Diagnosis and management of spinal muscular atrophy : Part 1: Recommendations for diagnosis, rehabilitation, orthopedic and nutritional care

Spinal muscular atrophy (SMA) is a severe neuromuscular disorder due to a defect in the survival motor neuron 1 (SMN1) gene. Its incidence is approximately 1 in 11,000 live births. In 2007, an International Conference on the Standard of Care for SMA published a consensus statement on SMA standard of care that has been widely used throughout the world. Here we report a two-part update of the topics covered in the previous recommendations. In part 1 we present the methods used to achieve these recommendations, and an update on diagnosis, rehabilitation, orthopedic and spinal management; and nutritional, swallowing and gastrointestinal management. Pulmonary management, acute care, other organ involvement, ethical issues, medications, and the impact of new treatments for SMA are discussed in part 2

Athyreosis, dysgenesis, and dyshormonogenesis in congenital hypothyroidism

PubMedID: 17551472Congenital hypothyroidism (CH) is most commonly caused by defects in thyroid development leading to thyroid dysgenesis (80-90%), which consists of thyroid agenesis, ectopy or hypoplasia. Thyroid dysgenesis occurs mostly as a sporadic disease. However, a small but significant proportion of the cases are due to defects in transcription factors. The remaining 10-20% of congenital hypothyroidism is due to better-defined defects in any of the steps in the thyroid hormone biosynthesis, collectively called thyroid dyshormonogenesis, which are inherited autosomal recessively. Studying multiplex and/or consanguineous families with carefully defined, original phenotypes by such recently popular techniques as genome wide SNP genotyping with linkage search is likely to reveal novel disease associated genes. Thus there is new insight into the pathophysiology of congenital hypothyroidism

Neurokinin B signaling in puberty: Human and animal studies

PubMedID: 20176081Recent reports of humans who have normosmic idiopathic hypogonadotropic hypogonadism due to TAC3 or TACR3 (encoding neurokinin B and its receptor, NK3R, respectively) mutations provided compelling evidence for the involvement of neurokinin B (NKB) signaling in puberty. This apparently stimulated the field to understand the exact mechanism through which NKB signaling exerts its effects. With the important findings from these recent studies a sketch of GnRH pulse generator has emerged in which NKB signaling appears to play a key role. In this communication, NKB involvement in puberty is reviewed from the perspective of the fundamental question of " what controls puberty?" . © 2010 Elsevier Ireland Ltd

Puberty: Gonadarche and Adrenarche

Puberty in humans is defined as the period of becoming capable of reproducing. It is marked by maturation of the genital organs, development of secondary sex characteristics, acceleration in linear growth velocity, and, in the female, the occurrence of menarche. Many factors influence the age at onset and the tempo at which puberty progresses. The age at puberty may be associated with health consequences later in adulthood. Normal function of the hypothalamic-pituitary-gonadal (HPG) axis is dependent on the meticulous spatio-temporal orchestration of gonadotropin-releasing hormone (GnRH) neuron development in the hypothalamus. While the neurobiological mechanisms that underlie GnRH pulse generation remain controversial, compelling evidence indicates the fundamental role of KNDy neurons in the arcuate nucleus. Identification and investigation of specific mutations in families with disorders of puberty have established some of the factors involved in GnRH neuron migration and gonadal function. This chapter reviews the disorders of puberty in the context of the development and maturation of the HPG axis. Elucidation of the neurobiology of the GnRH neurons and the developmental processes unfolding during gonadal and adrenal maturation will improve understanding of the pathophysiology of the disorders of puberty and, perhaps, lead to novel therapies. © 2019 Elsevier Inc. All rights reserved

Genetics of hypogonadotropic hypogonadism

PubMedID: 26680571Hypogonadotropic hypogonadism (HH) often manifests as pubertal delay. A considerable proportion of cases of HH is due to genetic mutations. Recognizing those mutated genes and associated phenotypes may improve our diagnostic capabilities. GNRHR and TACR3 should be the first two genes to be screened in a clinical setting for equivocal cases such as constitutional delay in puberty versus idiopathic HH. In Kallmann syndrome (KS), according to the presence of certain accompanying clinical features, genetic screening for particular gene(s) may be prioritized: synkinesia (KAL1), dental agenesis (FGF8/FGFR1), bony anomalies (FGF8/FGFR1), and hearing loss (CHD7, SOX10). FEZF1 has recently been added to the growing list of KS genes. Also, discovery of mutations in KISS1/KISS1R and TAC3/TACR3 in kisspeptin and neurokinin B signaling, respectively, has provided major advancements in our understanding of the biology of the gonadotropin-releasing hormone pulse generator. Identification of further causative mutations accounting for the HH phenotype, which is now more feasible with the increasing popularity of whole exome sequencing, may provide deeper insight into the biology of the hypothalamic-pituitary-gonadal axis. © 2016 S. Karger AG, Basel

Molecular causes of hypogonadotropic hypogonadism

PubMedID: 20543690Purpose of Review: What controls puberty remains largely unknown and current gene mutations account for only about one-third of the apparently genetic cases of idiopathic hypogonadotropic hypogonadism. Lately important developments have occurred in this field. Recent Findings: Substantial variation in clinical expression, from complete anosmia and hypogonadotropic hypogonadism to delayed puberty and normosmia, of the same Kallmann syndrome gene defects including in newer ones (FGF8 and CHD7) continues to be repeatedly observed. Digenic or oligogenic inheritance becomes another feature of Kallmann syndrome. Recent reports of mutations in TAC3 or TACR3 [encoding neurokinin B (NKB) and its receptor, NK3R, respectively] provided compelling evidence for the involvement of NKB signaling in puberty. This energized the field to understand the exact mechanism through which NKB signaling exerts its effects. With the important findings from these recent studies in association with the substantial data from kisspeptin studies in the last 6 years a sketch of GnRH pulse generator has emerged in which NKB signaling appears to play a key role. Summary: Autozygosity mapping may continue helping identify the other genes including those upstream to the GnRH pulse generator in this complex and elusive developmental process. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins

Neurokinin B signalling in the human reproductive axis

PubMedID: 21807065Recent human genetic studies have established that neurokinin B (NKB) signalling via the neurokinin 3 receptor (NK3R) is required for normal developmental activation of pulsatile GnRH secretion from the hypothalamus. As increasing numbers of patients with loss-of-function mutations have been described, evidence has emerged that peripheral NKB is not necessary for normal pregnancy despite high placental expression and high plasma levels of NKB in late gestation. Nevertheless many key questions about the role of NKB in the function of the GnRH pulse generator remain to be answered. Differences in requirement for NKB/NK3R for hypothalamic-pituitary-gonadal (HPG) maturation amongst different species, and their varied responses to stimulation with NKB represent a challenge for higher resolution studies. Neuroanatomical investigation has, however, identified key "KNDy" (Kisspeptin, Neurokinin B, Dynorphin) arcuate neurones that are conserved amongst different species and that are intimately connected both to each other and to the GnRH nerve termini. Several lines of evidence suggest that these may be the core of the GnRH pulse generator, and with experimental tools now in place in humans, monkeys and other experimental animals to pursue the function of these interconnected neurones and the functional hierarchy of their neuroendocrine inputs, understanding of the enigmatic GnRH pulse generator may at last be within reach. © 2011 Elsevier Ireland Ltd.Wellcome Trust: 080952/Z/06/Z 109S455A.K.T. is supported by grants from the Scientific and Technological Research Council of Turkey (TÜBİTAK) , Project No.: 109S455 . R.K.S. is supported by the Wellcome Trust (Intermediate Clinical Fellowship 080952/Z/06/Z )

Neurokinin B and its receptor in hypogonadotropic hypogonadism

PubMedID: 20389091The hypothalamus integrates multiple environmental and developmental cues relevant to reproductive function, serving to transduce these into a pulsatile output of gonadotropin-releasing hormone (GnRH). Although neuroanatomical and physiological studies have yielded key clues about the functional organisation of the so-called 'GnRH pulse generator', only in the last decade have the molecular components of the circuitry upstream from GnRH begun to be elucidated. A major contributor to this has been human genetics, through identification of mutations causing isolated hypogonadotropic hypogonadism (IHH) without developmental defects. The greatest success of this approach was the finding in 2003 that mutations of KISS1R cause IHH, producing a quantum leap in understanding of regulation of GnRH secretion, and energising the field. New evidence has now emerged that loss of function of neurokinin B (NKB) or its receptor, the neurokinin-3 receptor, produces IHH of similar severity to that caused by KISS1R mutations in humans. Preliminary evidence suggests that the role of NKB in reproductive function differs significantly between humans and rodents, posing challenges for future studies. We review the human genetics of NKB and its receptor, and discuss the future work required to elucidate their precise role in the regulation of human GnRH secretion. Copyright © 2010 S. Karger AG, Basel

The recent genetics of hypogonadotrophic hypogonadism - Novel insights and new questions

PubMedID: 19719764The complex organization and regulation of the human hypothalamic- pituitary-gonadal axis render it susceptible to dysfunction in the face of a variety of genetic insults, leading to different degrees of hypogonadotrophic hypogonadism (HH). Although the genetic basis of some HH was recognized more than 60 years ago the first specific pathogenic defect, in the KAL1 gene, was only identified within the last 20 years. In the past decade, the rate of genetic discovery has dramatically accelerated, with defects in more than 10 genes now associated with HH. Several themes have emerged as the genetic basis of HH has gradually been uncovered, including the association of some genes such as FGFR1, FGF8, PROK2 and PROKR2, both with HH in association with hyposmia/anosmia (Kallmann syndrome) and with normosmic HH, thus blurring the clinical distinction between ontogenic and purely functional defects in the axis. Many examples of digenic inheritance of HH have also been reported, sometimes producing variable reproductive and accessory phenotypes within a family with non-Mendelian inheritance patterns. In strictly normosmic HH, human genetics has made a particularly dramatic impact in the past 6 years through homozygosity mapping in consanguineous families, first through identification of a key role for kisspeptin in triggering GnRH release, and very recently through demonstration of a critical role for neurokinin B in normal sexual maturation. This review summarises current understanding of the genetic architecture of HH, as well as its diagnostic and mechanistic implications. © 2010 Blackwell Publishing Ltd

Neurokinin b signalling in human puberty

PubMedID: 20456599Recent identification of TAC3 or TACR3 (encoding neurokinin B and its receptor, NK3R, respectively) mutations as the causes of normosmic idiopathic hypogonadotrophic hypogonadism has provided compelling evidence for the involvement of neurokinin B (NKB) signalling in puberty. A surge of subsequent studies pointing towards an understanding of the exact mechanism through which NKB signalling exerts its effects in puberty led to a postulated sketch of the GnRH pulse generator, in which kisspeptin, NKB and dynorphin work in concert to elicit pulsatile gonadotrophin-releasing hormone release in the median eminence. © 2010 The Authors. Journal Compilation © 2010 Blackwell Publishing Ltd