Mevalonate kinase deficiency is a metabolic autoinflammatory syndrome caused by mutations in the MVK gene, mevalonate kinase, the key enzyme in the non-sterol isoprenoid biosynthesis pathway. Two phenotypes of mevalonate kinase deficiency are known based on the level of enzymatic deficiency, mevalonic aciduria and hyperimmunoglobulinemia D syndrome, but a wide spectrum of intermediate phenotypes has been reported. Currently one of the most effective treatments is biological therapy (with interleukin-1 antagonist anakinra or tumour necrosis factor-α inhibitor etanercept). The patient in this case has a phenotype contributing to a severe disease that caused the symptoms to manifest very early, in the prenatal period. Mevalonate kinase deficiency was suspected on the basis of clinical (hydrops fetalis, hepatosplenomegaly, hypotonia) and laboratory signs (anaemia, intense acute phase reaction, increased urinary excretion of mevalonic acid). Mutation analysis of the MVK gene confirmed the biochemical diagnosis. Treatment with the interleukin-1 antagonist anakinra was started (minimal dose of 1 mg/kg/day) and revealed its efficacy after three days. Our case highlights the need for a very detailed clinical and laboratory assessment in new-borns with any suggestion of autoinflammatory disorders. It is important that patients are diagnosed as early as possible to provide better multidisciplinary follow-up and therapy when needed.

Objectives To describe clinical and genetic findings in 2 siblings with slowly progressive ataxia. Methods We studied 2 adult siblings through detailed physical and instrumental examinations. Whole-exome sequencing was used to identify an underlying genetic cause. Results Both siblings presented with adolescence-onset ataxia, progressive sensorimotor polyneuropathy, and preserved cognition over time. The onset of symptoms was between 10 and 14 years of age. A brain MRI demonstrated mild cerebellar atrophy in the older brother at age 45 years. Exome sequencing revealed compound heterozygous loss-of-function variants c.2269del (p.(Thr757GlnfsTer10)) and c.2275_2276del (p.(Leu759AlafsTer4)) in PNPLA8. The novel variant c.2269del results in frameshift with a premature stop codon p.(Thr757GlnfsTer10) and loss of normal enzyme function. Discussion Our findings support the theory that biallelic loss-of-function PNPLA8 variants are involved in neurodegenerative mitochondrial disease. Compared with patients previously described, these patients9 phenotype may be interpreted as a milder phenotype associated with a slight progression of ataxia throughout adulthood.

This guideline summarizes diagnostic and therapeutic approaches based on a systematic literature review and evidence evaluation using the GRADE methodology. Given the limited high‐quality data, expert consensus was additionally obtained through a modified Delphi process. Remethylation disorders are rare inherited conditions that disrupt the methionine–homocysteine cycle and consecutively impair essential methylation dependent metabolic pathways. Remethylation disorders are caused by defects in the cobalamin or folate metabolism. The disorders typically result in elevated homocysteine and often low methionine; combined cobalamin‐related defects also affect mitochondrial methylmalonic acid clearance. The cblC‐ MMACHC defect is the most common cobalamin‐related remethylation disorder. Early‐onset patients usually present with severe neurological and eye symptoms. Late‐onset cases show variable symptoms (e.g., psychiatric, renal, thromboembolic events). Plasma total homocysteine, methionine, methylmalonic acid, serum vitamin B12 (and folates) should be assessed in suspected cases. Early detection through newborn screening is associated with improved clinical outcomes. Betaine as first‐line therapy for methylenetetrahydrofolate reductase deficiency and parenteral hydroxocobalamin for cobalamin‐related defects have reduced mortality and morbidity. Total homocysteine, methionine (and methylmalonic acid) should be kept as close to normal values as achievable. Emerging evidence suggests that early use of high‐dose hydroxocobalamin (> 0.35 mg/kg/day) may improve neurocognitive impairment and may ameliorate eye disease in severe cobalamin‐related defects. A major limitation in current practice is the lack of availability of high concentration hydroxocobalamin formulations for parenteral administration.

Chromosomal rearrangements are the major cause of multiple congenital abnormalities and intellectual disability. We report 2 first cousins with unbalanced chromosomal aberrations of chromosomes 1 and 21, resulting from balanced familial translocation. Chromosome microarray analysis revealed 8.5 Mb1q43q44 duplication/21q22.2q22.3 deletion and 6.8 Mb 1q43q44 deletion/21q22.2q22.3 duplication. Among other features, cognitive and motor development delay and craniofacial anomalies are present in both patients, whereas congenital heart defect and hearing impairment is only present in patient carrying 1q43q44 duplication/21q22.2q22.3 deletion. In this report, we provide detailed analysis of the phenotypic features of both patients as well as compare our data with previously published reports of similar aberrations and discuss possible functional effects of AKT3, CEP170, ZBTB18, DSCAM, and TMPRSS3 genes included in the deleted and/or duplicated regions. Partial trisomy 1q/monosomy 21q has only been reported once before, and this is the first report of partial monosomy 1q/trisomy 21q. The expressed phenotype of mirroring chromosomal aberrations in our patients supports the previous suggestion that the dosage effect of some of the genes included in deleted/duplicated regions may result in opposite phenotypes of the patients.

Background: Ellis-van Creveld syndrome (EvC) is a recessive disorder characterised by acromesomelic limb shortening, postaxial polydactyly, nail-teeth dysplasia and congenital cardiac defects, primarily caused by pathogenic variants in EVC or EVC2. Weyers acrofacial dysostosis (WAD) is an ultra-rare dominant condition allelic to EvC. The present work aimed to enhance current knowledge on the clinical manifestations of EvC and WAD and broaden their mutational spectrum. Methods: We conducted molecular studies in 46 individuals from 43 unrelated families with a preliminary clinical diagnosis of EvC and 3 affected individuals from a family with WAD and retrospectively analysed clinical data. The deleterious effect of selected variants of uncertain significance was evaluated by cellular assays. Main results: We identified pathogenic variants in EVC/EVC2 in affected individuals from 41 of the 43 families with EvC. Patients from each of the two remaining families were found with a homozygous splicing variant in WDR35 and a de novo heterozygous frameshift variant in GLI3, respectively. The phenotype of these patients showed a remarkable overlap with EvC. A novel EVC2 C-terminal truncating variant was identified in the family with WAD. Deep phenotyping of the cohort recapitulated ‘classical EvC findings’ in the literature and highlighted findings previously undescribed or rarely described as part of EvC. Conclusions: This study presents the largest cohort of living patients with EvC to date, contributing to better understanding of the full clinical spectrum of EvC. We also provide comprehensive information on the EVC/EVC2 mutational landscape and add GLI3 to the list of genes associated with EvC-like phenotypes.