Albinism (oculocutaneous albinism)

OMIM #203100, #203200, #203290, and #606574

At least four variations exist, all of which impact the production of the pigment melanin.

The varying types of albinism affect hair and skin pigments as well as vision to varying degrees.

There is no cure for albinism. Treatment is supportive, including any necessary visual/eye care as well as preventative care to prevent sunburn and skin cancers.

Variations that only affect the eyes (ocular albinism) are also known, which are all X-linked.

Type 1: Deficit in tyrosinase, the first enzyme in the melanin synthetic pathway. Variations of type 1 exist.

Type 1 albinism patients can have no, some, or even temperature-dependent (increased in cooler body parts) pigment formation. A variation affects predominately Amish/Mennonite peoples.

Type 2: Defect in the P-protein, which regulates melanocyte pH and affects pigment production. The melanocortin 1 receptor on melanocytes, which binds pituitary hormones called melanocortins (e.g., ACTH and MSH) also regulate the production and type of melanin produced in type 2 albinism.

Type 2 (the most common type) has some pigment production (e.g., moles, freckles, and light hair color) and less problems with vision.

Type 3: Defect in tyrosinase-related protein-1 (TRP-1), involved in melanin synthesis but also possibly affecting and regulating tyrosinase activity and melanocyte proliferation and death.

Type 3 is less understood but results in reddish hair, red-brown skin, and blue/gray eyes.

Type 4: Defect in membrane-associated transporter protein (MATP), regulating melanin synthesis and melanocyte differentiation.

Type 4 is usually found only in Japan, although a small German population has also been identified. Patients have white to yellow to even brown hair, light blue/gray to brown eyes, and visual problems.

Alkaptonuria (black urine disease)

OMIM #203500

Defect in the gene for homogentisic acid oxidase. Breakdown of phenylalanine and tyrosine is inhibited, leading to increase of the intermediate homogentisic acid (2,5-dihydroxyphenylacetic acid), also known as alkapton. Excessive alkapton is excreted in the urine and, when exposed to air, turns into a brown-black, melanin-like molecule.

Urine color changes (usually first detected in a baby’s diaper), higher incidence of kidney and prostate stones. Deposition of homogentisic acid in cartilage can damage joints (e.g., spine, hip, and shoulder). Heart valves may also be affected and coronary artery disease may be problematic. Pigment may also deposit in skin (e.g., at sweat glands), ear wax, and in the eye (sclera).

No absolute treatment method has been found, although reduction in phenylalanine and tyrosine in the diet is common. Added vitamin C to the diet helps to reduce cartilage damage. Other novel treatment methods are being developed.

Alkaptonuria was the first inherited disease involving an error in metabolism that was characterized (1859).

Glycine encephalopathy (nonketotic hyperglycinemia)

OMIM #605899

Defect in mitochondrial glycine cleavage enzyme system responsible for glycine degradation. This system includes (a) P-protein (pyridoxal phosphate-dependent glycine decarboxylase), (b) H-protein (a lipoic acid-containing protein), (c) T-protein (tetrahydrofolate-requiring enzyme), and L-protein (lipoamide dehydrogenase). Defects in any of these enzymes lead to increased glycine levels in blood, urine, and cerebrospinal fluid.

Presents in three forms:

1. 
   

   Neonatal form (first days of life): decreased muscle and nerve function, which can lead to cessation of breathing and death, seizures, and marked mental retardation.

   
   
2. 
   

   Infantile form (symptom-free up to 6 months): seizures and mental retardation.

   
   
3. 
   

   Atypical mild form (childhood): muscle and nerve symptoms (low muscle tone, abnormal movements, and seizures), mental retardation, developmental delay, behavioral and speech problems, and frequent infections.

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Histidinemia

OMIM #235800

Defective histidine ammonia-lyase, required for the removal of an amino group during histidine degradation (l-histidine to trans-urocanic acid).

The defect results in high levels of histidine, histamine, and imidazole in urine, blood, and cerebrospinal fluid. Usually clinically insignificant but may lend to developmental disorders (e.g., mental retardation, learning disability, hyperactivity, and speech deficits) in neonates, infants, and small children.

Most patients are asymptomatic and do not require treatment. A low histidine diet lowers levels of the metabolites but has never been conclusively shown to affect symptoms.

This inborn error of metabolism is the most common disorder in persons of Japanese descent.

Homocystinuria

OMIM #236200

Defect in cystathionine β-synthase, required for conversion of homocysteine to cystathionine, part of the breakdown pathway of methionine. Defect results in accumulation of homocysteine in blood/urine.

Increased levels of homocysteine and methionine are seen in the urine. Excessively long limbs and fingers, dislocation of lens of eye, neurological problems (seizures, mental retardation, and psychiatric illness), and increased risk of blockage of veins and arteries resulting in heart attacks and strokes.

Treated with high doses of vitamin B6, normal dose of folic acid, and/or addition of cysteine or trimethylglycine to diet. If unresponsive to these treatments, a decrease of methionine in diet is required.

Homocystinuria II (also known as. pyridoxine responsive) results from a defect of the synthase apoenzyme causing defective cofactor binding.

Hypervalinemia

OMIM #277100

Defect in valine transaminase, resulting in increased levels of valine in blood and urine (no increase of leucine or isoleucine).

Presents in infants with poor appetite and feeding, poor growth and weight gain (failure to thrive), drowsiness, diarrhea and vomiting, dehydration, poor muscle tone, rapid involuntary muscle and eye movements, poor concentration, and mental retardation.

Treated with diet restriction of valine.

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Isovaleric acidemia (sweaty feet disease)

OMIM #243500

Defect in the enzyme isovaleryl coenzyme A dehydrogenase. This enzyme is responsible for the third step in the degradation of leucine. Deficiency results in increased levels of isovaleric acid in blood and urine, which is toxic to the central nervous system. Toxic molecules can be alternatively broken down and excreted via glycine degradation.

Acute (fatal) form strikes newborns causing marked acidification of the blood, convulsions, lethargy, dehydration, moderately increased liver size, decreased platelets and white blood cells, and an unusual urinary odor like that of sweaty feet. Rapid death follows. Chronic intermittent (nonfatal) form results in periodic attacks of acidification of blood possibly resolving by glycine detoxification pathway.

Treated with reduction of leucine in diet and administration of glycine to help remove toxic isovaleric acid.

Hallmark sweaty feet odor results from increased butyric and hexanoic acids from unrelated but possibly linked error in fatty acid metabolism.

Ketotic hyperglycinemia (propionic acidemia)

OMIM #606054

Defect in propionyl-CoA carboxylase is an essential enzyme in the breakdown of propionyl-CoA, a product of the metabolism of several amino acids (valine, isoleucine, threonine, and methionine) and the oxidation of odd-numbered fatty acids.

Defect leads to increased glycine, propionyl-CoA, propionic acid, ketones, ammonia, and acid level in blood/urine. Presents in infants with damage to brain, heart and liver, vomiting, fatigue, low muscle tone, lowered levels or absent neutrophils and/or platelets and/or blood protein, seizures, developmental delay, and poor tolerance of dietary protein.

Treatment is by careful restriction of dietary protein. Frequent infections are sometimes seen because of a decrease of white blood cells.

Propionyl-CoA with oxaloacetate also forms methylcitrate, which inhibits the citric acid cycle.

Maple syrup urine disease

(branched-chain aminoaciduria)

OMIM #248600

Deficit of branched-chain α-keto acid dehydrogenase complex (three enzyme subunits), required for oxidative decarboxylation of the α-ketoacids produced by the removal of the amino group during degradation of branched-chain amino acids (leucine, isoleucine, and valine). Ketoacidosis results from the branched-chain α-ketoacid accumulation. The urine has a characteristic maple syrup odor.

Defect results in accumulation of these amino acids and branched-chain α-ketoacids in blood and urine.

Newborns are listless, have feeding difficulties, seizures, periods of interrupted breathing, global developmental delay, and growth deficiency. General muscle tone may be poor. Symptoms in acute episodes include: seizures, abdominal pain, muscle weakness, unsteadiness, and sometimes hallucinations. Left untreated, can lead to coma and death within the first months of life. Early and prompt treatment can prevent many of the neurological damage.

Treatment consists of restricting the dietary intake of branched-chain amino acids to the minimum that is needed for growth. These include dietary leucine restriction, high calorie, branched-chain amino acid-free formulas, and frequent monitoring of plasma amino acid concentrations. Additional thiamine pyrophosphate (vitamin B1), a cofactor for the enzyme, is also given. Treatment usually lowers levels of branched-chain amino acids and disease progression.

In certain Mennonites populations, incidence can be as high as 1 in 175. Studies have shown that it is possible to transfer subunits of the enzyme complex into cells using a retrovirus as a possible cure.

Methylmalonic acidemia (MMA)

OMIM #251000

Defect in methylmalonyl-CoA mutase, responsible for the breakdown of branched-chain amino acids (isoleucine, valine, and threonine) and methionine. The enzyme is also involved in lipid and cholesterol metabolism via the conversion of methylmalonyl-CoA into succinyl-CoA. Methylmalonyl-CoA requires vitamin B12; thus, deficiencies of this vitamin’s metabolism can lead to the same disease state. Defects in two other gene products (MMAA and MMBB) involved in the production of an active form of vitamin B12, adenosylcobalamin, and, therefore, the final enzyme can also cause disease.

Deficiency of this enzyme’s activity from any cause leads to the inability to metabolize certain amino acids and lipids/cholesterol. Patients present with nausea/vomiting and dehydration, poor growth, decreased muscle tone (hypotonia), and reduced energy (lethargy). Without treatment, varying mental deficits, kidney, liver and pancreatic disease, and coma/death may result.

Acute treatment involves stabilization of critically ill patients, which includes marked reduction or elimination of dietary proteins and replacement by simple carbohydrates to limit lipid metabolism.

Longer term treatment includes a diet of high calories but low protein (including restrictions of isoleucine, valine, threonine, and methionine), supplementation of vitamin B12 and carnitine (to promote fatty acid transport and metabolism).

Multiple forms exist, including an infantile, non- vitamin B12 responsive, intermediate, vitamin B12 responsive, early childhood, and benign/adult forms. The severity of the disease generally lessens from the infantile to the adult forms.

Phenylketonuria

OMIM #261600

Defect in phenylalanine hydroxylase, required for hydroxylation of phenylalanine as part of its degradation and for synthesis of tyrosine.

Defect results in decreased levels of α-ketoglutarate, due to transamination of the excess phenylalanine, which shuts down energy production and development of the brain. This results in severe mental retardation, decreased skin pigmentation, unusual posture, and epilepsy. Characteristic “mousy” odor of urine is also present due to the increased presence of phenylpyruvate, phenylacetate, and phenyllactate.

Phenylalanine must be carefully limited and extra tyrosine added to the diet for essential protein and neurotransmitter synthesis.

Less frequently the disease can result from a defect of the enzyme that regenerates the tetrahydrobiopterin cofactor for the reaction. Several disorders of elevated phenylalanine not related to this enzyme exist.

3-Phosphoglycerate dehydrogenase deficiency

OMIM #601815

Defect in 3-phosphoglycerate dehydrogenase, the enzyme responsible for the first step in the synthesis of serine.

The inability to produce serine, the major source of one-carbon groups for the new synthesis of purine nucleotides and deoxythymidine monophosphate, leads to severe neurological consequences, including a severely undersized brain (congenital microcephaly) and delay in neurological functions, seizures, failure to thrive, abnormal eye movements, and abnormal posture. Diagnosis can be made by measuring levels of serine and glycine in the plasma and cerebrospinal fluid.

Treatment is by supplementation with serine and glycine.

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Phosphoserine aminotransferase deficiency

OMIM #610992

Defect in phosphoserine aminotransferase, the second enzyme in serine biosynthetic pathway.

Deficiency of serine leads to a similar clinical picture as has been noted for 3-phosphoglycerate dehydrogenase deficiency above, including small brain upon birth and neurological deficiencies, severe seizures, and abnormal posture and muscle tone. Diagnosis is determined by low concentrations of serine and glycine in plasma and cerebrospinal fluid.

Treatment is by supplementation with serine and glycine.

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Smith-Magenis syndrome (SMS)

OMIM #182290

OMIM #182144

Defect in serine hydroxymethyltransferase, leading to decreased or absent conversion of serine to glycine. Exact mechanism unknown, but association with the NMDA receptor involved in learning and memory as well as glycine’s role in transmission of nerve signals may explain disease symptoms.

Patients have facial abnormalities, abnormal sleep cycles (possibly due to altered melatonin), behavioral problems, self-injury, short stature, abnormal spine curvature, reduced sensitivity to pain and temperature, hoarse voice, hearing and vision problems, and heart and kidney defects. Patients often display the unique characteristics of repetitive self-hugging and “lick and flip” activity—licking of fingers and flipping of book and magazine pages.

No cure. Treatment is supportive and is focused on controlling symptoms, including supplementation and regulation of melatonin, sleep aids, and behavioral modifiers.

Mutation occurs during egg/sperm or early fetal development.

Type I tyrosinemia (tyrosinosis)

OMIM #276700

Defect in fumarylacetoacetase. This enzyme is required for the last step in tyrosine degradation. Deficiency results in buildup of all intermediates of tyrosine degradation as well as phenylalanine byproducts.

Symptoms usually appear in the first few months of life, including poor growth/weight gain; cabbage-like odor; intestinal obstruction and/or bleeding; diarrhea; vomiting; enlargement and disease of heart, liver, and/or spleen with associated disease; kidney and pancreatic failure; abnormal blood clotting leading to increased tendency to bleed (e.g., nose); chronic muscle weakness, rickets; and intermittent paralysis and loss of feeling.

Only treatment is diet low in phenylalanine, methionine, and tyrosine. Liver transplantation is common.

Type I is the most severe form of the tyrosinemias, impacting multiple organ systems. Much more common in Quebec, Canada.

Type II tyrosinemia

OMIM #276600

Deficit of tyrosine transaminase, the enzyme required for the first step in tyrosine degradation. Deficiency leads to urinary excretion of tyrosine and the intermediates between phenylalanine and tyrosine.

Symptoms usually in early childhood including mental retardation (∼50%), growth retardation, eye problems (excessive tearing, abnormal sensitivity to light, pain, and redness), and skin problems (painful lesions on the palms/soles).

Treated with low-protein diet, especially decreased tyrosine and phenylalanine.

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Type III tyrosinemia

OMIM #276710

Deficit of 4-hydroxy phenylpyruvate dioxygenase, required for the second step in tyrosine degradation. Deficiency leads to elevated levels of tyrosine in the blood and marked excretion of degradation byproducts into urine.

Mild mental retardation, periodic loss of balance, and coordination and seizures.

Treated with low-protein diet, especially decreased tyrosine and phenylalanine.

Very rare. Heterozygous mutation in the same gene can cause Hawkinsinuria.

Cystinuria

OMIM #220100

Defect in the amino acid transporter for basic or positively charged amino acids (histidine, lysine, ornithine, arginine, and cysteine), leading to a defect in the transport of these amino acids in the kidney and the digestive tract.

Precipitation of cystine and the formation of stones in the urinary tract are the primary medical problems. Repetitive stone formation can lead to obstruction of urine flow that raises the risk of urinary infections and kidney failure.

Treatment is directed at prevention of stone formation through high fluid intake and the use of penicillamine.

One of the four, original inborn errors of metabolism described in 1908 and one of the most common (∼1 in 7,000).

Drummond’s syndrome (blue diaper syndrome)

OMIM #211000

Defect in T-type amino acid transporter-1. This transport protein is required for absorption of tryptophan from the intestine. It may also lead to increased urine calcium levels and kidney stones composed of calcium.

Symptoms include digestive problems, fever, irritability, visual difficulties, and sometimes kidney disease. Breakdown of excess tryptophan leads to formation of indigo blue excreted in urine, causing a bluish discoloration of the diaper.

Treatment involves a low tryptophan diet.

Autosomal or X-linked recessive.

Hartnup disease (neutral aminoaciduria)

OMIM #234500

Defect in sodium (Na+)- dependent transport protein for uncharged amino acids in the kidneys and intestine, resulting in poor absorption in the intestine and increased loss in the urine of uncharged amino acids, many of which are essential. One important example is tryptophan, required to make nicotinic acid, a B-vitamin, needed to produce the same transport protein. Low nicotinic acid levels cause transport protein levels to drop, making the problem worse.

Symptoms usually start in infancy, affecting mainly the brain and skin to include failure to thrive, mental retardation, short stature, headaches, altered gait (ataxia), tremor, fainting, irregular eye movements (nystagmus), and increased sun sensitivity. Psychiatric problems (anxiety, mood changes, delusions, and hallucinations) may also occur.

Treatment is usually via a diet high in neutral amino acids, sunblock and/or sun avoidance and, when needed, daily intake of nicotinamide. A period of poor nutrition usually precedes symptom outbreaks and attacks.

Low nicotinic acid also causes the disease pellagra, which causes the “four Ds”—skin inflammation (dermatitis), diarrhea, dementia, and death.

Hyperammonemia–hyperornithinemia–homocitrullinuria (HHH syndrome)

OMIM #238970

Defect in the mitochondrial ornithine transporter. As a result, ammonia accumulates in the blood.

Symptoms vary widely. Infantile form is usually more severe and may include lethargy, poor feeding and temperature control, seizures, coma, and even death. Later forms have symptoms of lethargy, confusion, blurred vision, poor coordination, and vomiting.

Infantile illness may coincide with the introduction of high-protein formulas or solid foods into the diet. Later forms may only show symptoms with high intake of protein, which increases ammonia levels.

Stress, illness, and/or fasting can also bring on symptoms.

Methionine malabsorption syndrome (Smith–Strang disease/Oasthouse urine disease)

OMIM #250900

Defect in the protein(s) essential for intestinal absorption of methionine (and other amino acids). Unabsorbed methionine is converted by intestinal bacteria to the chemical α-hydroxybutyric acid, which produces an urine odor of an “oasthouse” (building for drying hops).

Symptoms include strikingly white hair and blue eyes, increased rate of breathing, diarrhea, seizures, mental retardation, generalized swelling, and characteristic urine odor.

Because of extremely rare cases, no established treatment but dietary restriction of methionine is implied.

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Arginase deficiency (argininemia)

OMIM #207800

Defect in arginase, the fifth and final enzyme of the urea cycle, which removes nitrogen from arginine to produce a urea molecule. Guanidino metabolites are also found to increase in argininemia. The accumulation of guanidino metabolites contribute to the neurotoxicity of the disease.

The deficit blocks the urea cycle and leads to increased concentrations in ammonia in the blood. Symptoms include poor feeding and growth, developmental delay, mental retardation, lethargy, vomiting, confusion, personality disturbances, seizures, and coma. Death can occur without proper medical care.

Treatment is by low-protein diet (to reduce ammonia production) balanced with amino acid supplementation to allow continuation of the urea cycle as well to maintain cell growth (e.g., arginine, citrulline, valine, leucine, and isoleucine). Phenylacetate may be given to help remove accumulated glutamine via the kidneys. Vitamin and calcium supplements are also often given. Liver transplant is sometimes required.

Cytosolic protein.

Argininosuccinate synthetase (ASS) deficiency (citrullinemia, types I and II)

OMIM #215700, #603471, and #605814

Defective ASS, the enzyme involved in the third step in the urea cycle that synthesizes argininosuccinate from citrulline and aspartate. The mutation decreases production of the protein citrin, a mitochondrial aspartate/glutamate carrier and/or malate/aspartate shuttle. Deficiency affects molecules that are involved in the urea cycle and synthesis of proteins and nucleotides.

Type I patients have increased levels of ammonia in the blood within the first few days of life that leads to poor feeding and growth, seizures, and vomiting. Death can occur.

Type II usually appears in adult patients because of the buildup of ammonia and impacts the nervous system, including confusion, personality disturbances, and seizures/coma. Signs are sometimes triggered by alcohol use or in patients with neonatal intrahepatic cholestasis.

Same as arginase deficiency.

Cytosolic protein.

Argininosuccinic aciduria/acidemia

OMIM #207900

Defect in argininosuccinate lyase, the fourth enzyme of the urea cycle that cleaves argininosuccinate into arginine and fumarate.

Same as arginase deficiency.

Same as arginase deficiency.

Cytosolic protein.

Carbamoyl phosphate synthetase I (CPS-1) deficiency

OMIM #237300

Deficit of CPS1, the enzyme responsible for the transfer of ammonia to bicarbonate to produce carbamate using one ATP. A second ATP is used to produce carbamoyl phosphate. This is the first reaction of the urea cycle.

Same as arginase deficiency.

Same as arginase deficiency.

Mitochondrial protein.

N-Acetylglutamate synthase (NAGS) deficiency

OMIM #237310

Deficit of NAGS, the enzyme responsible for the production of N-acetylglutamate from acetyl-CoA and glutamate. NAGS is the activator of carbamoyl phosphate synthase I (see above).

Same as arginase deficiency.

Same as arginase deficiency.

Mitochondrial protein.

Ornithine transcarbamylase (OTC) deficiency

OMIM #311250

Deficit of OTC, the second urea cycle enzyme, producing citrulline from carbamoyl phosphate and ornithine. This is the most common urea cycle disorder.

The deficit blocks the urea cycle and leads to increased concentrations of ammonia in the blood. Excess carbamoyl phosphate is also converted to orotic acid via pyrimidine synthesis pathways. Symptoms are the same as arginase deficiency.

Same as arginase deficiency. Some childbirth deaths may be due to an unknown OTC deficiency carrier state, which is unmasked by the stress of childbirth.

Mitochondrial protein. Unlike the other urea cycle disorders, listed OTC deficiency is X-linked.

α-1-Antitrypsin (AAT) protease inhibitor deficiency

OMIM #107400

The defective anti-elastase allows degradation of extracellular fibrils such as elastin with gradual loss of pulmonary function, for example.

The association of emphysema and AAT deficiency (known to be a protease inhibitor) has been recognized for a long time. The disease results from the loss of anti-elastase activity and thus the lungs and liver especially are damaged by progressive proteolytic damage. Smoking causes oxidation of the methionine residue in the AAT molecule, which limits its binding to serine protease and reduces its inactivation function even further.

Intravenous concentrates of AAT combined with lifetime avoidance of smoking has been recommended but rigorous studies have not been done. Prognosis is dependent upon the severity of pulmonary and liver disease, which can be highly variable. Many patients succumb in the fifth decade.

Smoking cessation and avoidance of contaminated air is the key to patient health. However, recent studies show that AAT deficiency is probably only responsible for a minority of emphysema cases. Additional contributing factors are currently being sought.

Ehlers–Danlos syndrome (EDS) (cutis hyperelastica)

OMIM #130000

Defects involving the connective tissue protein collagen. Multiple mutations are all classified in the group of EDS.

EDS-affected collagen causes easy bruising and wounds with pigmented scarring, overly flexible joints, heart valve defects, uterine and bowel rupture, and/or gum problems.

There is no cure for EDS. Treatment is supportive for cardiovascular and internal organs. Corrective surgery is sometimes undertaken.

Type X involves a mutation of the glycoprotein that cross-links collagen.

Cutis laxa: A group of related disorders with varying inheritance patterns:

Dominant OMIM #123700: defects in elastin/fibulin

Recessive OMIM #219200: defects in fibulin

X-linked (occipital horn syndrome) OMIM #304150: defects in Cu2+-transporting ATPase, α-polypeptide

Elasticity of the skin is disrupted and is wrinkled and hangs loose. Effects on tendons and ligaments may make joints loose. Severe disease can involve the structure of internal organs, including heart and blood vessels (e.g., arteries), lungs, intestines, and bladder. Hernias can also develop. Easy bruising, low copper and ceruloplasmin, skeletal defects, and the namesake bone outgrowths from the back of the head (occiput) are seen in the X-linked form.

No known cure. Treatment is mainly supportive including monitoring of affected organs and medical/surgical treatments as required.

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Marfan syndrome

OMIM #154700

Defect in the extracellular glycoprotein fibrillin, which affects cysteine-rich, tertiary structural domains.

Mutations in fibrillin weaken connective tissue structure and also disrupt binding to TGF-β protein. Altered binding adversely affects the structure of smooth muscle and extracellular matrix, especially in lungs, blood vessels (e.g., aorta), and heart valves.

There is no cure for Marfan syndrome. Treatment involves monitoring of effects on heart, blood vessels, muscle, lungs, and eyes. β-blockers and angiotensin II receptor blockers (ARBs) also reduce levels of TGF-β and are sometimes used to control cardiovascular manifestations.

Autosomal dominant disorder.

Osteogenesis imperfecta (OI)

OMIM #166200

Defects in structure and function of collagen, type I. Multiple mutations are all categorized under the syndrome of OI.

OI causes marked fragility of bones, abnormal teeth, hearing, and soft-tissue disorders. Some types cause short stature and changes in the sclera of the eye (e.g., light, gray, or blue coloring). An infant form can cause premature birth, structural defects of the face and skull, and usually death in minutes to months because of heart or lung defects.

There is no cure for OI. Treatment is supportive and has included attempts to increase bone mass by bisphosphonates.

Four types of OI are currently known.

Fructosuria (hepatic fructokinase deficiency)

OMIM #229800

Defect in liver fructokinase, which metabolizes the first step in fructose metabolism (fructose to fructose-1-phosphate).