I-cell Disease

Overview

Definition

I-cell disease is a rare lysosomal storage disorder that presents in early childhood with severe skeletal abnormalities and failure to thrive Failure to Thrive Failure to thrive (FTT), or faltering growth, describes suboptimal weight gain and growth in children. The majority of cases are due to inadequate caloric intake; however, genetic, infectious, and oncological etiologies are also common. Failure to Thrive. A mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in the GNPTA gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics causes a deficiency in the enzyme uridine diphosphate Uridine diphosphate A uracil nucleotide containing a pyrophosphate group esterified to C5 of the sugar moiety. Purine and Pyrimidine Metabolism (UDP)-N-acetylglucosamine-1-phosphotransferase.

Epidemiology

• Autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritance
• Prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency: approximately 1 in 100,000–400,000 live births
• Male = female
• Disease most common in Japan

Etiology

• Mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations of GNPTA gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics: located on long arm Arm The arm, or “upper arm” in common usage, is the region of the upper limb that extends from the shoulder to the elbow joint and connects inferiorly to the forearm through the cubital fossa. It is divided into 2 fascial compartments (anterior and posterior). Arm: Anatomy of chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics 4 (4q21-q23)
• Phosphodiesterase deficiency: rare

Pathophysiology

• GNPTA mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations causes UDP-N-acetylglucosamine-1-phosphotransferase deficiency.
• Causes lysosomal targeting disfunction → lysosomal enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes are erroneously transported to extracellular matrix Extracellular matrix A meshwork-like substance found within the extracellular space and in association with the basement membrane of the cell surface. It promotes cellular proliferation and provides a supporting structure to which cells or cell lysates in culture dishes adhere. Hypertrophic and Keloid Scars 
• These enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes do not function outside of acidic lysosomes Lysosomes A class of morphologically heterogeneous cytoplasmic particles in animal and plant tissues characterized by their content of hydrolytic enzymes and the structure-linked latency of these enzymes. The intracellular functions of lysosomes depend on their lytic potential. The single unit membrane of the lysosome acts as a barrier between the enzymes enclosed in the lysosome and the external substrate. The activity of the enzymes contained in lysosomes is limited or nil unless the vesicle in which they are enclosed is ruptured or undergoes membrane fusion. The Cell: Organelles.
• Lysosomes Lysosomes A class of morphologically heterogeneous cytoplasmic particles in animal and plant tissues characterized by their content of hydrolytic enzymes and the structure-linked latency of these enzymes. The intracellular functions of lysosomes depend on their lytic potential. The single unit membrane of the lysosome acts as a barrier between the enzymes enclosed in the lysosome and the external substrate. The activity of the enzymes contained in lysosomes is limited or nil unless the vesicle in which they are enclosed is ruptured or undergoes membrane fusion. The Cell: Organelles lack requisite enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes for metabolism of absorbed cellular debris → debris accumulates within the cell, forming inclusion bodies:
  • Fatty substances: mucolipids
  • Complex carbohydrates Carbohydrates A class of organic compounds composed of carbon, hydrogen, and oxygen in a ratio of cn(H2O)n. The largest class of organic compounds, including starch; glycogen; cellulose; polysaccharides; and simple monosaccharides. Basics of Carbohydrates: mucopolysaccharides Mucopolysaccharides Heteropolysaccharides which contain an n-acetylated hexosamine in a characteristic repeating disaccharide unit. The repeating structure of each disaccharide involves alternate 1, 4- and 1, 3-linkages consisting of either n-acetylglucosamine or n-acetylgalactosamine. Basics of Carbohydrates
• Symptoms result from accumulation of mucolipids and mucopolysaccharides Mucopolysaccharides Heteropolysaccharides which contain an n-acetylated hexosamine in a characteristic repeating disaccharide unit. The repeating structure of each disaccharide involves alternate 1, 4- and 1, 3-linkages consisting of either n-acetylglucosamine or n-acetylgalactosamine. Basics of Carbohydrates.

Clinical Presentation

Clinical features evident by 6 months of age:

• Coarse facial features (often present at birth)
• Craniofacial abnormalities (often present at birth)
• Restricted joint movement
• Hypotonia Hypotonia Duchenne Muscular Dystrophy

Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship present in 1st year of life with:

• Severe psychomotor retardation
• Congenital Congenital Chorioretinitis hip dislocation 
• Inguinal hernias Inguinal Hernias An abdominal hernia with an external bulge in the groin region. It can be classified by the location of herniation. Indirect inguinal hernias occur through the internal inguinal ring. Direct inguinal hernias occur through defects in the abdominal wall (transversalis fascia) in Hesselbach’s triangle. The former type is commonly seen in children and young adults; the latter in adults. Inguinal Canal: Anatomy and Hernias
• Gingival hypertrophy Hypertrophy General increase in bulk of a part or organ due to cell enlargement and accumulation of fluids and secretions, not due to tumor formation, nor to an increase in the number of cells (hyperplasia). Cellular Adaptation
• Skeletal manifestations ( kyphoscoliosis Kyphoscoliosis Osteomalacia and Rickets, lumbar gibbus)
• Hepatomegaly
• Splenomegaly Splenomegaly Splenomegaly is pathologic enlargement of the spleen that is attributable to numerous causes, including infections, hemoglobinopathies, infiltrative processes, and outflow obstruction of the portal vein. Splenomegaly

Progressive, severe psychomotor impairment leads to death in early childhood.

Diagnosis

Prenatal diagnosis:

• Amniocentesis Amniocentesis Percutaneous transabdominal puncture of the uterus during pregnancy to obtain amniotic fluid. It is commonly used for fetal karyotype determination in order to diagnose abnormal fetal conditions. Polyhydramnios or chorionic villus sampling
• Low levels of UDP-N-acetylglucosamine-1-phosphotransferase enzyme activity is diagnostic.

Diagnostic tests Diagnostic tests Diagnostic tests are important aspects in making a diagnosis. Some of the most important epidemiological values of diagnostic tests include sensitivity and specificity, false positives and false negatives, positive and negative predictive values, likelihood ratios, and pre-test and post-test probabilities. Epidemiological Values of Diagnostic Tests performed after delivery:

• Elevated plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products lysosomal enzyme concentration and low level of lysosomal enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes in cultured fibroblasts Fibroblasts Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. Sarcoidosis
• Inclusion bodies visible in peripheral blood lymphocytes Lymphocytes Lymphocytes are heterogeneous WBCs involved in immune response. Lymphocytes develop from the bone marrow, starting from hematopoietic stem cells (HSCs) and progressing to common lymphoid progenitors (CLPs). B and T lymphocytes and natural killer (NK) cells arise from the lineage. Lymphocytes: Histology
• Low levels of UDP-N-acetylglucosamine-1-phosphotransferase enzyme activity

Management

No curative treatment is available for I-cell disease. Management is symptomatic and supportive:

• Nutritional supplements are recommended: iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements and vitamin B₁₂
• Physical therapy Physical Therapy Becker Muscular Dystrophy to slow degeneration of motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology function
• Speech therapy Speech Therapy Treatment for individuals with speech defects and disorders that involves counseling and use of various exercises and AIDS to help the development of new speech habits. Myotonic Dystrophies
• Hip replacement and other orthopedic surgeries may be recommended to maintain mobility. 
• Hearing aids AIDS Chronic HIV infection and depletion of CD4 cells eventually results in acquired immunodeficiency syndrome (AIDS), which can be diagnosed by the presence of certain opportunistic diseases called AIDS-defining conditions. These conditions include a wide spectrum of bacterial, viral, fungal, and parasitic infections as well as several malignancies and generalized conditions. HIV Infection and AIDS

Bone marrow transplantation Bone marrow transplantation Transfer of hematopoietic stem cells from bone marrow or blood between individuals within the same species (homologous transplantation) or transfer within the same individual (autologous transplantation). Hematopoietic stem cell transplantation has been used as an alternative to bone marrow transplantation in the treatment of a variety of neoplasms. Organ Transplantation may be helpful as a remedy for neurologic degeneration (currently under investigation).

Genetic counseling Genetic Counseling An educational process that provides information and advice to individuals or families about a genetic condition that may affect them. The purpose is to help individuals make informed decisions about marriage, reproduction, and other health management issues based on information about the genetic disease, the available diagnostic tests, and management programs. Psychosocial support is usually offered. Myotonic Dystrophies should be offered to families considering having additional children.

Differential Diagnosis

• Hurler syndrome Hurler syndrome Mucopolysaccharidoses (mucopolysaccharidosis type I): rare lysosomal storage disease Lysosomal storage disease Lysosomal storage diseases are a group of metabolic disorders caused by genetic mutations in the enzymes responsible for normal lysosomal function. The dysfunction of enzymatic processes causes an accumulation of undigested metabolites, resulting in cellular death. The main groups include sphingolipidoses, oligosaccharidoses, and mucolipidoses. Overview of Lysosomal Storage Diseases caused by deficiency in enzyme alpha-L-iduronidase, which causes accumulation of mucopolysaccharides Mucopolysaccharides Heteropolysaccharides which contain an n-acetylated hexosamine in a characteristic repeating disaccharide unit. The repeating structure of each disaccharide involves alternate 1, 4- and 1, 3-linkages consisting of either n-acetylglucosamine or n-acetylgalactosamine. Basics of Carbohydrates in various body tissues. Infants appear normal at birth, but they develop symptoms within the 1st year of life. These symptoms include skeletal abnormalities, abdominal and inguinal hernias Inguinal Hernias An abdominal hernia with an external bulge in the groin region. It can be classified by the location of herniation. Indirect inguinal hernias occur through the internal inguinal ring. Direct inguinal hernias occur through defects in the abdominal wall (transversalis fascia) in Hesselbach’s triangle. The former type is commonly seen in children and young adults; the latter in adults. Inguinal Canal: Anatomy and Hernias, coarse facial features, severe intellectual disability Disability Determination of the degree of a physical, mental, or emotional handicap. The diagnosis is applied to legal qualification for benefits and income under disability insurance and to eligibility for social security and workman’s compensation benefits. ABCDE Assessment, and loss of developmental milestones Developmental milestones Developmental milestones are the skills or abilities that most children are able to perform when they reach a certain age. Understanding the appropriate milestones and at what age they are reached helps clinicians identify symptoms of delayed development. Developmental milestones are divided into 5 important domains: gross motor, fine motor, language, social, and cognitive. Developmental Milestones and Normal Growth. As the patient ages, further symptoms become evident, including joint contractures Contractures Prolonged shortening of the muscle or other soft tissue around a joint, preventing movement of the joint. Wound Healing, vision Vision Ophthalmic Exam/hearing deficits, and cardiac dysfunction. The condition is fatal; 5 years is the average age at death. 
• Sialidosis Sialidosis Overview of Lysosomal Storage Diseases (mucolipidosis I): very rare autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritance lysosomal storage disease Lysosomal storage disease Lysosomal storage diseases are a group of metabolic disorders caused by genetic mutations in the enzymes responsible for normal lysosomal function. The dysfunction of enzymatic processes causes an accumulation of undigested metabolites, resulting in cellular death. The main groups include sphingolipidoses, oligosaccharidoses, and mucolipidoses. Overview of Lysosomal Storage Diseases caused by deficiency in enzyme alpha-neuraminidase leading to pathologic accumulation of oligosaccharides Oligosaccharides Carbohydrates consisting of between two (disaccharides) and ten monosaccharides connected by either an alpha- or beta-glycosidic link. They are found throughout nature in both the free and bound form. Basics of Carbohydrates. There are 2 forms of sialidosis Sialidosis Overview of Lysosomal Storage Diseases. Type 1 Type 1 Spinal Muscular Atrophy presents later in life with involuntary muscle contractions and cherry-red macules in the retina Retina The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outermost layer is pigmented, whereas the inner nine layers are transparent. Eye: Anatomy. Type 2 Type 2 Spinal Muscular Atrophy presents during infancy with skeletal dysplasia, intellectual disability Disability Determination of the degree of a physical, mental, or emotional handicap. The diagnosis is applied to legal qualification for benefits and income under disability insurance and to eligibility for social security and workman’s compensation benefits. ABCDE Assessment, and hepatosplenomegaly Hepatosplenomegaly Cytomegalovirus. Treatment is supportive.
• Pseudo-Hurler polydystrophy (mucolipidosis III): autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritance lysosomal storage disease Lysosomal storage disease Lysosomal storage diseases are a group of metabolic disorders caused by genetic mutations in the enzymes responsible for normal lysosomal function. The dysfunction of enzymatic processes causes an accumulation of undigested metabolites, resulting in cellular death. The main groups include sphingolipidoses, oligosaccharidoses, and mucolipidoses. Overview of Lysosomal Storage Diseases caused by a defect in UDP-N-acetylglucosamine-1-phosphotransferase and leading to accumulation of mucopolysaccharides Mucopolysaccharides Heteropolysaccharides which contain an n-acetylated hexosamine in a characteristic repeating disaccharide unit. The repeating structure of each disaccharide involves alternate 1, 4- and 1, 3-linkages consisting of either n-acetylglucosamine or n-acetylgalactosamine. Basics of Carbohydrates and mucolipids. Symptoms are similar to, but less severe than, those of I-cell disease and include progressive stiffness, hip dysfunction, growth delay, intellectual disability Disability Determination of the degree of a physical, mental, or emotional handicap. The diagnosis is applied to legal qualification for benefits and income under disability insurance and to eligibility for social security and workman’s compensation benefits. ABCDE Assessment, and mildly coarse facies Coarse facies Autosomal Dominant Hyperimmunoglobulin E Syndrome. Treatment is supportive and similar to that for I-cell disease.