Autosomal Recessive Osteogenesis Imperfecta Caused by a Novel Homozygous COL1A2 Mutation

Osteogenesis imperfecta (OI) is a skeletal dysplasia characterized by brittle bones and extraskeletal manifestations. The disease phenotype varies greatly. Most commonly, OI arises from monoallelic mutations in one of the two genes encoding type I collagen, COL1A1 and COL1A2 and is inherited as an autosomal dominant trait. Here, we describe a consanguineous family with autosomal recessive OI caused by a novel homozygous glycine substitution in COL1A2, NM_000089.3: c.604G > A, p.(Gly202Ser), detected by whole-genome sequencing. The index patient is a 31-year-old Greek woman with severe skeletal fragility. She had mild short stature, low bone mineral density of the lumbar spine and blue sclerae. She had sustained multiple long bone and vertebral fractures since childhood and had been treated with bisphosphonates for several years. She also had an affected sister with similar clinical manifestations. Interestingly, the parents and one sister, all carriers of the COL1A2 glycine mutation, did not have manifestations of OI. In summary, we report on autosomal recessive OI caused by a homozygous glycine-to-serine substitution in COL1A2, leading to severe skeletal fragility. The mutation carriers lacked OI manifestations. This family further expands the complex genetic spectrum of OI and underscores the importance of genetic evaluation for correct genetic counselling.Peer reviewe

The effect of phenylalanine on the activity of the enzymes affecting synaptic transmission of frontal cortex, hippocampus and hypothalamus of neonatal rats.

According to previous reports (Tsakiris et al 1998b), a 65% stimulationof rat whole brain Na+,K+-ATPase was found, after 1hpreincubation of brain homogenates with high phenylalanine (Phe) concentrations(0.9-12.1 mM). To explain this increase in Na+,K+-ATPaseactivity, DSP-4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine] wasused, in the absence and presence of high Phe levels, such as thoseobserved in phenylketonuria (PKU) (0.9 and 1.8 mM). Our experimentswere conducted on 21-day-old rat brain homogenates, which were incubatedwith Phe. An increased Na+,K+-ATPase activity was observed(up to 70%, compared to control), but when DSP-4 (3 mM) was added,a marked decrease (about 65%) was found. Therefore, DSP-4, byblocking noradrenaline (NA), can inhibit Na+,K+-ATPase activity. Theobserved stimulation of brain Na+,K+-ATPase by Phe, seems to be relatedto the transformation of Phe to NA (Doulgeraki et al 1999). Thealterations of Phe levels in the immature rat brain may affect the neuralexcitability and metabolic energy production.The next step was to investigate the effect of different Phe concentrations(0.12-12.1 mM) on acetylcholinesterase (AChE), Na+,K+-ATPase and Mg2+-ATPase activities. This effect was examined in homogenatesof suckling rat frontal cortex, hippocampus and hypothalamusat 37oC. AChE, (Na+,K+)-ATPase and Mg2+-ATPase activities weredetermined after preincubation with Phe. This amino acid, at high concentrations,reduced AChE activity in the frontal cortex by 18% (p<0.01)and in the hippocampus by 20% (p<0.01), but it did not affect the enzymeactivity of the hypothalamus. Na+,K+-ATPase was stimulated byhigh levels of Phe in both the frontal cortex and the hypothalamus by60% (p<0.01), but it was inhibited in the hippocampus by 40% (p<0.01).Mg2+-ATPase was not influenced by Phe.The above results suggest (Doulgeraki et al 2002):140a) In the frontal cortex, the acetylcholine (ACh) release by Phe may beimproper and, combined with the stimulation of Na+,K+-ATPase, possiblyexplains the problems of learning in PKU.b) In the hippocampus, inhibition of AChE by Phe could lead to problemsin memory (ACh is the key-neurotransmitter of the area), whileNa+,K+-ATPase inhibition by Phe may induce metabolic disordersand electrical instability of the synaptosomal membrane.c) AChE, in the hypothalamus, is not influenced by Phe, so the behavioralproblems in PKU may be related to NA levels, which are probablycorrelated with the stimulated (by Phe) Na+,K+-ATPase.d) There is a possible functional relation between the frontal cortex andthe hypothalamus, because behavior is often learned and the changesin AChE and Na+,K+-ATPase activities, caused by Phe, follow thesame pattern in these brain structures.Με αφορμή προηγούμενη δημοσίευση (Τσακίρης και συν.1998b), η οποία ανέφερε διέγερση κατά 65%, της Na+,Κ+-ΑΤΡάσηςστον ολικό εγκέφαλο του επίμυος, κατόπιν προεπώασης του ομογενο-ποιήματος για 1 ώρα με υψηλές συγκεντρώσεις φαινυλαλανίνης (Phe)(0.9-12.1 mM), έγινε προσπάθεια να εξηγηθεί αυτή η αύξηση της ενζυ-μικής δραστικότητας. Για το σκοπό αυτό, χρησιμοποιήθηκε η νευροτοξί-νη DSP-4 [Ν-(2-χλωροαιθυλο)-Ν-αιθυλο-2-βρωμοβενζυλαμίνη], με ήχωρίς ταυτόχρονη επίδραση υψηλών επιπέδων Phe, όπως αυτά πουπαρατηρούνται στη φαινυλοκετονουρία (PKU), δηλαδή 0.9 και 1.8 mM.Τα πειράματα διεξήχθησαν σε ομογενοποιήματα εγκεφάλου νεογέννη-των επίμυων 21 ημερών, τα οποία επωάστηκαν με Phe. Παρατηρήθηκεαύξηση της δραστικότητας της Na+,Κ+-ΑΤΡάσης (μέχρι 70%, σε σύγκρι-ση με το μάρτυρα), αλλά, όταν προστέθηκε DSP-4 (3 mM), βρέθηκε α-ξιοσημείωτη ελάττωση (περίπου 65%). Επομένως, το DSP-4, αναστέλ-λοντας της νοραδρεναλίνη (ΝΑ), μπορεί να μειώσει τη δραστικότητα τηςNa+,Κ+-ΑΤΡάσης. Η παρατηρούμενη διέγερση του ενζύμου από τη Phe,πιθανόν σχετίζεται με το μετασχηματισμό του αμινοξέος σε ΝΑ (Δουλ-γεράκη και συν. 1999). Οι αλλαγές των επιπέδων της Phe στον ανώρι-μο εγκέφαλο του επίμυος ίσως να επηρεάζουν τη νευρωνική διεγερσι-μότητα και την παραγωγή ενέργειας, στα πλαίσια του μεταβολισμού.Το επόμενο βήμα ήταν να διερευνηθεί η επίδραση διαφορετικώνσυγκεντρώσεων Phe (0.12-12.1 mM) στη δραστικότητα της ακετυλοχο-λινεστεράσης (AChE), της Na+,Κ+-ΑΤΡάσης και της Mg2+-ΑΤΡάσης. Ταπειράματα έγιναν σε ομογενοποιήματα μετωπιαίου φλοιού, ιπποκάμπουκαι υποθαλάμου επίμυων 21 ημερών, στους 37οC. Ο προσδιορισμόςτων δραστικοτήτων των παραπάνω ενζύμων έγινε μετά από προεπώα-ση με Phe. Το αμινοξύ αυτό, σε υψηλές συγκεντρώσεις, προκάλεσε ε-λάττωση της δραστικότητας της AChE κατά 18% (p<0.01) στο μετω-πιαίο φλοιό και κατά 20% (p<0.01) στον ιππόκαμπο, αλλά δεν επηρέα-σε την ενζυμική δραστικότητα στον υποθάλαμο. Διαπιστώθηκε διέγερσητης Νa+,Κ+-ΑΤΡάσης από υψηλά επίπεδα Phe, τόσο στο μετωπιαίοφλοιό, όσο και στον υποθάλαμο (κατά 60%, p<0.01), αλλά στον ιππό-καμπο βρέθηκε αναστολή του ενζύμου, κατά 40% (p<0.01). Η Mg2+-ΑΤΡάση δεν επηρεάστηκε από τη Phe. Τα αποτελέσματα αυτά δείχνουνότι (Δουλγεράκη και συν. 2002):α) Στο μετωπιαίο φλοιό, η απελευθέρωση της ακετυλοχολίνης (ACh) πι-θανόν διαταράσσεται από τη Phe και, σε συνδυασμό με την παρατη-ρούμενη διέγερση της Na+,Κ+-ΑΤΡάσης, ενδεχομένως να εξηγεί ταπροβλήματα μάθησης στην PKU.β) Στον ιππόκαμπο, η αναστολή της AChE από τη Phe, θα μπορούσενα οδηγήσει σε προβλήματα μνήμης (αφού η ACh είναι ο κύριος νευ-ροδιαβιβαστής αυτής της εγκεφαλικής περιοχής), ενώ η αναστολήτης Na+,Κ+-ΑΤΡάσης από τη Phe ίσως προκαλεί μεταβολικές διατα-ραχές και ηλεκτρική αστάθεια στη συναπτική μεμβράνη.γ) Η AChE του υποθαλάμου δεν επηρεάζεται από τη Phe, επομένως ταπροβλήματα συμπεριφοράς στους φαινυλοκετονουρικούς ασθενείςπιθανόν σχετίζονται με τα επίπεδα της ΝΑ, που με τη σειρά τους,φαίνονται να έχουν στενή σχέση με τη διεγερθείσα (από τη Phe)Na+,Κ+-ΑΤΡάση.δ) Υπάρχει πιθανόν μια λειτουργική σχέση μεταξύ του μετωπιαίου φλοι-ού και του υποθαλάμου, διότι συχνά η συμπεριφορά μαθαίνεται και οιαλλαγές στη δραστικότητα της AChE και της Na+,Κ+-ΑΤΡάσης μετάαπό την επίδραση με Phe, είναι ποιοτικά όμοιες σε αυτές τις εγκεφα-λικές δομές

Hypophosphatasia

Hypophosphatasia (HPP) is an inherited metabolic disease caused by loss-of-function mutations in the tissue non-specific alkaline phosphatase (TNAP) gene. Reduced activity of TNAP leads to the accumulation of its substrates, mainly inorganic pyrophosphate and pyridoxal-5′-phosphate, metabolic aberrations that largely explain the musculoskeletal and systemic features of the disease. More than 400 ALPL mutations, mostly missense, are reported to date, transmitted by either autosomal dominant or recessive mode. Severe disease is rare, with incidence ranging from 1:100,000 to 1:300,000 live births, while the estimated prevalence of the less severe adult form is estimated to be between 1:3100 to 1:508, in different countries in Europe. Presentation largely varies, ranging from death in utero to asymptomatic adults. In infants and children, clinical features include skeletal, respiratory and neurologic complications, while recurrent, poorly healing fractures, muscle weakness and arthropathy are common in adults. Persistently low serum alkaline phosphatase is the cardinal biochemical feature of the disease. Management requires a dedicated multidisciplinary team. In mild cases, treatment is usually symptomatic. Severe cases, with life-threating or debilitating complications, can be successfully treated with enzyme replacement therapy with asfotase alfa

Hypophosphatasia

Hypophosphatasia (HPP) is an inherited metabolic disease caused by loss-of-function mutations in the tissue non-specific alkaline phosphatase (TNAP) gene. Reduced activity of TNAP leads to the accumulation of its substrates, mainly inorganic pyrophosphate and pyridoxal-5 `-phosphate, metabolic aberrations that largely explain the musculoskeletal and systemic features of the disease. More than 400 ALPL mutations, mostly missense, are reported to date, transmitted by either autosomal dominant or recessive mode. Severe disease is rare, with incidence ranging from 1:100,000 to 1:300,000 live births, while the estimated prevalence of the less severe adult form is estimated to be between 1:3100 to 1:508, in different countries in Europe. Presentation largely varies, ranging from death in utero to asymptomatic adults. In infants and children, clinical features include skeletal, respiratory and neurologic complications, while recurrent, poorly healing fractures, muscle weakness and arthropathy are common in adults. Persistently low serum alkaline phosphatase is the cardinal biochemical feature of the disease. Management requires a dedicated multidisciplinary team. In mild cases, treatment is usually symptomatic. Severe cases, with life-threating or debilitating complications, can be successfully treated with enzyme replacement therapy with asfotase alfa

Serum Spexin is Correlated with Lipoprotein(a) and Androgens in Female Adolescents

The Spexin gene is considered the most dysregulated in obese human fat. Limited data suggest that the novel peptide spexin may potentially impact food intake, weight regulation and body adiposity. The aim of this case-control study was to compare fasting serum spexin concentrations between normal weight (NW) and overweight/obese (OB/OW) adolescent females and explore the relationship between circulating spexin and anthropometric, bone and fat mass, metabolic and hormonal parameters. Eighty post-menarcheal females (mean age &plusmn; SD 16.23 &plusmn; 2.26 years); 55 NW (mean BMI &plusmn; SD 19.72 &plusmn; 2.52 kg/m2) and 25 OB/OW (mean BMI &plusmn; SD 29.35 &plusmn; 3.89 kg/m2) participated in the study. Circulating spexin levels did not differ significantly (p = 0.378) between NW (median (interquartile range), 0.26 (0.17) ng/mL) and OB/OW (median (interquartile range), 0.28 (0.06) ng/mL) adolescents and did not correlate with BMI (rs = &minus;0.090, p = 0.438), % body fat (rs = &minus;0.173, p = 0.409), glucose or insulin resistance indices derived from fasting and oral glucose tolerance states. In the total study sample, spexin concentrations correlated positively with lipoprotein(a) (rs = 0.402, p = 0.046). In the OB/OW adolescents spexin levels correlated positively with testosterone (rs = 0.727, p = 0.011) and free androgen index (rs = 0.755, p = 0.007). In the NW adolescents, spexin concentrations correlated negatively with dehydroepiandrosterone sulphate (rs = &minus;0.445, p = 0.038). Results may suggest potential involvement of spexin in the regulation of lipoprotein(a) and of the reproductive/adrenal axis in post-menarcheal adolescent females