Population screening in a Druze community: the challenge and the reward

Falik‐Zaccai, Tzipora C.; Kfir, Nechama; Frenkel, Pnina; Cohen, Carl M.; Tanus, Mary; Mandel, Hanna; Shihab, Shihab; Morkos, Siman; Aaref, Salameh; Summar, Marshall; Khayat, Morad

doi:10.1097/gim.0b013e31818d0e0f

Cited by 40 publications

(42 citation statements)

References 31 publications

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“…Consistent with this, high CTX gene carrier frequencies have been reported for these populations (Berginer and Abeliovich 1981;Rosner et al 2009;Falik-Zaccai et al 2008) (Table 1). Genetic screening programs have been implemented in these communities at high risk for CTX (Falik-Zaccai et al 2008;Rosner et al 2009), enabling early identification and treatment of affected newborns, thereby preventing CTX symptoms in these individuals (Falik-Zaccai et al 2008;Berginer et al 2009). …”

Section: Epidemiologysupporting

confidence: 81%

Epidemiology, diagnosis, and treatment of cerebrotendinous xanthomatosis (CTX)

Salen

Steiner

2017

J of Inher Metab Disea

147

150

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Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder of bile acid synthesis caused by mutations in the cytochrome P450 CYP27A1 gene that result in production of a defective sterol 27‐hydroxylase enzyme. CTX is associated with abnormally high levels of cholestanol in the blood and accumulation of cholestanol and cholesterol in the brain, tendon xanthomas, and bile. Hallmark clinical manifestations of CTX include chronic diarrhea, bilateral cataracts, tendon xanthomas, and neurologic dysfunction. Although CTX is a rare disorder, it is thought to be underdiagnosed, as presenting signs and symptoms may be nonspecific with significant overlap with other more common conditions. There is marked variability in signs and symptoms, severity, and age of onset between patients. The disease course is progressive and potentially debilitating or fatal, particularly with respect to neurologic presentations that can include intellectual disability, autism, behavioral and psychiatric problems, and dementia, among others. Treatment with chenodeoxycholic acid (CDCA; chenodiol) is the current standard of care. CDCA can help restore normal sterol, bile acid, bile alcohol, and cholestanol levels. CDCA also appears to be generally effective in preventing adverse clinical manifestations of the disease from occurring or progressing if administered early enough. Improved screening and awareness of the condition may help facilitate early diagnosis and treatment.

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Section: Epidemiologysupporting

confidence: 81%

Epidemiology, diagnosis, and treatment of cerebrotendinous xanthomatosis (CTX)

Salen

Steiner

2017

J of Inher Metab Disea

147

150

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“…Testing of 1,000 Japanese individuals in another study failed to detect a single PD patient [Endo and Matsuda, 1981]. However, population screening of 1,425 residents in a Druze village in northern Israel revealed a very high carrier frequency of 1:21 [Falik-Zaccai et al, 2008].…”

Section: Introductionmentioning

confidence: 88%

A broad spectrum of developmental delay in a large cohort of prolidase deficiency patients demonstrates marked interfamilial and intrafamilial phenotypic variability

Falik‐Zaccai

Khayat

Luder

et al. 2009

American J of Med Genetics Pt B

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Prolidase deficiency (PD) is a rare, pan-ethnic, autosomal recessive disease with a broad phenotypic spectrum. Seventeen causative mutations in the PEPD gene have been reported worldwide. The purpose of this study is to characterize, clinically and molecularly, 20 prolidase deficient patients of Arab Moslem and Druze origin from 10 kindreds residing in northern Israel. All PD patients manifested developmental delay and facial dysmorphism. Typical PD dermatological symptoms, splenomegaly, and recurrent respiratory infections presented in varying degrees. Two patients had systemic lupus erythematosus (SLE), and one a novel cystic fibrosis phenotype. Direct DNA sequencing revealed two novel missense mutations, A212P and L368R. In addition, a previously reported S202F mutation was detected in 17 patients from seven Druze and three Arab Moslem kindreds. Patients homozygous for the S202F mutation manifest considerable interfamilial and intrafamilial phenotypic variability. The high prevalence of this mutation among Arab Moslems and Druze residing in northern Israel, and the presence of an identical haplotype along 500,000 bp in patients and their parents, suggests a founder event tracing back to before the breakaway of the Druze from mainstream Moslem society.

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“…The ionization interface was operated in the positive mode using the following settings: TEM 500°C, IS 5.0 kV; and CUR, GS2, and GS1 nitrogen gas fl ow rates, 40, 40, and 30 psi, respectively. For QAO derivatives and underivatized ketosterols, the multiple reaction monitoring (MRM) transitions monitored for quantifi cation were as follows (all at EP 10 V with dwell times of 40 ms): for QAO 7 ␣ C4, m/z 515.7 → 152.3 quantifi er (CE 65eV, DP 71eV, and CXP 4eV) and m/z 515.7 → 438.6 qualifi er (CE 65eV, DP 76eV and CXP 6eV); for QAO 7 ␣ 12 ␣ C4, m/z 531.7 → 152.1 qualifi er (CE 65eV, DP 71eV, and CXP 4eV), and m/z 531.7 → 454.5 qualifi er (CE 65eV, DP 76eV, and CXP 6eV); for QAO 7 ␣ C4-d 7 , m/z 522.7 → 152.2 (CE 70eV, DP 71eV, and CXP 8eV); for QAO-d 3 7 ␣ C4, m/z 518.7 → 152.3 (with CE 70eV, DP 85eV, and CXP 8eV); and for QAO-d 3 7 ␣ 12 ␣ C4, m/z 534.7 → 152.1 (CE 65eV, DP 71eV, and CXP 4eV). For underivatized 7 ␣ C4 (monitored to ensure complete derivatization), the MRM transition was m/z 401.6 → 97.2 (CE 50eV, DP 71eV, and CXP 8eV).…”

Section: Lc-esi-ms/ms Optimizationmentioning

confidence: 99%

“…Preparation of QAO-d 3 7 ␣ C4 and QAO-d 3 7 ␣ 12 ␣ C4 internal standards 7 ␣ C4 and 7 ␣ 12 ␣ C4 were tagged with isotopically enriched QAO reagent to prepare internal standards by derivatization of 30 ng of 7 ␣ C4 and 7 ␣ 12 ␣ C4 using 942 l QAO-d 3 reagent (2.8 mg/ml) in methanol at 5% acetic acid. This reaction was kept at room temperature for 18 h; the underivatized ketosterols were monitored to ensure greater than 98% derivatization.…”

Section: Preparation Of Calibrators and Samples For Lc-ms/ms Measuremmentioning

confidence: 99%

“…We describe here development and application of this methodology utilizing QAO derivatization for LC-ESI-MS/MS quantifi cation of ketosterol BA precursors in very small volumes of plasma (4 l) or 3.2 mm DBS punches. The availability of isotopically enriched CTX; for example, in an isolated Israeli Druze community, a carrier frequency of 1:11 for the deleterious c.355delC mutation was reported ( 7,8 ). Despite these observations, only around three hundred cases of CTX have been described worldwide ( 9 ), although large series of patients have been described by physicians with experience in recognizing the disorder in Italy ( 9,10 ), the Netherlands ( 3, 4 ), Japan ( 11 ), Spain ( 5 ), the United States, and Israel ( 12 ).…”

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confidence: 99%

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