An intriguing “silent” mutation and a founder effect in <i>antiquitin (ALDH7A1)</i>

Salomons, Gajja S.; Bok, Levinus A.; Struys, Eduard A.; Pope, Lorna; Darmin, Patricia S.; Mills, Philippa; Clayton, Peter T.; Willemsen, M.A.A.P.; Jakobs, Cornelis

doi:10.1002/ana.21206

Cited by 59 publications

(54 citation statements)

References 7 publications

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“…The metabolic and genetic defect of PDS has recently been elucidated [24], which gives the opportunity for prenatal Table 2 Patients in the present study compared with published data on antenatal treatment Author Hunt [17] Scriver [32] Bejsov [8] Iinuma [18] Pettit [28] Nabbout [18] Rankin [30] In both families, the affected children were homozygous for the-common-c.[1195G>C] mutation, which has a relatively high frequency in the Netherlands (15 of 20 alleles [31]) and has also been frequently identified by others (12 of 36 alleles [29]; 11 of 30 alleles [9]). The mutation leads to substitution of glutamate at position 399 by glutamine (Glu399Gln) and is predicted to have a negative effect on the binding capacity of α-AASA dehydrogenase to the required cofactor NAD + , resulting in decreased enzyme activity [35].…”

Section: Discussionmentioning

confidence: 99%

“…In two of these families, the mother used pyridoxine daily during the second pregnancy from the first trimester onwards. Methodology and results of α-AASA measurements and ALDH7A1 mutation analysis have previously been reported [10,31]. Table 1 presents patient data on the clinical course, imaging and outcome.…”

Section: Methods and Patientsmentioning

confidence: 99%

“…In 2006, mutations in the ALDH7A1 gene were shown to be present in the majority of patients with a clinical diagnosis of PDS [20,24,29,31]. ALDH7A1 encodes the enzyme α-aminoadipic semialdehyde (α-AASA) dehydrogenase that plays a role in the degradation of the amino acid lysine.…”

Section: Introductionmentioning

confidence: 99%

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Antenatal treatment in two Dutch families with pyridoxine-dependent seizures

et al. 2009

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Incidental reports suggest that antenatal treatment of pyridoxine dependent seizures (PDS) may improve neurodevelopmental outcome of affected patients. Two families with PDS are reported, both with two affected siblings. Antenatal treatment with pyridoxine was instituted during the second pregnancy in each family (50 and 60 mg daily from 3 and 10 weeks of gestation, respectively). Perinatal characteristics and neurodevelopmental outcome at 4 (Family A) and 12 (Family B) years of age were compared between the untreated and treated child within each family. Meconium-stained amniotic fluid was present in both first pregnancies and abnormal foetal movements were noticed in one. In the treated infants, pregnancy and birth were uncomplicated. In family A, postnatal pyridoxine supplementation prevented neonatal seizures. Both children in family A were hypotonic and started walking after 2 years of age; both had white matter changes on MRI, and the first child was treated for squint. IQ was 73 and 98 in the antenatally untreated and treated child, respectively. The second child in family B developed seizures on the seventh day, because pyridoxine maintenance therapy had not been instituted after birth. Seizures responded rapidly to pyridoxine supplementation. MRI showed large ventricles and a mega cisterna magna. IQ was 80 and 106 in the antenatally untreated and treated child respectively. Both children had normal motor development. These results suggest that antenatal pyridoxine supplementation may be effective in preventing intrauterine seizures, decreasing the risk of complicated birth and improving neurodevelopmental outcome in PDS.

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Section: Discussionmentioning

confidence: 99%

Section: Methods and Patientsmentioning

confidence: 99%

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Antenatal treatment in two Dutch families with pyridoxine-dependent seizures

et al. 2009

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“…Sequence analysis of the ALDH7A1 gene (RefSeq NM_001182.3) revealed compound heterozygosity for a missense mutation c.1279G>C (p.E427Q) in exon 14 and a cryptic splicing mutation c.834G>A (p.V250V) in exon 9. Both mutations have been reported previously (Salomons et al 2007). Further detail is provided in a supplementary footnote.…”

Section: Investigationsmentioning

confidence: 54%

Long-Term Follow-up of a Successfully Treated Case of Congenital Pyridoxine-Dependent Epilepsy

et al. 2012

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Autosomal recessive disorders affecting pyridoxine (vitamin B6) metabolism are a rare but well-recognized cause of neonatal seizures. Antiquitin deficiency, caused by mutations in ALDH7A1, is a disorder of the lysine degradation pathway causing accumulation of an intermediate that complexes with pyridoxal phosphate. Reports of long-term followup of neonatal pyridoxine-dependent seizures (PDS) remain scarce and prognostic information is varied. We report a case of PDS in a 47-year-old lady who originally presented shortly after birth in 1964. Pyridoxine replacement was successful and diagnostic confirmation was obtained later in life, initially by biochemical analysis of serum pipecolic acid. Subsequently we organized genetic analysis of ALDH7A1, which revealed compound heterozygous mutations. To our knowledge, this represents the longest duration of follow-up published to date. Case Clinical HistoryOur patient was born full term weighing 3.6 kg; hours after delivery, generalized convulsions began. No cause was immediately apparent for the continuous seizures. Her sibling had died shortly after birth with uncontrollable seizures of unknown aetiology. After 24 h of unsuccessful treatment with anti-convulsants and sedatives, pyridoxine was prescribed. Convulsions ceased 5 min after administration of 75 mg IV. Maintenance therapy with oral pyridoxine, 20 mg 8 hourly, was commenced. EEG demonstrated excess generalized theta.Confirmatory testing of PDS was performed aged 8 months. After 48 h of pyridoxine withdrawal, there were frank convulsions and recurrence of encephalopathy. Recovery after reinstitution of pyridoxine was prompt. Oral replacement therapy was continued long term.Developmental assessment aged 6 years revealed mild developmental delay despite freedom from seizures. At 11 years, a further EEG was performed. An excess of theta and relative paucity of rhythmic alpha activity was noted. She attended a school for children with learning difficulties and has relatively poor literacy.Aged 20 years, she was reviewed in the adult neurology clinic, querying the necessity of continued pyridoxine therapy. Pyridoxine, then 50 mg three times daily, was withdrawn for 2 weeks. Seizure recurred and pyridoxine recommenced. A subsequent EEG revealed minimal epileptiform activity.

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“…However, such variants may affect proper splicing and are potentially pathogenic. 5 We therefore not only tested if such variants could be properly analyzed by studying previously classified variants, but also subjected 28 novel variants to these tools. Moreover, to facilitate worldwide diagnostic and research laboratories interested in the SLC6A8 gene, we developed a novel LOVD database (http://www.LOVD.nl/SLC6A8), which includes clinically and genetically relevant data.…”

Section: Introductionmentioning

confidence: 99%

Characterization of novel SLC6A8 variants with the use of splice-site analysis tools and implementation of a newly developed LOVD database

et al. 2010

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The X-linked creatine transporter defect is caused by mutations in the SLC6A8 gene. Until now, 66 synonymous and intronic variants in SLC6A8 were detected in our laboratory. To gain more insight in the effect of the detected variants, we applied five free web-based splice-site analysis tools to 25 published variants that were stratified as (non-)disease causing. All were correctly predicted to have no effect (n¼18) or to cause erroneous splicing (n¼7), with the exception of a pathogenic de novo 24 bp intronic deletion. Second, 41 unclassified variants, including 28 novel, were subjected to analysis by these tools. At least four splice-site analysis tools predicted that three of the variants would affect splicing as the mutations disrupted the canonical splice site. Urinary creatine/creatinine and brain MRS confirmed creatine transporter deficiency in five patients (four families), including one female. Another variant was predicted to moderately affect splicing by all five tools. However, transient transfection of a minigene containing the variant in a partial SLC6A8 segment showed no splicing errors, and thus was finally classified as non-disease causing. This study shows that splice tools are useful for the characterization of the majority of variants, but also illustrates that the actual effect can be misclassified in rare occasions. Therefore, further laboratory studies should be considered before final conclusions on the disease-causing nature are drawn. To provide an accessible database, the 109 currently known SLC6A8 variants, including 35 novel ones, are included in a newly developed LOVD DNA variation database.

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An intriguing “silent” mutation and a founder effect in antiquitin (ALDH7A1)

Cited by 59 publications

References 7 publications

Antenatal treatment in two Dutch families with pyridoxine-dependent seizures

Antenatal treatment in two Dutch families with pyridoxine-dependent seizures

Long-Term Follow-up of a Successfully Treated Case of Congenital Pyridoxine-Dependent Epilepsy

Characterization of novel SLC6A8 variants with the use of splice-site analysis tools and implementation of a newly developed LOVD database

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