Familial chylomicronemia syndrome (FCS) (OMIM: 238600) is a rare autosomal recessive disease caused by a biallelic loss- of-function mutation in the lipoprotein lipase (LPL) complex which includes LPL and its co-factors. Patients with FCS have severe hypertiglyceridemia (> 2000 mg/dL). We describe a 15-month-old boy with repeated pancreatitis episodes caused by severe hypertriglyceridemia. Genetic analysis revealed a novel homozygous mutation in the LPL gene, i.e. c.626T>G; p.(Leu209*). The mutation, carried by both parents, has been classified as a type 4 mutation which is likely pathogenic. Treatment aims at decreasing hypertriglyceridaemia by a low-fat diet (< 20g/day) eventually supplemented with medium chain triglyceride (MCT) fat to ensure caloric intake. In 2019, volanesorsen was approved by the European Medicines Agency (EMA) as adjunct treatment for adult patients with genetically proven FCS and persisting episodes of pancreatitis despite the diet.

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Objective Due to the incidental finding of two NR3C2 gene variants in young MS patients, we investigated the possibility that NR3C2 might be a suspectibility gene for multiple sclerosis (MS) and autoimmune disease. Methods In two unrelated MS cases we found respectively a deletion and a point mutation within the coding region of the NR3C2 gene using array-comparative genomic hybridization (Agilent 180k) and Sanger sequencing of NR3C2. The latter was also performed in an independent cohort of 100 MS probands. Results Case 1 is a male 12 years-old MS patient. Array-comparative genomic hybridization revealed a 112–181 kb deletion in NR3C2, compatible with the diagnosis of type 1 pseudohypoaldosteronism. He had no symptoms of this disease but serial blood investigations confirmed a mild elevation of aldosterone. Segregation analysis revealed that his mother and maternal aunt, both of which developed autoimmune thyroiditis, carried the same microdeletion. Case 2 is the mother of a child with pseudohypoaldosteronism. She presented at age 28 with MS and was known to carry the same mutation (c.1757+1G>C) as her daughter in the splice donor site of intron 2 of NR3C2. The mother had elevated aldosterone levels. In an independent MS cohort, we detected a loss-of-function mutation (p.Ser585X) in a single patient with early-onset MS and a positive familial history. She had no symptoms of pseudohypoaldosteronism but a mild but reproducible elevation of aldosterone was detected. Conclusion Our data suggest that NR3C2 loss-of-function variants may associate with a genetic predisposition for developing autoimmune disease, particularly for MS. Though further validation of our findings in a larger cohort is necessary the possible involvement of the renin-angiotensin-aldosterone system in the pathogenesis of MS may have important implications in counselling and follow up of patients with NR3C2 mutations and opens novel perspectives for MS treatment. Due to the incidental finding of two NR3C2 gene variants in young MS patients, we investigated the possibility that NR3C2 might be a suspectibility gene for multiple sclerosis (MS) and autoimmune disease. In two unrelated MS cases we found respectively a deletion and a point mutation within the coding region of the NR3C2 gene using array-comparative genomic hybridization (Agilent 180k) and Sanger sequencing of NR3C2. The latter was also performed in an independent cohort of 100 MS probands. Case 1 is a male 12 years-old MS patient. Array-comparative genomic hybridization revealed a 112–181 kb deletion in NR3C2, compatible with the diagnosis of type 1 pseudohypoaldosteronism. He had no symptoms of this disease but serial blood investigations confirmed a mild elevation of aldosterone. Segregation analysis revealed that his mother and maternal aunt, both of which developed autoimmune thyroiditis, carried the same microdeletion. Case 2 is the mother of a child with pseudohypoaldosteronism. She presented at age 28 with MS and was known to carry the same mutation (c.1757+1G>C) as her daughter in the splice donor site of intron 2 of NR3C2. The mother had elevated aldosterone levels. In an independent MS cohort, we detected a loss-of-function mutation (p.Ser585X) in a single patient with early-onset MS and a positive familial history. She had no symptoms of pseudohypoaldosteronism but a mild but reproducible elevation of aldosterone was detected. Our data suggest that NR3C2 loss-of-function variants may associate with a genetic predisposition for developing autoimmune disease, particularly for MS. Though further validation of our findings in a larger cohort is necessary the possible involvement of the renin-angiotensin-aldosterone system in the pathogenesis of MS may have important implications in counselling and follow up of patients with NR3C2 mutations and opens novel perspectives for MS treatment.

Background: Mutations in the TUBA1A gene have been reported in patients with lissencephaly and perisylvian pachygyria. Methods: Twenty-five patients with malformations of cortical development ranging from lissencephaly to polymicrogyria were screened for mutations in TUBA1A. Results: Two novel heterozygous missense mutations in TUBA1A were identified: c.629A>G (p.Tyr210Cys) occurring de novo in a boy with lissencephaly, and c.13A>C (p.Ile5Leu) affecting 2 sisters with polymicrogyria whose mother presented somatic mosaicism for the mutation. Conclusions: Mutations in TUBA1A have been described in patients with lissencephaly and pachygyria. We report a mutation in TUBA1A as a cause of polymicrogyria. So far, all mutations in TUBA1A have occurred de novo, resulting in isolated cases. This article describes familial recurrence of TUBA1A mutations due to somatic mosaicism in a parent. These findings broaden the phenotypic spectrum associated with TUBA1A mutations and have implications for genetic counseling.

We describe a patient in whom abdominal pain and vomiting were the presenting symptoms of Mitochondrial Myopathy Encephalopathy, Lactic Acidosis with Stroke-like episodes syndrome (MELAS). Mitochondrial disorders usually present with neurological symptoms or with myopathic features at any age. Although many patients develop visceral symptoms at a certain moment during the course of the disease, only in a minority of patients these symptoms are the unique presenting ones. The proband was initially diagnosed as having gastro-oesophageal reflux and it was only after detailed clinical history that an underlying metabolic defect was suspected and the molecular defect identified.