Type B mandibuloacral dysplasia with congenital myopathy due to homozygous ZMPSTE24 missense mutation

Abstract Types A and B Niemann-Pick disease (NPD) result from the deficient activity of acid sphingomyelinase (ASM; E.C. 3.1.4.12) and the resultant lysosomal accumulation of sphingomyelin. Type A disease is a fatal, neurodegenerative disorder of infancy, whereas type B disease has no neurologic manifestations and is characterized primarily by reticuloendothelial involvement and survival into adulthood. Both disorders occur more frequently among individuals of Ashkenazi Jewish ancestry than in the general population. Recently, a missense mutation in the ASM gene (designated R496L) was detected in more than 30% of the ASM alleles from Ashkenazi Jewish type A NPD patients. We report a second, common mutation that resulted from a T to C transition at nucleotide 905 and predicted a leucine to proline substitution at ASM codon 302 (designated L302P). Notably, the L302P mutation occurred in 23.5% (8 of 34) of the Ashkenazi Jewish type A NPD alleles studied. In contrast, it was not found in any of the ASM alleles from non-Jewish type A patients, in 36 alleles from type B patients, or in 100 ASM alleles from normal Ashkenazi Jewish individuals. To confirm the authenticities of the L302P and R496L mutations, each nucleotide change was separately introduced into the full-length ASM cDNA by site- directed mutagenesis and transiently expressed in COS-1 cells. Neither mutation expressed ASM catalytic activity, consistent with the type A phenotype of homoallelic patients. The identification of the L302P mutation should further facilitate molecular carrier detection for NPD in the Ashkenazi Jewish population, particularly because the L302P mutation can be easily detected using the restriction enzyme, AlwNl.

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Mandibuloacral Dysplasia Type B in an Infant

JAMA Dermatology ◽

10.1001/jamadermatol.2014.5068 ◽

2015 ◽

Vol 151 (5) ◽

pp. 561 ◽

Cited By ~ 5

Author(s):

Julia M. Kwan

Keyword(s):

Type B ◽

Mandibuloacral Dysplasia

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Congenital myopathy caused by a novel missense mutation in the CFL2 gene

Neuromuscular Disorders ◽

10.1016/j.nmd.2012.03.008 ◽

2012 ◽

Vol 22 (7) ◽

pp. 632-639 ◽

Cited By ~ 36

Author(s):

C.W. Ockeloen ◽

H.J. Gilhuis ◽

R. Pfundt ◽

E.J. Kamsteeg ◽

P.B. Agrawal ◽

...

Keyword(s):

Missense Mutation ◽

Congenital Myopathy

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Case of mandibuloacral dysplasia with type B lipodystrophy

Indian Journal of Paediatric Dermatology ◽

10.4103/ijpd.ijpd_77_20 ◽

2021 ◽

Vol 22 (4) ◽

pp. 349

Author(s):

SanoberBurzin Daruwalla ◽

RachitaS Dhurat ◽

Smita Ghate ◽

Rutuja Arali

Keyword(s):

Type B ◽

Mandibuloacral Dysplasia

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Identification and expression of a common missense mutation (L302P) in the acid sphingomyelinase gene of Ashkenazi Jewish type A Niemann-Pick disease patients

Blood ◽

10.1182/blood.v80.8.2081.bloodjournal8082081 ◽

1992 ◽

Vol 80 (8) ◽

pp. 2081-2087

Author(s):

O Levran ◽

RJ Desnick ◽

EH Schuchman

Keyword(s):

Missense Mutation ◽

Neurodegenerative Disorder ◽

Type A ◽

Acid Sphingomyelinase ◽

Common Mutation ◽

Ashkenazi Jewish ◽

Type B ◽

Niemann Pick Disease ◽

Niemann Pick ◽

Pick Disease

Types A and B Niemann-Pick disease (NPD) result from the deficient activity of acid sphingomyelinase (ASM; E.C. 3.1.4.12) and the resultant lysosomal accumulation of sphingomyelin. Type A disease is a fatal, neurodegenerative disorder of infancy, whereas type B disease has no neurologic manifestations and is characterized primarily by reticuloendothelial involvement and survival into adulthood. Both disorders occur more frequently among individuals of Ashkenazi Jewish ancestry than in the general population. Recently, a missense mutation in the ASM gene (designated R496L) was detected in more than 30% of the ASM alleles from Ashkenazi Jewish type A NPD patients. We report a second, common mutation that resulted from a T to C transition at nucleotide 905 and predicted a leucine to proline substitution at ASM codon 302 (designated L302P). Notably, the L302P mutation occurred in 23.5% (8 of 34) of the Ashkenazi Jewish type A NPD alleles studied. In contrast, it was not found in any of the ASM alleles from non-Jewish type A patients, in 36 alleles from type B patients, or in 100 ASM alleles from normal Ashkenazi Jewish individuals. To confirm the authenticities of the L302P and R496L mutations, each nucleotide change was separately introduced into the full-length ASM cDNA by site- directed mutagenesis and transiently expressed in COS-1 cells. Neither mutation expressed ASM catalytic activity, consistent with the type A phenotype of homoallelic patients. The identification of the L302P mutation should further facilitate molecular carrier detection for NPD in the Ashkenazi Jewish population, particularly because the L302P mutation can be easily detected using the restriction enzyme, AlwNl.

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Mandibuloacral dysplasia type B (MADB): a cohort of eight patients from Suriname with a homozygous founder mutation in ZMPSTE24 (FACE1), clinical diagnostic criteria and management guidelines

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-019-1269-0 ◽

2019 ◽

Vol 14 (1) ◽

Cited By ~ 1

Author(s):

M. M. Hitzert ◽

S. N. van der Crabben ◽

G. Baldewsingh ◽

H. K. Ploos van Amstel ◽

A. van den Wijngaard ◽

...

Keyword(s):

Diagnostic Criteria ◽

Clinical Features ◽

Founder Mutation ◽

Type B ◽

Management Guidelines ◽

Clinical Criteria ◽

Clinical Diagnostic ◽

Mandibuloacral Dysplasia ◽

Minor Criteria ◽

Clinical Diagnostic Criteria

Abstract Background Mandibuloacral Dysplasia with type B lipodystrophy (MADB) is a rare premature aging disorder with an autosomal recessive inheritance pattern. MADB is characterized by brittle hair, mottled, atrophic skin, generalized lipodystrophy, insulin resistance, metabolic complications and skeletal features like stunted growth, mandibular and clavicular hypoplasia and acro-osteolysis of the distal phalanges. MADB is caused by reduced activity of the enzyme zinc metalloprotease ZMPSTE24 resulting from compound heterozygous or homozygous mutations in ZMPSTE24. Methods In 2012, and again in 2018, eight related patients from the remote tropical rainforest of inland Suriname were analysed for dysmorphic features. DNA analysis was performed and clinical features were documented. We also analysed all previously reported genetically confirmed MADB patients from literature (n = 12) for their clinical features. Based on the features of all cases (n = 20) we defined major criteria as those present in 85–100% of all MADB patients and minor criteria as those present in 70–84% of patients. Results All the Surinamese patients are of African descent and share the same homozygous c.1196A > G, p.(Tyr399Cys) missense variant in the ZMPSTE24 gene, confirming MADB. Major criteria were found to be: short stature, clavicular hypoplasia, delayed closure of cranial sutures, high palate, mandibular hypoplasia, dental crowding, acro-osteolysis of the distal phalanges, hypoplastic nails, brittle and/or sparse hair, mottled pigmentation, atrophic and sclerodermic skin, and calcified skin nodules. Minor criteria were (generalized or partial) lipoatrophy of the extremities, joint contractures and shortened phalanges. Based on our detailed clinical observations, and a review of previously described cases, we propose that the clinical diagnosis of MADB is highly likely if a patient exhibits ≥4 major clinical criteria OR ≥ 3 major clinical criteria and ≥ 2 minor clinical criteria. Conclusions We report on eight related Surinamese patients with MADB due to a homozygous founder mutation in ZMPSTE24. In low-income countries laboratory facilities for molecular genetic testing are scarce or lacking. However, because diagnosing MADB is essential for guiding clinical management and for family counselling, we defined clinical diagnostic criteria and suggest management guidelines.

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