Abstract
We report a consanguineous family with a homozygous and heterozygous membrane metallo-endopeptidase (MME) mutation (c.467delC) and two clinical conditions: fetomaternal alloimmune membranous glomerulopathy (FMG) and hereditary motor and sensory axonal neuropathy. The penetrance of both phenotypes was variable. Some individuals experienced unusually fast neurological degradation. Pain and vasomotor signs were frequent complaints, possibly due to a loss of the neutral endopeptidase (NEP, the MME gene product) function and its subsequent inability to degrade substance P and vasomotor peptides. Electrophysiological and nerve biopsy findings were consistent with predominantly axonal neuropathy. This specific clinical phenotype was attributed to a c.467delC MME gene mutation. Diagnosis of such a mutation is important but can be challenging, due to allele dropout. Heterozygous subjects who had already reached the expected age of disease onset had peripheral neuropathy, but also suffered from additional diseases. Neurologists should advise women of childbearing age with MME mutations to seek pre-pregnancy genetic advice and nephrologists should search for neuropathy in patients with FMG.
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Acknowledgements
We thank Dr P Delrée and Mr. S Brohée (Institute of Pathology and Genetics, Gosselies, Belgium) for performing nerve pathological examination and TA repeat analysis, respectively. We thank Prof. H Takashima (Kagoshima University, Kagoshima, Japan) for his help in the first genetic analyses and Prof. V Lupo (Unit of Genetics and Genomics of Neuromuscular and Neurodegenerative Disorders, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain) for raising the possibility of allele dropout during amplification of MME gene. We thank Dr M Andrade (medicalwriting.be) who provided editorial assistance. No commercial funding was received for this purpose.
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13760_2020_1275_MOESM1_ESM.xlsx
Sets of primers used in the study. Initial sets 1 and 2 should not be used, because, under certain circumstances, amplification fails, and a false result occurs (allele dropout) (XLSX 9 kb)
13760_2020_1275_MOESM3_ESM.xlsx
Allele dropout (ADO) with incorrect sets of primers. Wild-type MME allele originating from the mother I.2 has been transmitted to subject II.5. On this allele, a longer TA repeat (> 9 repeats, in bold) interferes with PCR amplification done with initial primer sets 1&2 (see Supplementary Table 1), so that only the mutated allele c.467delC is found and the initial PCR results falsely indicated homozygous status. Correct genotyping was made by Panel kit SeqCap EZ analysis and using a new set of primers not susceptible to ADO in these conditions. In subject II.1, the mother transferred the mutated allele and the father the WT allele. Since no TA repeat >9 was seen in these alleles, correct initial diagnosis of heterozygote was made (XLSX 9 kb)
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Dupuis, M., Raymackers, J.M., Ackermans, N. et al. Hereditary axonal neuropathy related to MME gene mutation in a family with fetomaternal alloimmune glomerulonephritis. Acta Neurol Belg 120, 149–154 (2020). https://doi.org/10.1007/s13760-020-01275-9
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DOI: https://doi.org/10.1007/s13760-020-01275-9