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Symptoms are either present at birth or develop within early in life. Many infants with ML I experience excessive swelling throughout the body at birth. Usually born with coarse facial features, such as a flat nasal bridge, puffy eyelids, enlargement of the gums, and excessive tongue size. Many are also born with skeletal malformations such as hip dislocation. Infants often develop sudden involuntary muscle contractions and have red spots in their eyes (called cherry-red macules). They are often unable to coordinate voluntary movement (called ataxia). Tremors, impaired vision, and seizures also occur in children with ML I. Abnormal enlargement of the liver and spleen and extreme abdominal swelling, impaired intellect initially or that gets progressively severe. Many suffer from failure to thrive and from recurring respiratory infections. Most individuals die before 1 year.

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Being a particularly severe form of ML, physical signs, such as abnormal skeletal development, coarse facial features, and restricted joint movement, may be present at birth. Individuals (typically children) with ML II usually have enlargement of certain organs (such as the liver or spleen, and sometimes even the heart valves). They typically fail to grow and develop in the first months of life, have development delays in their motor skills and cognitive skills, corneal clouding, and recurrent respiratory tract infections. Individuals with ML II generally die before their seventh year of life.

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Mucolipidoses are group of inherited metabolic diseases that affect the body’s ability to carry out the normal turnover of various materials within cells.

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While you cant cure it you can fix/treat some of the symptoms that come with it such as: Corneal clouding, motor delays, language delays, growth failure, respiratory infections and overall health.

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While you cant cure it you can fix/treat some of the symptoms that come with it such as: Corneal clouding, motor delays, language delays, growth failure, respiratory infections and overall health.

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Diagnosis of ML I, II, and III can be confirmed though a blood test that measures enzyme activity in the patient's white blood cells. Lower than normal activity levels indicate specific enzyme deficiencies.

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Another way of testing is through skin biopsy. A small sample of skin is taken from the patient and grown in a cell culture. The activity of a particular enzyme in the cultured skin cells is then measured and the conclusion is drawn.

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The mucolipidoses are inherited through a recessive gene, meaning they occur only when a child inherits two copies of the defective gene, one from each parent. When that requirement is met, each of their children faces a one in four chance of developing one of the MLs. Additionally, each child faces a one in two chance of inheriting only one copy of the defective gene. Individuals possessing only one defective gene do not develop the disease but they can pass it on to their children.

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The are four types of mucolipidoses: I, II, III, and IV.

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Generally of normal intelligence or only possessing mild cognitive problems. These individuals typically have skeletal abnormalities, coarse facial features, short stature, and corneal clouding. Some individuals survive until their fourth or fifth decade of life.

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Most patients with ML IV have a delay of movement development and coordination, clouding of the cornea of the eye, and severely reduced vision. Most have an unsteady gait and do not walk independently. Patients are occasionally misdiagnosed as having cerebral palsy. Speech is usually severely impaired. However, some are more mildly affected and can walk and have better speech.

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What are the mucolipidoses?

The mucolipidoses (ML) are a group of inherited metabolic diseases that affect the body's ability to carry out the normal turnover of various materials within cells. In ML, abnormal amounts of carbohydrates and fatty materials (lipids) accumulate in cells. Because our cells are not able to handle such large amounts of these substances, damage to the cells occurs, causing symptoms that range from mild learning disabilities to severe intellectual impairment and skeletal deformities. 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.

What causes the mucolipidoses?

The MLs are classified as lysosomal storage diseases because they involve increased storage of substances in the lysosomes, which are specialized sac-like components within most cells. Lysosomes play a critical role in the metabolic function of our bodies. One of their primary roles is to pick up substances such as carbohydrates and lipids and break them down into smaller molecules so that they can be used again in the metabolic process. This process is possible because lysosomes contain enzymes, which are proteins that help the body's chemistry work better and faster. Working continuously, enzymes break down carbohydrates and lipids and assist in the transfer of their byproducts throughout the rest of the cell for the production of energy or excretion.

Patients with ML are born with a genetic defect in which their bodies either do not produce enough enzymes or, in some instances, produce ineffective forms of enzymes. Without functioning enzymes, which are proteins, lysosomes cannot break down carbohydrates and lipids and transport them to their normal destination. The molecules then accumulate in the cells of various tissues in the body, leading to sdamage of organs. In patients with ML, the molecules accumulate in nerve, liver, and muscle tissue as well as in bone marrow, and this abnormal storage causes the various symptoms associated with ML. For example, excess storage of these molecules in nerve tissues can cause mental retardation, accumulation in the tissues of the spleen and liver can cause poor functioning of these vital organs, and excess storage in the bone marrow can damage bones, leading to skeletal deformities.

The accumulation of carbohydrates and lipids in tissue is not the result of just one deficient enzyme. Lysosomes contain as many as 40 or 50 different enzymes, each responsible for a highly specialized function. Therefore, a deficiency in one particular enzyme or activator protein causes symptoms that may be somewhat different from the symptoms caused by the deficiency of another type of enzyme.

There are four types of ML and each is classified according to the enzyme(s) or other protein that is deficient or mutated (altered). Symptoms can range from mild to severe.

The MLs are similar to another group of lysosomal storage diseases known as the mucopolysaccharidoses. While both conditions produce similar symptoms and are caused by the lack of enzymes necessary to break down and transport carbohydrates and lipids, the mucopolysaccharidoses result in an excess of sugars, known as mucopolysaccharides, in the urine. Mucopolysaccharides are not seen in urine of patients with ML, therefore screening of the urine can help doctors distinguish between the two groups of disorders.

What are the different types of mucolipidoses?

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

Mucolipidosis type I (ML I) or sialidosis results from a deficiency in one of the digestive enzymes known as sialidase. The role of sialidase is to remove a particular form of sialic acid (a sugar-like molecule) from sugar-protein complexes (referred to as glycoproteins), which allows the cell to function properly. Because the enzyme is deficient, small chains containing the sugar-like material accumulate in neurons, bone marrow, and various cells that defend the body against infection.

Symptoms of ML I are either present at birth or develop within the first year of life. In many infants with ML I, excessive swelling throughout the body is noted at birth. These infants are often born with coarse facial features, such as a flat nasal bridge, puffy eyelids, enlargement of the gums, and excessive tongue size (macroglossia). Many infants with ML I are also born with skeletal malformations such as hip dislocation. Infants often develop sudden involuntary muscle contractions (called myoclonus) and have red spots in their eyes (called cherry-red macules). They are often unable to coordinate voluntary movement (called ataxia). Tremors, impaired vision, and seizures also occur in children with ML I. Tests reveal abnormal enlargement of the liver and spleen and extreme abdominal swelling. Infants with ML I generally lack muscle tone (hypotonia) and have impaired intellect that is either initially or progressively severe. Many patients suffer from failure to thrive and from recurrent respiratory infections. Most infants with ML I die before the age of 1 year.

Other diseases that result from a deficiency in the sialidase enzyme are categorized in a broader group known as sialidoses. Because ML I is classified as a sialidosis, it is sometimes referred to as sialidosis type II.

A rarer form of sialidosis - sialidosis type I - occurs in children and adolescents and is often referred to as the juvenile form of the disorder. Children usually begin to show symptoms during the second decade of life, and myoclonus (brief, involuntary twitching of muscles) and cherry-red macules in the retina are often the initial symptoms. Patients usually develop seizures and progressive deterioration of coordinated muscular and mental activities.

Mucolipidosis types II and III (ML II and ML III) result from a deficiency of the enzyme N-acetylglucosamine-1-phosphotransferase. Just as luggage in an airport is tagged to direct it to the correct destination, enzymes are often "tagged." In ML II and ML III, the deficient enzyme is supposed to tag other enzymes (activator proteins) so that they can initiate certain metabolic processes in the cell. Because the activator proteins are not properly tagged, they escape into spaces outside the cell and therefore cannot do their usual work of breaking down substances inside the cells.

ML II is also referred to as inclusion-cell (I-cell) disease because waste products, thought to include carbohydrates, lipids, and proteins, accumulate into masses known as inclusion bodies. When tissues are examined under a microscope, the detection of inclusion bodies often provides a diagnosis of the disease.

ML II is a particularly severe form of ML that resembles one of the mucopolysaccharidoses called Hurler syndrome. Some physical signs, such as abnormal skeletal development, coarse facial features, and restricted joint movement, may be present at birth. Children with ML II usually have enlargement of certain organs, such as the liver or spleen, and sometimes even the heart valves. Affected children often fail to grow and develop in the first months of life. Delays in the development of their motor skills are usually more pronounced than delays in their cognitive (mental processing) skills. Children with ML II eventually develop a clouding on the cornea of their eyes and, because of their lack of growth, develop short-trunk dwarfism (underdeveloped trunk). These young patients are often plagued by recurrent respiratory tract infections, including pneumonia, otitis media (middle ear infections), and bronchitis. Children with ML II generally die before their seventh year of life, often as a result of congestive heart failure or recurrent respiratory tract infections.

In contrast, symptoms of ML III are often not noticed until the child is 3-5 years of age. One of the milder forms of the MLs, ML III (sometimes referred to as pseudo-Hurler polydystrophy) also results from a deficiency or defect of the enzyme N-acetylglucosamine-1-phosphotransferase that is characteristic of ML II. However, ML III produces less severe symptoms and progresses more slowly, probably because the deficient enzyme retains some of its activity, resulting in a smaller accumulation of carbohydrates, lipids, and proteins in the inclusion bodies.

Patients with ML III are generally of normal intelligence or have only mild cognitive problems. These individuals usually have skeletal abnormalities, coarse facial features, short height, and corneal clouding. Some individuals with ML III survive until their fourth or fifth decade of life.

Mucolipidosis type IV (ML IV) is caused by harmful alterations of a protein in the cell that is believed to be involved in the movement of molecules such as calcium across cell membranes. Many cells throughout the body are filled with granules. Most patients with ML IV have delay of movement development and coordination, clouding of the cornea of the eye, and severely reduced vision. Typical patients usually have an unsteady gait and do not walk independently. ML IV patients have occasionally been misdiagnosed as having cerebral palsy. Speech is usually severely impaired. However, some patients with ML IV are more mildly affected and can walk and have better speech. Rare ML IV patients may even have only the eye abnormality with no associated brain problems. Such patients are not cognitively impaired, just visually impaired. ML IV patients have a dramatic reduction of secretion of acid by the stomach. This alteration results in an increase of a hormone called gastrin in the blood.

How are the mucolipidoses inherited?

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.

How are the mucolipidoses diagnosed?

The diagnosis of ML is based on clinical symptoms, a complete medical history, and certain laboratory tests. Diagnosis of ML I, II, and III can be confirmed by a blood test that measures enzyme activity in the patient's white blood cells. Activity levels that are lower than normal indicate specific enzyme deficiencies.

Another way to confirm the diagnosis is through skin biopsy. A small sample of skin is taken from the patient and grown in a cell culture. The activity of a particular enzyme in the cultured skin cells is then measured.

ML IV is suspected when cells that are easily obtained by conjunctival swabbing are found to have numerous inclusions. In addition, measurement of the level of gastrin in the blood, which is significantly increased in ML IV patients, helps to confirm the diagnosis.

Scientists have identified the genes responsible for all four types of MLs. In 2000, scientists at NINDS laboratories and other research institutions identified the gene responsible for ML IV. This gene, MCOLN1, makes the protein mucolipin-1. Due to mutations in the gene, mucolipin-1 is missing or dysfunctional in people with ML IV. This important genetic finding allows for the accurate diagnosis of patients as well as prenatal (before birth) diagnosis and the screening of carriers of the disease.

Prenatal diagnosis for ML is accomplished using a procedure known as chorionic villus sampling, or CVS. It is usually done around the 8th or 10th week of pregnancy and involves removing and testing a very small sample of the placenta. For ML types I, II, and III, placental cells called amniocytes are grown in culture and then tested to measure enzyme activity levels. For ML IV, no culture is required. DNA is obtained directly from the amniocytes and analyzed to find if mutations consistent with ML IV have occurred in the DNA. This technique is called genotyping.

Genetic testing for ML IV is available at specialized laboratories. Genetic counselors can help explain how the MLs are inherited and the effect of these diseases on patients and their families. Counselors can also help adults who might have a defective gene decide whether or not they wish to have children. Psychological counseling and support groups for people with genetic diseases may also help patients and their families cope with ML.

Are there any treatments?

No cure or specific therapies for ML currently exists. Therapies are generally geared toward treating symptoms and providing supportive care to the child. For individuals with corneal clouding, surgery to remove the thin layer over the eye has been shown to reduce the cloudiness in the eye. However, this improvement may be only temporary. Physical and occupational therapy may help children with motor delays. Children with language delays may benefit from speech therapy.

Care also should be taken to maintain the overall health of patients with ML. For example, children at risk for failure to thrive (growth failure) may need nutritional supplements, especially iron and vitamin B12 for patients with ML IV. Respiratory infections should be treated immediately and fully with antibiotics.

What research is being done?

The National Institute of Neurological Disorders and Stroke (NINDS), a component of the National Institutes of Health (NIH), is the federal agency with primary responsibility for conducting and funding research on disorders of the brain and nervous system, including the MLs.

Discovery of the ML genes is enabling NINDS researchers to study the genes' function and will facilitate studies on drugs that may lead to effective treatments. In addition, investigators at grantee institutions are conducting studies on an animal model, C aenorhabditis elegans, which is frequently used to determine the effects of genetic mutations. Other grantees are using the fruit fly model, Drosophila, to study a mutation in the ML IV gene. And one of the research teams involved in the discovery of the ML IV gene is conducting further genetic studies to explore the normal and abnormal functions of the ML IV gene.

Through these and other research efforts, scientists are optimistic that they will one day discover treatments or even prevention strategies for the MLs.

Where can I get more information?

For more information on neurological disorders or research programs funded by the National Institute of Neurological Disorders and Stroke, contact the Institute's Brain Resources and Information Network (BRAIN) at:

Information also is available from the following organizations:

Mucolipidosis IV (ML4) Foundation
3500 Piedmont Road, Suite 500
Atlanta, GA 30305
ML4www@aol.com
Tel: 877-ML4-5459 (654-5459)

National Tay-Sachs and Allied Diseases Association
2001 Beacon Street
Suite 204
Boston, MA 02135
info@ntsad.org
Tel: 800-90-NTSAD (906-8723)
Fax: 617-277-0134

Genetic Alliance
4301 Connecticut Avenue, N.W.
Suite 404
Washington, DC 20008-2369
info@geneticalliance.org
Tel: 202-966-5557; 800-336-GENE (4363)
Fax: 202-966-8553

"Mucolipidoses Fact Sheet", NINDS, Publication date September 2015.

NIH Publication No. 15-4899

Back to Mucolipidoses Information Page
See a list of all NINDS disorders Publicaciones en Español Mucolipidosis
Prepared by:
Office of Communications and Public Liaison
National Institute of Neurological Disorders and Stroke
National Institutes of Health
Bethesda, MD 20892

NINDS health-related material is provided for information purposes only and does not necessarily represent endorsement by or an official position of the National Institute of Neurological Disorders and Stroke or any other Federal agency. Advice on the treatment or care of an individual patient should be obtained through consultation with a physician who has examined that patient or is familiar with that patient's medical history.

All NINDS-prepared information is in the public domain and may be freely copied. Credit to the NINDS or the NIH is appreciated.

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What are the mucolipidoses? What causes the mucolipidoses? What are the different types of mucolipidoses? How are the mucolipidoses inherited? How are the mucolipidoses diagnosed? Are there any treatments? What research is being done? Where can I get more information?

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Mucolipidosis

The mucolipidoses are classified into four categories; mucolipidosis (ML) I is now included under the neuraminidase deficiency disorders. ML II and III have the same enzyme defect ( N-acetylglucosamine-1-phosphotransferase), the gene for which has been located to chromosome 16p. ML IV is caused by mutations in the MCOLN1 gene that encodes for mucolipin, a member of the transient receptor potential gene family, located on chromosome 19p.

Neuronal storage of lipid-like material in spinal ganglia has been reported from an autopsy of a patient with ML II, which is also known as I-cell disease. However, autopsies of four patients with ML II found no inclusions in DRG or parasympathetic neurons, but did find basophilic stored material in motor neurons that was seen to be identical to zebra bodies under the electron microscope. Neuronal storage of PAS- and Sudan black-positive material in the central and peripheral nervous systems has been reported in cases of ML IV.

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URL: https://www.sciencedirect.com/science/article/pii/B978072169491750034X

Mucolipidosis III

Mucolipidosis III (pseudo-Hurler polydystrophy) is a milder form of mucolipidosis II with a late clinical onset, between 2 and 4 years. The enzyme deficiency in mucolipidosis III is a phosphotransferase similar to the one in I-cell disease. Patients with this disease may live to adulthood, and some may not be retarded. Linear growth is severely affected, and they may experience joint stiffness, claw hand deformities, and aortic regurgitation. Coarseness of the face is minimal. Corneal clouding may be associated in some of the patients. Radiologic examination of the skeletal system shows moderate dysostosis multiplex. The biosynthetic pathway of mannose-6-phosphate, which is essential for lysosomal enzymes, showed that the defect in I-cell disease and mucolipidosis III is identical with the exception that in mucolipidosis III there is more residual activity of this enzyme. In general, there is a spectrum of deficiency level of this enzyme activity. In addition to this primary defect, fibroblasts from patients with mucolipidosis III similar to fibroblasts from I-cell disease show deficiency of a large number of lysosomal enzymes, whereas the culture media contain higher activity of these enzymes. Diagnosis can be made by increased activity of lysosomal enzymes in plasma or urine as well as by the direct assay of the N-acetylphosphotransferase.

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URL: https://www.sciencedirect.com/science/article/pii/B9780124105294000322

Mucolipidoses

ML II (I-cell disease) and ML III (pseudo-Hurler polydystrophy) represent two ends of the same clinical spectrum caused by mutations in the gene encoding for the enzyme UDP-N-acetylglucosamine: lysosomal hydrolase N-acetylglucosamine-1-phosphotransferase (GlcNAc-PT) (Cathey et al., 2009). This enzyme is responsible for catalyzing the initial step in the synthesis of the mannose-6-phosphate (M6P) recognition marker that targets newly produced enzymes to the lysosomes. In ML II and III absence of GlcNac-PT results in the release of enzymes into the intercellular space and body fluids where they are unable to carry out their normal catabolic functions. GlcNac-PT is a hexameric protein (α2β2γ2) and the α and β subunits are encoded by the GNPTAB gene on chromosome 12q23.3, while the γ subunit is encoded by the GNPTG gene on chromosome 16p13.3. Mutations in GNPTAB can result in both ML II and ML III phenotypes whereas mutations in GNPTG are only associated with an ML III phenotype (Cathey et al., 2008).

Patients with ML II present in the newborn period with Hurler-like facies and often have a severe bone dysplasia characterized by changes similar to those seen in hyperparathyroidism (Sathasivam et al., 2006). Intrauterine and/or neonatal fractures can be present (Yuksel et al., 2007). The clinical course is dominated by feeding and breathing difficulties and a small subpopulation of patients have severe cardiomyopathy. In those patients surviving the newborn period, the progressive disorder results in severe learning difficulties, microcephaly, coarse facies, hernias, and a severe skeletal dysplasia. Although some patients survive into the teenage years, the majority die from cardiac or respiratory disease in the first decade of life.

ML III is an attenuated form of ML II and is very heterogeneous. Most patients have mild learning impairment, short stature, cardiac valve lesions, and skeletal disease primarily affecting the ball and socket joints of the hips and shoulders as well as the spine (Robinson et al., 2002). Prolonged survival is usual.

Many patients present with clinical phenotypes between the classically described ML II and ML III phenotypes described here.

ML I is caused by a deficiency of the lysosomal hydrolase neuraminidase (NEU1, sialidase) and is characterized by two major clinical phenotypes. Type I is also known as the "cherry-red spot myoclonus syndrome," a chronic disorder presenting with myoclonus and ataxia associated with a macular cherry-red spot. Dementia occurs very late, if at all, in this variant and prolonged survival is usual. There is often mild dysostosis multiplex. Type II presents before birth (as hydrops fetalis) or soon after birth with dysmorphic, Hurler-like facies, hepatomegaly, skeletal dysplasia, and severe learning difficulties. These infants, if they survive the newborn period, usually die in very early childhood (Seyrantepe et al., 2003).

ML IV is caused by mutations in the TRPML1 (also known as mucolipin 1 or MCOLN1) gene, which encodes a protein belonging to the subfamily of transient receptor potential (TRP) proteins (Dong et al., 2008). Although panethnic, the disorder is common in those of Ashkenazi descent and affected patients have motor impairment, severe mental retardation, retinal degeneration, corneal clouding, iron deficiency anemia, and achlorhydria with elevated blood gastrin levels. The biochemical defect is associated with a defect in autophagy but prolonged survival is usual (Venugopal et al., 2009).

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2.5.1 Mucolipidosis Type II and III

Mucolipidosis type II (I-Cell disease) (OMIM# 252500) and Mucolipidosis type III (pseudo-Hurler polydystrophy) (OMIM#252600) are autosomal lysosome storage disorders caused due to N-acetylglucosamine-1-phosphotransferase subunits alpha/beta deficiency (Gene Symbol: GNPTAB; UniProt ID: Q3T906; Chromosomal Location: 12q23.2) resulting in the accumulation of large molecules within lysosomes. It is a rare condition seen at a frequency of 1 in 1,00,000-4,00,000 individuals. Congenital dislocation of the hip, thoracic deformities, hernia, and hyperplastic gums are evident for this disorder.

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URL: https://www.sciencedirect.com/science/article/pii/S1876162315000723

103.1.4.1 Clinically Delineated Syndromes

103.1.4.1.1 ML II or I-Cell Disease

ML II is a slowly progressive disorder with clinical onset at birth and fatal outcome in childhood. It may be suspected prenatally when ultrasonographic examination in the last trimester of pregnancy finds punctate extraosseous calcifications around the ankles, wrists, spine, or pelvis in a small-for-date fetus. The neonate with I-Cell disease has on average a low birth weight, a plump and somewhat edematous, flat facies, and a skin that is thick and stiff in particular about the earlobes. Congenital inguinal herniae are consistently present in males. One or more orthopedic abnormalities are common: clubfoot, dislocation of the hip(s), thoracic deformity, with or without kyphosis. Despite generalized hypotonia, the range of motion in the shoulders is limited. In the more severely affected neonates, crying is weak, respiration may temporarily need support, and alertness is below normal. Head size is proportional to stature. Growth failure is always severe and the final height of 80 cm is rarely exceeded. Unlike in the patient with Hurler disease (MPS IH: MIM # 607014), there is no temporary acceleration of statural growth around the age of 1 year. Instead, growth decelerates within 6 months from birth and ceases often before 15 months of age. Stiffening of all joints, large and small, occurs from the first year of life. Neurodevelopmental delay is severe in some, but more moderate in others. Only few patients come to unaided ambulation. Social interaction is better than the patient's hoarse speech that rarely reaches the stage of two-word sentences. Upper respiratory infection and otitis recur frequently. Hearing deficit that worsens over time is often evident. Breathing is noisy from the start and remains so even in the absence of bronchitis or lung infection. Because of the narrow airway, the gradually decreasing mobility of the neck compounded by hypertrophic gums, both intubation and detubation are difficult assignments for the anesthesiologist. The face of the ML II patients is reminiscent from that in MPS IH, but shows consistent differences including small orbits, hypoplastic supraorbital ridges, mildly proptotic eyes, a tortuous pattern of periorbital veins, telangiectatic capillaries over midface and cheeks, impressive gingival hyperplasia precluding adequate eruption of deciduous teeth, and a prominent mouth (Figure 103-2). The corneae are often considered clear clinically, but slit-lamp examination consistently shows haziness. Facial features are gradually coarsening in the longer-surviving patients and wrists, hands, and fingers broaden, become more immobile, and adopt a clawlike configuration in radial deviation. Cardiac murmurs increase gradually with slowly worsening insufficiency of several cardiac valves. The abdomen is protuberant and an umbilical hernia often noticed. Hepatosplenomegaly is moderate or equivocal. Bronchopneumonia and congestive heart failure are the usual causes of fatal outcome, usually before the age of 5 years. See original reference in Reference (( 1) and/or in other extensive reviews 37, 38).

Affected siblings are clinically more similar than patients in different families.

Qualitatively, the radiological abnormalities in ML II are indistinguishable from the ones in MPS IH (OMIM #) and in G(((((( M1-type I GS (OMIM # 230500). ML II shares with the latter the most severe form of "Dysostosis multiplex," the osteochondrodysplasia (OCD) common to most oligo- and mucopolysaccharidoses and expertly described by Spranger et al. 39). At this stage, attention is due to some transient radiographic and related phenomena observed in or from the perinatal stage of ML II that include: (1) punctate or dot-like extra-osseous calcifications mainly in hands and feet, but also over the pelvic region and about the spinal column. These puncta, when detectable by prenatal ultrasonography, were initially considered to be the more typical feature in "Pacman" dysplasia 40, 41), an OCD that was thought of as sharing features with ML II, but with perinatal fatal outcome. Meanwhile proof has been provided that most instances of Pacman type OCD represent the prenatal expression of I-Cell disease (ML II) 41, 39); (3) Severe diaphyseal widening in the small tubular hand bones concomitantly rendering the metaphyseal ends very narrow, a process that may last until early childhood 43); (4) Perinatal hyperparathyroidism supported by relevant biochemical findings in plasma 42, 44). It is unknown at present whether hyperparathyroidism represents the true cause of the transient bony abnormalities or the consequence of an as-yet unknown effect of the mutant genotype set in motion at or before birth. Also, the transient nature of the described set of phenomena awaits pathogenetic explanation. 42); (2) Excessive periosteal new bone formation alongside the diaphyses of the large tubular bones, a phenomenon also called "periosteal cloaking," the term used to describe the double outline of the bone cortex in the large tubular bones. The phenomenon is no longer visible from the age of 18 months when the calcified outline seems to coalesce with the diaphyseal cortex

In patients with ML II, the urinary excretion of SOSs is excessive and that of glycosaminoglycans (GAGs) is normal. This finding is nonspecific as it is hardly distinguishable from the results in urine from patients with sialidosis (Section 103.1.1) or galactosialidosis (Section 103.1.3), when studied by routine laboratory methodology. More advanced technology, not commonly available, is able to improve chemical differentiation ( 6, 45, 46). At present, the latter methodology has interesting potential in more effective newborn screening, but has become of secondary importance in the field of diagnosis since the introduction of mutation screening.

103.1.4.1.2 ML IIIα/β; Pseudo-Hurler Polydystrophy

Delineated and named Pseudo-Hurler polydystrophy (PHP) by Maroteaux in 1966, it was called ML III by Spranger and Wiedemann in 1970 before its alignment with ML II was proved. Since the elucidation of the enzyme defect and of its oligomeric structure, it has been shown that two nonallelic types of PHP exist. The nomenclature has been adapted accordingly ( 47). In addition to ML IIIα/β at hand, there is ML IIIγ, the subject of the next paragraph.

Complaints of physical slowness, worsening stiffness in one or more of the large joints, and sometimes slow growth around the average age of 3 years mark the clinical onset. Slow cognitive development is rarely among the initial parental concerns. ML IIIα/β patients retain family facial characteristics, but the facies is rather flat and coarsens gradually throughout the long and slowly progressive clinical course. Motion range, particularly in shoulders and hips, is reduced from the early stages of the disorder. The slowly progressive flexion contractures in hips and knees are evident early in the standing patient viewed from the side. Raising the arms above the head is difficult and soon impossible. Birth weight and length are normal in ML III, but below average and gradually decreasing statural growth rate is evident in childhood. The head circumference remains proportional to stature (Figure 103-3). The corneae are clear by clinical inspection, but show opacities on slit-lamp examination. Liver and spleen are not usually enlarged. Intellectual deficiency is mild and nonprogressive or absent. Speech and language development are normal. In the patient with later clinical onset of the disorder, the diagnosis may be postponed because of earlier referral to and follow-up in the rheumatology clinic. The early radiographs may show only mild dysostosis multiplex and are sometimes read as normal. However, skeletal age is found to be considerably delayed and moderate osteopenia already noticed. Contrary to the severe OCD in the hands of ML II patients, the hand bones themselves remain normal or near normal, but the progressive hardening of the soft connective tissue around the small joints results in worsening flexion contractures in the fingers. Already from preadolescence, ML IIIα/β patients consistently have moderate but often severe and very painful hip disease. It is an almost consistent reason why the patients cease walking on average from the early teens. Unfortunately, the pain is not effectively dealt with even in the more immobile wheelchair-bound patient, because it results not only from the destructive hip dysplasia, but also from worsening osteopenia throughout the skeleton. In the older patients, the deficient function of some of the heart valves apparently due to connective tissue hardening, becomes of increasing concern. Throughout the clinical course, respiratory infections are not significantly more frequent than in the patients' peers, unlike their morbid role in ML II. ML III patients surviving beyond the fifth decade of life have been reported, but comprehensive data on life expectancy and on specific causes of fatal outcome remain unavailable.

The distinct dividing line between ML II and ML IIIα/β has been documented in a recent large genotype-phenotype correlation study supported by the results of mutation screening ( 43). Significant clinical differences include growth rate and final statural height, hand abnormality, qualitative differences of dysostosis multiplex, neuromotor and speech and language development, intellectual functioning, rate of clinical progression, and life expectancy. The rather rare phenotypically intermediate patients have specific mutant genotypes. See subsequent paragraphs on molecular genetics.

103.1.4.1.3 ML IIIγ (PHP)

Because the first report on the molecular basis of an ML IIIγ has preceded any comparable result on either ML II or ML IIIα/β (( 48), the clinical phenotype of this disorder deserves separate attention. From the few reports with useful clinical information already available, the ML IIIγ phenotype is probably not distinguishable from ML IIIα/β, but as the latter quite distinct from ML II. The age of onset, natural course, and the major sites of morbidity as well as life expectancy appear to be rather congruent to what has been recorded for ML IIIα/β. Remarkably, the majority of observations reported so far concerns families in various parts of the Middle East. Parental consanguinity is noticed in most of these families. Nevertheless, the intrafamilial clinical variability among them may be larger than in ML IIIα/β. Slowly, progressive stiffening of the shoulder joints, of the hands with claw-type deformity, slow growth, and short stature are among the first parental concerns. Intellectual disability is mild or more often absent. Radiographic evidence of mild dysostosis multiplex is initially often overlooked unless osteochondrodystrophy of the hip joints is already present. Some young patients have been observed with "isolated" hip involvement. From adolescence or even earlier, painful hip joints at walking and pain in the lower limbs also when immobile, become the patients' major handicap. Facial coarsening is late and possibly milder than in ML IIIα/β. Thickening of some cardiac valves slowly leading to dysfunction is often recorded and probably consistent in the older patient 48- 51).

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9.4.2 Sialidosis or Mucolipidoses I (ML I)

Mucolipidoses (ML I) is a severe condition caused a deficiency of lysosomal α-neuraminidase due to mutations of the NEU1 gene. Neuraminidase catalyzes sialic acid removal from sialylated glycoproteins and oligosaccharides. Deficiency of neuraminidase results in lysosomal storage of sialylated glycopeptides and sialo-oligosaccharides and their urinary excretion. Recently, neuraminidase has been found to play important role in desialylation of LAMP1 (lysosomal associated membrane protein). In turn, abnormally desialylated LAMP1 leads to increased lysosomal enzyme exocytosis and relevant clinical symptoms.

The variability of patients encompasses two ends of a clinical spectrum. Type I, the milder form, presents later in life with macular cherry red spots, seizures, and generalized myoclonus. Prolonged survival is common with preserved cognitive function and fewer somatic changes. Type II is the more severe disease form, which presents prenatally with hydrops fetalis or soon after birth with dysmorphic facial features, hepatosplenomegaly, skeletal dysplasia, and many other clinical features similar to Hurler syndrome. Clinical outcome is poor and patients with type II ML I usually die in very early childhood.

Abnormal urinary oligosaccharides and sialic acid (bound form) and deficiency of neuraminidase activity in leukocytes or fibroblasts are diagnostic for ML I. The disorder can be further confirmed with identification of disease causing mutations of the NEU1 gene.

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Mucolipidoses

The five described mucolipidoses (ML) result from abnormal lysosomal enzyme phosphorylation. ML I, also known as sialidosis, presents with two subtypes: type 1 with macular cherry-red spots, seizures, and myoclonus; type 2 as short stature and mild developmental delay. ML II (I-cell disease) presents in infancy with neurodevelopmental regression accompanied by marked dysmorphism and dysostosis multiplex. ML III (pseudo-Hurler) is less severe with a later presentation. ML IV shows visual disturbance including corneal opacities. ML V predominantly affects skeletal and cardiac muscles. Also known as type II glycogenosis or Pompe disease, it results from defective acid maltase (α-glucosidase) activity.

All ML patients show vacuolated lymphocytes with inclusions but there are no glycosaminoglycans in urine. Skeletal survey is often informative with characteristic boney changes. White cell enzymes are abnormal but the diagnosis should be confirmed by assay of enzyme activity on cultured fibroblasts.

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Mucolipidosis IV (ML-IV)

Mucolipidosis IV is a neurodegenerative lysosomal storage disorder resulting from mutations in the MCOLN1 gene that codes for the membrane protein mucolipin-1, a Ca 2 +-permeable cation channel that is involved in the interactions between endosomes and lysosomes. ML-IV affects mostly Ashkenazi Jews. More than 15 mutations of MCOLN1, on chromosome 19p13.2-13.3, have been reported. These mutations result in lysosomal storage of gangliosides, phospholipids, neutral lipids, and mucopolysaccharides. The clinical manifestation includes psychomotor retardation, visual disturbance, and corneal opacity. Kyphosis, kyphoscoliosis, microcephaly, pectus carinatum, mild facial dysplasia, and delayed bone maturation have been reported. Vacuolization of numerous cell types has been reported. Bone marrow macrophages are enlarged and vacuolated, stain intensely with Sudan black and weakly with PAS, and show weak metachromasia with toluidine blue stain. Autopsy findings on a 23-year-old male included coarse facial features, severe kyphoscoliosis with deformed thoracic cage, and bilateral short fourth metatarsal bones. There was no organomegaly. The patient's 30-year-old brother had similar but less severe skeletal anomalies. Vacuolated chondrocytes, which stained with LFB, were noted along with osteopenia. ConA and RCA-I ( Figure 18) staining, indicating storage of N-linked oligosaccharides with terminal α-mannosyl and β-galactosyl residues, respectively, was noted. Ultrastructural examination of the rib cartilage revealed chondrocytes that contain osmophilic granular material and a few lamellated membrane structures.

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Mucolipidoses

The mucolipidoses are a group of diseases with features overlapping those of the mucopolysaccharidoses and sphingolipidoses. Mucolipidoses are lysosomal storage diseases with evidence of multiple primary defects of mucopolysaccharide, lipid and glycoprotein metabolism in various combinations. 1140,1161-1163

Mucolipidosis I (sialidosis)

Mucolipidosis I is a rare syndrome caused by a deficiency in lysosomal sialidase (neuraminidase) resulting in defective intralysosomal catabolism of sialylated glycoconjugates and sialic acid transport out of the lysosomes. Mutations in the sialidase gene NEU1, located on chromosome 6p21.3, result in the progressive lysosomal storage of sialylated glycopeptides and oligosaccharides.

Two major forms are recognized. Sialidosis type I (Salla disease) is a milder, late-onset, nondysmorphic form of the disorder; patients develop visual defects, myoclonus syndrome, cherry-red macular spots, ataxia, hyperreflexia and seizures. Type II, the severe infantile form, is characterized by gargoyle-like facial dysmorphism, and dysostosis is apparent by 4 or 5 years of age. Peripheral neuropathy develops, with muscular weakness and difficulties in coordination. Findings include corneal opacities, impaired hearing and hepatosplenomegaly. Vacuolated lymphocytes are found in all cases. An increased amount of bound sialic acid is excreted in the urine, a finding that can be used as a simple screening test.

Definitive diagnosis is established by demonstration of a deficiency of sialidase in peripheral leukocytes or cultured fibroblasts of both type I and type II patients. Some patients with similar features appear deficient in both sialidase and β-galactosidase, a disease termed galactosialidosis (gene map locus 20q13). Sialidase can also be measured in cells from amniotic fluid, but special fresh preparations are necessary. A mouse model of sialidosis is currently used to evaluate enzyme replacement therapy.

Light microscopy of the liver reveals marked enlargement of portal macrophages and Kupffer cells, both of which have a foamy cytoplasm. Ultrastructurally, hepatocytes contain membrane-bound vacuoles that are electron-lucent. The vacuoles frequently contain numerous osmiophilic droplets as well as a reticulogranular or flocculent material. Riches and Smuckler also described multilamellar bodies and fragments of membrane-like material in the vacuoles. Similar vacuoles are found in Kupffer cells and to a lesser extent in endothelial cells, stellate cells and biliary epithelial cells.

Mucolipidosis II (I-cell disease) and mucolipidosis III (pseudo-Hurler polydystrophy)

Mucolipidosis II and III (MLII and MLIII) are biochemically related diseases with different clinical manifestations. These disorders of lysosomal enzyme targeting are caused by a defective N-acetylglucosamine 1-phosphotransferase (termed phosphotransferase) activity in Golgi compartments of the cells and lead to the impaired formation of mannose 6-phosphate recognition markers in soluble lysosomal enzymes, followed by their defective transport to lysosomes and increased excretion into the serum. The diseases are autosomal recessive and linked to chromosome 4q21-23.

MLII presents in the first year of life, with severe psychomotor retardation, early growth retardation, facial dysmorphism with characteristic gingival hyperplasia, equivocal or absent corneal clouding, hepatomegaly, skeletal dysplasia and severe dysostosis multiplex, which may resemble Pacman dysplasia. MLIII has similar symptoms, but these are milder and present later in life. Patients may survive into adulthood with the milder form of the disease.

Fibroblasts cultured from patients with MLII contain numerous dense inclusions (thus the term 'I cell') which are best seen on phase-contrast microscopy. Vacuolated lymphocytes of B-cell lineage in lymph nodes, spleen and kidney have been found to contain large amounts of hexosamine. Cytoplasmic vacuoles were also noted in Kupffer cells, fibroblasts in the myocardium, renal podocytes and acinar cells of the pancreas. The vacuolated cells stain positively with Hale colloidal iron method.

Diagnosis is made by measurement of the activity of the phosphotransferase in patient's fibroblasts or by demonstration of elevated levels of serum lysosomal enzymes (as a result of hypersecretion rather than targeting into the lysosomes). Prenatal diagnosis is possible by measurement of lysosomal enzymes or phosphotransferase activity on cultured amnion cells. There is no definitive treatment, although BMT in one MLII patient has been followed by neurodevelopmental gains and prevention of cardiopulmonary complications.

Light microscopy may show no changes in hepatocytes, but there is enlargement of Kupffer cells and portal macrophages that have a foamy cytoplasm, and granulomas composed of finely vacuolated epithelioid cells may be seen in portal areas. The vacuoles are limited by single membranes and contain fibrillogranular material, membranous lamellae or lipid globules. Hepatocytes are generally only slightly affected but may contain different types of dense polymorphic inclusions. 1128,1174,1180 Vacuoles in hepatocytes correspond to triglyceride droplets and membranous inclusions, as well as enlarged lysosomes containing granular material on EM. Kupffer cells contain electron-dense membranous lamellae.

Vacuolated cells (leukocytes and, in MLIII, bone marrow cells) similar to those of mucolipidosis I are present. Cultured fibroblasts show inclusions resembling those of the I cells of MLII. Ultrastructural findings in the liver include slightly enlarged secondary lysosomes without storage of any abnormal material, while Kupffer cells are relatively rich in unstructured osmiophilic material.

Mucolipidosis IV (sialolipidosis)

The rare disease of sialolipidosis is postulated to result from a defect in intracellular packaging or transport of lysosomal enzymes. Chromosome assignment is to 19p13.2-13.3. Most often seen among Ashkenazi Jews, mucolipidosis IV is characterized by an early onset of corneal opacification and psychomotor retardation; a small head circumference is common. Gargoyle-like facies, skeletal deformities and organomegaly are absent.

Diagnosis is made by demonstration of characteristic inclusions in epithelial cells and conjunctival biopsies. Biochemically, mucolipidosis IV is characterized by the accumulation of gangliosides, phospholipids and acidic mucopolysaccharides in skin fibroblasts. The heterogeneity of the stored material accounts for cell vacuoles being variably stained with PAS, Sudan Black and Luxol fast blue. Prenatal diagnosis of mucolipidosis IV is performed by TEM to demonstrate lamellar bodies in endothelial cells of chorionic villi.

Ultrastructural studies of conjunctival biopsies from four patients have shown two types of abnormal inclusion bodies, both in stromal fibroblasts and in epithelial cells: (1) single-membrane-limited cytoplasmic vacuoles containing both fibrillogranular material and membranous lamellae and (2) lamellar and concentric bodies similar to those found in Tay-Sachs disease. In liver biopsy material, Berman et al. have shown that hepatocytes contain inclusions composed predominantly of concentric lamellae, whereas vacuoles in Kupffer cells have clear contents. The prenatal diagnosis of mucolipidosis IV was reported by Kohn et al. A partial ganglioside sialidase deficiency has been found in cultured fibroblasts, but it is doubtful that this is the primary enzyme defect.

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Mucolipidosis Type III (Pseudo-Hurler Polydystrophy)

Mucolipidosis type III is less severe, and also less common, than type II, and is due to a deficiency of the same phosphotransferase enzyme. In type III, the enzymic activity is less severely reduced, and the manifestations are less severe. There is a fair amount of variability in clinical severity. ⁵⁹ This is likely due to various genetic defects leading to different levels of enzymic activity. Patients are usually spared the joint manifestations of I-cell disease early in life, and often present with joint stiffness at the age of 4 or 5 years. Growth is moderately retarded, and corneal clouding is present by the age of 7 or 8 years. The patients are disabled by carpal tunnel syndrome and destruction of the hip joints. Cardiac involvement, particularly aortic regurgitation, does occur but is usually not sufficiently severe to cause clinical problems. Patients with pseudo-Hurler polydystrophy survive into the fourth decade.

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The mucolipidoses are classified into four categories; mucolipidosis (ML) I is now included under the neuraminidase deficiency disorders. ML II and III have the same enzyme defect ( N-acetylglucosamine-1-phosphotransferase), the gene for which has been located to chromosome 16p.