About inborn metabolic diseases

A brief glossary on Rare Diseases and in particular metabolic diseases. We know we are people working for people.

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A rare disease is any disease that affects a small percentage of the population (e.g., 5 people in 10,000 in Europe; less than 200,000 people in United States of America; 1 person in 2,500 in Japan).


Metabolic diseases consist of diseases or disorders that disrupt normal metabolism, i.e. the process of converting food to energy at a cellular level.
Metabolic diseases affect the cells’ ability to perform critical biochemical reactions involving the processing or transportation of proteins (amino acids), carbohydrates (sugars and starches), and/or lipids (fatty acids).
Metabolic diseases are rare, but they are not that uncommon when considered all together. As a group, it is estimated that metabolic disorders affect approximately 1 in 1,000 individuals.
Metabolic diseases are typically hereditary, yet most people affected by them may appear healthy for days, months, or even years. The onset of symptoms usually occurs when the body’s metabolism comes under stress.


Phenylketonuria (PKU) is a genetic disease characterised by the accumulation of Phenylalanine (Phe) in the organism due to inefficient or totally absent metabolism of Phe into tyrosine, resulting in severe mental retardation, brain function abnormalities, microcephaly, mood disorders, irregular motor functioning, and behavioural problems. If PKU is diagnosed and treated early enough, an affected newborn can grow up with normal brain development. Treatments include strictly controlled phenylalanine (Phe) intake amounts through diet and / or the use of a specific medication: Sapropterin.2HCl

1 person in 10,000.

Diets for PKU patients require severely restricting or even eliminating foods of high phenylalanine content, such as meat, fish, nuts, cheese, legumes, and other dairy products.
Starchy foods such as potatoes, bread, pasta, and corn must be monitored. Infants may still be breastfed to provide all of the benefits of breast milk, but the quantity may have to be limited, resulting in necessary supplementation of missing nutrients. Many diet foods and diet soft drinks containing aspartame sweetener must also be avoided. In the past, PKU-affected people were allowed to go off diet after approximately 8, and then 18 years of age. Today most physicians recommend that PKU patients must monitor their Phe levels throughout their entire life.


Type I Gaucher disease is a genetic disease characterised by a defect in the enzyme called glucocerebrosidase (also known as acid β–glucosidase). When this enzyme does not function, its substrate glucocerebroside accumulates, which in turn causes liver and spleen enlargement, changes in the bone marrow and blood, and bone disease.

1 person in 50,000. Gaucher disease is particularly frequent among the Ashkenazi Jews (about 1 in 300)

Painless hepatomegaly and splenomegaly: the size of the spleen can reach 1500- 3000 ml, as opposed to the normal size of 50- 200 ml. Splenomegaly may decrease the affected individual’s capacity for eating by exerting pressure on the stomach. While painless, spleen enlargement increases the risk of splenic rupture. Severe pain associated with joints and bones occurs, mainly in hips and knees. Neurological symptoms are also very common.

First line treatment generally consists of Enzyme Replacement Therapy, that is administration of a functioning version of the mutated enzyme. Second line treatment (for those patients who are no more eligible for ERT) consists of Miglustat: this small molecule works by preventing the formation of the substance that builds up when the enzyme does not work (substrate reduction therapy).


Niemann–Pick type C is a genetic disease characterised by unique abnormalities of intracellular transport of cholesterol with sequestration of unesterified cholesterol in lysosomes and late endosomes.

1 person in 100,000.

The clinical presentation of NPC is extremely heterogeneous, with an onset age ranging from the perinatal period until adult age (as late as the seventh decade of life).
Typically, patients experience the following symptoms: prolonged unexplained neonatal jaundice or cholestasis, isolated unexplained splenomegaly, and progressive, often severe neurological symptoms such as cognitive decline, cerebellar ataxia, vertical supranuclear gaze palsy (VSGP), dysarthria, dysphagia, dystonia, seizures, gelastic cataplexy, and psychiatric disorders.

There is no available treatment yet for NPC itself, but miglustat has proved to treat derived neurological symptoms and to slow the progression of the disease for some patients.


Type 1 tyrosinemia is a genetic disease characterised by the defective activity of fumarylacetoacetate hydrolase (FAH), an enzyme responsible for the degradation of the amino acid tyrosine. Such deficiency leads to a toxic accumulation of fumaryl- and maleyl-acetoacetate and their derivatives, as succinyl- acetone (SA) and succinyl- acetoacetate (SAA). As they are highly toxic to the liver, these substances are mainly responsible for the symptoms of the disease.

1 person in 120,000. This type of tyrosinemia is much more common in Quebec, Canada.
The overall incidence in Quebec is about 1 in 16,000 individuals. In the Saguenay- Lac- Saint- Jean region of Quebec, type 1 tyrosinemia even affects around 1 person in 2000.

Type 1 tyrosinemia typically presents in infancy as failure to thrive and hepatomegaly. The primary effects are progressive liver and kidney dysfunctions. The liver disease causes cirrhosis, conjugated hyperbilirubinemia, elevated AFP, hypoglycemia and coagulation abnormalities. This can lead to jaundice, ascites and haemorrhage. There is also an increased risk of hepatocellular carcinoma. The kidney dysfunction presents as Fanconi syndrome: renal tubular acidosis, hypophosphatemia and aminoaciduria. Cardiomyopathy, neurologic and dermatologic manifestations are also possible.

The primary treatment for type 1 tyrosinemia is nitisinone and restriction of Tyrosine/Phenylalanine in the diet. Nitisinone inhibits the conversion of 4-hydroxyphenylpyruvate to homogentisic acid by 4- hydroxyphenylpyruvate dioxygenase enzyme, the second step in tyrosine degradation. By inhibiting this enzyme, the accumulation of the fumarylacetoacetate is prevented. Previously, liver transplantation was the primary treatment option and is still used in patients in whom nitisinone fails.


The urea cycle involves a series of biochemical steps in which nitrogen, a waste product of protein metabolism, is removed from the blood and is converted to a compound called urea in the blood.
The onset and severity of urea cycle disorders are highly variable, and depends on the specific mutations involved and correlate with the level of urea cycle enzyme function:
– Severe mutations result in very little to zero enzyme function and consequent inability to detoxify the body from ammonia, finally causing severe urea cycle disorders.
– Mild to moderate mutations represent a broad spectrum of enzyme function, providing some ability to detoxify blood from ammonia, resulting in mild to moderate urea cycle disorders.

1 person in 8,500.

Urea cycle disorders occur in both children and adults.
Newborns with severe mutations become catastrophically ill within 36-48 hours of birth.
Children with less severe mutations can remain undiagnosed because symptoms are not properly recognised.
Adults with mild urea cycle disorders often go undiagnosed since they are still able to produce enough of the urea cycle enzymes to effectively remove ammonia until a stressor interferes with enzyme function, or causes massive amounts of ammonia to be produced. These adults may have subtle symptoms in their lifetime that go unrecognised or disregarded.

Metabolic stressors
Viruses, high protein intake, excessive exercise or dieting, surgery, or medicines (valproic acid, prednisone or other corticosteroids) can create excessive production of ammonia in the body and overwhelm the individual’s urea cycle enzyme function, resulting in severe neurological symptoms.

Dietary management helps to limit ammonia production in conjunction with medications and/or supplements which provide alternative pathways for the removal of ammonia from the bloodstream.


Wilson’s disease (WD), which results from the defective ATP7B gene, is characterised by impaired copper metabolism and consequent copper intoxication.
The prevalence of WD, is similar in most world regions, corresponding to approximately 3 case per 30,000 inhabitants or the most common figure 30 cases per million.
Clinical consequences vary from an asymptomatic state to fulminant hepatic failure, chronic liver disease with or without cirrhosis, neurological, and psychiatric manifestations.

Treatment should ideally commence upon diagnosis in pre-symptomatic subjects, or in symptomatic subjects, immediately after prompt diagnosis. If treatment is initiated promptly, deterioration can be prevented and life expectancy can be comparable to healthy subjects. Prognosis for WD patients is excellent, provided compliance to therapy is adequate.
Treatment is based on the removal of copper excess by use of chelating agents such as penicillamine, trientine, or tetrathiomolybdate or by blocking intestinal copper absorption with zinc salts, with the ultimate goal of normalising free plasmatic copper.


Homocystinuria is a genetic disease characterised by a deficiency in the enzyme cystathionine β-synthase (CBS), the latter being required for the metabolism of the amino acid methionine. Defects in the enzyme lead to the accumulation of homocysteine in the serum and to increased excretion of homocysteine in the urine.
The most common symptoms mainly appear in the eye, the brain, the bones and the vascular system. The major eye symptoms include severe short sightedness (myopia), dislocation of the lens (ectopia lentis) and glaucoma. Eye symptoms are often the earliest signs of the condition and may bring the underlying diagnosis to light. Homocystinuria may also cause developmental delay and learning difficulties. In untreated older patients, psychiatric problems have been reported. Very high homocysteine levels increase the blood’s tendency to clot and therefore even young people with homocystinuria may develop athero or venous thrombosis which may present as strokes, heart attacks and vein thrombosis.
In newborn babies diagnosed with homocystinuria, the aim is to prevent the development of symptoms and to ensure the development of normal growth and intelligence.

Treatment options include administration of vitamin B6, B12 and folic acid, a methionine restricted diet and betaine anhydrous.


Hereditary cholestasis refers to a heterogeneous group of autosomal recessive disorders of childhood that disrupt bile formation and present with cholestasis of hepatocellular origin. Lack of correct bile formation and secretion leads to impaired absorption of liposoluble Vitamins, most importantly Vitamin E.
Vitamin E deficiency can result in peripheral neuropathy, hemolysis and failure to thrive (anorexia, poor nutrient use, hormonal disturbances, and secondary tissue injury).

1 person in 70,000

The only approved treatment is the administration of Tocofersolan, a water soluble form of Vitamin E, which can be absorbed even in absence of bile secretion.