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Niemann-Pick Disease

Niemann-Pick disease (NPD), also known as sphingomyelinase deficiency, is a rare, inherited, lysosomal storage disorder. The disease is classified on the basis of the genetic 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. Type A and type B result from mutations in the SMPD-1 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, resulting in acid sphingomyelinase enzyme deficiency. Type C results from NPC1 or NPC2 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 mutations, which are needed for intracellular transport of lipids Lipids Lipids are a diverse group of hydrophobic organic molecules, which include fats, oils, sterols, and waxes. Fatty Acids and Lipids. These mutations result in 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 that are unable to properly metabolize fat, such as sphingomyelin Sphingomyelin A class of sphingolipids found largely in the brain and other nervous tissue. They contain phosphocholine or phosphoethanolamine as their polar head group so therefore are the only sphingolipids classified as phospholipids. Neonatal Respiratory Distress Syndrome and cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism, resulting in progressive intracellular lipid accumulation and organ damage. Clinical manifestations may include 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, hepatosplenomegaly Hepatosplenomegaly Cytomegalovirus, thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia, interstitial lung disease, cognitive and motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology impairment, and macular cherry-red spots. Progressive neurodegeneration and a short life expectancy Life expectancy Based on known statistical data, the number of years which any person of a given age may reasonably expected to live. Population Pyramids are seen in NPD-A, while NPD-B is typically nonneurogenic. Diagnosis of NPD is based on clinical suspicion and can be confirmed by the measurement of sphingomyelinase activity or biomarkers, genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies, or biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma. There is currently no cure for NPD, so management is supportive and focuses on controlling symptoms.

Last updated: Sep 13, 2022

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Overview

Classification and etiology

Niemann-Pick disease (NPD) is an 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 disorder that is classified on the basis of the gene mutation Gene Mutation Myotonic Dystrophies and enzyme deficiency:

  • Types A (NPD-A) and B (NPD-B):
    • Sphingomyelin Sphingomyelin A class of sphingolipids found largely in the brain and other nervous tissue. They contain phosphocholine or phosphoethanolamine as their polar head group so therefore are the only sphingolipids classified as phospholipids. Neonatal Respiratory Distress Syndrome phosphodiesterase 1 (SMPD-1) gene mutation Gene Mutation Myotonic Dystrophies 
    • Results in acid sphingomyelinase (ASM) enzyme deficiency
    • Considered a spectrum of 1 disorder based on enzyme activity:
      • NPD-A: severe, < 5% of enzyme activity
      • NPD-B: 5%–10% of enzyme activity
  • Type C (NPD-C):

Epidemiology

  • NPD-A and B:
    • Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency: 1 in 250,000 people
    • More common in those of Ashkenazi Jewish descent
  • NPD-C: 
    • Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency: 1 in 150,000 people

Pathophysiology

Normal 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:

  • Intracellular digestive units that break down complex structures to be recycled or discarded
  • ASM normally converts sphingomyelin Sphingomyelin A class of sphingolipids found largely in the brain and other nervous tissue. They contain phosphocholine or phosphoethanolamine as their polar head group so therefore are the only sphingolipids classified as phospholipids. Neonatal Respiratory Distress Syndrome to ceramide and phosphocholine
  • NPC1 and NPC2 proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis are needed for intracellular transport of cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism and lipids Lipids Lipids are a diverse group of hydrophobic organic molecules, which include fats, oils, sterols, and waxes. Fatty Acids and Lipids.

In NPD-A and B:

  • ASM deficiency → accumulation of sphingomyelin Sphingomyelin A class of sphingolipids found largely in the brain and other nervous tissue. They contain phosphocholine or phosphoethanolamine as their polar head group so therefore are the only sphingolipids classified as phospholipids. Neonatal Respiratory Distress Syndrome in 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
  • Results in cellular damage and tissue deposition → organ damage

In NPD-C:

  • Lack of function in NPC1 or NPC2 → accumulation of cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism in 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 and mitochondria Mitochondria Semiautonomous, self-reproducing organelles that occur in the cytoplasm of all cells of most, but not all, eukaryotes. Each mitochondrion is surrounded by a double limiting membrane. The inner membrane is highly invaginated, and its projections are called cristae. Mitochondria are the sites of the reactions of oxidative phosphorylation, which result in the formation of ATP. They contain distinctive ribosomes, transfer RNAs; amino Acyl tRNA synthetases; and elongation and termination factors. Mitochondria depend upon genes within the nucleus of the cells in which they reside for many essential messenger RNAs. Mitochondria are believed to have arisen from aerobic bacteria that established a symbiotic relationship with primitive protoeukaryotes. The Cell: Organelles
  • ↑ Mitochondrial cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism → mitochondrial dysfunction →  apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage → organ damage
Lysosomal storage pathway

The lysosomal storage pathway:
Niemann-Pick disease (types A and B) results from acid sphingomyelinase deficiency, resulting in a buildup of sphingomyelin Sphingomyelin A class of sphingolipids found largely in the brain and other nervous tissue. They contain phosphocholine or phosphoethanolamine as their polar head group so therefore are the only sphingolipids classified as phospholipids. Neonatal Respiratory Distress Syndrome.

Image by Lecturio.

Clinical Presentation

The clinical presentation of NPD depends on the type and severity of the disease.

Niemann-Pick disease type A

Disease course:

  • Severe 
  • Presents within the 1st few months of life
  • Rapidly progressive neurodegenerative course
  • Death by 3 years of age

Signs and symptoms:

Cherry-red spot

Fundoscopic image demonstrating a cherry-red spot, which may be seen in Niemann-Pick disease

Image: “Cherry red spot” by Jonathan Trobe, M.D. License: CC BY 3.0

Niemann-Pick disease type B

Disease course:

  • Later onset and less severe than NPD-A
  • Progessive hypersplenism Hypersplenism Condition characterized by splenomegaly, some reduction in the number of circulating blood cells in the presence of a normal or hyperactive bone marrow, and the potential for reversal by splenectomy. Splenomegaly and pulmonary failure
  • Not typically neurodegenerative
  • Life expectancy Life expectancy Based on known statistical data, the number of years which any person of a given age may reasonably expected to live. Population Pyramids: early adulthood

Signs and symptoms:

  • Short stature and delayed skeletal maturation
  • Hepatomegaly
  • Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis
  • Hypersplenism Hypersplenism Condition characterized by splenomegaly, some reduction in the number of circulating blood cells in the presence of a normal or hyperactive bone marrow, and the potential for reversal by splenectomy. Splenomegaly thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia 
  • Interstitial lung disease → dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea and hypoxia Hypoxia Sub-optimal oxygen levels in the ambient air of living organisms. Ischemic Cell Damage
  • Cognitive impairment and psychiatric disturbance
  • Macular cherry red spot
  • Hyperlipidemia

Niemann-Pick disease type C

Disease course:

  • Onset from prenatal period Prenatal period Prenatal and Postnatal Physiology of the Neonate to adulthood
  • Progressive neurodegenerative disorder
  • Highly variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables presentation
  • Life expectancy Life expectancy Based on known statistical data, the number of years which any person of a given age may reasonably expected to live. Population Pyramids: early adulthood (most patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship)

Signs and symptoms:

  • Ataxia Ataxia Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharynx, larynx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. Ataxia-telangiectasia
  • Dystonia Dystonia Dystonia is a hyperkinetic movement disorder characterized by the involuntary contraction of muscles, resulting in abnormal postures or twisting and repetitive movements. Dystonia can present in various ways as may affect many different skeletal muscle groups. Dystonia
  • Dysarthria Dysarthria Disorders of speech articulation caused by imperfect coordination of pharynx, larynx, tongue, or face muscles. This may result from cranial nerve diseases; neuromuscular diseases; cerebellar diseases; basal ganglia diseases; brain stem diseases; or diseases of the corticobulbar tracts. The cortical language centers are intact in this condition. Wilson’s Disease
  • Dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming “stuck.” Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia
  • Vertical supranuclear gaze palsy Palsy paralysis of an area of the body, thus incapable of voluntary movement Cranial Nerve Palsies (inability to look in a vertical direction)
  • Gelastic cataplexy Cataplexy A condition characterized by transient weakness or paralysis of somatic musculature triggered by an emotional stimulus or physical exertion. Cataplexy is frequently associated with narcolepsy. During a cataplectic attack, there is a marked reduction in muscle tone similar to the normal physiologic hypotonia that accompanies rapid eye movement sleep (sleep, rem). Narcolepsy (loss of muscle tone Muscle tone The state of activity or tension of a muscle beyond that related to its physical properties, that is, its active resistance to stretch. In skeletal muscle, tonus is dependent upon efferent innervation. Skeletal Muscle Contraction triggered by laughter)
  • Cognitive impairment
  • Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
  • Prolonged neonatal jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice
  • Hepatosplenomegaly Hepatosplenomegaly Cytomegalovirus
  • Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy disease → ascites Ascites Ascites is the pathologic accumulation of fluid within the peritoneal cavity that occurs due to an osmotic and/or hydrostatic pressure imbalance secondary to portal hypertension (cirrhosis, heart failure) or non-portal hypertension (hypoalbuminemia, malignancy, infection). Ascites
  • Psychiatric and behavioral disorders
  • Alveolar proteinosis (buildup of lipoproteinaceous material in alveoli Alveoli Small polyhedral outpouchings along the walls of the alveolar sacs, alveolar ducts and terminal bronchioles through the walls of which gas exchange between alveolar air and pulmonary capillary blood takes place. Acute Respiratory Distress Syndrome (ARDS))
  • Aspiration pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia
  • Respiratory failure Respiratory failure Respiratory failure is a syndrome that develops when the respiratory system is unable to maintain oxygenation and/or ventilation. Respiratory failure may be acute or chronic and is classified as hypoxemic, hypercapnic, or a combination of the two. Respiratory Failure

Diagnosis and Management

Diagnosis

Suspicion for NPD is raised on the basis of the clinical features. The diagnosis can be confirmed with the following investigations:

  • NPD-A and B: 
    • Measurement of WBC ASM activity in WBCs
    • Molecular analysis for SMPD-1 mutations
    • Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types marrow biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma for lipid-laden foam cells Foam cells Lipid-laden macrophages originating from monocytes or from smooth muscle cells. Atherosclerosis ( macrophages Macrophages The relatively long-lived phagocytic cell of mammalian tissues that are derived from blood monocytes. Main types are peritoneal macrophages; alveolar macrophages; histiocytes; kupffer cells of the liver; and osteoclasts. They may further differentiate within chronic inflammatory lesions to epithelioid cells or may fuse to form foreign body giant cells or langhans giant cells. Innate Immunity: Phagocytes and Antigen Presentation)
  • NPD-C: 
    • Measurement of plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products oxysterols
    • Molecular analysis for NPC1 and NPC2 mutations 
    • Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma:
      • Fibroblasts Fibroblasts Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. Sarcoidosis are grown in culture and monitored for their ability to transport and store cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism.
      • Largely replaced by the above testing methods
  • Prenatal screening Screening Preoperative Care can be done for all types via 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.
Visceral symptoms as a key diagnostic sign for the early infantile form of niemann-pick disease

Histopathological liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma showing swollen Kupffer cells Kupffer cells Specialized phagocytic cells of the mononuclear phagocyte system found on the luminal surface of the hepatic sinusoids. They filter bacteria and small foreign proteins out of the blood, and dispose of worn out red blood cells. Benign Liver Tumors with a foamy cytoplasm, typical for NPD-C

Image: “Histopathological liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma findings” by Federal State Budget Institution, Research Research Critical and exhaustive investigation or experimentation, having for its aim the discovery of new facts and their correct interpretation, the revision of accepted conclusions, theories, or laws in the light of newly discovered facts, or the practical application of such new or revised conclusions, theories, or laws. Conflict of Interest Center for Obstetrics, Gynecology and Perinatology, Federal State Budget Institution, 117997 Oparina str. 4, Moscow, Russia. License: CC BY 4.0

Management

There is no cure for NPD. Management is supportive and multidisciplinary. 

  • Physical and occupational therapy Occupational Therapy Skilled treatment that helps individuals achieve independence in all facets of their lives. It assists in the development of skills needed for independent living. Fetal Alcohol Spectrum Disorder
  • Nutritional support
  • Antibiotic treatment for recurrent pulmonary infections Recurrent pulmonary infections Selective IgA Deficiency
  • Investigational therapies:
    • Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types marrow and stem cell transplantation
    • Enzyme replacement Enzyme replacement Therapeutic replacement or supplementation of defective or missing enzymes to alleviate the effects of enzyme deficiency (e.g., glucosylceramidase replacement for gaucher disease). Severe Combined Immunodeficiency (SCID)
    • 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 therapy

Differential Diagnosis

  • Gaucher disease Gaucher disease Gaucher Disease (GD) is an autosomal recessive lysosomal storage disorder caused by a deficiency of glucocerebrosidase enzyme activity, resulting in accumulation of glucocerebroside in cells and certain organs. The disease is categorized into 3 types with variable clinical presentation. Gaucher Disease: most common lysosomal storage disorder. Gaucher disease Gaucher disease Gaucher Disease (GD) is an autosomal recessive lysosomal storage disorder caused by a deficiency of glucocerebrosidase enzyme activity, resulting in accumulation of glucocerebroside in cells and certain organs. The disease is categorized into 3 types with variable clinical presentation. Gaucher Disease results from glucocerebrosidase deficiency. There are 3 types of Gaucher disease Gaucher disease Gaucher Disease (GD) is an autosomal recessive lysosomal storage disorder caused by a deficiency of glucocerebrosidase enzyme activity, resulting in accumulation of glucocerebroside in cells and certain organs. The disease is categorized into 3 types with variable clinical presentation. Gaucher Disease. The different types have varying presentations and severity, which can include hepatosplenomegaly Hepatosplenomegaly Cytomegalovirus, thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia, easy bruising Easy bruising Chédiak-Higashi Syndrome, bone fractures Bone fractures Breaks in bones. Bones: Remodeling and Healing, and progressive neurologic deterioration. The diagnosis is made with DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure or enzyme analysis. Management depends on the type and includes enzyme replacement Enzyme replacement Therapeutic replacement or supplementation of defective or missing enzymes to alleviate the effects of enzyme deficiency (e.g., glucosylceramidase replacement for gaucher disease). Severe Combined Immunodeficiency (SCID), splenectomy Splenectomy Surgical procedure involving either partial or entire removal of the spleen. Rupture of the Spleen, glucosylceramide inhibitors, and bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types marrow or stem cell transplantation. 
  • Tay-Sachs disease Tay-Sachs disease Tay-Sachs disease is an autosomal recessive lysosomal storage disorder caused by genetic mutations in the hexosaminidase A (HEXA) gene, leading to progressive neurodegeneration. Classic symptoms in infants include rapid degeneration of cognitive and neuromuscular abilities, progressive blindness, and a macular cherry-red spot on physical examination. Tay-Sachs Disease: lysosomal storage disorder resulting from hexosaminidase A Hexosaminidase A A mammalian beta-hexosaminidase isoform that is a heteromeric protein comprised of both hexosaminidase alpha and hexosaminidase beta subunits. Deficiency of hexosaminidase A due to mutations in the gene encoding the hexosaminidase alpha subunit is a case of Tay-sachs disease. Deficiency of hexosaminidase A and hexosaminidase B due to mutations in the gene encoding the hexosaminidase beta subunit is a case of Sandhoff disease. Tay-Sachs Disease deficiency. There are 3 types of Tay-Sachs disease Tay-Sachs disease Tay-Sachs disease is an autosomal recessive lysosomal storage disorder caused by genetic mutations in the hexosaminidase A (HEXA) gene, leading to progressive neurodegeneration. Classic symptoms in infants include rapid degeneration of cognitive and neuromuscular abilities, progressive blindness, and a macular cherry-red spot on physical examination. Tay-Sachs Disease, and these have variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables onsets. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship may present with macular cherry-red spots, blindness Blindness The inability to see or the loss or absence of perception of visual stimuli. This condition may be the result of eye diseases; optic nerve diseases; optic chiasm diseases; or brain diseases affecting the visual pathways or occipital lobe. Retinopathy of Prematurity, deafness, cognitive and motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology deterioration, dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming “stuck.” Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia, dysarthria Dysarthria Disorders of speech articulation caused by imperfect coordination of pharynx, larynx, tongue, or face muscles. This may result from cranial nerve diseases; neuromuscular diseases; cerebellar diseases; basal ganglia diseases; brain stem diseases; or diseases of the corticobulbar tracts. The cortical language centers are intact in this condition. Wilson’s Disease, spasticity Spasticity Spinal Disk Herniation, ataxia Ataxia Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharynx, larynx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. Ataxia-telangiectasia, seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures, and psychosis. The diagnosis is made with enzyme activity testing and molecular analysis. Management is supportive. 
  • Pompe disease ( glycogen storage disease Glycogen storage disease A group of inherited metabolic disorders involving the enzymes responsible for the synthesis and degradation of glycogen. In some patients, prominent liver involvement is presented. In others, more generalized storage of glycogen occurs, sometimes with prominent cardiac involvement. Benign Liver Tumors II): lysosomal and glycogen storage disorder caused by acid alpha glucosidase (GAA) deficiency. There are 3 types of Pompe disease, and these have variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables onset and presentations. Clinical manifestations include 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, feeding difficulty, hypotonia Hypotonia Duchenne Muscular Dystrophy, progressive muscle weakness, hypertrophic cardiomyopathy Cardiomyopathy Cardiomyopathy refers to a group of myocardial diseases associated with structural changes of the heart muscles (myocardium) and impaired systolic and/or diastolic function in the absence of other heart disorders (coronary artery disease, hypertension, valvular disease, and congenital heart disease). Cardiomyopathy: Overview and Types, and respiratory failure Respiratory failure Respiratory failure is a syndrome that develops when the respiratory system is unable to maintain oxygenation and/or ventilation. Respiratory failure may be acute or chronic and is classified as hypoxemic, hypercapnic, or a combination of the two. Respiratory Failure. The diagnosis is made by measuring enzyme activity and molecular 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 analysis. Management includes supportive measures and enzyme replacement Enzyme replacement Therapeutic replacement or supplementation of defective or missing enzymes to alleviate the effects of enzyme deficiency (e.g., glucosylceramidase replacement for gaucher disease). Severe Combined Immunodeficiency (SCID).
  • Fabry disease Fabry disease Fabry disease (FD), also known as Anderson-Fabry disease, is an X-linked recessive lysosomal storage disorder and the 2nd most common of the lysosomal storage disorders. Fabry disease is caused by a deficiency in the alpha-galactosidase enzyme (alpha-Gal A), resulting in the accumulation of the glycosphingolipid globotriaosylceramide (Gb3) in lysosomes. Fabry Disease: lysosomal storage disorder caused by alpha-galactosidase Alpha-galactosidase An enzyme that catalyzes the hydrolysis of terminal, non-reducing alpha-d-galactose residues in alpha-galactosides including galactose oligosaccharides, galactomannans, and galactolipids. Fabry Disease A (GLA) deficiency. This deficiency results in glycophospholipid deposition in the vascular endothelium Endothelium A layer of epithelium that lines the heart, blood vessels (vascular endothelium), lymph vessels (lymphatic endothelium), and the serous cavities of the body. Arteries: Histology and smooth muscle cells. Clinical manifestations include paresthesias Paresthesias Subjective cutaneous sensations (e.g., cold, warmth, tingling, pressure, etc.) that are experienced spontaneously in the absence of stimulation. Posterior Cord Syndrome involving the hands and feet, purplish skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions lesions (angiokeratomas), decreased sweating, cardiovascular complications, and renal disease. The diagnosis is made by measuring GLA enzyme activity. Management includes supportive measures and enzyme replacement Enzyme replacement Therapeutic replacement or supplementation of defective or missing enzymes to alleviate the effects of enzyme deficiency (e.g., glucosylceramidase replacement for gaucher disease). Severe Combined Immunodeficiency (SCID).

References

  1. Patterson, M.C. (2020). Overview of Niemann-Pick disease. In Dashe, J.F. (Ed.), UpToDate. Retrieved May 10, 2021, from https://www.uptodate.com/contents/overview-of-niemann-pick-disease
  2. Patel, J.M., Dankhara, N. (2020). Sphingomyelinase deficiency. In Rohena, L.O. (Ed.), Medscape. Retrieved May 10, 2021, from https://emedicine.medscape.com/article/951564-overview
  3. Demczko, M. (2020). Niemann-Pick disease. MSD Manual Professional Version. Retrieved May 10, 2021, from https://www.msdmanuals.com/professional/pediatrics/inherited-disorders-of-metabolism/niemann-pick-disease
  4. Bajwa, H., Azhar, W. (2021). Niemann-Pick disease. StatPearls. Retrieved May 10, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK556129/
  5. Torres, S., et al. (2017). Lysosomal and mitochondrial liaisons in Niemann-Pick disease. Frontiers in Physiology. https://doi.org/10.3389/fphys.2017.00982

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