Infantile cerebellar-retinal degeneration associated with a mutation in mitochondrial aconitase, ACO2.

Degeneration of the cerebrum, cerebellum, and retina in infancy is part of the clinical spectrum of lysosomal storage disorders, mitochondrial respiratory chain defects, carbohydrate glycosylation defects, and infantile neuroaxonal dystrophy. We studied eight individuals from two unrelated families who presented at 2-6 months of age with truncal hypotonia and athetosis, seizure disorder, and ophthalmologic abnormalities. Their course was characterized by failure to acquire developmental milestones and culminated in profound psychomotor retardation and progressive visual loss, including optic nerve and retinal atrophy. Despite their debilitating state, the disease was compatible with survival of up to 18 years. Laboratory investigations were normal, but the oxidation of glutamate by muscle mitochondria was slightly reduced. Serial brain MRI displayed progressive, prominent cerebellar atrophy accompanied by thinning of the corpus callosum, dysmyelination, and frontal and temporal cortical atrophy. Homozygosity mapping followed by whole-exome sequencing disclosed a Ser112Arg mutation in ACO2, encoding mitochondrial aconitase, a component of the Krebs cycle. Specific aconitase activity in the individuals' lymphoblasts was severely reduced. Under restrictive conditions, the mutant human ACO2 failed to complement a yeast ACO1 deletion strain, whereas the wild-type human ACO2 succeeded, indicating that this mutation is pathogenic. Thus, a defect in mitochondrial aconitase is associated with an infantile neurodegenerative disorder affecting mainly the cerebellum and retina. In the absence of noninvasive biomarkers, determination of the ACO2 sequence or of aconitase activity in lymphoblasts are warranted in similarly affected individuals, based on clinical and neuroradiologic grounds.

Risk of Preterm Birth among Secundiparas with a Previous Cesarean due to a Failed Vacuum Delivery.

BACKGROUND: Studies have found an association between second-stage cesarean sections (SSCSs) and subsequent preterm birth (PTB). We aimed to evaluate if secundiparas with previous second-stage cesarean sections due to a failed vacuum delivery (SSCS-F-VD) are associated with PTB in the subsequent delivery compared with secundiparas with previous spontaneous vaginal birth (SVB) at term. A secondary aim was to compare this association with secundiparas with a previous SSCS at term. METHODS: A historical, prospective, longitudinal cohort study was conducted in a large tertiary university hospital between 2006 and 2019. Matched mothers who experienced first and second births at the indexed hospital, excluding those with a previous miscarriage or multiple pregnancy in either the first or second birth were grouped based on the mode of delivery and gestational week of the first birth. RESULTS: Parturients with term SVB and term SSCSs were less likely to experience PTB in the following delivery compared with those who underwent an SSCS-F-VD, with 496/14,551 (3.4%) versus 6/160 (3.8%) versus 5/61 (8.2%), respectively, at p < 0.001. A logistic regression model revealed that secundiparas with previous SSCS-F-VD had an association with PTB in the following delivery compared with term SVB, with an OR of 2.756 (1.097; 6.922, p = 0.031). CONCLUSION: Previous SSCS-F-VD is associated with PTB in the following delivery, offering valuable insights for pregnancy management and patient counseling.

A novel mutation of the CLN8 gene: is there a Mediterranean phenotype?

We report the first known case in Israel of a patient with an early childhood onset of ceroid-lipofuscinosis who is homozygous to a mutation of the CLN8 gene. This patient further expands the clinical varieties of CLN8, initially reported in Finland and Turkey and recently in Italy. The ultrastructural pathology of a skin biopsy specimen revealed abundant typical fingerprint profiles, but rare granular osmiophilic bodies and curvilinear structures. Sequencing of exon 3 of the CLN8 gene revealed a novel C>G missense mutation at a conserved amino acid glutamine 256 to glutamic acid. Our findings further raise the possibility of the existence of a Mediterranean CLN8 variant.