Familial disorders

- Cystinosis

- Galactosemia

- Glycogen storage disease (type I)

- Hereditary fructose intolerance

- Lowe syndrome

- Tyrosinemia

- Wilson's disease

Acquired disorders

- Amyloidosis

- Multiple myeloma

- Paroxysmal nocturnal hemoglobinuria

- Toxins, such as HAART, ifosfamide, lead, and cadmium

Proximal renal tubular acidosis (pRTA) or Type 2 Renal tubular acidosis (RTA) is a type of RTA caused by a failure of the proximal tubular cells to reabsorb filtered bicarbonate from the urine, leading to urinary bicarbonate wasting and subsequent acidemia. The distal intercalated cells function normally, so the acidemia is less severe than dRTA and the urine can acidify to a pH of less than 5.3. pRTA also has several causes, and may occasionally be present as a solitary defect, but is usually associated with a more generalised dysfunction of the proximal tubular cells called Fanconi syndrome where there is also phosphaturia, glycosuria, aminoaciduria, uricosuria and tubular proteinuria.

Patients with type 2 RTA are also typically hypokalemic due to a combination of secondary hyperaldosteronism, and potassium urinary losses - though serum potassium levels may be falsely elevated because of acidosis. Administration of bicarbonate prior to potassium supplementation might lead to worsened hypokalemia, as potassium shifts intracellularly with alkanization.

The principal feature of Fanconi syndrome is bone demineralization (osteomalacia or rickets) due to phosphate and vitamin D wasting.

Type 4 RTA is not actually a tubular disorder at all nor does it have a clinical syndrome similar to the other types of RTA described above. It was included in the classification of renal tubular acidoses as it is associated with a mild (normal anion gap) metabolic acidosis due to a "physiological" reduction in proximal tubular ammonium excretion (impaired ammoniagenesis), which is secondary to hypoaldosteronism, and results in a decrease in urine buffering capacity. Its cardinal feature is hyperkalemia, and measured urinary acidification is normal, hence it is often called hyperkalemic RTA or tubular hyperkalemia.

Causes include:

- Aldosterone deficiency (hypoaldosteronism): Primary vs. hyporeninemic (including diabetic nephropathy)

- Aldosterone resistance

1. Drugs: NSAIDs, ACE inhibitors and ARBs, Eplerenone, Spironolactone, Trimethoprim, Pentamidine

2. Pseudohypoaldosteronism

Renal tubular acidosis (RTA) is a medical condition that involves an accumulation of acid in the body due to a failure of the kidneys to appropriately the urine. In renal physiology, when blood is filtered by the kidney, the passes through the tubules of the nephron, allowing for exchange of salts, acid equivalents, and other before it drains into the bladder as urine. The metabolic acidosis that results from RTA may be caused either by failure to reabsorb sufficient bicarbonate ions (which are alkaline) from the filtrate in the early portion of the nephron (the proximal tubule) or by insufficient secretion of hydrogen ions (which are acidic) into the latter portions of the nephron (the distal tubule). Although a metabolic acidosis also occurs in those with renal insufficiency, the term RTA is reserved for individuals with poor urinary acidification in otherwise well-functioning kidneys. Several different types of RTA exist, which all have different syndromes and different causes.

The word "acidosis" refers to the tendency for RTA to cause an excess of acid, which lowers the blood's pH. When the blood pH is below normal (7.35), this is called "acidemia". The metabolic acidosis caused by RTA is a normal anion gap acidosis.

Gillespie syndrome, also called aniridia, cerebellar ataxia and mental deficiency. is a rare genetic disorder. The disorder is characterized by partial aniridia (meaning that part of the iris is missing), ataxia (motor and coordination problems), and, in most cases, intellectual disability. It is heterogeneous, inherited in either an autosomal dominant or autosomal recessive manner. Gillespie syndrome was first described by American ophthalmologist Fredrick Gillespie in 1965.

Brain MRI shows vermis atrophy or hypoplasic. Cerebral and cerebellar atrophy with white matter changes in some cases.

The overall incidence of myotubular myopathy is 1 in 50,000 male live births. The incidence of other centronuclear myopathies is extremely rare, with there only being nineteen families identified with CNM throughout the world. The symptoms currently range from the majority who only need to walk with aids, from a stick to a walking frame, to total dependence on physical mobility aids such as wheelchairs and stand aids, but this latter variety is so rare that only two cases are known to the CNM "community".

Approximately 80% of males with a diagnosis of myotubular myopathy by muscle biopsy will have a mutation in MTM1 identifiable by genetic sequence analysis.

Many patients with myotubular myopathy die in infancy prior to receiving a formal diagnosis. When possible, muscle biopsy and genetic testing may still be helpful even after a neonatal death, since the diagnostic information can assist with family planning and genetic counseling as well as aiding in the accurate diagnosis of any relatives who might also have the same genetic abnormality.

As with other myopathies, the clinical manifestations of MTM/CNM are most notably muscle weakness and associated disabilities. Congenital forms often present with neonatal low muscle tone, severe weakness, delayed developmental milestones (particularly gross motor milestones such as head control, crawling, and walking) and pulmonary complications (presumably due to weakness of the muscles responsible for respiration). While some patients with centronuclear myopathies remain ambulatory throughout their adult life, others may never crawl or walk and may require wheelchair use for mobility. There is substantial variability in the degree of functional impairment among the various centronuclear myopathies. Although this condition only affects the voluntary muscles, several children have suffered from cardiac arrest, possibly due to the additional stress placed on the heart.

Other observed features have been high arched palate, long digits, bell shaped chest and long face.

Myotubular myopathy only affects muscles and does not impact intelligence in any shape or form.

X-linked myotubular myopathy was traditionally a fatal condition of infancy, with life expectancy of usually less than two years. There appears to be substantial variability in the clinical severity for different genetic abnormalities at that same MTM1 gene. Further, published cases show significant differences in clinical severity among relatives with the same genetic abnormality at the MTM1 gene. Most truncating mutations of MTM1 cause a severe and early lethal phenotype, while some missense mutations are associated with milder forms and prolonged survival (up to 54 years).

Centronuclear myopathies typically have a milder presentation and a better prognosis. Recently, researchers discovered mutations at the gene dynamin 2 (DNM2 on chromosome 19, at site 19p13.2), responsible for the autosomal dominant form of centronuclear myopathy. This condition is now known as dynamin 2 centronuclear myopathy (abbreviated DNM2-CNM). Research has indicated that patients with DNM2-CNM have a slowly progressive muscular weakness usually beginning in adolescence or early adulthood, with an age range of 12 to 74 years.

Galactosemia is one of the most mysterious of the heavily-researched metabolic diseases. It is a hereditary disease that results in a defect in, or absence of, galactose-metabolizing enzymes. This inborn error leaves the body unable to metabolize galactose, allowing toxic levels of galactose to build up in human body blood, cells, and tissues. Although treatment for galactosemic infants is a strict galactose-free diet, endogenous (internal) production of galactose can cause symptoms such as long-term morbidity, presenile development of cataract, renal failure, cirrhosis, and cognitive, neurologic, and female reproductive complications. Galactosemia used to be confused with diabetes due to the presence of sugar in a patient's urine. However, screening advancements have allowed the exact identity of those sugars to be determined, thereby distinguishing galactosemia from diabetes.

The presence of presenile cataract, noticeable in galactosemic infants as young as a few days old, is highly associated with two distinct types of galactosemia: GALT deficiency and to a greater extent, GALK deficiency.

An impairment or deficiency in the enzyme, galactose-1-phosphate uridyltransferase (GALT), results in classic galactosemia, or Type I galactosemia. Classic galactosemia is a rare (1 in 47,000 live births), autosomal recessive disease that presents with symptoms soon after birth when a baby begins lactose ingestion. Symptoms include life-threatening illnesses such as jaundice, hepatosplenomegaly (enlarged spleen and liver), hypoglycemia, renal tubular dysfunction, muscle hypotonia (decreased tone and muscle strength), sepsis (presence of harmful bacteria and their toxins in tissues), and cataract among others. The prevalence of cataract among classic galactosemics is markedly less than among galactokinase-deficient patients due to the extremely high levels of galactitol found in the latter. Classic galactosemia patients typically exhibit urinary galactitol levels of only 98 to 800 mmol/mol creatine compared to normal levels of 2 to 78 mmol/mol creatine.

Galactokinase (GALK) deficiency, or Type II galactosemia, is also a rare (1 in 100,000 live births), autosomal recessive disease that leads to variable galactokinase activity levels: ranging from high GALK efficiency to undetectably-low GALK efficiency. The early onset of cataract is the main clinical manifestation of Type II galactosemics, most likely due to the high concentration of galactitol found in this population. GALK deficient patients exposed to high-galactose diets show extreme levels of galactitol in blood and urine. Studies on galactokinase-deficient patients have shown that nearly two-thirds of ingested galactose can be accounted for by galactose and galactitol levels in the urine. Urinary levels of galactitol in these subjects approach 2500 mmol/mol creatine as compared to 2 to 78 mmol/mol creatine in control patients.

A decrease in activity in the third major enzymes of galactose metabolism, UDP galactose-4'-epimerase (GALE), is the cause of Type III galactosemia. GALE deficiency is an extremely rare, autosomal recessive disease that appears to be most common among the Japanese population (1 in 23,000 live births among Japanese population). While the link between GALE deficiency and cataract prevalence seems to be ambiguous, experiments on this topic have been conducted. A recent 2000 study in Munich, Germany analyzed the activity levels of the GALE enzyme in various tissues and cells in patients with cataract. The experiment concluded that while patients with cataract seldom exhibited an acute decrease in GALE activity in blood cells, "the GALE activity in the lens of cataract patients was, on the other hand, significantly decreased". The study's results are depicted below. The extreme decrease in GALE activity in the lens of cataract patients seems to suggest an irrefutable connection between Type III galactosemia and cataract development.

A 2006 study followed 223 patients for a number of years. Of these, 15 died, with a median age of 65 years. The authors tentatively concluded that this is in line with a previously reported estimate of a shortened life expectancy of 10-15 years (12 in their data).

The precise symptoms of a primary immunodeficiency depend on the type of defect. Generally, the symptoms and signs that lead to the diagnosis of an immunodeficiency include recurrent or persistent infections or developmental delay as a result of infection. Particular organ problems (e.g. diseases involving the skin, heart, facial development and skeletal system) may be present in certain conditions. Others predispose to autoimmune disease, where the immune system attacks the body's own tissues, or tumours (sometimes specific forms of cancer, such as lymphoma). The nature of the infections, as well as the additional features, may provide clues as to the exact nature of the immune defect.

Primary immunodeficiencies are disorders in which part of the body's immune system is missing or does not function normally. To be considered a "primary" immunodeficiency, the cause of the immune deficiency must not be secondary in nature (i.e., caused by other disease, drug treatment, or environmental exposure to toxins). Most primary immunodeficiencies are genetic disorders; the majority are diagnosed in children under the age of one, although milder forms may not be recognized until adulthood. While there are over 100 recognized PIDs, most are very rare. About 1 in 500 people in the United States are born with a primary immunodeficiency. Immune deficiencies can result in persistent or recurring infections, autoinflammatory disorders, tumors, and disorders of various organs. There are currently no cures for these conditions; treatment is palliative and consists of managing infections and boosting the immune system.

Spinal and bulbar muscular atrophy (SBMA) is a progressive debilitating neurodegenerative disorder resulting in muscle cramps and progressive weakness due to degeneration of motor neurons in the brainstem and spinal cord.

The condition is associated with mutation of the androgen receptor ("AR") gene and is inherited in an X-linked recessive manner. As with many genetic disorders, no cure is known, although research continues. Because of its endocrine manifestations related to the impairment of the "AR" gene, SBMA can be viewed as a variation of the disorders of the androgen insensitivity syndrome (AIS). It is also related to other neurodegenerative diseases caused by similar mutations, such as Huntington's disease.

This condition is rare with an estimated incidence of 1/40,000 males. Although this condition is not normally fatal eventually 20% of those affected may need a wheelchair.

5α-Reductase is an enzyme that converts testosterone to 5α-dihydrotestosterone (DHT) in peripheral tissues. These enzymes also participate in the creation of such neurosteroids as allopregnanolone and THDOC, convert progesterone into dihydroprogesterone (DHP), and convert deoxycorticosterone (DOC) into dihydrodeoxycorticosterone (DHDOC). 5-ARD is biochemically characterized by low to low-normal levels of testosterone and decreased levels of DHT, creating a higher testosterone/DHT ratio.

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

Individuals with CAIS are raised as females. They are born phenotypically female and almost always have a heterosexual female gender identity; the incidence of homosexuality in women with CAIS is thought to be less than unaffected women. However, at least two case studies have reported male gender identity in individuals with CAIS.

The condition affects only those with a Y-chromosome because dihydrotestosterone (DHT) has no known role in development of XX fetuses.

Challenges presented to people affected by this condition include: psychologically coming to terms with the condition, difficulties with sexual function, infertility. Long-term studies indicate that with appropriate medical and psychological treatment, women with CAIS can be satisfied with their sexual function and psychosexual development. CAIS women can lead active lives and expect a normal lifespan.

In contrast to EIS, androgen insensitivity syndrome (AIS), a condition in which the androgen receptor (AR) is defective, is relatively common. This can be explained by the genetics of each syndrome. AIS is a X-linked recessive condition and thus carried over, by females, into future generations (although the most severe form, complete androgen insensitivity syndrome (CAIS), results in sterility, and hence cannot be passed on to offspring). EIS is not compatible with reproduction, thus each occurrence in humans would have to be a "de novo" mutation and is not transmitted to offspring.

GPER knockout mice have also been generated, and exhibit obesity, cardiovascular dysfunction, insulin resistance, glucose intolerance, differences in mammary carcinogenesis and metastasis, and differences in central nervous system function.

All forms of androgen insensitivity are associated with infertility, though exceptions have been reported for both the mild and partial forms. Lifespan is not thought to be affected by AIS.

Due to its mild presentation, MAIS often goes unnoticed and untreated. Management of MAIS is currently limited to symptomatic management; methods to correct a malfunctioning androgen receptor protein that result from an AR gene mutation are not currently available. Treatment includes surgical correction of mild gynecomastia, minor hypospadias repair, and testosterone supplementation. Supraphysiological doses of testosterone have been shown to correct diminished secondary sexual characteristics in men with MAIS, as well as to reverse infertility due to low sperm count. As is the case with PAIS, men with MAIS will experience side effects from androgen therapy (such as the suppression of the hypothalamic-pituitary-gonadal axis) at a higher dosage than unaffected men. Careful monitoring is required to ensure the safety and efficacy of treatment. Regular breast and prostate examinations may be necessary due to comorbid association with breast and prostate cancers.

Catecholaminergic polymorphic ventricular tachycardia (CPVT), also called familial polymorphic ventricular tachycardia (FPVT) or catecholamine-induced polymorphic ventricular tachycardia, is a disorder characterized by an abnormal heart rhythm (arrhythmia). Thought to affect as many as one in ten thousand people, it is estimated to cause 15% of all unexplained sudden cardiac deaths in young people.

First recognized in 1975, this condition is due to mutations in genes encoding a calcium channel or proteins related to this channel. All mutated proteins participate in the regulation of calcium ion flow in and out of the sarcoplasmatic reticulum of cardiac cells. Therefore, reduced electrical stability of cardiomyocytes may cause the heart to enter a life-threatening state of ventricular arrhythmia as response to the natural release of catecholamines from nerve endings on the heart muscle and from the adrenal glands into the circulation. This rhythm disturbance prevents the heart from pumping blood appropriately. Ventricular tachycardia may self-terminate or degenerate into ventricular fibrillation, causing sudden death unless immediate cardiopulmonary resuscitation is applied.

Estimates for the incidence of androgen insensitivity syndrome are based on a relatively small population size, thus are known to be imprecise. CAIS is estimated to occur in one of every 20,400 46,XY births. A nationwide survey in the Netherlands based on patients with genetic confirmation of the diagnosis estimates that the minimal incidence of CAIS is one in 99,000. The incidence of PAIS is estimated to be one in 130,000. Due to its subtle presentation, MAIS is not typically investigated except in the case of male infertility, thus its true prevalence is unknown.

Depending on the mutation, a person with a 46,XY karyotype and AIS can have either a male (MAIS) or female (CAIS) phenotype, or may have genitalia that are only partially masculinized (PAIS). The gonads are testes regardless of phenotype due to the influence of the Y chromosome. A 46,XY female, thus, does not have ovaries or a uterus, and can neither contribute an egg towards conception nor gestate a child.

Several case studies of fertile 46,XY males with AIS have been published, although this group is thought to be a minority. Additionally, some infertile males with MAIS have been able to conceive children after increasing their sperm count through the use of supplementary testosterone. A genetic male conceived by a man with AIS would not receive his father's X chromosome, thus would neither inherit nor carry the gene for the syndrome. A genetic female conceived in such a way would receive her father's X chromosome, thus would become a carrier.