Hereditary tyrosinaemia type II in a consanguineous Ashkenazi Jewish family: Intrafamilial variation in phenotype; absence of parental phenotype effects on the fetus

Chitayat, David; Balbul, A.; Hani, V.; Mamer, Orval; Clow, Carol L.; Scriver, Charles R.

doi:10.1007/bf01799631

Cited by 23 publications

(10 citation statements)

References 21 publications

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“…Hypertyrosinemia has been reported in the literature in an asymptomatic sibling of an affected individual, similar to the present proband's sister . Mental retardation related to tyrosinemia type II is variable.…”

Section: Discussionsupporting

confidence: 80%

Tyrosinemia type II: Novel mutations in TAT in a boy with unusual presentation

Gökay

Kendirci

Ustkoyuncu

et al. 2016

Pediatrics International

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Tyrosinemia type II is a rare autosomal recessive disorder caused by deficiency of tyrosine aminotransferase (TAT). It may occur with ocular and cutaneous symptoms with or without mental retardation, but epileptic seizure is a rare presentation of this disease. Herein we report the clinical, biochemical and genetic features of a 4-year-old boy who presented with afebrile seizure and photophobia. Genomic DNA was obtained from peripheral blood leukocytes from the whole family. Sequencing analysis was performed using the MiSeq next-generation sequencing platform. Sequencing of TAT indicated two new homozygous mutations p.L312P (c.935T>C) and p.T408M (c.1223C>T) for the proband and his asymptomatic sister. During a 2 year follow-up period, the patient had overall poor compliance with protein-restricted diet, but his asymptomatic sister had good compliance with the diet. Cognitive function of the patient worsened steadily, but his asymptomatic sister maintained normal mental status. Tyrosinemia type II should be considered in the differential diagnosis of children presenting with epileptic seizure and photophobia; furthermore, early diagnosis and protein-restricted regimen are important to reduce the risk of long-term complications of tyrosinemia type II such as mental disability.

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Section: Discussionsupporting

confidence: 80%

Tyrosinemia type II: Novel mutations in TAT in a boy with unusual presentation

Gökay

Kendirci

Ustkoyuncu

et al. 2016

Pediatrics International

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“…The nucleophilic sulfur atom, strengthened by the proton abstraction, then attacks the carbonyl carbon of S-acyldihydrolipoamide on the lipoyl-bearing domain of the same subunit, forming the putative tetrahedral intermediate. Israeli MSUD patients are important ethnic groups for mutational studies because of the relatively high incidence of homozygosity associated with consanguinity (12). In this study, we show that among the eight Israeli MSUD patients studied, six are homozygously affected, each carrying one of the four novel point mutations (Table I).…”

Section: Discussionsupporting

confidence: 50%

“…To synthesize the first-strand E2 cDNA, the primer 5Ј-CAGCTAGGGTTTACATACTC-3Ј (positions 1523-1504) was utilized. The ensuing PCR amplification was performed with the forward primer 5Ј-TCCGGGGTAAGATGGCTG-3Ј (positions [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] and the reverse primer 5Ј-GCTCAAAAAGTTCAAGAATGTCTTATCAGT-3Ј (positions 1496 -1467). PCR products were sequenced with an ABI Prism TM model 377 automated DNA sequencer manufactured by Applied Biosystems (Foster City, CA).…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Structural and Biochemical Basis for Novel Mutations in Homozygous Israeli Maple Syrup Urine Disease Patients

Chuang

Wynn

Moss

et al. 2004

Journal of Biological Chemistry

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Maple syrup urine disease (MSUD) results from mutations affecting different subunits of the mitochondrial branched-chain ␣-ketoacid dehydrogenase complex. In this study, we identified seven novel mutations in MSUD patients from Israel. These include C219W-␣ (TGC to TGG) in the E1␣ subunit; H156Y-␤ (CAT to TAT), V69G-␤ (GTT to GGT), IVS 9 del[؊7:؊4], and 1109 ins 8bp (exon 10) in the E1␤ subunit; and H391R (CAC to CGC) and S133stop (TCA to TGA) affecting the E2 subunit of the branched-chain ␣-ketoacid dehydrogenase complex. Recombinant E1 proteins carrying the C219W-␣ or H156Y-␤ mutation show no catalytic activity with defective subunit assembly and reduced binding affinity for cofactor thiamin diphosphate. The mutant E1 harboring the V69G-␤ substitution cannot be expressed, suggesting aberrant folding caused by this mutation. These E1 mutations are ubiquitously associated with the classic phenotype in homozygous-affected patients. The H391R substitution in the E2 subunit abolishes the key catalytic residue that functions as a general base in the acyltransfer reaction, resulting in a completely inactive E2 component. However, wild-type E1 activity is enhanced by E1 binding to this full-length mutant E2 in vitro. We propose that the augmented E1 activity is responsible for robust thiamin responsiveness in homozygous patients carrying the H391R E2 mutation and that the presence of a full-length mutant E2 is diagnostic of this MSUD phenotype. The present results offer a structural and biochemical basis for these novel mutations and will facilitate DNA-based diagnosis for MSUD in the Israeli population. Maple syrup urine disease (MSUD)1 or branched-chain ␣-ketoaciduria is an autosomal recessive metabolic disorder caused by deficiency in the mitochondrial branched-chain ␣-ketoacid dehydrogenase (BCKD) complex. The BCKD complex catalyzes the oxidative decarboxylation (Reaction 1) of three branchedchain ␣-ketoacids (BCKAs) derived from branched-chain amino acids (BCAAs) leucine, isoleucine, and valine (1).

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“…In our patients (aged 7-30 years), the lack of eye lesions is not unexpected, since some patients may only have their first ophthalmic manifestation in their forties. 5 Moreover, the presenting complaint and the manifestations may be confined only to the skin, 4,12,13 as in our patients, or to the eyes.…”

Section: Discussionmentioning

confidence: 56%