Mevalonate kinase deficiency (MKD) is a rare genetic disorder, resulting in the lack of the mevalonate kinase enzyme (MVK), which is involved in the biosynthesis of cholesterol, non-sterol isoprenoids, and coenzyme Q10 (CoQ10). The more severe phenotype of MKD is known as mevalonic aciduria (MA), typically presenting as a multisystemic inflammatory syndrome with possible neurological manifestations, such as developmental delay, cerebellar ataxia, and retinopathy. Myopathy or isolated hyperCKemia have been rarely reported in association with MA. However, a few studies evidenced mitochondrial dysfunction in MVK deficient cells. To point out the connection between MKD, myopathy, and mitochondrial dysfunction, describing two cases of MA. We report on two unrelated patients with myopathy and ataxia, providing clinical, histological, biochemical, and genetic data of MKD. Both patients were referred to the Neurology Department in the first year of life, due to muscle weakness, gait disturbances, and increased levels of CK value. Muscle biopsy was performed, showing some mitochondrial alterations and mild lipid storage. Interestingly, biochemical studies on muscle homogenate revealed a reduction of mitochondrial respiratory chain activities and CoQ10 levels. Genetic analysis confirmed the MKD diagnosis, evidencing a homozygous MVK gene mutation in the first case, and compound heterozygous mutations in the second one. This report describes two MKD cases with clinical and morphological evidence of muscle involvement in the spectrum of MA related to mitochondrial dysfunction.

The aim of this study was to present a case of early-onset mevalonic aciduria (MA) in a neonate and summarize the relevant phenotypic and genotypic spectra of MA. We describe a neonate who presented with elevated inflammatory marker after birth. Liver function tests revealed liver injury, and enzyme-linked immunosorbent assay (ELISA) confirmed increased mevalonic acid levels in blood and urine. Whole-genome sequencing identified a novel homozygous mutation (c.928G>A, p.Val310Met) in the MVK gene. To date, only 16 neonate cases of MA have been reported in the literature. Affected individuals typically present recurrent fever, hepatosplenomegaly, lymphadenopathy, vomiting, diarrhea, and neurological damage symptoms. This case emphasizes that in patients presenting with recurrent fever accompanied by vomiting, diarrhea, hepatosplenomegaly, and lymphadenopathy, clinicians should pay close attention to differentiating MA from infectious diseases and autoinflammatory disorders to avoid misdiagnosis or underdiagnosis. We report one of the youngest neonates with early-onset MA diagnosed promptly, caused by the novel homozygous MVK variant, c.928G>A (p.Val310Met), and expand the genotypic and clinical phenotypic spectrum of MVK variants related with MA.

Hyperimmunoglobulin D syndrome is a rare autosomal recessive autoinflammatory syndrome caused by mevalonate kinase enzyme deficiency. It is characterized by recurrent febrile attacks beginning in the first year of life. Treatment is mainly supportive, and there are successful reports of trials of novel therapies such as anakinra and canakinumab. We present a case of a 3-month-old girl from Tanzania, East Africa, who experienced recurrent febrile attacks, sepsis, and anemia since her first week of life. She also exhibited arthritis, generalized lymphadenopathy, urticaria, dermatitis, and failure to thrive. After multiple hospital admissions for similar symptoms, a diagnosis of primary immunodeficiency was considered and genetic testing revealed two heterozygous-like pathogenic variants in the mevalonate kinase gene. This case highlights the importance of clinicians in low-resource settings to have a high index of suspicion for primary immunodeficiencies when managing patients with recurrent febrile infections and to consider genetic studies for accurate diagnosis.

Mevalonate kinase deficiency (MKD) is a rare autoinflammatory disease, and mevalonic aciduria (MA) is a severe phenotype of MKD. The present study reports the characteristics of MKD and four novel mutations in the mevalonate kinase (MVK) gene in a Chinese cohort. A retrospective study was conducted on patients diagnosed with MKD from July 2013 to December 2024. The clinical, immunological, and follow-up data were collected from electronic medical records. Next-generation sequencing and Sanger sequencing were performed to identify gene mutations. A literature review was performed on MKD patients to further investigate the associations between genotype and phenotype. Eleven MKD patients were enrolled from a Chinese cohort of prolonged and recurrent fever of unknown origin. Ten patients were classified as having hyperimmunoglobulin D syndrome (HIDS), and one patient was classified as having MA. The median follow-up duration was 5 years (IQR: 1.5-6 years). Recurrent fever and gastrointestinal symptoms were the most common symptoms. Anemia was observed in 8 of the 11 patients, including one patient with severe hematological complications. Growth restriction (5/11 patients) and developmental delay (4/11 patients) were also observed. IgD levels were measured in ten patients, and the median IgD level was 85.23 µg/ml (IQR: 18.74-385.19 µg/ml). Four novel mutation sites in the MVK gene were discovered: c.78G > A, c.463G > A, c.1076C > T and c.1088G > A. Etanercept was the effective biological agent tested, leading to complete or partial remission in 5 of the 6 patients. A literature review of 20 MA patients suggested that homozygous MVK gene mutations are more frequently associated with MA. Moreover, MA patients with the homozygous A334T mutation present a milder phenotype, and those with the I268T homozygous mutation present a more severe phenotype. This study is the largest case series of MKD pediatric patients from China. Four new mutation sites in MVK were identified, further expanding the phenotypic and genotypic spectrum of MKD and emphasizing the significance of MVK mutation patterns in influencing disease severity.

Mevalonate kinase deficiency is an inherited autoinflammatory disorder that can present with a wide clinical spectrum, ranging from mild forms with recurrent episodes of fever, lymphadenopathy, splenomegaly and skin rash to the much rarer severe form, which is characterized by additional occurrences of psychomotor impairment, cholestatic jaundice, ophthalmological symptoms, and failure to thrive. The few cases described with perinatal onset often showed a very severe clinical course. Here, we report the case of a preterm infant born at 30 + 2 weeks of gestation with a prenatal genetic diagnosis of mevalonate kinase deficiency presenting with intrauterine bowel dilatation, mild hydrops fetalis, and microcephaly. Laparotomy on the second day of life revealed intestinal obstruction necessitating partial ileum resection and ileostomy. The neonate had recurrent inflammatory reactions with elevated C-reactive protein levels, severe cholestasis, a progressive liver dysfunction, and an increasingly distended abdomen with subsequent respiratory insufficiency. Urinary mevalonic acid was highly elevated. The patient received anti-inflammatory therapy with prednisone and anakinra. Unfortunately, the patient died at the age of 77 days due to cardiorespiratory failure. This case shows that intestinal obstruction with dilated fetal bowel loops can be an initially leading clinical symptom of severe mevalonate kinase deficiency. Diagnostics should be considered at an early stage, especially in the presence of other anomalies such as hydrops fetalis, growth restriction, or microcephaly. Data on the neonatal course of severe mevalonate kinase deficiency are still scarce and further studies are needed, particularly on treatment in neonates and young infants.