An MFN2-related Charcot-Marie-Tooth Disease Patient with Optic Nerve Atrophy,Neurogenic Bladder Dysfunction,and Diaphragmatic Weakness

Charcot-Marie-Tooth disease (CMT) is a common hereditary peripheral polyneuropathy encompassing distinct monogenetic disorders. Pathogenic mutations in mitofusin 2 (MFN2) are the most frequent cause of its axonal type, CMT type 2A, with diverse phenotypes. We herein report a Japanese patient with a novel heterozygous MFN2 pathogenic variant (c.740 G>C, p.R247P) and severe CMT phenotypes, including progressive muscle weakness, optic atrophy, urinary inconsistency, and restrictive pulmonary dysfunction with eventration of the diaphragm that developed over her 60-year disease course. Our case expands the clinico-genetic features of MFN2-related CMT and highlights the need to evaluate infrequent manifestations during long-term care of CMT patients.     

Torin1 restores proliferation rate in Charcot-Marie-Tooth disease type 2A cells harbouring MFN2 (mitofusin 2) mutation

ObjectiveMitofusin 2 (MFN2) is a mitochondrial outer membrane protein that serves primarily as a mitochondrial fusion protein but has additional functions including the tethering of mitochondrial-endoplasmic reticulum membranes, movement of mitochondria along axons, and control of the quality of mitochondria. Intriguingly, MFN2 has been referred to play a role in regulating cell proliferation in several cell types such that it acts as a tumour suppressor role in some forms of cancer. Previously, we found that fibroblasts derived from a Charcot-Marie-Tooth disease type 2A (CMT2A) patient with a mutation in the GTPase domain of MFN2 exhibit increased proliferation and decreased autophagy.MethodsPrimary fibroblasts from a young patient affected by CMT2A harbouring c.650G > T/p.Cys217Phe mutation in the MFN2 gene were evaluated versus a healthy control to measure the proliferation rate by growth curves analysis and to assess the phosphorylation of protein kinase B (AKT) at Ser473 in response to different doses of torin1, a selective catalytic ATP-competitive mammalian target of rapamycin complex (mTOR) inhibitor, by immunoblot analysis.ResultsHerein, we demonstrated that the mammalian target of rapamycin complex 2 (mTORC2) is highly activated in the CMT2A^MFN2 fibroblasts to promote cell growth via the AKT(Ser473) phosphorylation-mediated signalling. We report that torin1 restores CMT2A^MFN2 fibroblasts’ growth rate in a dose-dependent manner by decreasing AKT(Ser473) phosphorylation.ConclusionsOverall, our study provides evidence for mTORC2, as a novel molecular target that lies upstream of AKT to restore the cell proliferation rate in CMT2A fibroblasts.Key words: Charcot-Marie-Tooth type 2A2, mitofusin2, AKT, cell proliferation, mTORC2     

MFN2-related Charcot-Marie-Tooth Disease with Atypical Ocular Manifestations

We herein describe a Charcot-Marie-Tooth disease (CMT) family with a MFN2 mutation with atypical ocular manifestations. The proband, his mother, his third daughter, and his deceased maternal grandfather all had symptoms of CMT and a visual impairment (either cataracts or severe astigmatism). On whole-exome sequencing for the proband having CMT and congenital cataracts, we identified a c.314C＞T (p.Thr105Met) mutation in MFN2, but no mutation in the causative genes associated with cataracts. This missense mutation in MFN2 co-segregated with CMT and the atypical ocular manifestations in this family. The findings of this study might help to expand the clinical phenotype of heterogeneous MFN2-related CMT.     

Sibling Cases of Charcot-Marie-Tooth Disease Type 4H with a Homozygous FGD4 Mutation and Cauda Equina Thickening

Charcot-Marie-Tooth disease type 4H (CMT4H) is an autosomal recessive inherited demyelinating neuropathy caused by an FYVE, RhoGEF, and a PH domain-containing protein 4 (FGD4) gene mutation. CMT4H is characterized by an early onset, slow progression, scoliosis, distal muscle atrophy, and foot deformities. We herein present sibling cases of CMT4H with a homozygous mutation in the FGD4 gene. Both patients exhibited cauda equina thickening on magnetic resonance imaging, which had not been reported among the previous CMT4H cases. This is the first report of CMT4H with a homozygous FGD4 c.1730G>A (p.Arg577Gln) mutation showing mild progression and cauda equina thickening.     

A Novel PRPS1 Mutation in a Japanese Patient with CMTX5

The PRPS1 gene encodes phosphoribosyl pyrophosphate synthetase 1 (PRS-1). The phenotypes associated with PRPS1 mutations include DFN2 (mild PRS-1 deficiency), X-linked Charcot-Marie-Tooth disease type 5 (CMTX5) (moderate PRS-1 deficiency), Arts syndrome (severe PRS-1 deficiency), and PRS-1 superactivity1. CMTX5 is a very rare hereditary neuropathy characterized by deafness, optic atrophy, and polyneuropathy. We herein report a Japanese patient with CMTX5 who had a novel hemizygous mutation c.82 G>C in PRPS1. Despite showing a typical clinical picture, the decrease in enzyme activity measured in the patient''s erythrocytes was milder than in previously reported cases.     

Charcot-Marie-Tooth 4B2 caused by a novel mutation in the MTMR13/SBF2 gene in two related Portuguese families

Introduction. CMT4B2 is a rare subtype of CMT caused by pathogenic mutations in the myotubularin-related protein-13/set binding factor 2 (MTMR13/SBF2) gene. Nerve conduction velocities are markedly reduced and focally folded myelin sheaths are present on nerve biopsies. We presented two patients from two related Portuguese families with peripheral neuropathy caused by a novel mutation in the MTMR13/SBF2 gene.Case report. Family 1: Patient 1: A 30-year-old woman, with disease onset in early childhood presented pes cavus and hammertoes and walked with a steppage gait. Muscle weakness was present distally, myotactic reflexes were abolished and sensory examination revealed a stocking and glove pattern of hypoesthesia to all sensory modalities.Family 2: Patient 2: A 43-year-old man, second degree cousin of patient 1, born of a consanguineous marriage. At the age of 9 months, he was diagnosed with congenital glaucoma on the left eye, with progressive visual loss up to total blindness. He presented bilateral claw hand deformity, pes cavus and hammertoes and walked with a steppage gait. Myotactic reflexes were abolished and muscle weakness was severe distally in the upper and lower limbs. Sensory examination revealed a stocking and glove pattern of hypoesthesia to all modalities. In both patients electrodiagnostic studies evidenced an uniform and generalized sensorimotor demyelinating polyneuropathy and the molecular study found a frameshift/truncating homozygous novel mutation c.5073_5074del (p.Ser1692Tyrfs*42) in the MTMR13/SBF2 gene. Conclusions. We report a novel mutation in the MTMR13/SBF2 gene associated with a classical CMT phenotype. Congenital glaucoma associated with a frameshift/truncating mutation in CMT4B2 is reported for the first time.Key words: CMT4B2, MTMR13/SBF2 gene, autosomal recessive CMT, congenital glaucoma     

The Prevalence of the Prothrombin (F2) 20210G>A Mutation in a Cohort of Sri Lankan Patients with Thromboembolic Disorders

Prothrombin (F2) 20210G>A [rs1799963 G>A] mutation is a genetic variant which predisposes to inherited thrombophilia. Highest prevalence of this rare mutation has been reported among Caucasian and Mediterranean populations with thrombophilic conditions compared to healthy controls. It is absent or occurs in a very low frequency in both thrombophilic patients and healthy controls of most South Asian populations. A previous study has demonstrated that the mutant allele is absent among Sri Lankan healthy controls. This study was conducted to determine the prevalence of the F2 20210G>A mutation among Sri Lankan patients with thrombo-embolic disorders. F2 20210G>A mutation analysis was carried out on 825 patients. These included 374 with arterial thromboembolic disorders, 303 with venous thromboembolic disorders (VTE) and 148 with pregnancy related complications. Genotyping was done using polymerase chain reaction followed by restriction fragment length polymorphism. The overall prevalence of the individuals detected with the mutation was 0.8 % (7/825) with a mutant allele frequency of 0.4 % (7/1,650), and all were heterozygotes. Further classification according to the types of thrombotic events showed a prevalence of 0.5 % (2/374), 1.3 % (4/303), and 0.7 % (1/148) respectively, in the three groups with arterial thrombosis, VTE and pregnancy complications. The respective mutant allele frequencies in the three different groups were 0.3 % (2/748), 0.7 % (4/606) and 0.3 % (1/296). Although these figures are lower than that of Caucasian and Mediterranean populations, they are relatively higher compared to other South Asian populations. Therefore, the F2 20210G>A mutant allele is not entirely absent among Sri Lankan patients with thrombo-embolic disorders.     

Myelin protein zero gene mutated in Charcot-Marie-tooth type 1B patients.

Autosomal dominant of Charcot-Marie-Tooth disease (CMT), whose gene is type 1B (CMT1B), has slow nerve conduction with demyelinated Schwann cells. In this study the abundant peripheral myelin protein zero (MPZ) gene, MPZ, was mapped 130 kb centromeric to the Fc receptor immunoglobulin gene cluster in band 1q22, and a major MPZ point mutation was found to cosegregate with CMT1B in one large CMT1B family. The MPZ point mutation in 18 of 18 related CMT1B pedigree 1 patients converts a positively charged lysine in codon 96 to a negatively charged glutamate. The same MPZ locus cosegregates with the CMT1B disease gene in a second CMT1B family [total multipoint logarithm of odds (lod) = 11.4 at theta = 0.00] with a splice junction mutation. Both mutations occur in MPZ protein regions otherwise conserved identically in human, rat, and cow since these species diverged 100 million years ago. MPZ protein, expressed exclusively in myelinated peripheral nerve Schwann cells, constitutes > 50% of myelin protein. These mutations are anticipated to disrupt homophilic MPZ binding and result in CMT1B peripheral nerve demyelination.     

A novel compound heterozygous COL4A4 mutation in a Chinese family with Alport syndrome: A care case report

Rationale:Alport syndrome (AS) is an inherited progressive renal failure, characterized by kidney disease, hearing loss, and eye abnormalities.Patient concerns:A 7-year-old male child was admitted for persistent microscopic hematuria and proteinuria.Diagnoses:Combined with clinical manifestations, laboratory testing, pathological changes of kidney and sequencing results, the patient was diagnosed as AS.Interventions:The patient was treated with ACEI and tacrolimus drugs for 2 years, but continued to have hematuria and proteinuria. Thus, a genetic analysis was performed using next-generation sequencing in four affected members from the family.Outcomes:The findings revealed triple compound heterozygous mutation of COL4A4: three novel variations, c.1045C>T (p. R349X), c.3505+1G>A (splicing), and c.2165G>A (p. G722D).Lessons:This study was novel in finding that a triple variant of the COL4A4 gene simultaneously in trans and in cis. The effects of multiple mutation sites and the type of gene mutation in AS were also underlined.     

Novel and Novel De Novo Mutations in NTRK1 Associated With Congenital Insensitivity to Pain With Anhidrosis: A Case Report

Congenital insensitivity to pain with anhidrosis (CIPA) is a very rare autosomal recessively inherited disorder. The main clinical features of the disorder consist of absence of reactions to noxious stimuli and inability to sweat under any conditions.In this case report, a 3-year-old Chinese boy diagnosed with CIPA presented with the core features of CIPA, including insensitivity to noxious stimuli, self-mutilation, inability to sweat, and developmental delay. Clinical and genetic analyses were conducted on the affected boy.Sequencing analysis revealed an inherited novel mutation, c.1635G>C, and a novel de novo mutation, c.2197G>A, in the NTRK1 gene. In silico studies suggested that the mutations described are detrimental to the function of the protein encoded by the NTRK1 gene.The two novel mutations described here widen the genetic spectrum of CIPA, and this knowledge will benefit studies addressing this disease and pain medicine in the future.     

Novel homozygous nonsense mutation associated with Bardet–Biedl syndrome in fetuses with congenital renal malformation

Background:The Bardet–Biedl syndrome (BBS) is a rare autosomal recessive disorder, characterized by clinical and genetic heterogeneity. BBS is more commonly reported in adults and children than in fetuses. Here, a retrospective study on 210 fetuses with congenital renal malformation was conducted.Methods:The fetuses were diagnosed using invasive prenatal tests, including chromosome karyotype analysis, whole exome sequencing (WES), and single-nucleotide polymorphism array. We found the intrauterine phenotype of a fetus presenting enlarged kidneys, enhanced echo, and oligohydramnios; therefore, the fetus was characterized to have BBS.Results:Chromosome karyotype analysis presented normal results. Analysis using an Affymetrix CytoScan 750K array revealed 2 homozygous regions. However, WES revealed a homozygous mutation of c.1177C>T (p.Arg393*) on exon 12 of BBS1 and a heterozygous variation of c.2704G>A (p.Asp902Asn) on exon 22 of CC2D2A. The American College of Medical Genetics and Genomics guidelines identified c.1177C>T and c.2704G>A as a pathogenic mutation and of uncertain significance, respectively. Sanger sequencing identified heterozygous mutation, that is, c.1177C>T and heterozygous variation, that is, c.2704G>A in the parents of the fetus.Conclusions:WES identified a novel homozygous nonsense mutation c.1177C>T in BBS1 of a Chinese fetus with congenital renal malformation. This finding provides insight into the BBS1 mutations in Asian populations in general and shows the necessity of genetic counseling.     

TRMT10A Mutation in a Child with Diabetes,Short Stature,Microcephaly and Hypoplastic Kidneys

A new syndrome of diabetes, short stature, microcephaly and intellectual disability has been described in association with mutations in the tRNA methyltransferase 10 homologue A (TRMT10A) gene. We report a patient who presented with fasting hyperglycemia, a raised hemoglobin A1c and positive islet cell autoantibodies. Additional clinical features included intellectual disability, hypoplastic kidneys and short stature. In view of the syndromic features coexistant with diabetes, genetic evaluation was carried out, revealing a homozygous mutation in the TRMT10A gene (c.616G>A, p.G206R). The case highlights the importance of genetic evaluation of patients with diabetes with atypical features that can further progress our understanding of the pathophysiology of the rarer subtypes of diabetes.     

MORC2 gene de novo mutation leads to Charcot–Marie–Tooth disease type 2Z: A pediatric case report and literature review

Rationale:Mutations of the MORC2 gene have most commonly been associated with autosomal-dominant Charcot–Marie–Tooth disease type 2Z (CMT 2Z), while the impact of MORC2 mutations in CMT 2Z on neuronal biology and their phenotypic consequences in patients remain to be clarified.Patient concerns:We reported a 27-month-old child with a developmental lag of more than 1 year. He had progressive fatigue for 4 months, accompanied by dysphagia, choking while eating, and progressive aggravation. A genetic study revealed a de novo variant of MORC2, which has not yet been reported.Diagnosis:According to the child''s clinical manifestations, genetic pattern, and American College of Medical Genetics and Genomics pathogenicity analysis, the patient was diagnosed with CMT 2Z caused by MORC2 gene mutation.Interventions:Mitochondrial cocktail therapy (arginine, vitamin B1 tablets, vitamin B2 tablets, coenzyme Q10 capsules, L-carnitine oral liquid, idebenone tablets, etc) was given.Outcomes:Mitochondrial cocktail therapy did not significantly improve the child''s condition, head magnetic resonance imaging lesions were not significantly improved at outpatient follow-up more than 1 month later, and the lesions were basically unchanged.Lessons:The clinical manifestations of the disease were similar to those of Leigh syndrome, and they were not significantly improved by cocktail therapy. This site has not been reported in the literature domestically or abroad, and the pathogenesis of CMT 2Z caused by this site mutation is indeed not related to mitochondrial dysfunction. Our study is helpful for clinicians with regard to the differential diagnosis of Leigh syndrome and CMT 2Z and improvement of clinicians’ understanding of CMT 2Z disease.     

Germline mutation analysis of MLH1 and MSH2 in Malaysian Lynch syndrome patients

AIM: To investigate the protein expression profile of mismatch repair (MMR) genes in suspected cases of Lynch syndrome and to characterize the associated germline mutations.METHODS: Immunohistochemical analysis of tumor samples was performed to determine the protein expression profile of MMR protein. Germline mutation screening was carried out on peripheral blood samples. The entire exon regions of MLH1 and MSH2 genes were amplified by polymerase chain reaction, screened by denaturing high performance liquid chromatography (dHPLC) and analyzed by DNA sequencing to characterize the germline mutations.RESULTS: Three out of 34 tissue samples (8.8%) and four out of 34 tissue samples (11.8%) showed loss of nuclear staining by immunohistochemistry, indicating the absence of MLH1 and MSH2 protein expression in carcinoma cells, respectively. dHPLC analysis followed by DNA sequencing showed these samples to have germline mutations of MSH2 gene. However, no deleterious mutations were identified in any of the 19 exons or coding regions of MLH1 gene, but we were able to identify MLH1 promoter polymorphism, -93G > A (rs1800734), in 21 out of 34 patients (61.8%). We identified one novel mutation, transversion mutation c.2005G > C, which resulted in a missense mutation (Gly669Arg), a transversion mutation in exon 1, c.142G > T, which resulted in a nonsense mutation (Glu48Stop) and splice-site mutation, c.2006-6T > C, which was adjacent to exon 13 of MSH2 gene.CONCLUSION: Germline mutations were identified in four Malaysian Lynch syndrome patients. Immunohistochemical analysis of tumor tissue proved to be a good pre-screening test before proceeding to germline mutation analysis of DNA MMR genes.     

Analysis of the molecular mechanism and pedigree investigation of para-Bombay phenotype caused by combined mutations at position h649 and h768 of FUT1 gene

BackgroundThe para-Bombay phenotype is a rare red blood cell phenotype characterised by the lack of ABH antigens on red blood cells, but ABH substances can be found in saliva. The aim of this research was to study the mechanism of mutation of FUT1 and FUT2 genes and the pedigree of a family with the para-Bombay phenotype.Material and methodsThe blood group was detected by a conventional serological method, H antigen adsorption-elution test, and testing saliva for A, B, and H antigens. We amplified and sequenced the ABO, FUT1, and FUT2 genes of the proband and her family using a polymerase chain reaction method, and performed TA cloning and sequencing on the amplified products of the FUT1 gene to determine its genotype.ResultsWith the conventional serological method, it was found that the red blood cell phenotype of the proband and her sister lacked H antigen, while the adsorption-elution test of H antigen could detect weak H antigen. Through FUT1 cloning and sequencing, it was found that the proband had a compound heterozygous mutation of c.649G>T and c.768delC, and the genotype was FUT1*01W.24/FUT1*01N.20; the proband’s father and mother had heterozygous mutations of c.768delC and c.649G>T, and their genotypes were FUT1*01N.20/FUT1*01 and FUT1*01W.24/FUT1*01. The sister’s FUT1 mutation site and genotype were the same as the those of the proband. FUT2 gene sequencing revealed that the proband and sister had a synonymous mutation of c.357C>T, while their parents both had a synonymous mutation of c.357C>T and a missense mutation of c.385A>T. The Lewis blood types of the four samples all showed Le (a–b+), all of which were secretory.ConclusionBlood group serology and molecular diagnostic techniques showed that the compound heterozygous mutations of the proband and her sister were inherited from their father and mother.     

Targeted Genetic Analysis in a Chinese Cohort of 208 Patients Related to Familial Hypercholesterolemia

Aim: Familial hypercholesterolemia (FH) is the most commonly encountered genetic condition that predisposes individuals to severe autosomal dominant lipid metabolism dysfunction. Although more than 75% of the European population has been scrutinized for FH-causing mutations, the genetic diagnosis proportion among Chinese people remains very low (less than 0.5%). The aim of this study was to identify genetic mutations and help make a precise diagnosis in Chinese FH patients.Methods: We designed a gene panel containing 20 genes responsible for FH and tested 208 unrelated Chinese possible/probable or definite FH probands. In addition, we called LDLR copy number variation (CNVs) with the panel data by panelcn.MOPS, and multiple ligation-dependent probe amplification (MLPA) was used to search for CNVs in LDLR, APOB, and PCSK9.Results: A total of 79 probands (38.0%) tested positive for a (likely) pathogenic mutation, most of which were LDLR mutations, and three LDLR CNVs called from the panel data were all successfully confirmed by MLPA analysis. In total, 48 different mutations were identified, including 45 LDLR mutations, 1 APOB mutation, 1 ABCG5 mutation, and 1 APOE mutation. Among them, the five most frequent mutations (LDLR c.1879G>A, c.1747C>T, c.313+1G>A, c.400T>C, and APOB c.10579C>T) were detected. Moreover, we also found that patients with LDLR variants of CNVs and splicing and nonsense had increased low-density lipoprotein cholesterol levels when compared with those who carried missense variants.Conclusions: The spectrum of FH-causing mutations in the Chinese population is refined and expanded. Analyses of FH causal genes have been a great help in clinical diagnosis and have deep implications in disease treatment. These data can serve as a considerable dataset for next-generation sequencing analysis of the Chinese population with FH and contribute to the genetic diagnosis and counseling of FH patients.     

Association between CYP2B6 c.516G >T variant and acute leukaemia: A protocol for systematic review and meta-analysis

Background:Acute leukemia (AL) is a kind of malignant tumor of hematopoietic system. A number of studies have suggested that Single Nucleotide Polymorphisms are significantly associated with risk of AL. Present study performs meta-analysis to evaluate the association between CYP2B6 c.516G>T variant and AL risk.Methods:Databases including PubMed, EMBASE, Chinese National Knowledge Infrastructure (CNKI), and Wanfang were searched for literatures to September 30, 2019, both in English and Chinese. Relative risk and its 95% confidence intervals were used to assess the associations. Statistical analyses of this meta-analysis were conducted by using STATA 13.0. software.Results:A total of 7 studies, including 1038 cases and 1648 controls, were analyzed. Our results indicated that CYP2B6 c.516G>T variant was significantly related to an increased the risk of AL under dominant model, recessive model, homozygote model, and allelic model. In addition, subgroup analyses were also performed by disease classification, country, and study design. No significant associations were obtained between CYP2B6 c.516G>T variant and the risk of AL under the recessive model in the design of hospital-based (relative risk = 0.98; 95% confidence interval: 0.95–1.01; P = 0.118).Conclusion:Our meta-analysis indicated that the CYP2B6 variant is significantly associated with AL risk, in which CYP2B6 c.516G>T is related to an increased risk of AL.     

Gene diagnosis and pedigree analysis of two Han ethnicity families with propionic acidemia in Fujian

Propionic acidemia is associated with pathogenic variants in PCCA or PCCB gene. We investigated the potential pathogenic variants in PCCA or PCCB genes in Fujian Han population.Two probands and their families of Han ethnicity containing two generations were subject to newborn screening using tandem mass spectrometry, followed by diagnosis using urine gas chromatography mass spectrometry. Sanger sequencing was used to identify potential mutations in PCCA and PCCB genes.Compound heterozygous variants were identified in PCCB gene in two siblings of the first family, the youngest girl showed a novel missense variant c.1381G>C (p.Ala461Pro) in exon 13 and a heterozygous missense variant c.1301C>T (p.Ala434Val) in exon 13, which were inherited respectively from their parents. The oldest boy is a carrier with a novel missense variant c.1381G>C (p.Ala461Pro) in exon 13 which were inherited from his father. In the second family, c.1535G>A homozygous mutations were identified in the baby girl, which were inherited respectively from their parents. In silico analysis, several different types of bioinformatic software were utilized, which predicted that the novel variant c.1381G>C in PCCB gene was damaged. According to ACMG principle, the missense variant c.1381G>C (p.Ala461Pro) in exon 13 was a Variant of Undetermined Significance (VUS).One novel missense variant and two missense variants in PCCB gene were identified in the study. The novel variant of PCCB gene identified VUS was identified for the first time in the Chinese population, which enriched the mutational spectrum of PCCB gene.     

Pathogenic variants of PROC gene caused type II activity deficiency in a Chinese family: A case report

Rationale:Hereditary Protein C (PC) deficiency is a rare genetic disorder caused by PROC gene mutation. In this article, we report a case of PC deficiency in a Chinese family due to a novel PROC gene mutation.Study Subject:The proband presented with recurrent cerebral infarction over the course of the previous 3 years. He was admitted to the hospital due to signs of mental retardation.Diagnoses:Physical examination, laboratory tests, and magnetic resonance imaging demonstrated that the proband had a manifestation of PC deficiency that included acute cerebral infarction. DNA sequencing analysis revealed a missense variant, c.1015G > A (p.V339 M from valine to methionine) in exon 9 of the PROC gene. In addition, Sanger sequencing confirmed that the proband''s son was heterozygous for the same variant. Therefore, the PROC gene mutation was transmitted in an autosomal dominant inheritance manner.Interventions:The patient was treated with a daily dosage of Warfarin (3.5 mg) and was scheduled to undergo regular blood coagulation tests.Outcomes:At the 3-month follow-up appointment, the patient showed improvements in his overall health condition.Lessons:We identified a novel missense mutation in the PROC gene in a Chinese family which caused a decrease in the PC antigen level and recurrent cerebral infarction.     

Hereditary renal glycosuria,diabetes and responses to SGLT2 inhibitor

AimsTo present the clinical features of two rare cases with hereditary renal glycosuria and diabetes, explore their responses to sodium‐glucose cotransporter 2 (SGLT2) inhibitor, and summarize the reported solute carrier family 5 member 2 (SLC5A2) mutations and related phenotypes.MethodsTwo patients were followed up for 6.5 and 3 years respectively. SLC5A2 and hepatocyte nuclear factor 1‐alpha (HNF1A) gene were sequenced. We used the flash glucose monitoring system to evaluate the efficacy of SGLT2 inhibitor treatment. Then we retrieved all the literature and analyzed SLC5A2 gene mutations and the phenotypes.ResultsDuring long‐time follow up, the two patients had frequent unproportional renal glycosuria in the morning even when their fasting serum glucose was only slightly increased. A novel rare mutation V359G and a pathogenic rare mutation ivs7 + 5G > A in SLC5A2 gene were found respectively. In Case 1, the 24 h glucose excretion was 2.2 g/d and increased to 103 g/d after dapaglifozin treatment, whereas the average glucose (6.33 ± 1.56 vs. 6.28 ± 1.74 mmol/L), and time in range (TIR) (95% vs. 93%) were similar. In Case 2, the 24 h glycosuria was 121.4 g/d and increased to 185.8 g/day after dapaglifozin add‐on therapy, with a further reduction of average glucose (9.11 ± 2.63 vs. 7.54 ± 2.39 mmol/L, p < 0.001) and better TIR (70% vs. 84%). We reviewed 139 cases with hereditary renal glycosuria and SLC5A2 gene mutation. The urine glucose was highest in patients with homozygous mutations [64.0(36.6–89.6)g/24 h] compared with compound heterozygous mutations [25.9(14.4–41.2)g/24 h] and heterozygous mutations [3.45(1.41–7.50)g/24 h] (p < 0.001).ConclusionsGenetic renal glycosuria could not protect individuals completely from developing diabetes. Patients with SGLT2 gene mutations are still responsive to the SGLT2 inhibitor treatment.