Biomarker for Mucolipidosis Disorder Type I, II, III, IV (BioML)
Biomarker for Mucolipidosis Disorder Type I, II, III, IV (BioML)
Development of a new MS-based biomarker for the early and sensitive diagnosis of
 Mucolipidosis Disorder type I,II,III or IV from blood (plasma)
Mucolipidoses (ML) are a group of inherited metabolic diseases in which both
 glycosaminoglycans (GAGs) and another group of substances called sphingolipids build up in
 the body. GAGs are long, repeating chains of complex sugar molecules, and sphingolipids are
 fats. ML disorders may also be referred to as "targeting defects" because affected
 individuals are lacking the enzyme (a protein that produces chemical reactions in the body)
 that "targets" other enzymes to the lysosome (a sac-like structure found in a cell).

 Symptoms of ML can be congenital (present at birth) or begin in early childhood or
 adolescence. Early symptoms can include vision problems and developmental delays. Over time,
 many children with ML develop poor mental capacities, have difficulty reaching normal
 developmental milestones, and, in many cases, eventually die of the disease.

 Changes in specific genes results in the deficiency or absence of the targeting enzyme. The
 ML disorders are categorized into four groups based on the clinical features and enzyme
 deficiencies. ML-II and ML-III are the more common forms of ML. An individual is usually
 suspected of having an ML disorder based on clinical features. The diagnosis is further
 confirmed by laboratory testing.

 The mucolipidoses are inherited in an autosomal recessive manner, that is, they occur only
 when a child inherits two copies of the defective gene, one from each parent. When both
 parents carry a defective gene, each of their children faces a one in four chance of
 developing one of the MLs. At the same time, each child also faces a one in two chance of
 inheriting only one copy of the defective gene. People who have only one defective gene are
 known as carriers. These individuals do not develop the disease but they can pass the
 defective gene on to their own children. Because the defective genes involved in certain
 forms of ML are known, tests can identify people who are carriers in some instances.

 The four types of ML are Sialidosis (sometimes referred to as ML I), and types II, III, and
 IV.

 • Mucolipidosis type I (Sialidosis) The Sialidoses are autosomal recessive lysosomal storage
 disorders resulting from mutations in the NEU1 gene (6p21.3) which lead to an intracellular
 accumulation of glycoproteins containing sialic acid residues. Both types I and II are caused
 by mutations in the same gene.

 ML1 (NEU1 deficiency) is a neurodegenerative disorder with progressive deterioration of
 muscle and central nervous system functions. Myoclonus, mental deterioration,
 hepatosplenomegaly, muscle weakness and atrophy are common. The defect in neuraminidase
 activity leads to abnormal amounts of sialyl-oligosaccharides in the urine. Spinal
 deformities such as kyphosis are common. Deep tendon reflexes are exaggerated. Ataxia and
 hearing loss may be present. Coarse facies, a barrel chest, and short stature are
 characteristic. Hepatic cells contain numerous vacuoles and numerous inclusions.

 A cherry red spot is may be seen in late childhood or early adolescence. It occurs in nearly
 100% of patients with type I while only 75% of type II patients have this feature possibly
 because their early death from the more severe systemic disease prevents full ascertainment.
 Visual acuity is reduced, sometimes severely. Some but not all individuals have corneal and
 lens opacities. A subtle corneal haze has also been seen. Nystagmus has been reported.

 Sialidosis types I and II are both caused by mutations in the neuraminidase gene. Type I is
 associated with milder disease than type II which has an earlier age of onset and may present
 in infancy or even begin in utero. Early death within two years of age is common in the
 congenital or infantile forms. There is, however, significant variability in age of onset and
 the course of disease among types.

 • Mucolipidosis type II (I-Cell Disease) I-cell disease (mucolipidosis II) is a rare
 inherited metabolic disorder characterized by coarse facial features, skeletal abnormalities
 and mental retardation. The symptoms of I-cell disease are similar to but more severe than
 those of Hurler syndrome. The symptoms associated with this disorder typically become obvious
 during infancy and may include multiple abnormalities of the skull and face and growth
 delays.

 This disorder belongs to a group of diseases known as lysosomal storage disorders. Lysosomes
 are particles bound in membranes within cells that break down certain fats and carbohydrates.
 Multiple enzyme deficiencies associated with I-cell disease lead to the accumulation of
 certain fatty substances (mucolipids) and certain complex carbohydrates (mucopolysaccharides)
 within the cells of many tissues of the body.

 I-cell disease is caused by a mutation in the GNPTAB gene that leads to a deficiency in the
 enzyme UDP-N-acetylglucoseamine-1-phosphotransferase. I-cell disease is inherited as an
 autosomal recessive genetic trait.

 • Mucolipidosis type III (Pseudo-Hurler Polydystrophy) Mucolipidosis III alpha/beta is a
 slowly progressive disorder that affects many parts of the body. Signs and symptoms of this
 condition typically appear around age 3.

 Individuals with mucolipidosis III alpha/beta grow slowly and have short stature. They also
 have stiff joints and dysostosis multiplex, which refers to multiple skeletal abnormalities
 seen on x-ray. Many affected individuals develop low bone mineral density (osteoporosis),
 which weakens the bones and makes them prone to fracture. Osteoporosis and progressive joint
 problems also cause pain in people with mucolipidosis III alpha/beta, which becomes more
 severe over time.

 People with mucolipidosis III alpha/beta often have heart valve abnormalities and mild
 clouding of the clear covering of the eye (cornea). Their facial features become slightly
 thickened or "coarse" over time. Affected individuals may also develop frequent ear and
 respiratory infections. About half of people with this condition have mild intellectual
 disability or learning problems. Individuals with mucolipidosis III alpha/beta generally
 survive into adulthood, but they may have a shortened lifespan.

 Mucolipidosis III alpha/beta is a rare disorder, although its exact prevalence is unknown. It
 is estimated to occur in about 1 in 100,000 to 400,000 individuals worldwide Mutations in the
 GNPTAB gene cause mucolipidosis III alpha/beta. This gene provides instructions for making a
 part (subunit) of an enzyme called GlcNAc-1-phosphotransferase. This enzyme helps prepare
 certain newly made enzymes for transport to lysosomes. Lysosomes are compartments within the
 cell that use digestive enzymes to break down large molecules into smaller ones that can be
 reused by cells. GlcNAc-1-phosphotransferase is involved in the process of attaching a
 molecule called mannose-6-phosphate (M6P) to specific digestive enzymes. Just as luggage is
 tagged at the airport to direct it to the correct destination, enzymes are often "tagged"
 after they are made so they get to where they are needed in the cell. M6P acts as a tag that
 indicates a digestive enzyme should be transported to the lysosome.

 Mutations in the GNPTAB gene that cause mucolipidosis III alpha/beta result in reduced
 activity of GlcNAc-1-phosphotransferase. These mutations disrupt the tagging of digestive
 enzymes with M6P, which prevents many enzymes from reaching the lysosomes. Digestive enzymes
 that do not receive the M6P tag end up outside the cell, where they have increased activity.
 The shortage of digestive enzymes within lysosomes causes large molecules to accumulate.
 Conditions that cause molecules to build up inside lysosomes, including mucolipidosis III
 alpha/beta, are called lysosomal storage disorders. The signs and symptoms of mucolipidosis
 III alpha/beta are most likely due to the shortage of digestive enzymes inside lysosomes and
 the effects these enzymes have outside the cell.

 Mutations in the GNPTAB gene can also cause a similar but more severe disorder called
 mucolipidosis II alpha/beta. These mutations completely eliminate the function of
 GlcNAc-1-phosphotransferase. Mucolipidosis III alpha/beta and mucolipidosis II alpha/beta
 represent two ends of a spectrum of disease severity.

 • Mucolipidosis type IV Mucolipidosis type IV (caused by mutations in the MCOLN1 gene) is an
 inherited disorder characterized by delayed development and progressive vision loss. The
 severe form of the disorder is called typical mucolipidosis type IV, and the mild form is
 called atypical mucolipidosis type IV.

 Approximately 95 percent of individuals with this condition have the severe form. People with
 typical mucolipidosis type IV have delayed development of mental and motor skills
 (psychomotor delay). Motor skills including: sitting, standing, walking, grasping objects,
 and writing. Psychomotor delay is moderate to severe and usually becomes apparent during the
 first year of life. Affected individuals have intellectual disability, limited or absent
 speech, difficulty chewing and swallowing, weak muscle tone (hypotonia) that gradually turns
 into abnormal muscle stiffness (spasticity), and problems controlling hand movements. Most
 people with typical mucolipidosis type IV are unable to walk independently. In about 15
 percent of affected individuals, the psychomotor problems worsen over time.

 Vision may be normal at birth in people with typical mucolipidosis type IV, but it becomes
 increasingly impaired during the first decade of life. Individuals with this condition
 develop clouding of the clear covering of the eye (cornea) and progressive breakdown of the
 light-sensitive layer at the back of the eye (retina). By their early teens, affected
 individuals have severe vision loss or blindness.

 People with typical mucolipidosis type IV also have impaired production of stomach acid
 (achlorhydria). Achlorhydria does not cause any symptoms in these individuals, but it does
 result in unusually high levels of gastrin in the blood. Gastrin is a hormone that regulates
 the production of stomach acid. Individuals with mucolipidosis type IV may not have enough
 iron in their blood, which can lead to a shortage of red blood cells (anemia). People with
 the severe form of this disorder usually survive to adulthood; however, they may have a
 shortened lifespan.

 About 5 percent of affected individuals have atypical mucolipidosis type IV. These
 individuals usually have mild psychomotor delay and may develop the ability to walk. People
 with atypical mucolipidosis type IV tend to have milder eye abnormalities than those with the
 severe form of the disorder. Achlorhydria also may be present in mildly affected individuals.

 Mucolipidosis type IV is estimated to occur in 1 in 40,000 people. About 70 percent of
 affected individuals have Ashkenazi Jewish ancestry.

 Mutations in the MCOLN1 gene cause mucolipidosis type IV. This gene provides instructions for
 making a protein called mucolipin-1. This protein is located in the membranes of lysosomes
 and endosomes, compartments within the cell that digest and recycle materials. While its
 function is not completely understood, mucolipin-1 plays a role in the transport
 (trafficking) of fats (lipids) and proteins between lysosomes and endosomes. Mucolipin-1
 appears to be important for the development and maintenance of the brain and retina. In
 addition, this protein is likely critical for normal functioning of the cells in the stomach
 that produce digestive acids.

 Most mutations in the MCOLN1 gene result in the production of a non-functional protein or
 prevent any protein from being produced. A lack of functional mucolipin-1 impairs transport
 of lipids and proteins, causing these substances to build up inside lysosomes. Conditions
 that cause molecules to accumulate inside the lysosomes, including mucolipidosis type IV, are
 called lysosomal storage disorders. Two mutations in the MCOLN1 gene account for almost all
 cases of mucolipidosis type IV in people with Ashkenazi Jewish ancestry. It remains unclear
 how mutations in this gene lead to the signs and symptoms of mucolipidosis type IV.

 New methods, like mass-spectrometry give a good chance to characterize specific metabolic
 alterations in the blood (plasma) of affected patients that allow diagnosing in the future
 the Disorder earlier, with a higher sensitivity and specificity.

 Therefore it is the goal of the study to identify and validate a new biochemical marker from
 the plasma of the affected patients helping to benefit other patients by an early diagnose
 and thereby with an earlier treatment. Examining blood samples will allow determining whether
 measurement is feasible in blood samples and will further promote early detection of
 mucolipidosis disorder type I, II, III or IV.
INCLUSION CRITERIA

 -  Informed consent will be obtained from the parents before any study related
 procedures.

 -  Patients of both genders older than 2 month

 -  The patient has a diagnosis of Mucolipidosis Disorder type I,II,III or IV or
 high-grade suspicion for Mucolipidosis Disorder type I,II,III or IV

 -  High-grade suspicion present, if one or more inclusion criteria are valid:

 Positive family anamnesis for Mucolipidosis Disorder type I,II,III or IV

 Skeletal abnormalities

 Psychomotor retardation

 Progressive failure to thrive

 Hoarse voice

 EXCLUSION CRITERIA

 -  No Informed consent from the parents before any study related procedures.

 -  Patients of both genders younger than 2 month

 -  No diagnosis of Mucolipidosis Disorder type I,II,III or IV or no valid criteria for
 profound suspicion of Mucolipidosis Disorder type I,II,III or IV