Bi-allelic Mutations in the Mitochondrial Ribosomal Protein MRPS2 Cause Sensorineural Hearing Loss, Hypoglycemia, and Multiple OXPHOS Complex Deficiencies.

Biogenesis of the mitochondrial oxidative phosphorylation system, which produces the bulk of ATP for almost all eukaryotic cells, depends on the translation of 13 mtDNA-encoded polypeptides by mitochondria-specific ribosomes in the mitochondrial matrix. These mitoribosomes are dual-origin ribonucleoprotein complexes, which contain mtDNA-encoded rRNAs and tRNAs and ∼80 nucleus-encoded proteins. An increasing number of gene mutations that impair mitoribosomal function and result in multiple OXPHOS deficiencies are being linked to human mitochondrial diseases. Using exome sequencing in two unrelated subjects presenting with sensorineural hearing impairment, mild developmental delay, hypoglycemia, and a combined OXPHOS deficiency, we identified mutations in the gene encoding the mitochondrial ribosomal protein S2, which has not previously been implicated in disease. Characterization of subjects' fibroblasts revealed a decrease in the steady-state amounts of mutant MRPS2, and this decrease was shown by complexome profiling to prevent the assembly of the small mitoribosomal subunit. In turn, mitochondrial translation was inhibited, resulting in a combined OXPHOS deficiency detectable in subjects' muscle and liver biopsies as well as in cultured skin fibroblasts. Reintroduction of wild-type MRPS2 restored mitochondrial translation and OXPHOS assembly. The combination of lactic acidemia, hypoglycemia, and sensorineural hearing loss, especially in the presence of a combined OXPHOS deficiency, should raise suspicion for a ribosomal-subunit-related mitochondrial defect, and clinical recognition could allow for a targeted diagnostic approach. The identification of MRPS2 as an additional gene related to mitochondrial disease further expands the genetic and phenotypic spectra of OXPHOS deficiencies caused by impaired mitochondrial translation.

A novel phenotype associated with cutis laxa, abnormal fat distribution, cardiomyopathy and cataract.

Cutis laxa (CL) is a connective tissue disorder, characterized by loose, inelastic, sagging skin. Both acquired and inherited (dominant, recessive, and X-linked) forms exist. Here, we describe a new phenotype, which overlaps with other known CL syndromes. Our patient has a unique combination of features in association with sagging, inelastic, wrinkled skin, including cataract, severe cardiomyopathy, abnormal fat distribution, improvement of skin-wrinkling with age, and white matter abnormalities but no significant histologic collagen or elastin abnormalities. Mutation analysis of known CL genes was negative. We suggest that our patient has a novel syndrome, with the main features of CL, intellectual disability, abnormal fat distribution, cardiomyopathy, and cataract.

[Best possible start for child and parent]. / Kansrijke start voor kind en ouder.

The health of women during the periconception period and pregnancy is important for a healthy start of the child. All care providers can make a major contribution to this. In this learning article we provide answers to a number of questions that have been collected from the professional field about preconception care and care for vulnerable pregnant women. Our aim is to inform general practitioners and specialists who assist women with a (possible) desire to have children about proactive care in pregnancy, childbirth and child care. Included are concrete actions of the general practitioner when healthy women wish to become pregnant, which medical history and other characteristics of a pregnant woman negatively affects the health of her (unborn) child, and which signals in a first pregnancy predispose for problems after and in a subsequent pregnancy and what role can the GP play in this. Furthermore, we discuss signs of vulnerability in the consulting room, how transmural risk selection can be applied and we provide an overview of interventions applicable in primary care or where to refer to.

Comparison of the CollaboRATE and SDM-Q-9 questionnaires to appreciate the patient-reported level of shared decision-making.

OBJECTIVE: To compare CollaboRATE and SDM-Q-9 questionnaires when appreciating patient-perceived level of shared decision-making (SDM) in doctor-patient consultations. METHODS: Data were harvested from five separate studies on SDM, conducted in three university and one large community hospital in the Netherlands, using Dutch versions of both questionnaires. CollaboRATE and SDM-Q-9 scores were expressed as percentages. Correlation was assessed using Spearman's Rho coefficient. Bland&Altman analysis was used to assess the degree of agreement. Top scores were calculated to assess possible ceiling effects. RESULTS: The five studies included 442 patients. Median CollaboRATE scores (88.9%, IQR 81.5-100%) were significantly higher (p < 0.001) than SDM-Q-9 scores (80.0%, IQR 64.4-100%). Correlation was moderate (Rho=0.53, p < 0.001). A systematic, 12.5-point higher score was found across the range of scores when using CollaboRATE. Top scores for CollaboRATE and SDM-Q-9 were present in 37.5% and 17% of questionnaires, respectively. CONCLUSIONS: Overall, CollaboRATE and SDM-Q-9 questionnaires showed a high level of patient-perceived SDM. However, CollaboRATE only moderately correlated with SDM-Q-9 and had a stronger ceiling effect. PRACTICE IMPLICATIONS: When choosing a SDM-measurement tool, its benefits and limitations should be weighed. These metrics should be combined with objective scores of SDM, as these may differ from the patients' subjective interpretation.

Duplication at Xq28 involving IKBKG is associated with progressive macrocephaly, recurrent infections, ectodermal dysplasia, benign tumors, and neuropathy.

Duplications on Xq28 are common, although quite variable in size, but usually include the MECP2 gene. Here, we present a patient with a unique, small, 167-kb duplication at Xq28, not including MECP2. The most important gene in the duplicated region was IKBKG, mutations in which can cause a variety of distinct syndromes. Our patient's symptoms overlapped with different IKBKG-associated phenotypes, including hypohidrotic ectodermal dysplasia, incontinentia pigmenti, immunodeficiency, recurrent isolated invasive pneumococcal disease and anhidrotic ectodermal dysplasia with immunodeficiency, osteopetrosis, and lymphedema. In addition, she also had peripheral neuropathy, gastroparesis and various benign tumors, but no intellectual disability. Mixed syndromal presentation in several patients with IKBKG defect implies that IKBKG-related phenotypes are more like a spectrum, rather than distinct syndromes. We also suggest our patient's multisystem phenotype to be a novel contiguous gene syndrome, in which the key features include immune deficiency, macrocephaly, skin abnormalities, gastroparesis, peripheral small-fiber neuropathy, and benign tumors.

Cutis laxa, fat pads and retinopathy due to ALDH18A1 mutation and review of the literature.

Autosomal recessive cutis laxa (ARCL) is a connective tissue disorder characterized by wrinkled, inelastic skin, frequently associated with a neurologic involvement and multisystem disease. Next generation sequencing was performed in genetically unsolved patients with progeroid features, neurological and eye involvement to assess the underlying etiology. We describe an 6 month old child, diagnosed with a novel, homozygous nonsense mutation c.2339T>C in exon 18 of the ALDH18A1 gene, and reviewed all reported P5CS patients. So far 10 patients were described with mutations in ALDH18A1. Features of our patient that have been described in literature included cutis laxa on hands and feet, visible veins on thorax and abdomen, joint laxity, failure to thrive, short stature, microcephaly, and severe developmental and speech delay. Furthermore, abnormal fat distribution, retinal abnormalities, undescended testis, and retinitis pigmentosa have never been described in ALDH18A1. Some features described as unique in ALDH18A1 have been observed in PYCR1 patients, thus suggesting that the phenotypic overlap is higher than previously shown. In conclusion, the clinical phenotype caused by ALDH18A1 mutations is diverse, with variable degree of progeria in children, but always in association with neurologic disease. We suggest genetic testing for possible ALDH18A1 mutations in all patients with progeroid features, like wrinkled or parchment-like skin, abnormal growth, especially with central nervous system involvement and microcephaly.