Perinatal Onset Mevalonate Kinase Deficiency

Abstract

Defects in mevalonate kinase, a critical rate-limiting enzyme in cholesterol and isoprene metabolism, have been associated with 2 clinical phenotypes: mevalonic aciduria, which presents in infancy or early childhood with growth failure, dysmorphic features, and neurologic disease; and hyperimmunoglobulinemia D and periodic fever syndrome, which usually presents outside the neonatal period as an autoinflammatory periodic fever syndrome. This report describes a kindred with 2 siblings affected by severe mevalonate kinase deficiency (mevalonic aciduria) with perinatal onset. Dysmorphic and central nervous system abnormalities, anemia, and cholestasis were prominent features in 1 sibling. Both cases were fatal, 1 in the immediate neonatal period and 1 in utero. The small number of cases of mevalonate kinase deficiency presenting in the perinatal period have typically been severely affected, with signs and symptoms of a severe multisystem disorder. Predominant features of perinatal onset mevalonate kinase deficiency include intrauterine growth restriction, cerebral ventriculomegaly, dysmorphic features, skeletal abnormalities, dyserythropoietic anemia with extramedullary erythropoiesis, thrombocytopenia, cholestatic liver disease, persistent diarrhea, renal failure, recurrent sepsis-like episodes, and failure to thrive. Clinical findings may mimic severe intrauterine viral infection, a chromosomal abnormality, or an acute sepsis syndrome, potentially contributing to delays in diagnosis of this rare condition. Perinatal onset mevalonate kinase deficiency is associated with a very poor prognosis, with death in utero or in early infancy. Detailed autopsy findings in mevalonate kinase deficiency have rarely been reported.

11‐Month‐Old Infant With Periodic Fevers, Recurrent Liver Dysfunction, and Perforin Gene Polymorphism

“…While the patient presented here is on the severe end of MKD spectrum, she lacks the dysmorphic features and global developmental delay classically seen in MA (11). Similarly, significant liver dysfunction as reported here has only been reported in severely affected MA patients (6–9). Although there is some genotype-phenotype correlation in MKD, these associations are imprecise (22).…”

“…Hepatosplenomegaly is commonly reported in MKD; however, there are only rare reports of hepatitis (28, 41) or more severe cholestatic liver disease in some children with severe MA (6–9) (Table 2). These children are all on the severe end of the disease spectrum, with most progressing to death or end-stage liver disease.…”

“…Another consideration is mevalonic aciduria (MA), a severe deficiency in mevalonate kinase in the isoprenoid biosynthesis pathway, leading to dysmorphic features, progressive neonatal onset psychomotor retardation, cerebellar ataxia, visual impairment and recurrent febrile crises (5). Additionally there are rare reports of severe liver dysfunction associated with MA (6–9). …”

Severe phenotypic spectrum of mevalonate kinase deficiency with minimal mevalonic aciduria

“…Case one presented with antenatal hydrops and case two was symptomatic from the perinatal period. Phenotypic features of severe MK deficiency can include hydrops, hepatosplenomegaly, cholestatic jaundice, recurrent fevers, morbilliform rash, arthralgia, lymphadenopathy, anemia, vomiting, diarrhea, facial dysmorphism, ataxia, hypotonia, cataracts and retinal involvement [3,4,17,[21][22][23][24][25]. In both our patients the excretion of mevalonic acid was below the range of > 4000 mg/g creatinine which is typical for classic MK deficiency [26].…”

“…[11]) [11]. Homozygosity for I268T has also been identified in severe presentations [17,25]. Patient two is the first patient identified to be homozygous for the rare R388X mutation and indicates that this mutation causes a severe presentation of MVK deficiency.…”