5-alpha-reductase deficiency (5-ARD) is an autosomal recessive intersex condition caused by a mutation of the 5-alpha reductase type 2 gene.[1]

5-alpha-reductase is an enzyme that converts testosterone to dihydrotestosterone (DHT) in peripheral tissues. 5-alpha-reductase deficiency-2 is biochemically characterized by low to low normal levels of testosterone and decreased levels of 5a-DHT, creating a higher testosterone/DHT ratio.

DHT is a potent androgen, necessary for the development of male external genitalia in utero.

The condition affects only males (i.e. those with a Y chromosome) because DHT has no known role in female development.[2]

Individuals with 5-ARD can have normal male external genitalia, ambiguous genitalia, or normal female genitalia. They are born with male gonads, including testicles and Wolffian structures, but usually appear to have female primary sex characteristics. Consequently they are often raised as girls and may develop a female gender identity. Individuals with obvious undervirilisation at birth, e.g. hypospadias, micropenis, or complete ambiguous genitalia, are currently raised as boys.

Individuals with 5-ARD are generally capable of producing viable sperm. In individuals with feminised or ambiguous genitalia, there is a tendency towards a macroclitoris or microphallus, and the urethra may attach to the phallus. This structure may be capable of ejaculations as well as erections, however artificial insemination techniques or in-vitro fertilisation are necessary, due to one’s inability to engage in intercourse.

At puberty, individuals often have primary amenorrhoea, and may experience virilisation. This may include descending of the testes, hirsutism (facial/body hair considered normal in males –not to be confused with hypertrichosis), and deepening of the voice. In adulthood, individuals do not experience male-pattern baldness.[1] As DHT is a far more potent androgen than testosterone alone, virilisation in those lacking DHT may be absent or reduced compared to males with functional 5-alpha reductase. It is hypothesized that rising testosterone levels at the start of puberty (around age twelve) are able to generate sufficient levels of DHT by either the action of 5-alpha-reductase type 1 (active in the adult liver, non-genital skin and some brain areas) or through the expression of low levels of 5-alpha-reductase type 2 in the testes.

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3-Methylglutaconic aciduria (MGA) is used to describe at least five different disorders that impair the body’s ability to make energy in the mitochondria. As a result of this impairment, 3-methylglutaconic acid and 3-methylglutaric acid build up and can be detected in the urine.

3-Methylglutaconic acid is classified as an organic acid. The double carboxylic acid functions are the principal cause of the strength of this acid. 3-methylglutaconic acid can be detected by the presence of the acid function and the double connection that involves reactivity with some specific substances.

There are currently 5 known subgroups of MGA; MGA type I,II,III,IV & V.

3-Methylglutaconic aciduria, seems to be most prevalent amongst the Jewish population of Iraq. However, a high concentration of one type is found in the Saguenay region of Canada. This tends to show that the disease is more frequent in insular areas where there is more chance that both parents be carriers, a higher birth rate, and higher number of congenital marriages. As all types of 3-Methylglutaconic aciduria are known to be genetic diseases and show a recessive pattern it is likely that congenital marriages where both partners are carriers increase the chance to have a baby with the condition.

The four major forms of 3-methylglutaconic aciduria are numbered types I, II, III, and IV. Types I-III are caused by mutations in three different genes and have distinct signs and symptoms. The genetic cause of 3-methylglutaconic aciduria type IV has not been established.

The characteristic features of 3-methylglutaconic aciduria type I include speech delay, delayed development of both mental and motor skills (psychomotor delay), elevated levels of acid in the blood and tissues (metabolic acidosis), abnormal muscle tone (dystonia), and spasms and weakness affecting the arms and legs (spastic quadriparesis). Fewer than 20 cases of 3-methylglutaconic aciduria type I have been reported.

Barth syndrome is a common name for 3-methylglutaconic aciduria type II. The main features of Barth syndrome include a weakened and enlarged heart (dilated cardiomyopathy), recurrent infections due to low numbers of white blood cells (neutropenia), skeletal problems, and delayed growth. The incidence of 3-methylglutaconic aciduria type II is approximately 1 in 200,000 male infants.

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3-Methylcrotonyl-CoA carboxylase deficiency (3MCC deficiency), also known as 3-Methylcrotonylglycinuria type 1 or BMCC deficiency is an inherited disorder in which the body is unable to process certain proteins properly. People with this disorder have inadequate levels of an enzyme that helps break down proteins containing the amino acid leucine. This condition affects an estimated 1 in 50,000 individuals worldwide.

Infants with this disorder appear normal at birth but usually develop signs and symptoms during the first year of life or in early childhood. The characteristic features of this condition, which can range from mild to life-threatening, include feeding difficulties, recurrent episodes of vomiting and diarrhea, excessive tiredness (lethargy), and weak muscle tone (hypotonia). If untreated, this disorder can lead to delayed development, seizures, and coma. Early detection and lifelong management (following a low-protein diet and using appropriate supplements) may prevent many of these complications. In some cases, people with gene mutations that cause 3-methylcrotonyl-CoA carboxylase deficiency never experience any signs or symptoms of the disorder.

The characteristic features of this condition are similar to those of Reye syndrome, a severe disorder that develops in children while they appear to be recovering from viral infections such as chicken pox or flu. Most cases of Reye syndrome are associated with the use of aspirin during these viral infections.

The MCCC1 and MCCC2 genes make protein subunits that come together to form an enzyme called 3-methylcrotonyl-CoA carboxylase. This enzyme plays an essential role in breaking down proteins from the diet. Specifically, the enzyme is responsible for the fourth step in processing leucine. If a mutation in the MCCC1 or MCCC2 gene reduces or eliminates the activity of 3-methylcrotonyl-CoA carboxylase, the body is unable to process leucine properly. As a result, toxic byproducts of leucine processing build up to harmful levels, damaging the brain and nervous system. This condition is inherited in an autosomal recessive pattern.

It is one of the 29 conditions currently recommended for newborn screening by the American College of Medical Genetics.

This article incorporates public domain text from The U.S. National Library of Medicine

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3-hydroxy-3-methylglutaryl-CoA lyase deficiency also referred to as HMG-CoA lyase deficiency or Hydroxymethylglutaric aciduria, is an uncommon inherited disorder in which the body cannot properly process the amino acid leucine. Additionally, the disorder prevents the body from making ketones, which are used for energy during fasting.

This disorder usually appears within the first year of life. The signs and symptoms of HMG-CoA lyase deficiency include vomiting, dehydration, lethargy, convulsions, and coma. When episodes occur in an infant or child, blood sugar becomes extremely low (hypoglycemia), and harmful compounds can build up and cause the blood to become too acidic (metabolic acidosis). These episodes are often triggered by an infection, fasting, strenuous exercise, or sometimes other types of stress.

This condition is sometimes mistaken for Reye syndrome, a severe disorder that develops in children while they appear to be recovering from viral infections such as chicken pox or flu. Most cases of Reye syndrome are associated with the use of aspirin during these viral infections.

Mutations in the HMGCL gene cause 3-hydroxy-3-methylglutaryl-CoA lyase deficiency. The enzyme made by the HMGCL gene plays an essential role in breaking down dietary proteins and fats for energy. Specifically, the enzyme is responsible for processing leucine, an amino acid that is part of many proteins. This enzyme also produces ketones during the breakdown of fats. If a mutation in the HMGCL gene reduces or eliminates the activity of this enzyme, the body is unable to process leucine or make ketones properly. A lack of ketones leads to hypoglycemia, and compounds called organic acids (which are formed as products of amino acid and fat breakdown) can cause the blood to become too acidic. Metabolic acidosis and hypoglycemia impair tissue function, especially in the central nervous system.

This is a rare condition that has been reported in fewer than 100 individuals throughout the world. This condition is inherited in an autosomal recessive pattern.

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2-hydroxyglutaric aciduria is a rare, autosomal recessive neurometabolic disorder characterized by the significant elevation of urinary levels of hydroxyglutaric acid.

2-hydroxyglutaric aciduria is an organic aciduria, and has two distinct isometric variants:

The L-2 form is more common, severe, and mainly affects the central nervous system. The basal ganglia are affected, and cystic cavitations in the white matter of the brain are common, beginning in infancy. This form is chronic, with early symptoms such as hypotonia, tremors, and epilepsy declining into spongiform leukoencephalopathy, muscular choreodystonia, mental retardation, and psychomotor regression.[1]

It is associated with L2HGDH.[2]

The D2 form is rare, with symptoms including macrocephaly, cardiomyopathy, mental retardation, hypotonia, and cortical blindness.[3]

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17-beta-hydroxysteroid dehydrogenase III deficiency is a rare disorder of sexual development affecting testosterone biosynthesis, which can produce impaired virilization (traditionally termed male pseudohermaphroditism) of genetically male infants and children and excessive virilization of female adults.

It is an autosomal recessive[1] condition and is one of the few disorders of sexual development that can affect the primary and/or secondary sex characteristics of both males and females.

In the Netherlands, 17-beta-hydroxysteroid dehydrogenase III deficiency is estimated to occur in 1:147,000 newborns.[2]

17-beta-hydroxysteroid dehydrogenase III deficiency is clinically characterized by either ambiguous external genitalia or complete female external genitalia at birth; as a consequence of impaired male sexual differentiation in 46,XY individuals. Further investigations on ambiguous genitalia will eventually lead to findings of intersexuality. Severely impaired virilization (often complete absence of male sexual differentiation) can lead to development of female external genitalia. These children are raised as female, and their diagnosis is often discovered when there is absence of menarche (first menstruation) and when they begin to virilize during puberty (slowly become more like a man; deepening of the voice, acne, male musculature etc). At careful examination, testis can often be found in the inguinal channel.

17-beta-hydroxysteroid dehydrogenase III deficiency is characterized biochemically by decreased levels of testosterone and increased levels of androstenedione as a result of the defect in conversion of androstenedione into testosterone. This leads to clinically important higher ratio of androstenedione to testosterone (A’dion/T) (see figure).

17-beta-hydroxysteroid dehydrogenase III deficiency is caused by mutations found in the 17Beta Hydroxysteroid dehydrogenase (17BHSD3) gene.[3] 17BHSD3 deficiency is an autosomal recessive disorder.

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1p36 deletion syndrome is a congenital genetic disorder characterized by moderate to severe intellectual disability, delayed growth, hypotonia, seizures, limited speech ability, malformations,caesiatomi, hearing and vision impairment, and distinct facial features. The disorder is also known as monosomy 1p36.

The condition is caused by a genetic deletion (loss of a segment of DNA) on the outermost band on the short arm (p) of chromosome 1. It is one of the most common deletion syndromes. It is estimated that the syndrome occurs in one in every 5,000 to 10,000 births. Knowledge of the disorder has increased a great deal over the last decade, mainly because more patients have been accurately diagnosed and described in international medical literature.

The facial features in monosomy 1p36 have been considered to be characteristic, although few patients have been diagnosed solely on the basis of facial appearance. These features may include microcephaly, small, possibly slanted, deep-set eyes, a flat nose and nasal bridge, anomalous, low-set and small ears, a small mouth with down-turned corners and a pointed chin. Distinguishing features in another study were a large or late-closing anterior fontanelle (up to 85% of patients) and facial asymmetry.

The first cases of 1p36 deletion syndrome were described in the 1980s. However, since many of these individuals also had other chromosomal imbalances, symptoms varied widely. The reason it took so long to recognize the condition as a distinct chromosome deletion syndrome is that the deletions causing the disorder are too small to be detected in a routine chromosomal analysis. FISH (fluorescent in situ hybridization) and DNA-based technology known as MPLA (multiple ligation probe amplification) used in testing have aided in diagnosing an increasing number of cases since the 1990s.

1p36 Deletion Syndrome is a congenital genetic disorder caused by the deletion of the most distal light band of the short arm of chromosome 1. Chromosome 1 is the largest human chromosome and represents about 8 percent of the total DNA in human cells. The “p” stands for the short or ‘petite’ arm of the chromosome. ’36′ stands for the location of the deletion on the chromosome.

Notice the breakpoints in the picture of chromosome 1. The breakpoints for 1p36 Deletion Syndrome have been variable and have ranged from bands 1p36.13 to 1p36.33. Studies have suggested that the larger the deletion, the more severe the symptoms exhibited in the individual, but this has not been proven definitively.

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22q11.2 deletion syndrome, also known as Velocardiofacial Syndrome, DiGeorge Syndrome, conotruncal anomaly face syndrome, Congenital Thymic Aplasia, and Strong Syndrome is a disorder caused by the deletion of a small piece of chromosome 22. The deletion occurs near the middle of the chromosome at a location designated q11.2 i.e., on the long arm of one of the pair of chromosomes 22. It has a prevalence estimated at 1:4000.[1]

The features of this syndrome vary widely, even among members of the same family, and affect many parts of the body. Characteristic signs and symptoms may include birth defects such as congenital heart disease, defects in the palate, most commonly related to neuromuscular problems with closure (velo-pharyngeal insufficiency), learning disabilities, mild differences in facial features, and recurrent infections. Infections are common in children due to problems with the immune system’s T-cell mediated response that in a minority of patients is due to an absent or hypoplastic thymus. 22q11.2 deletion syndrome may be first spotted when an affected newborn has convulsions from hypocalcemia due to malfunctioning the parathyroid glands and low levels of parathyroid hormone (parathormone). Affected individuals may also have any other kind of birth defect including kidney abnormalities and significant feeding difficulties as babies. Autoimmune disorders such as hypothyroidism and hyperparathyroidism or thrombocytopenia (low platelet levels), and psychiatric illnesses are common late-occurring features.[2] Microdeletions in chromosomal region 22q11.2 are associated with a 20 to 30-fold increased risk of schizophrenia. [3] Studies provide various rates of 22q11.2 deletion syndrome in schizophrenia, ranging from 0.5 to 2% and averaging about 1%, compared with the overall estimated 0.025% risk of the 22q11.2 deletion syndrome in the general population.[4]Medical students may use the mnemonic CATCH 22 to describe DiGeorge’s syndrome:
Cardiac defects
Abnormal facial features
Thymic aplasia
Cleft palate
Hypocalcemia
and chromosome 22.

Because the signs and symptoms of 22q11.2 deletion syndrome are so varied, different groupings of features were once described as separate conditions. These included the velo-cardio-facial syndrome, Shprintzen syndrome,DiGeorge syndrome, Sedlackova syndrome and conotruncal anomaly face syndrome,

Individuals with a 22q11.2 deletion can suffer from many possible features, ranging in number of associated features and from the mild to the very serious. Symptoms shown to be common include:

The syndrome is caused by genetic deletions (loss of a small part of the genetic material) found on the long arm of one of the two 22nd chromosomes. Very rarely, patients with somewhat similar clinical features may have deletions on the short arm of chromosome 10.

The mechanism that causes all of the associated features of the syndrome is unknown. Some believe that 22q11.2 deletion syndrome may involve migration defects of neural crest-derived tissues, particularly affecting development of the third and fourth branchial pouches (pharyngeal pouches). Also affected is the thymus gland; a mediastinal organ largely responsible for differentiation and induction of tolerance in T-cells. Impaired immune function results principally from this aetiology.

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3 hydroxyisobutyric aciduria is a disorder of valine metabolism characterised by urinary excretion of 3 hydroxyisobutyric acid.

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3-Methylcrotonic aciduria is a disorder characterised by urine that contains increased amounts of 3-methylcrotonic acid. It is caused by defects in a biotin-dependent reaction that forms 3-methylglutaconic acid.

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