Vasculitis in a patient with mevalonate kinase deficiency (MKD): a case report

Abstract Background Mevalonate kinase deficiency (MKD) is a rare autoinflammatory condition caused by biallelic loss-of-function (LOF) mutations in mevalonate kinase (MVK) gene encoding the enzyme mevalonate kinase. Patients with MKD display a variety of non-specific clinical manifestations, which can lead to diagnostic delay. We report the case of a child presenting with vasculitis that was found by genetic testing to be caused by MKD, and now add this autoinflammatory disease to the ever-expanding list of causes of monogenic vasculitides. Case presentation A 2-year-old male presented with an acute 7-day history of high-grade fever, abdominal pain, diarrhoea, rectal bleeding and extensive purpuric and necrotic lesions, predominantly affecting the lower limbs. He had been suffering from recurrent episodes of fever from early in infancy, associated with maculopapular/petechial rashes triggered by intercurrent infection, and after vaccines. Extensive infection screen was negative. Skin biopsy revealed small vessel vasculitis. Visceral digital subtraction arteriography was normal. With a diagnosis of severe idiopathic cutaneous vasculitis, he was treated with corticosteroids and mycophenolate mofetil. Despite that his acute phase reactants remained elevated, fever persisted and the vasculitic lesions progressed. Next-generation sequencing revealed compound heterozygous mutation in MVK c.928G > A (p.V310M) and c.1129G > A (p.V377I) while reduced mevalonate enzyme activity was confirmed suggesting a diagnosis of MKD as a cause of the severe vasculitis. Prompt targeted treatment with IL-1 blockade was initiated preventing escalation to more toxic vasculitis therapies and reducing unnecessary exposure to cytotoxic treatment. Conclusions Our report highlights the broad clinical phenotype of MKD that includes severe cutaneous vasculitis and emphasizes the need to consider early genetic screening for young children presenting with vasculitis to exclude a monogenic vasculitis which may be amenable to targeted treatment.

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Mevalonate kinase deficiency syndrome: Single center experience

Rheumatology Science and Practice ◽

10.47360/1995-4484-2021-326-334 ◽

2021 ◽

Vol 59 (3) ◽

pp. 326-334

Author(s):

A. L. Kozlova ◽

V. O. Bludova ◽

V. I. Burlakov ◽

E. V. Raykina ◽

T. V. Varlamova ◽

...

Keyword(s):

Clinical Laboratory ◽

Molecular Genetic ◽

Clinical Manifestations ◽

Deficiency Syndrome ◽

Compound Heterozygous ◽

Mevalonate Kinase Deficiency ◽

Mevalonate Kinase ◽

Single Center Experience ◽

Full Remission ◽

Molecular Genetic Data

The aim of this study was to analyze the clinical, laboratory and molecular genetic data of 26 patients (15 boys, 11 girls) diagnosed with mevalonate kinase deficiency syndrome (MKD).Subjects and methods. The age of MKD manifestation ranged from 0 to 30.0 months (M – 1.5 months). Clinical manifestations and their severity were extremely diverse: from symptoms resembling Marshall’s syndrome to severe systemic manifestations with respiratory failure, hepatosplenomegaly and pancytopenia.Results/Conclusion. All patients had homozygous/compound-heterozygous mutations in the MVK gene, including 10 newly described variants. In all 20 patients, who have been treated with IL-1 inhibitors long enough to assess the effect of the treatment, drastic improvement of the condition was noted, but only in 17/20 patients achieved full remission.

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MEVALONATE KINASE DEFICIENCY IN AN INFANT: KEY ASPECTS OF DIAGNOSIS AND TREATMENT

PEDIATRIA Journal named after G N SPERANSKY ◽

10.24110/0031-403x-2021-100-2-276-283 ◽

2021 ◽

Vol 100 (2) ◽

pp. 276-283

Author(s):

M.F. Dubko ◽

◽

R.K. Raupov ◽

M.A. Kaneva ◽

E.N. Suspitsyn ◽

...

Keyword(s):

Late Onset ◽

Interleukin 1 ◽

Clinical Manifestations ◽

Specific Treatment ◽

Autosomal Recessive Inheritance ◽

Compound Heterozygous ◽

Mevalonate Kinase Deficiency ◽

Mevalonate Kinase ◽

Pathogenic Variants ◽

Severe Type

Mevalonate kinase deficiency (MKD) is a rare autoinflammatory disease with an autosomal recessive inheritance. The severity of the disease is correlated with the residual enzyme activity. There are two types of mevalonate kinase deficiency: a less severe type called hyperimmunoglobulinemia D syndrome (HIDS) and a more severe type called mevalonic aciduria. A little more than 300 cases with MDK have been described worldwide. The rarity of this disease, and polymorphism of clinical manifestations lead to late diagnosis and late onset of specific treatment. We described the 7-month-old infant with pathogenic variants c.118C> T (p.R40W) and c.206_207del (p.S69fs) in the MVK gene in a compound heterozygous state with the successful use of an interleukin-1 blocker.

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Unique three-site compound heterozygous mutation in the WFS1 gene in Wolfram syndrome

BMC Endocrine Disorders ◽

10.1186/s12902-021-00823-5 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Ziyu Ren ◽

Jixiu Yi ◽

Min Zhong ◽

Yunting Wang ◽

Qicong Liu ◽

...

Keyword(s):

Genetic Disease ◽

Target Genes ◽

Novel Mutation ◽

Clinical Manifestations ◽

Wolfram Syndrome ◽

Compound Heterozygous Mutation ◽

Heterozygous Mutation ◽

Compound Heterozygous ◽

Compound Heterozygous Mutations ◽

Wfs1 Gene

Abstract Background Wolfram syndrome (WFS) is a rare autosomal recessive genetic disease whose main cause is mutations in the WFS1 and CISD2 genes. Its characteristic clinical manifestations are diabetes insipidus, diabetes mellitus, optic atrophy and deafness. Methods In this study, two patients from this particular family underwent complete routine biochemical and ophthalmic tests. Blood, urine, routine stool test, visual acuity (VA) examination, visual field assessment, funduscope, optical coherence tomography and periorbital magnetic resonance imaging (MRI) scans were performed for each patient to evaluate whether the nerve fiber layer around the optic nerve head was atrophied and next-generation sequencing of target genes was performed in two patients. Results When the patients were diagnosed with Wolfram syndrome, their genetic analyses suggested unique three-site compound heterozygous mutations (c.2314C > T + c.2194C > T + c.2171C > T) in exon 8 of both patients’ chromosome 4. One mutation (c.2314C > T) was a novel mutation in the known reports of Wolfram syndrome. As a degenerative genetic disease, the types of gene mutations in the Chinese population are generally homozygous mutations at the unit point or compound heterozygous mutations at two nucleotide change sites. However, the two patients reported in this study are the first known cases of compound heterozygous mutations with three mutation sites coexisting on the WFS1 gene in China or even globally. Conclusions This study expands the phenotypic spectrum of Wolfram syndrome and may reveal a novel mutation pattern of pathogenesis of Wolfram syndrome. The implications of this discovery are valuable in the clinical diagnosis, prognosis, and treatment of patients with WFS1.

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Hereditary Spherocytosis Caused by a Novel Compound Heterozygous Mutation of the SPTA1 Gene and Autoimmune Hepatitis in a Pediatric Patient

10.21203/rs.3.rs-1023423/v1 ◽

2021 ◽

Author(s):

Yu-mei Qin ◽

Yan-yun Chen ◽

Lin Liao ◽

Yang-yang Wu ◽

Min Chen ◽

...

Keyword(s):

Autoimmune Hepatitis ◽

Hereditary Spherocytosis ◽

Clinical Manifestations ◽

Liver Function Tests ◽

Compound Heterozygous Mutation ◽

Heterozygous Mutation ◽

Compound Heterozygous ◽

Concomitant Disease ◽

Genetic Characteristics ◽

Paternal Grandmother

Abstract Objective: Patients suffering from both hereditary spherocytosis (HS) and autoimmune hepatitis (AIH) are very rare. We analyzed the clinical and genetic characteristics of a seven-year-old girl with yellow sclerae and abnormal liver function tests, but no further symptoms. Methods: Blood samples were collected from the proband, her parents, and her paternal grandmother, and analyzed using routine laboratory tests, as well as subjected to next-generation and Sanger sequencing.Results: Compound heterozygous mutations of the spectrin alpha, erythrocytic 1 (SPTA1) gene were identified in the proband. Thec.134G>A (p.R45K) and c.6544G>C (p.D2182H) mutations were inherited from her mother and father, respectively. The proband’s father and paternal grandmother had the same mutation. Neither mutation is described in the Human Gene Mutation Database. Conclusions: HS has clinical manifestations similar to AIH, it may be difficult to diagnose when it coexists with AIH. When laboratory results cannot be explained by autoimmune liver disease alone, the possibility of a concomitant disease should be considered. Pedigree investigation and genetic analyses might be required to arrive at the final diagnosis.

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Novel PTPRQ Mutations Identified in Three Congenital Hearing Loss Patients With Various Types of Hearing Loss

Annals of Otology Rhinology & Laryngology ◽

10.1177/0003489415575041 ◽

2015 ◽

Vol 124 (1_suppl) ◽

pp. 184S-192S ◽

Cited By ~ 8

Author(s):

Naoko Sakuma ◽

Hideaki Moteki ◽

Hela Azaiez ◽

Kevin T. Booth ◽

Masahiro Takahashi ◽

...

Keyword(s):

Hearing Loss ◽

Clinical Manifestations ◽

Vestibular Dysfunction ◽

Compound Heterozygous Mutation ◽

Heterozygous Mutation ◽

Caloric Test ◽

Compound Heterozygous ◽

Site Mutation ◽

Vestibular Evoked Myogenic Potential ◽

Phenotypic Features

Objectives: We present 3 patients with congenital sensorineural hearing loss (SNHL) caused by novel PTPRQ mutations, including clinical manifestations and phenotypic features. Methods: Two hundred twenty (220) Japanese subjects with SNHL from unrelated and nonconsanguineous families were enrolled in the study. Targeted genomic enrichment with massively parallel DNA sequencing of all known nonsyndromic hearing loss genes was performed to identify the genetic cause of hearing loss. Results: Four novel causative PTPRQ mutations were identified in 3 cases. Case 1 had progressive profound SNHL with a homozygous nonsense mutation. Case 2 had nonprogressive profound SNHL with a compound heterozygous mutation (nonsense and missense mutation). Case 3 had nonprogressive moderate SNHL with a compound heterozygous mutation (missense and splice site mutation). Caloric test and vestibular evoked myogenic potential (VEMP) test showed vestibular dysfunction in Case 1. Conclusion: Hearing loss levels and progression among the present cases were varied, and there seem to be no obvious correlations between genotypes and the phenotypic features of their hearing loss. The PTPRQ mutations appeared to be responsible for vestibular dysfunction.

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Hepatic Manifestations of 3-Hydroxy-3-Methylglutaryl-Coenzyme-A Lyase Deficiency in Saudi Patients: Experience of a Tertiary Care Center

Journal of Pediatric Genetics ◽

10.1055/s-0040-1714698 ◽

2020 ◽

Author(s):

Sinan Holdar ◽

Zuhair Rahbeeni ◽

Khushnooda Ramzan ◽

Faiqa Imtiaz

Keyword(s):

Coenzyme A ◽

Care Center ◽

Tertiary Care ◽

Clinical Manifestations ◽

Research Centre ◽

Compound Heterozygous Mutation ◽

Heterozygous Mutation ◽

Compound Heterozygous ◽

Laboratory Findings ◽

Saudi Patients

Abstract3-Hydroxy-3-methylglutaryl-coenzyme-A lyase (HMGCL) deficiency, a rare autosomal recessive disorder, is caused by a homozygous or compound heterozygous mutation in the HMGCL gene (chromosome 1p36.11). HMGCL catalyzes the final step of leucine degradation and plays a key role in ketone body formation. Several studies have reported general hepatic findings (e.g., hepatomegaly) in patients with HMGCL deficiency, but currently, there are no available data regarding the incidence and epidemiology of liver involvement. The main objective of our study was to investigate the overall clinical manifestations, laboratory findings, genotype, and presence of hepatic involvement in Saudi patients with HMGCL deficiency. A retrospective chart review of patients with HMGCL deficiency including those with a documented hepatic manifestation was performed at the King Faisal Specialist Hospital & Research Centre in Riyadh, Saudi Arabia. We evaluated 50 cases of HMGCL deficiency. Hepatic findings were found in 17 patients at the time of diagnosis. The mean age of hepatic presentation was 135 days, and the median age was 56 days (range: 2–315 days). Hepatomegaly was found in 65%, abnormal biochemical profile in 47%, and an abnormal imaging in 53% of patients. The most frequent mutation in this cohort was the p.Arg41Gln founder mutation (59%). In comparison to data from the current literature, HMGCL deficiency can be considered as a diagnostic metabolite for hepatic manifestations and requires appropriate evaluation, including molecular genetic analysis.

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A216 CLINICAL MANIFESTATIONS OF LYSOSOMAL ACID LIPASE DEFICIENCY (LAL-D): THE INTERNATIONAL LAL-D REGISTRY

Journal of the Canadian Association of Gastroenterology ◽

10.1093/jcag/gwab002.214 ◽

2021 ◽

Vol 4 (Supplement_1) ◽

pp. 248-249

Author(s):

M Francis ◽

M Balwani ◽

W Balistreri ◽

L D’Antiga ◽

S Fang ◽

...

Keyword(s):

Diagnostic Delay ◽

Clinical Manifestations ◽

Term Treatment ◽

Compound Heterozygous ◽

Acid Lipase ◽

Lysosomal Acid ◽

Lysosomal Acid Lipase ◽

Lysosomal Acid Lipase Deficiency ◽

Long Term Treatment ◽

History Of

Abstract Background Lysosomal acid lipase deficiency (LAL-D) is a rare, autosomal recessive disease caused by pathogenic variants in the LIPA gene. Lysosomal accumulation of cholesteryl esters and triglycerides leads to cirrhosis and dyslipidemia across a clinical spectrum, and affect both infants and children/adults. Aims An international registry (NCT01633489; Alexion Pharmaceuticals, Inc.; 2013–ongoing) was established to better understand the natural history of lysosomal acid lipase deficiency (LAL-D) and to evaluate long-term treatment outcomes. Methods Baseline findings for patients enrolled through July 1, 2019 are presented. Of 190 patients enrolled, 35 were excluded from this analysis (LIPA carrier, deceased at enrollment, unconfirmed LAL-D diagnosis); 155 patients with confirmed LAL-D diagnosis were included (12 infants, 143 children/adults). LAL enzyme activity analysis was performed for 145/154 patients (94%) and genetic testing for 128/154 patients (83%). Results Of 105 children/adults with reported LIPA mutations, 39 were homozygous and 34 were compound heterozygous for the common LIPA mutation E8SJM (c.894G>A); 6 infants with reported LIPA mutations were homozygotes and 2 were compound heterozygotes. Of the 155 patients, 62% were <18 years, 52% were male, and 85% were white. Median (range) age at clinical onset was 0.2 years (0.0–0.7) among infants and 6.0 years (0.0–41.3) among 133 children/adults with data; median (range) age at diagnosis was 0.2 years (−0.1 to 1.2) among infants and 10.8 years (0.2–53.6) among 135 children/adults with data. Manifestations that raised suspicion of LAL-D were reported in 149/155 patients. Infants (12 with data) presented predominantly with hepatomegaly (75%), splenomegaly (58%), nausea/vomiting (58%), and diarrhea (50%), and 50% had a known family history of LAL-D. Children/adults (n=143) presented predominantly with elevated alanine aminotransferase levels (67%), hepatomegaly (66%), and elevated aspartate aminotransferase levels (65%). Of 74 children/adults with baseline liver biopsy, 58% had microvesicular steatosis, 16% had micro- and macrovesicular steatosis, and 32% had lobular inflammation. Of the 155 patients, 6% had a medical history of cirrhosis. Analyses exploring the genotype-phenotype relationship will be presented. Conclusions Registry data of >150 LAL-D patients demonstrate early symptom onset, variable clinical manifestations, and a significant diagnostic delay in children/adults. Funding Agencies Alexion Pharmaceuticals, Inc.

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Gene Expression Analysis of Mevalonate Kinase Deficiency Affected Children Identifies Molecular Signatures Related to Hematopoiesis

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18031170 ◽

2021 ◽

Vol 18 (3) ◽

pp. 1170

Author(s):

Simona Pisanti ◽

Marianna Citro ◽

Mario Abate ◽

Mariella Caputo ◽

Rosanna Martinelli

Keyword(s):

Gene Ontology ◽

Differentially Expressed Genes ◽

Molecular Mechanisms ◽

Genetic Disorder ◽

Clinical Manifestations ◽

Differentially Expressed ◽

Clinical Feature ◽

Recurrent Fever ◽

Mevalonate Kinase Deficiency ◽

Mevalonate Kinase

Mevalonate kinase deficiency (MKD) is a rare autoinflammatory genetic disorder characterized by recurrent fever attacks and systemic inflammation with potentially severe complications. Although it is recognized that the lack of protein prenylation consequent to mevalonate pathway blockade drives IL1β hypersecretion, and hence autoinflammation, MKD pathogenesis and the molecular mechanisms underlaying most of its clinical manifestations are still largely unknown. In this study, we performed a comprehensive bioinformatic analysis of a microarray dataset of MKD patients, using gene ontology and Ingenuity Pathway Analysis (IPA) tools, in order to identify the most significant differentially expressed genes and infer their predicted relationships into biological processes, pathways, and networks. We found that hematopoiesis linked biological functions and pathways are predominant in the gene ontology of differentially expressed genes in MKD, in line with the observed clinical feature of anemia. We also provided novel information about the molecular mechanisms at the basis of the hematological abnormalities observed, that are linked to the chronic inflammation and to defective prenylation. Considering the broad and unspecific spectrum of MKD clinical manifestations and the difficulty in its diagnosis, a better understanding of MKD molecular bases could be translated to the clinical level to facilitate diagnosis, and improve management and therapy.

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AGRN Gene Mutation Leads to Congenital Myasthenia Syndromes: A Pediatric Case Report and Literature Review

Neuropediatrics ◽

10.1055/s-0040-1708534 ◽

2020 ◽

Vol 51 (05) ◽

pp. 364-367

Author(s):

Siyi Gan ◽

Haiyan Yang ◽

Ting Xiao ◽

Zou Pan ◽

Liwen Wu

Keyword(s):

Gene Mutation ◽

Muscle Weakness ◽

Motor Development ◽

Neuromuscular Junctions ◽

Age Of Onset ◽

Lower Limbs ◽

Compound Heterozygous Mutation ◽

Heterozygous Mutation ◽

Compound Heterozygous ◽

Congenital Myasthenia

AbstractThe congenital myasthenia syndromes (CMS) are a group of autosomal recessive or autosomal dominant diseases that affect neuromuscular junctions. CMS caused by AGRN mutations is very uncommon typically characterized by ptosis, mild weakness, and proximal limb weakness. We report the case of an 8-year-old female who exhibited the onset of motor development retardation from infancy and slow progression to proximal muscle weakness. Repeated nerve stimulation at 3 Hz showed a clear decrement with 17%. Whole exon sequencing showed an AGRN gene compound heterozygous mutation (c.5009C >T and c.5078T > C). She was treated with salbutamol but without improvement. Then pseudoephedrine was adapted as a treatment choice and obtained remarkable curative effect. We have summarized and analyzed 12 patients who have been reported in the literature. An early age of onset and muscle weakness in the lower limbs are the main feature of an early AGRN gene mutation. Both types of AGRN-related CMS respond favorably to ephedrine. This is the first report showing that pseudoephedrine is effective as a choice for the treatment of AGRN-related CMS.

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The genetics and clinical manifestations of patients with vitamin D dependent rickets type 1A

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2020-0691 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Ayse Ozden ◽

Hakan Doneray

Keyword(s):

Vitamin D ◽

Clinical Manifestations ◽

Autosomal Recessive Disorder ◽

Treatment Modalities ◽

Compound Heterozygous Mutation ◽

Heterozygous Mutation ◽

Compound Heterozygous ◽

Laboratory Findings ◽

Day Range ◽

The Mean

Abstract Objectives Vitamin D dependent rickets type 1A (VDDR-1A) is a very rare autosomal recessive disorder caused by mutations in the CYP27B1, which encodes vitamin D 1α-hydroxylase. We report the genetics and clinical manifestations of nine patients with VDDR-1A and compare our patients to other cases with the same mutations in the literature. Methods The clinical presentations, clinical and laboratory findings and treatment modalities of the patients were evaluated retrospectively. Results The mean age of the patients at the time of diagnosis was 39.9 months (range: 4.5–111). At the time of diagnosis, six patients had received stoss vitamin D therapy. Clinical findings related to rickets were obvious in seven patients and unclear in two patients. Except for one case, all patients had laboratory findings of rickets. A novel variant and four previously reported mutations in CYP27B1 were identified. The mean calcitriol and elemental calcium dose were 45.5 ng/kg/day (range: 20–70) and 75.6 mg/kg/day (range: 45–125), respectively. Conclusions We found a novel compound heterozygous mutation consisting of a reported duplication [(p.F443Pfs*24 (c.1319_1325 dup CCCACCC)] in exon 8 and a novel deletion [p.D507Efs*34 (c.1521 delC)] in exon 9. Our study suggests that the clinical manifestations and laboratory findings of the patients with VDDR1A are variable even among the patients with the same mutation.

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