were present in archived nervous tissues from such patients.Arsenic was increased 18 ×, cadmium ~ 10 ×, cobalt 2.5 × and manganese 2.3 ×; the largest increase was in mercury content 16,000 × compared to contemporaneous fresh-frozen normal nervous tissues.In the Four Corner's region of NM the life span is reduced compared to other parts of the United States and in our patients with MPV17-NNH the average life span was 5.4 years ± 2.7 (SE) years.We now live in the Anthropocene an epoch characterized by large additions to the biosphere of neurotoxins. The effects of such toxic loads on human health and disease remain to be assessed.We speculate how such high neurotoxin content in tissues, which is likely to increase during the Anthropocene, may have influenced MPV17-NNH and similar phenotypes in different parts of the world.Our results imply that selenium supplementation to the diet in the Four Corner's region of NM might be beneficial to normal people and in the management of patients with MPV17-NNH syndrome.

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Section: Introductionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 98%

MPV17-related hepatocerebral mitochondrial DNA depletion syndrome (MPV17-NNH) revisited

et al. 2016

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“…Because every individual can be expected to carry heterozygous mutations for several recessive conditions, offspring of consanguineous parents may become homozygous for more than one mutation in unlinked genes, and co‐occurrence of two recessive conditions may mimic a single syndromic disorder. We have previously described this in families with suspected Navajo neurohepatopathy and Usher syndrome [Ebermann et al., ; Ebermann et al., ]. In the WES data of the index patient, there was no indication for such a scenario.…”

Section: Discussionmentioning

confidence: 94%

Mutation ofPOC1Bin a Severe Syndromic Retinal Ciliopathy

et al. 2014

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We describe a consanguineous Iraqi family with Leber congenital amaurosis (LCA), Joubert syndrome (JBTS), and polycystic kidney disease. Targeted NGS for excluding mutations in known LCA and JBTS genes, homozygosity mapping and whole-exome sequencing identified a homozygous missense variant, c.317G>C (p.Arg106Pro), in POC1B, a gene essential for ciliogenesis, basal body and centrosome integrity. In silico modeling suggested a requirement of p.Arg106 for formation of the third WD40 repeat and a protein interaction interface. In human and mouse retina, POC1B localized to the basal body and centriole adjacent to the connecting cilium of photoreceptors and in synapses of the outer plexiform layer. Knockdown of Poc1b in zebrafish caused cystic kidneys and retinal degeneration with shortened and reduced photoreceptor connecting cilia, compatible with the human syndromic ciliopathy. A recent study describes homozygosity for p.Arg106ProPOC1B in a family with non-syndromic cone-rod dystrophy. The phenotype associated with homozygous p.Arg106ProPOC1B may thus be highly variable, analogous to homozygous p.Leu710Ser in WDR19 causing either isolated retinitis pigmentosa or Jeune syndrome. Our study indicates that POC1B is required for retinal integrity, and we propose POC1B mutations as a probable cause for JBTS with severe polycystic kidney disease.

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“…Since there was little homology between breakpoint flanking sequences in exon 27 and intron 27, a mechanism for this large deletion could be non-homologous end-joining, which is thought to be responsible for deletions in genetic diseases (24)(25)(26). Very recently, another large deletion has been reported in an Egyptian patient (6). Thus, our case is the second large deletion in AGL.…”

Section: Discussionmentioning

confidence: 82%

“…A majority of AGL mutations have been point mutations, small deletions, insertions, or splicing mutations. However, a large deletion has been reported in the single case (6). Since eight missense mutations have been reported in AGL (7-10), whether these are responsible for GSD III remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Egyptian glycogen storage disease type III – identification of six novel AGL mutations, including a large 1.5 kb deletion and a missense mutation p.L620P with subtype IIId

Endo¹,

Fateen²,

Shabrawy³

et al. 2009

Clinical Chemistry and Laboratory Medicine

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Background: Glycogen storage disease type III (GSD III) is caused by mutations in AGL which encodes for a single protein with two enzyme activities: oligo-1, 4-1, 4-glucantransferase (transferase) and amylo-1, 6-glucosidase. Activity of both enzymes is lost in most patients with GSD III, but in the very rare subtype IIId, transferase activity is deficient. Since the spectrum of AGL mutations is dependent on the ethnic group, we investigated the clinical and molecular characteristics in Egyptian patients with GSD III. Methods: Clinical features were examined in five Egyptian patients. AGL was sequenced and AGL haplotypes were determined. Results: Six novel AGL mutations were identified: a large deletion (c.3481-3588q1417del1525 bp), two insertions (c.1389insG and c.2368insA), two small deletions (c.2223-2224delGT and c.4041delT), and a missense mutation (p.L620P). p.L620P was found in a patient with IIId. Each mutation was located on a different AGL haplotype. Conclusions: Our results suggest that there is allelic and phenotypic heterogeneity of GSD III in Egypt. This is the second description of a large deletion in AGL. p.L620P is the second mutation found in GSD IIId.

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DOUBLE HOMOZYGOSITY FOR MUTATIONS OF AGL AND SCN9A MIMICKING NEUROHEPATOPATHY SYNDROME

Cited by 8 publications

References 5 publications

MPV17-related hepatocerebral mitochondrial DNA depletion syndrome (MPV17-NNH) revisited

MPV17-related hepatocerebral mitochondrial DNA depletion syndrome (MPV17-NNH) revisited

Mutation ofPOC1Bin a Severe Syndromic Retinal Ciliopathy

Egyptian glycogen storage disease type III – identification of six novel AGL mutations, including a large 1.5 kb deletion and a missense mutation p.L620P with subtype IIId

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