X-Linked Dominant Disorders

Genetics as a Tool in Neurology

Dennis R. Johnson , Fuki M. Hisama , in Molecular Neurology, 2007

4. X-linked Dominant Inheritance

X-linked dominant disorders are seen more commonly in females than in males, or in the instance of some diseases, touch on merely females. In the latter case, it is thought that the hemizygous males are so severely afflicted, they do not survive. This may be reflected in the pedigree by multiple miscarriages or male infant deaths. Examples of 10-linked dominant disorders include Rett syndrome, the 10-linked lissencephaly and double-cortex syndrome, and incontinentia pigmenti type 1, characterized by dermatological, ocular, dental, and neurological abnormalities.

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Genetic and Perinatal Disease

Thomas C. King MD, PhD , in Elsevier'south Integrated Pathology, 2007

X-linked Dominant Disorders

X-linked dominant disorders are uncommon relative to other types of mendelian diseases and prove an backlog of affected females in a family, since women accept two X chromosomes ( Fig. 4-xi). X-linked dominant disorders practise not evidence male parent to son transmission, and afflicted males (hemizygous for the mutant allele) are ordinarily more severely affected than female person heterozygotes.

Renal phosphate transport disorder is an X-linked ascendant disease that results in abnormalities of os and teeth due to aberrant vitamin D metabolism, resulting in dumb resorption of phosphate by renal tubules. Patients have lacking bone mineralization and, if untreated, bear witness failure to thrive and short stature with thin, curved bones (rickets). The lacking gene PHEX is located on the brusk arm of the X chromosome, but its normal function is non clearly divers. Patients respond to treatment with hydroxylated vitamin D.

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Vitamin D Deficiency, Rickets and Osteomalacia☆

C.R. Paterson , in Reference Module in Biomedical Sciences, 2017

Ten-Linked Hypophosphatemic Rickets

This Ten-linked dominant disorder is caused past lacking phosphate reabsorption in the proximal renal tubules (Carpenter et al., 2011). Afflicted children may non present before 6-12 months of age and may develop deformities similar to those of vitamin D deficiency rickets including enlargement of the wrists and knees, and bow legs. Impaired growth is common. Dental abnormalities may occur. Afflicted adults may accept symptomatic osteomalacia and bone pain. Despite the hypophosphatemia calcitriol levels are frequently low or normal suggesting that one component of the disorder is abnormal regulation of the 1-hydroxylase. Treatment includes calcitriol or alfacalcidol together with phosphate supplements.

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Metabolic Bone Diseases

Erik A. Imel , ... David B. Burr , in Basic and Applied Bone Biology, 2014

X-Linked Hypophosphatemia

The X-linked dominant disorder, 10-linked hypophosphatemia (XLH), is the most common class of inherited hypophosphatemia. Patients with XLH take inactivating mutations in the PHEX gene [which encodes phosphate-regulating neutral endopeptidase (PHEX)], with many different mutations of different types reported. Disease severity is highly variable, in terms of severity of the biochemical skeletal phenotypes. However, it is still unclear whether this cistron normally has a part in phosphate metabolism. PHEX overexpression does not effect in a phosphate disorder, although deficiency does.

PHEX is expressed in osteocytes/osteoblasts and odontoblasts. Patients with PHEX deficiency accept increased expression and secretion of the FGF-23 peptide hormone, which has a clear role in renal phosphate metabolism. FGF-23 interaction with the FGF receptor (FGFR) and Klotho in the kidney decreases the surface expression of sodium phosphate cotransporters NPT2a (encoded by SLC34A1) and NPT2c (encoded by SLC34A3), resulting in impaired phosphate reabsorption. As phosphate is freely filtered at the glomerulus, reabsorption is critical to maintain normal phosphate homeostasis. FGF-23 also inhibits the 1α-hydroxylase, resulting in inappropriately depression 1,25(OH)iiD concentrations. Consequently, FGF-23 excess causes the biochemical phenotype of XLH: hyperphosphaturia, hypophosphatemia, and inappropriately depression or normal 1,25(OH)2D concentrations. Hypophosphatemia itself decreases apoptosis of growth plate hypertrophic chondrocytes, resulting in the histologic and clinical phenotype of rickets. In addition, in PHEX (Phex)-scarce mice, reduced chondrocyte expression of the sodium-dependent phosphate transporter one (PiT-1) contributes to reduced cellular phosphate uptake and reduced chondrocyte apoptosis. Clinical features of XLH are similar to those of nutritional rickets. Additionally, dental abscesses are common. Odontoblast PHEX deficiency results in abnormalities in the dentin and cementum layers, making the teeth prone to infection. Patients with XLH besides develop calcification of entheses, which limits their range of motion at joints, causing stiffness. Secondary hyperparathyroidism occurs commonly, probably due to effects of FGF-23 on 1,25(OH)2D production and the effects of treatment with phosphate.

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Noncystic Hereditary Diseases of the Kidney

Russell Westward. Chesney , in Therapy in Nephrology & Hypertension (Tertiary Edition), 2008

Primary or X-Linked Hypophosphatemic Rickets

This Ten-linked dominant disorder is the virtually common of the phosphaturic syndromes and involves a double renal tubular defect: (1) failure of Na+/PO4 3 − cotransport across the brush border membrane of the proximal tubule and (two) reduction in the conversion of 25-hydroxyvitamin D3 to i,25-dihydroxyvitamin D3 by proximal tubule prison cell mitochondria. ii, 4 A defective phosphate regulatory protein (PHEX) that fails to degrade fibroblast growth cistron 23 is the cause of this status.

The electric current recommendation regarding the most appropriate form of handling is a combination of oral 1,25-dihydroxyvitamin Diii in every bit low a dose as possible (5-l ng/day) plus oral phosphate supplements (70 mg/kg/day). 1,4,eight Although this therapy has been shown to improve calcium and phosphate retention, phosphate must be administered every 4 to 5 hours because the renal phosphate leak persists (see Tabular array 46-1). Therapy is probably needed throughout the life of the patient. Not but will the rachitic growth plate lesion be improved but endosteal os trabecular lesions will likewise meliorate, a change not credible when using vita-min Dii or D3 alone. Oral phosphate tin exist administered equally Joulie solution 8 or as neutral phosphate. 9 The latter is commercially available and far easier to use. This form of therapy should exist given during childhood. Medical noncompliance is a major problem, as are excessively loose stools due to oral sodium phosphate. Hydrochlorothiazide and amiloride may be used in some cases in which there appears to exist resistance to the combination of vitamin D and phosphate supplementation in terms of calcium malabsorption and hypercalciuria.

No long-term studies have been reported that confirm the office of lifetime phosphorus supplementation in adults with this disorder. However, studies indicate that calcification of ligaments and joints (enthesopathy) tin occur in untreated developed patients, 10 suggesting the demand for therapy during adult life. Severely affected adults who go along to have osteodystrophy, stress fractures, and dental caries require prolonged treatment, withal those who are asymptomatic may not e'er demand to go along treatment. Normal pregnancies accept been reported both in mothers treated with vitamin D/phosphate supplementation and in those not treated. The concomitant use of recombinant man growth hormone, as an adjunct to standard therapy, probably improves growth.

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Pediatric Neurology Office 3

Petr Jira , in Handbook of Clinical Neurology, 2013

The conradi–hünermann–happle syndrome

In this Ten-linked ascendant disorder the nigh striking features are of cutaneous, skeletal, and ocular origin. Well-nigh patients have significant developmental filibuster, hypotonia, seizures, patchy scarring alopecia of the scalp, ichthyosiform erythroderma, and hypopigmentation distributed along Blaschko lines from nascency. The erythroderma usually resolves spontaneously during the first year of life. Further congenital anomalies included unilateral cataract, ptosis, microphthalmia, microcornea, glaucoma, atrophy of the retina and optic nerve, esotropia, crossed renal ectopia, stenotic ear canals, and failure to thrive, requiring G-tube placement. Curt stature, skeletal asymmetry, frontal bossing, malar hypoplasia, apartment nasal bridge, vertebral malformations, hip dysplasia, are described as well chondrodysplasia punctata on skeletal survey. The Blaschkolinear distribution of peel manifestations reflects the functional mosaicism that occurs in females as a effect of lyonization (Milunsky et al., 2003).

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Genetic and epigenetic influences on the phenotype of Rett syndrome

Jenny Downs , ... Helen Leonard , in Chromatin Signaling and Neurological Disorders, 2019

ix.6.one X chromosome inactivation

RTT is an X-linked dominant disorder, meaning that heterozygous females are specifically affected. Female cells are mosaic for expression of heterozygous X-linked mutations or alleles due to the random choice of X chromosome inactivation patterns that get established in each cell lineage effectually the fourth dimension of implantation. XCI is established and maintained in subsequent daughter cells through the differential expression of oppositely oriented lncRNAs, Xist and Tsix, expressed from the inactive or active alleles, respectively [171]. The random choice of maternal versus paternal X chromosome for XCI in each cell ensures an approximately 50:fifty ratio of Ten-linked allelic expression in females, on boilerplate. Yet, bear witness of nonrandom XCI, also chosen "skewed XCI" is observed in carrier mothers of X-linked mutations as well as in women with recurrent miscarriages [172,173].

In RTT, most girls showroom apparently random XCI patterns in blood and encephalon [146,174,175]. In rare cases of maternal inheritance of MECP2 mutations, still, XCI is highly favorably skewed, explaining the asymptomatic carrier mother [176]. For RTT girls with defined mutations (i.e., p.Arg168∗, p.Thr158Met), the percentage of mutant-expressing cells correlated with clinical severity [177]. Although XCI ratios are a clearly important modifier of clinical severity, several curious exceptions to this rule perhaps could exist explained past the potential for inaccuracies in this assay. For example, a few RTT girls with highly skewed XCI did not explicate clinical diagnosis of classical versus preserved spoken communication variant [178], and 1 asymptomatic carrier mother of a MECP2 mutation showed an XCI pattern in blood favoring mutant expression [179]. Most puzzling was the study of MECP2 c806delG monozygotic twins discordant for RTT severity who both showed random XCI in blood, fibroblasts, and buccal cells [180]. These discrepancies may indicate to other genetic and nongenetic influences that may serve to modify the clinical severity of RTT that accept been underinvestigated, only will exist discussed later.

Although RTT is a monogenic disorder potentially treatable by gene therapy approaches, the mosaic nature of this X-linked dominant disorder creates a very difficult problem of reexpressing Mecp2 considering wild-type expressing cells would overexpress MeCP2 and mutant-expressing cells could have a dominant-negative effect of coexpression of both wild-type and mutant Mecp2 alleles in the aforementioned cell (Fig. nine.six). As MECP2 duplications are a known genetic etiology of autism in males [182], overexpression of MeCP2 is expected to be detrimental to the wild-type expressing neurons. In female mouse models of RTT, this mixture of Mecp2 mutant and wild-type neurons and glial cells in the encephalon also creates both cell-democratic and noncell-autonomous "bad neighborhood" effects in which astrocytes spread MeCP2 deficiency, affecting neuronal maturation even in wild-type expressing neurons [41,181]. These findings enhance the question of whether several nongenetic factors could be investigated and utilized for "neighborhood" therapeutic comeback on the wild-blazon expressing cells and neuronal networks in the mosaic RTT encephalon.

Effigy 9.half-dozen. Consideration of Mosaicism due to XCI in Rett syndrome treatments. Center image is from a sagittal section of a female mouse model of Rett syndrome stained for MeCP2 immunofluorescence and imaged by laser scanning cytometry [181]. Cells expressing the mutant copy of Mecp2 are colored in blue, while jail cell expressing the wild-blazon Mecp2 are colored in either greenish or red based on low or high MeCP2 levels, respectively. The left console represents the electric current challenges associated with gene therapy strategies for introducing MECP2 into mosaic females, because wild-type expressing cells volition have overexpression and mutant-expressing cells may have a dominant-negative effect on the wild-type allele. The right console represents opportunities for therapeutic strategies or environmental effects on improving the "bad neighborhood" that results from wild-blazon expressing cells with low MeCP2 levels due to noncell democratic effects of the mutant-expressing cells in the brain.

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Vitamin D Deficiency, Rickets, and Osteomalacia

David Feldman , Peter J. Malloy , in Encyclopedia of Endocrine Diseases, 2004

X-Linked Hypophosphatemic Rickets

XLH is an 10-linked dominant disorder acquired by renal phosphate wasting and results in severe skeletal abnormalities and growth retardation. The primary machinery is defective phosphate reabsorption in the renal proximal tubule that results in excessive phosphaturia. The clinical presentation is commonly not apparent until 6–12 months of historic period and ranges from balmy abnormalities of the bones to severe rickets and osteomalacia. Children exhibit rachitic bone deformities, including enlargement of the wrists and knees and bowing of the lower extremities. Defects in molar development and premature cranial synostoses may also be present. Low or inappropriately normal circulating levels of calcitriol are institute, despite the hypophosphatemia (Table Ii). The low serum phosphate normally should crusade an increase in 1α-hydroxylase activity and enhanced calcitriol production, suggesting that XLH may also outcome in abnormal regulation of 1α-hydroxylase.

Table II. Comparison of Genetic Causes of Rickets a

VDDR-I HVDRR XLH ADHR
Gene CYP27B1 VDR PHEX FGF23
1,25(OH)iiD3 Low Loftier (Normal) b (Normal) b
PTH High High Normal Normal
Calcium Low Low Normal Normal
Phosphate Depression Depression Low Depression
Alopecia No Yes No No
a
Abbreviations used: VDDR-I, vitamin D-dependent rickets type I; HVDRR, hereditary vitamin D-resistant rickets; XLH, Ten-linked hypophosphatemic rickets; ADHR, autosomal dominant hypophosphatemic rickets.
b
Inappropriately normal relative to decreased serum phosphate concentration.

The cistron causing XLH has been cloned and named PHEX, which is a phosphate-regulating gene with homologies to endopeptidases located on the Ten-chromosome. The PHEX cistron is homologous to a family unit of endopeptidases that includes endothelin-converting enzyme-1 and neutral endopeptidase. The PHEX factor encodes a 749-amino acid membrane-bound protein that is expressed in bone, adult ovary, lung, and fetal liver. A number of genetic defects in the PHEX gene have been institute in patients with XLH. Since many of the mutations are inactivating mutations, the X-linked dominant expression of the disorder is probable caused by a haploinsufficiency rather than the consequence of a ascendant negative effect. The hypothesis for action is that the PHEX enzyme inactivates a phosphaturic factor (phosphatonin) of import for reabsorbing phosphate from the glomerular filtrate. Inactivating mutations lead to excessive phosphaturia due to inadequate destruction of phosphatonin and therefore backlog urinary phosphate loss.

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Volume I

Kenneth Due east. White , ... Michael J. Econs , in Endocrinology: Adult and Pediatric (7th Edition), 2016

Ten-Linked Hypophosphatemic Rickets (OMIM No. 307800)

XLH is an Ten-linked ascendant disorder and the nearly common form of heritable rickets. 131 XLH is fully penetrant with variable severity. XLH patients present with laboratory findings that include hypophosphatemia with normocalcemia and inappropriately normal or depression 1,25(OH)2D concentrations. 131 Skeletal defects include lower-extremity deformities from rickets, os pain, osteomalacia, fracture, and enthesopathy (calcification of the tendons and ligaments). Information technology was adamant by the Hyp Consortium that XLH is caused by inactivating mutations in PHEX ( p hosphate-regulating gene with h omologies to east ndopeptidases on the X chromosome). 132 Based upon sequence homology, PHEX encodes a poly peptide that is a fellow member of the M13 family of membrane-bound metalloproteases. Other members of this enzyme class include neutral endopeptidase (NEP) and endothelin-converting enzymes ane and 2 (ECE-one and ECE-2). 132,133 This family is known to cleave pocket-sized peptides. Over 300 inactivating PHEX mutations accept been described in XLH patients, including genomic variations that cause missense, nonsense, frameshift, and splicing changes (see PHEX Locus database: www.phexdb.mcgill.ca ). Of notation, although XLH is a renal Pi-wasting disorder, PHEX shows the highest expression in bone cells such equally osteoblasts, osteocytes, and odontoblasts in teeth, as well equally lower expression in the parathyroid glands, lung, brain, and skeletal muscle but no expression in kidney. 134

A valuable tool for the study of the pathophysiology of XLH has been the Hyp mouse, which has a 3′ deletion in the Phex gene from intron 15 through the 3′ UTR 134 and does non brand a stable Phex transcript. 134 This rodent model parallels the XLH phenotype, characterized past hypophosphatemia with inappropriately normal one,25(OH)iiD levels and normal serum calcium, also as growth retardation and os mineralization defects. 135 Parabiosis studies between the Hyp mouse and a normal mouse pointed to the presence of a humoral factor, a phosphatonin, beingness transferred through the circulation of the Hyp mouse to the normal mouse to crusade isolated renal Pi wasting. 136 Subsequently the identification of PHEX/Phex, it was logically postulated that the enzyme may directly degrade a phosphaturic substance; however, studies suggest a more complex pathophysiology.

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Built Cardiomyopathies

Jeffrey A. Towbin , ... John Lynn Jefferies , in Musculus, 2012

Danon Illness

Danon affliction is an 10-linked dominant disorder characterized by intracytoplasmic vacuoles containing autophagic material and glycogen in cardiac and skeletal muscle cells in patients with cardiomyopathy and skeletal myopathy, with or without conduction defect, WPW syndrome, visual acuity abnormalities due to choriocapillary ocular atrophy, or mental retardation (66,78). The underlying abnormality affects lysosomal office and is due to mutations in the lysosomal-associated membrane protein 2 (LAMP2). The clinical phenotypic expression of Danon illness is variable only commonly presents in males with HCM and skeletal myopathy, electrocardiographic show of Wolff–Parkinson–White syndrome and high voltage QRS complexes, and high creatine kinase plasma levels. Late-onset LV dilation and dysfunction with symptoms of HF in affected males and their carrier mothers, as well equally atrial and ventricular arrhythmias and conduction affliction, occur.

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