Genesis of a Fact: Tay-Sachs Disease as a "Simple Recessive".

"Obvious" recessive inheritance of Tay-Sachs disease (TSD; OMIM # 272800) took over half a century to be established. Points now taken for granted were problematic, that: (1) TSD is a biological entity, not an artificial selection of concurrent findings, (2) manifestations have narrow limits, (3) it was not part of a spectrum of disorders, and can be differentiated from other conditions, (4) it will not change to another disease, (5) it is due to a single specific gene, (6) there are no secondary causes, (7) the gene has no apparent clinical effects unrelated to TSD, and (8) the gene is inherited only as a clinical recessive. To a large extent, resolution reflected biochemical understanding that took until mid-20th century, and beyond, to change how physicians viewed diseases in general. With this, biochemical carrier screening and prenatal biochemical diagnosis have become routinely available, and it is a model for carrier population screening, while gene therapy for the disease has been reported with some degree of success. Here, the history of medical ideas about TSD and its inheritance are reviewed to show how it achieved its current status as a distinct recessive disorder.

Historical note: Horace Dobell's report of cystic fibrosis in 1872.

In 1872, Horace Dobell, a respected Victorian physician, described the key features of cystic fibrosis, with pancreatic insufficiency, pulmonary disease, and familial recurrence, plus effective treatment of steatorrhea with a pancreatic extract, and was aware of the combination of digestive and pulmonary disease in the pediatric population! This antedated modern descriptions of the full disorder by over 60 years.

Delineating septo-optic dysplasia.

BACKGROUND: Septo-optic dysplasia (SOD), once a variable triad of septum pellucidum defects (SPDs), optic nerve hypoplasia (ONH), and hypopituitarism, has had multiple findings added, with uncertain causes, definitions, and limits. METHOD: Literature review. RESULTS: SOD is a complex vascular sequence with confounders. CONCLUSIONS: Proximal anterior cerebral artery trunk disruptions cause overlapping primary effects, giving ONH alone most often, and isolated SPD less. ONH disruptions can spread to pituitary, SPD disruptions to the cerebral cortex, causing schizencephaly and related anomalies. Pituitary defects are rare without ONH, and cortical findings are rare without SPD. Extensions are unidirectional, so isolated pituitary or cortical defects are separate from SOD. Micro- an- ophthalmia, a suggested ONH variant, is not part of SOD. Disruption by-products can affect development, causing cognitive and endocrine issues, and structural anomalies such as corpus callosum thinning, ventriculomegaly, and hippocampal and olfactory findings. Limbic extensions may also contribute to the same structural defects as by-products. Midline CNS developmental anomalies can act as disruptive foci, most likely through vascular variants, but have separate pathogenesis. Relative frequencies of specific pituitary hormone defects change as SOD rates increase. Increasing relative rates of midline CNS developmental defects and cortical anomalies are consistent with rising levels of exogenous exposures sensitizing to midline predispositions.

Hypothesis: By-products of vascular disruption carried in the CSF affect prenatal brain development.

Prenatal CNS disruptions can be associated with physically separate findings. Examples include cognitive issues in septo-optic dysplasia and sporadic and WNT1-related unilateral cerebellar hypoplasia, and physical findings such as thinning of the corpus callosum, ventriculomegaly, hippocampal abnormalities, olfactory tract and bulb hypoplasia, and distant cortical dysplasias with schizencephaly. Similar effects to toxicities with intraventricular hemorrhage in prematurity could occur earlier in development. CSF transportation of disruption by-products would provide access to vulnerable areas through inflammatory effects on blood-brain barrier permeability. Outcomes are influenced by location and volume of byproducts in the CSF, timing, transport, and inflammatory responses. A particular association of vermis disruption with cognitive issues may be related to CSF flow distortions that avoid toxin dilutions in the third ventricle. Symmetrical contralateral cortical dysplasia with schizencephaly may reflect immunovascular field-related vulnerabilities seen in situations such as vitiligo.

Back pain associated with centrally administered parenteral nutrition.

Parenteral nutrition (PN) is well recognized for its ability to provide nutrition to patients without the ability to digest enterally; however, PN must also be seen as a medication with associated adverse drug events similar to any other pharmacological agent that is administered to patients. Here we present a case report of localized lower back pain with central PN infusion. The initial areas of concern were the intravenous lipid emulsion, peripherally inserted central catheter placement, osmolarity of the formula, and the additives. The patient's back pain was ultimately felt to be an adverse reaction to the multivitamin component of the infusion based on an elimination trial of the PN components.

The VACTERL association: mosaic mitotic aneuploidy as a cause and a model.

While mitotic errors commonly cause aneuploid clones soon after conception, the embryos often normalize as clones are rapidly eliminated. Although generally considered benign, evidence suggests clone elimination as the primary cause of the vertebral, ano-rectal, cardiac, tracheo-esophageal, renal, and limb (VACTERL) association of anomalies, and possibly other adverse outcomes as well. Here, clone elimination-related development disruption at specific locations is used as the basis of a comprehensive theoretical VACTERL association model that also elucidates mitotic mosaic aneuploidy effects. For the association, the model explains random temporal and spatial origins during a limited time frame and overlapping clusters of component anomalies. It supports early developmental effects involving the stage of determination, where the position in a specific morphogen field controls what a cell will become and where it will be located. Developmental properties related to determination also create specific vulnerabilities to the midline and distal defects, the latter explaining exclusively radial and tibial defects with duplications and deficiencies. The model also supports isolated anomalies as part of the association and, for mosaic mitotic aneuploidy, indicates that clone elimination nears completion at the time of lower limb determination. Although mosaic clone elimination may cause other defects, occurrences in different developmental fields separate them from VACTERL anomalies. Clone elimination may also be related to risks for a single umbilical artery and for non-structural adverse pregnancy outcomes such as losses, prematurity, and growth delays, while a paucity of clone lethality in non-humans explains the rarity of the association and of single umbilical arteries in animals.

Evolutionary justifications for human reproductive limitations.

Common human reproductive inefficiencies have multiple etiologies. Going against chance, many effects, such as polycystic ovaries, endometriosis, and folate metabolic issues, have genetic components, while aneuploid losses arise from diverse mitotic and meiotic errors at different stages, some transitory. This can be advantageous, since greater overall survival with fewer offspring can increase reproductive success. Benefits primarily accrue to mothers, who bear most child related costs, and for whom early losses are less costly than late. Different adaptations to different situations reflect human evolutionary history. For early speciation, periodic climate extremes repeatedly reduced resources, favoring limitations while contracted populations helped fix relevant genes. Later, under better conditions, evolving social cooperation could increase fecundity faster than it added resources, further supporting reproductive suppression through mitotic aneuploidy, with very early losses minimizing maternal costs. The grandmother hypothesis suggests benefits in limiting reproduction as maternal age increased pregnancy risks in order to support grandchildren as they arrived, selecting for maternal age-related meiotic aneuploidy. Finally, with variable short-term agricultural shortages, acute reproductive responses arose through chromatin "nutrient sensor"-regulated epigenetic effects that also shifted some lethal effects earlier, reducing both maternal and mutation load costs. Overall, despite suggestions to the contrary, it is likely that human selective pressures have not decreased with civilization, but that many of the costs have been shifted to early reproduction.

An epigenetic association of malformations, adverse reproductive outcomes, and fetal origins hypothesis related effects.

VACTERL, the prototype for associated congenital anomalies, also has connections with functional issues such as pregnancy losses, prematurity, growth delays, perinatal difficulties, and parental subfertility. This segues into a broader association with similar connections even in the absence of malformations. DNA methylation disturbances in the ovum are a likely cause, with epigenetic links to individual components and to folate effects before conception, explaining diverse fetal and placental findings and providing a link to fetal origin hypothesis-related effects. The association encompasses the following: (1) Pre- and periconceptual effects, with frequent fertility issues and occasional imprinting disorders. (2) Early malformations. (3) Adverse pregnancy outcomes (APOs), as above. (4) Developmental destabilization that resolves soon after birth. This potentiates other causes of association findings, introducing multiple confounders. (5) Long-term fetal origins hypothesis-related risks. The other findings are exceptional when the same malformations have Mendelian origins, supporting a distinct pathogenesis. Expressions are facilitated by one-carbon metabolic issues, maternal and fetal stress, and decreased embryo size. This may be one of the commonest causes of adverse reproductive outcomes, but multifactorial findings, variable onsets and phenotypes, and interactions with multiple confounders make recognition difficult. This association supports VACTERL as a continuum that includes isolated malformations, extends the fetal origins hypothesis, explains adverse effects linked to maternal obesity, and suggests possible interventions.

Correction to: An epigenetic association of malformations, adverse reproductive outcomes, and fetal origins hypothesis related effects.

[This corrects the article DOI: 10.1007/s10815-018-1197-2.].

Periodontal disease and FAM20A mutations.

Enamel-renal-gingival syndrome (ERGS; OMIM #204690), a rare autosomal recessive disorder caused by mutations in FAM20A, is characterized by nephrocalcinosis, nephrolithiasis, amelogenesis imperfecta, hypoplastic type, gingival fibromatosis and other dental abnormalities, including hypodontia and unerupted teeth with large dental follicles. We report three patients and their families with findings suggestive of ERGS. Mutation analysis of FAM20A was performed in all patients and their family members. Patients with homozygous frameshift and compound heterozygous mutations in FAM20A had typical clinical findings along with periodontitis. The other had a novel homozygous missense mutation in exon 10, mild gingival fibromatosis and renal calcifications. The periodontitis in our patients may be a syndrome component, and similar findings in previous reports suggest more than coincidence. Fam20a is an allosteric activator that increases Fam20c kinase activity. It is hypothesized that lack of FAM20A activation of FAM20C in our patients with FAM20A mutations might have caused amelogenesis imperfecta, abnormal bone remodeling and periodontitis. Nephrocalcinosis appears not to be a consistent finding of the syndrome and the missense mutation may correlate with mild gingival fibromatosis. Here we report three patients with homozygous or compound heterozygous mutations in FAM20A and findings that extend the phenotypic spectrum of this disorder, showing that protein truncation is associated with greater clinical severity.

Making extra teeth: Lessons from a TRPS1 mutation.

A Thai mother and her two daughters were affected with tricho-rhino-phalangeal syndrome type I. The daughters had 15 and 18 supernumerary teeth, respectively. The mother had normal dentition. Mutation analysis of TRPS1 showed a novel heterozygous c.3809_3811delACTinsCATGTTGTG mutation in all. This mutation is predicted to cause amino acid changes in the Ikaros-like zinc finger domain near the C-terminal end of TRPS1, which is important for repressive protein function. The results of our study and the comprehensive review of the literature show that pathways of forming supernumerary teeth appear to involve APC and RUNX2, the genes responsible for familial adenomatous polyposis syndrome and cleidocranial dysplasia, respectively. The final pathway resulting in supernumerary teeth seems to involve Wnt, a morphogen active during many stages of development. © 2016 Wiley Periodicals, Inc.

Embryonic hypocellularity, blastogenetic malformations, and fetal growth restriction.

An association between congenital malformations and fetal growth restriction (FGR) can be largely explained by a relationship with early embryonic hypocellularity. The malformations include the VACTERL association, which is exceptional as a Mendelian syndrome, but is commonly associated with monozygotic twinning, maternal diabetes, and some forms of aneuploidy, all characterized by a small embryo early in development. Parsimony suggests that these different links to VACTERL are related to the hypocellularity as a single common factor, rather than as an expression of three independent pathogenetic processes. A distinct non-genetic pathogenesis is further supported by increased frequencies in the same conditions of a single umbilical artery (SUA), which is also unusual in Mendelian disorders. SUA often involves the atrophy of one artery, which may be facilitated by altered hemodynamics in a smaller embryo, providing a direct link to hypocellularity. Hypocellularity may also explain a possible connection between VACTERL and certain mitochondrial disorders, where reduced energy might slow early cell division and growth, reducing the size of the embryo. © 2016 Wiley Periodicals, Inc.

Syndromes with supernumerary teeth.

While most supernumerary teeth are idiopathic, they can be associated with a number of Mendelian syndromes. However, this can also be a coincidental finding, since supernumerary teeth occur in 6% or more of the normal population. To better define this relationship, we analyzed the evidence for specific associations. We excluded conditions with a single affected patient reported, supernumerary teeth adjacent to clefts or other forms of alveolar disruption (as secondary rather than primary findings), and natal teeth, which can involve premature eruption of a normal tooth. Since, the cause of supernumerary teeth shows considerable heterogeneity, certain findings are less likely to be coincidental, such as five or more supernumerary teeth in a single patient, or locations outside of the premaxilla. We found only eight genetic syndromes with strong evidence for an association: cleidocranial dysplasia; familial adenomatous polyposis; trichorhinophalangeal syndrome, type I; Rubinstein-Taybi syndrome; Nance-Horan syndrome; Opitz BBB/G syndrome; oculofaciocardiodental syndrome; and autosomal dominant Robinow syndrome. There is also suggestive evidence of an association with two uncommon disorders, Kreiborg-Pakistani syndrome (craniosynostosis and dental anomalies), and insulin-resistant diabetes mellitus with acanthosisnigricans. An association of a Mendelian disorder with a low frequency manifestation of supernumerary teeth is difficult to exclude without large numbers, but several commonly cited syndromes lacked evidence for clear association, including Hallermann-Streiff syndrome, Fabry disease, Ehlers-Danlos syndrome, Apert and Crouzon syndromes, Zimmermann-Laband syndrome, and Ellis-van Creveld syndrome. © 2016 Wiley Periodicals, Inc.

The VACTERL Association as a disturbance of cell fate determination.

Cases diagnosed as the VACTERL Association are heterogeneous, and can involve other associations arising from different developmental processes with midline effects. However, these often lack the classic radial ray anomalies that help make VACTERL distinct. A more specific association can be delineated based on teratogenic disturbances affecting vulnerabilities associated with the establishment of cell fate through positional information, with two basic weaknesses: (i) The midline, where topological properties such as reduced lateral information should make information losses more likely; (ii) Increased distal sensitivity at the end of a morphogen gradient in the limbs, where both duplications and deficiencies can arise from similar disturbances. Vertebral, cardiac, anal-rectal, and tracheo-esophaeal findings are primary midline derivatives. While the kidneys are bilateral, they can be influenced by the midline, although there may also be effects on the ureteral buds as distal structures. The pre-axial area is the most distal in limb development, giving radial/tibial deficiencies and duplications. Alternatively, spina bifida and orofacial clefts originate from bilateral structures that are less likely to be affected by problems with midline determination, explaining the rarity of these disorders with VACTERL. Suggested human genetic models typically involve the midline, but lack radial findings, and true Mendelian forms are rare. However, developmental genes such as Sonic Hedgehog may have a pathogenetic role without being causal.

Blastogenetic associations: General considerations.

Associations of anomalies, with VACTERL as the prototype, have been the source of much debate, including questions about the validity and definition of this category. Evidence is presented for a teratologic basis for associations involving interactions between disruptive events and specific vulnerabilities. Because the embryo is organized in time and space, differences in the timing, location, and severity of exposures will create variable sequelae for any specific vulnerability, creating associations. The blastogenetic stage of development involves distinct properties that affect the nature of associations arising during this time, including relatively undifferentiated developmental fields and causally nonspecific malformations. With this, single anomalies can be part of the spectrum of findings that comprise a specific association. A specific defect defines a subset of disturbances, biasing frequencies of other defects. Processes are basic, integrated, and general, so disruptions are often lethal, and can have multiple effects, accounting for high incidences of multiple anomalies, and overlaps between associations. Blastogenetic disturbances also do not affect the late "fine tuning" of minor anomalies, although pathogenetic sequences can occur. This model suggests that certain combinations of congenital anomalies can arise from causally nonspecific teratogenetic fields determined by timing, location, and vulnerabilities, rather than polytopic developmental fields.

Sonic Hedgehog, VACTERL, and Fanconi anemia: Pathogenetic connections and therapeutic implications.

Three systems with VACTERL association findings- mutations of the Sonic Hedgehog (SHH) signaling pathway in mice, murine adriamycin teratogenicity, and human Fanconi anemia (FA) pathway mutations, may all involve a similar mechanism. SHH is up-regulated in irradiated cells, and DNA breaks common with radiation damage in the adriamycin and FA systems are plausible signals for such effects, which would affect development. Since FA related DNA breakage occurs throughout life, SHH disturbances may account for later FA related findings involving hematopoietic and malignancy issues. In support, androgen, a standard treatment for FA hematologic failure, down-regulates SHH, and common FA malignancies such as squamous cell carcinomas and acute myeloid leukemia have been linked to enhanced SHH function. This suggests that interventions lowering SHH levels may be useful therapeutically. Also supporting a connection between pre- and post- natal findings, the frequency and number of VACTERL anomalies with FA correlate with the severity and onset of hematopoietic and malignancy issues. In FA, radial anomalies are the most common of these defects, followed by renal findings, while vertebral and gastrointestinal anomalies are relatively uncommon, a pattern that differs from observations of the VACTERL association. Genes with more severe effects also show a greatly increased incidence of brain abnormalities, and a paucity of such findings with other FA genes suggests that brain development is relatively refractory to SHH related effects, accounting for the rarity of such findings with the association.

A vascular and thrombotic model of gastroschisis.

A binary vascular/thrombotic pathogenesis for gastroschisis, a form of congenital bowel herniation, is proposed, where normal right umbilical vein involution creates a possible site for thrombosis adjacent to the umbilical ring. If thrombosis occurs, it weakens the area, explaining overwhelmingly right-sided lesions. The model arises from the existence of two groups of risk factors with different maternal age associations. Older mothers show a greater association with vascular factors (although this may actually represent a lack of any significant maternal age effect), consistent with associations of gastroschisis with congenital heart lesions and with amyoplasia. Alternatively, other predispositions, and especially decreased maternal age, the greatest known risk factor, associate with factors raising maternal estrogen, with evidence that estrogen in turn acts here as a predisposition to thrombosis. Absorption of thrombotic by-products from the amniotic fluid can explain the unusual amniocyte inclusions that are common with gastroschisis, while a role for estrogens suggests a connection between rising gastroschisis prevalence and increasing environmental contamination with estrogen disruptors. This model explains a variety of structural and epidemiological findings, and suggests that stratification of data based on binary effects may clarify associated risks and mechanisms. The model also shows that what is often referred to as vascular disruption may actually reflect alternative or additional factors instead, including thrombosis as a primary mechanism.