Clinical, biomarker and genetic spectrum of Niemann‐Pick type C in Egypt: The detection of nine novel <i>NPC1</i> mutations

Mahmoud, Iman G.; Elmonem, Mohamed A.; Elkhateeb, Nour; Elnaggar, Walaa; Sobhi, Ahmed; Girgis, Marian; Kamel, Mona M.; Shaheen, Yara; Samaha, Mona; Ramadan, Areef; Zaki, Maha S.; El-Hawary, Bahaa; Hassan, Sawsan; Khalifa, Iman; Mossad, Fawzya; Al-Menabawy, Nihal M; Zielke, Susanne; Gleeson, Joseph G.; Rolfs, Arndt; Selim, Laila

doi:10.1111/cge.13492

Cited by 4 publications

(4 citation statements)

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“…A total of 23 NPC1 patients were reported from Egypt in a study designed to describe the spectrum of clinical, biochemical and molecular profile of the disease [ 43 ]. Disease onset was reported as neonatal in eight patients (presenting <3 months of age), EIF in six (presentation from 3 months–2 years of age), LIF in three (2–6 years), and juvenile in six patients (6–15 years), nevertheless, adult patients were not reported in this cohort [ 43 ]. Nineteen patients were offspring of consanguineous marriages (82.6%), while positive family history was reported in 13 families (65%) [ 43 ].…”

Section: Resultsmentioning

confidence: 99%

“…Disease onset was reported as neonatal in eight patients (presenting <3 months of age), EIF in six (presentation from 3 months–2 years of age), LIF in three (2–6 years), and juvenile in six patients (6–15 years), nevertheless, adult patients were not reported in this cohort [ 43 ]. Nineteen patients were offspring of consanguineous marriages (82.6%), while positive family history was reported in 13 families (65%) [ 43 ]. Age of neurological onset varied between 8 and 18 months in the EIF group while all of these cases had also visceral symptoms [ 43 ].…”

Section: Resultsmentioning

confidence: 99%

“…Nineteen patients were offspring of consanguineous marriages (82.6%), while positive family history was reported in 13 families (65%) [ 43 ]. Age of neurological onset varied between 8 and 18 months in the EIF group while all of these cases had also visceral symptoms [ 43 ].…”

Section: Resultsmentioning

confidence: 99%

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Clinical and Molecular Features of Early Infantile Niemann Pick Type C Disease

Yılmaz

Baruteau

Rahim

et al. 2020

IJMS

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Niemann Pick disease type C (NPC) is a neurovisceral disorder due to mutations in NPC1 or NPC2. This review focuses on poorly characterized clinical and molecular features of early infantile form of NPC (EIF) and identified 89 cases caused by NPC1 (NPC1) and 16 by NPC2 (NPC2) mutations. Extra-neuronal features were common; visceromegaly reported in 80/89 NPC1 and in 15/16 NPC2, prolonged jaundice in 30/89 NPC1 and 7/16 NPC2. Early lung involvement was present in 12/16 NPC2 cases. Median age of neurological onset was 12 (0–24) and 7.5 (0–24) months in NPC1 and NPC2 groups, respectively. Developmental delay and hypotonia were the commonest first detected neurological symptoms reported in 39/89 and 18/89 NPC1, and in 8/16 and 10/16 NPC2, respectively. Additional neurological symptoms included vertical supranuclear gaze palsy, dysarthria, cataplexy, dysphagia, seizures, dystonia, and spasticity. The following mutations in homozygous state conferred EIF: deletion of exon 1+promoter, c.3578_3591 + 9del, c.385delT, p.C63fsX75, IVS21-2delATGC, c. 2740T>A (p.C914S), c.3584G>T (p.G1195V), c.3478-6T>A, c.960_961dup (p.A321Gfs*16) in NPC1 and c.434T>A (p.V145E), c.199T>C (p.S67P), c.133C>T (p.Q45X), c.141C>A (p.C47X) in NPC2. This comprehensive analysis of the EIF type of NPC will benefit clinical patient management, genetic counselling, and assist design of novel therapy trials.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Clinical and Molecular Features of Early Infantile Niemann Pick Type C Disease

Yılmaz

Baruteau

Rahim

et al. 2020

IJMS

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“…The presence in both alleles of very severe variants (frameshift and nonsense) usually results in severe phenotype in NPC1 patients. 13,22 All nine patients with two null variants were classified as a severe phenotype in this cohort (Table S4).…”

Section: Genotype-phenotype Correlationsmentioning

confidence: 99%

Development and validation of a new genotype–phenotype correlation for Niemann‐Pick disease type C1

Liang,

Zhan,

Wang

et al. 2023

J of Inher Metab Disea

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Hundreds of NPC1 variants cause highly heterogeneous phenotypes. This study aims to explore the genotype–phenotype correlation of NPC1, especially for missense variants. In a well‐characterized cohort, phenotypes are graded into three clinical forms: mild, intermediate, and severe. Missense residue structural location was stratified into three categories: surface, partially, and fully buried. The association of phenotypes with the topography of the amino acid substitution in the protein structure was investigated in our cohort and validated in two reported cohorts. One hundred six unrelated NPC1 patients were enrolled. A significant correlation of genotype–phenotype was found in 81 classified individuals with two or one (the second was null variant) missense variant (p < 0.001): of 25 patients with at least one missense variant of surface (group A), 19 (76%) mild, six (24%) intermediate, and none severe; of 31 cases with at least one missense variant of partially buried without surface variants (group B), 11 (35%) mild, 16 (52%) intermediate, and four (13%) severe; of the remaining 25 patients with two or one buried missense variants (group C), eight (32%) mild, nine (36%) intermediate, and eight (32%) severe. Additionally, 7‐ketocholesterol, the biomarker, was lower in group A than in group B (p = 0.024) and group C (p = 0.029). A model was proposed that accurately predicted phenotypes of 72 of 90 (80%), 73 of85 (86%), and 64 of 69 (93%) patients in our cohort, Italian, and UK cohort, respectively. This study proposed a novel genotype–phenotype correlation in NPC1, linking the underlying molecular pathophysiology with clinical phenotype and aiding genetic counseling and evaluation in clinical practice.

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