This document summarizes various inborn errors of metabolism, including:
- Disorders of amino acid metabolism such as phenylketonuria (PKU), tyrosinemia, maple syrup urine disease (MSUD), homocystinuria, and nonketotic hyperglycinemia.
- Urea cycle defects which result in abnormal nitrogen metabolism and elevated ammonia levels.
- Disorders of organic acid metabolism including propionic acidemia, methylmalonic acidemia, isovaleric acidemia, and glutaric aciduria type 1.
- A disorder of fatty acid metabolism, medium-chain acyl-CoA dehydrogenase deficiency (MCAD), is also mentioned.
Maple syrup urine disease is an inherited disorder in which the body is unable to process certain protein building blocks (amino acids) properly. The condition gets its name from the distinctive sweet odor of affected infants' urine.
Homocystinuria is a disorder of methionine metabolism, leading to an abnormal accumulation of homocysteine and its metabolites (homocystine, homocysteine-cysteine complex, and others) in blood and urine. Normally, these metabolites are not found in appreciable quantities in blood or urine.
Maple syrup urine disease is an inherited disorder in which the body is unable to process certain protein building blocks (amino acids) properly. The condition gets its name from the distinctive sweet odor of affected infants' urine.
Homocystinuria is a disorder of methionine metabolism, leading to an abnormal accumulation of homocysteine and its metabolites (homocystine, homocysteine-cysteine complex, and others) in blood and urine. Normally, these metabolites are not found in appreciable quantities in blood or urine.
Gaucher disease is an inherited disorder that
affects many of the body's organs and tissues. The signs and symptoms of this
condition vary widely among affected individuals. Researchers have described
several types of Gaucher disease based on their characteristic features.
Type 1 Gaucher disease is the most common
form of this condition. Type 1 is also called non-neuronopathic Gaucher disease
because the brain and spinal cord (the central nervous system) are usually not
affected. The features of this condition range from mild to severe and may
appear anytime from childhood to adulthood. Major signs and symptoms include
enlargement of the liver and spleen (hepatosplenomegaly), a low number of red
blood cells (anemia), easy bruising caused by a decrease in blood platelets
(thrombocytopenia), lung disease, and bone abnormalities such as bone pain,
fractures, and arthritis.
Types 2 and 3 Gaucher disease are known as
neuronopathic forms of the disorder because they are characterized by problems
that affect the central nervous system. In addition to the signs and symptoms
described above, these conditions can cause abnormal eye movements, seizures,
and brain damage. Type 2 Gaucher disease usually causes life-threatening
medical problems beginning in infancy. Type 3 Gaucher disease also affects the
nervous system, but tends to progress more slowly than type 2.
The most severe type of Gaucher disease is
called the perinatal lethal form. This condition causes severe or
life-threatening complications starting before birth or in infancy. Features of
the perinatal lethal form can include extensive swelling caused by fluid
accumulation before birth (hydrops fetalis); dry, scaly skin (ichthyosis) or
other skin abnormalities; hepatosplenomegaly; distinctive facial features; and
serious neurological problems. As its name indicates, most infants with the
perinatal lethal form of Gaucher disease survive for only a few days after
birth.
Another form of Gaucher disease is known as
the cardiovascular type because it primarily affects the heart, causing the
heart valves to harden (calcify). People with the cardiovascular form of
Gaucher disease may also have eye abnormalities, bone disease, and mild
enlargement of the spleen (splenomegaly).
This is a powerpoint file of an MBBS practical class taken by Dr. Karthikeyan Pethusamy at All India Institute of Medical Sciences - NewDelhi.
Disclaimer: The views expressed here are of the author only not of the institution.
A lysosomal storage disease caused by acid sphingomyelinase deficiency (ASMD), which catalyzes the hydrolysis of sphingomyelin (SM) to ceramide and phosphocholine.
Inborn errors of metabolism- focusing on its predominant adult onset forms, neurological perspective, clinical & biochemical approach to diagnosis, and neuroimaging findings.
Gaucher disease is an inherited disorder that
affects many of the body's organs and tissues. The signs and symptoms of this
condition vary widely among affected individuals. Researchers have described
several types of Gaucher disease based on their characteristic features.
Type 1 Gaucher disease is the most common
form of this condition. Type 1 is also called non-neuronopathic Gaucher disease
because the brain and spinal cord (the central nervous system) are usually not
affected. The features of this condition range from mild to severe and may
appear anytime from childhood to adulthood. Major signs and symptoms include
enlargement of the liver and spleen (hepatosplenomegaly), a low number of red
blood cells (anemia), easy bruising caused by a decrease in blood platelets
(thrombocytopenia), lung disease, and bone abnormalities such as bone pain,
fractures, and arthritis.
Types 2 and 3 Gaucher disease are known as
neuronopathic forms of the disorder because they are characterized by problems
that affect the central nervous system. In addition to the signs and symptoms
described above, these conditions can cause abnormal eye movements, seizures,
and brain damage. Type 2 Gaucher disease usually causes life-threatening
medical problems beginning in infancy. Type 3 Gaucher disease also affects the
nervous system, but tends to progress more slowly than type 2.
The most severe type of Gaucher disease is
called the perinatal lethal form. This condition causes severe or
life-threatening complications starting before birth or in infancy. Features of
the perinatal lethal form can include extensive swelling caused by fluid
accumulation before birth (hydrops fetalis); dry, scaly skin (ichthyosis) or
other skin abnormalities; hepatosplenomegaly; distinctive facial features; and
serious neurological problems. As its name indicates, most infants with the
perinatal lethal form of Gaucher disease survive for only a few days after
birth.
Another form of Gaucher disease is known as
the cardiovascular type because it primarily affects the heart, causing the
heart valves to harden (calcify). People with the cardiovascular form of
Gaucher disease may also have eye abnormalities, bone disease, and mild
enlargement of the spleen (splenomegaly).
This is a powerpoint file of an MBBS practical class taken by Dr. Karthikeyan Pethusamy at All India Institute of Medical Sciences - NewDelhi.
Disclaimer: The views expressed here are of the author only not of the institution.
A lysosomal storage disease caused by acid sphingomyelinase deficiency (ASMD), which catalyzes the hydrolysis of sphingomyelin (SM) to ceramide and phosphocholine.
Inborn errors of metabolism- focusing on its predominant adult onset forms, neurological perspective, clinical & biochemical approach to diagnosis, and neuroimaging findings.
Drug-induced liver disease (DILD) is a potentially fatal, often debilitating outcome of drug treatment. The range of drugs associated with adverse reactions involving the liver is extensive, but in clinical practice is dominated by alcohol, antibiotics, antiseizure medications and acetaminophen. Complementary and herbal medicines also contribute disproportionately to this disease burden.
nausea and vomiting in pregnancy is very common. it may be a manifestation of some medical - surgical - gynecological complications. hyperemesis gravidarum is a severe type of vomiting in pregnancy which has got deleterious effects on the health of the mother. it is a very important topic and it is also a topic in obstetrics. we should encourage and help young mothers to identify the symptoms. please read it and get knowledge about nausea and vomiting in pregnancy. stay tuned.
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
NVBDCP.pptx Nation vector borne disease control programSapna Thakur
NVBDCP was launched in 2003-2004 . Vector-Borne Disease: Disease that results from an infection transmitted to humans and other animals by blood-feeding arthropods, such as mosquitoes, ticks, and fleas. Examples of vector-borne diseases include Dengue fever, West Nile Virus, Lyme disease, and malaria.
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
HOT NEW PRODUCT! BIG SALES FAST SHIPPING NOW FROM CHINA!! EU KU DB BK substit...GL Anaacs
Contact us if you are interested:
Email / Skype : kefaya1771@gmail.com
Threema: PXHY5PDH
New BATCH Ku !!! MUCH IN DEMAND FAST SALE EVERY BATCH HAPPY GOOD EFFECT BIG BATCH !
Contact me on Threema or skype to start big business!!
Hot-sale products:
NEW HOT EUTYLONE WHITE CRYSTAL!!
5cl-adba precursor (semi finished )
5cl-adba raw materials
ADBB precursor (semi finished )
ADBB raw materials
APVP powder
5fadb/4f-adb
Jwh018 / Jwh210
Eutylone crystal
Protonitazene (hydrochloride) CAS: 119276-01-6
Flubrotizolam CAS: 57801-95-3
Metonitazene CAS: 14680-51-4
Payment terms: Western Union,MoneyGram,Bitcoin or USDT.
Deliver Time: Usually 7-15days
Shipping method: FedEx, TNT, DHL,UPS etc.Our deliveries are 100% safe, fast, reliable and discreet.
Samples will be sent for your evaluation!If you are interested in, please contact me, let's talk details.
We specializes in exporting high quality Research chemical, medical intermediate, Pharmaceutical chemicals and so on. Products are exported to USA, Canada, France, Korea, Japan,Russia, Southeast Asia and other countries.
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
263778731218 Abortion Clinic /Pills In Harare ,sisternakatoto
263778731218 Abortion Clinic /Pills In Harare ,ABORTION WOMEN’S CLINIC +27730423979 IN women clinic we believe that every woman should be able to make choices in her pregnancy. Our job is to provide compassionate care, safety,affordable and confidential services. That’s why we have won the trust from all generations of women all over the world. we use non surgical method(Abortion pills) to terminate…Dr.LISA +27730423979women Clinic is committed to providing the highest quality of obstetrical and gynecological care to women of all ages. Our dedicated staff aim to treat each patient and her health concerns with compassion and respect.Our dedicated group ABORTION WOMEN’S CLINIC +27730423979 IN women clinic we believe that every woman should be able to make choices in her pregnancy. Our job is to provide compassionate care, safety,affordable and confidential services. That’s why we have won the trust from all generations of women all over the world. we use non surgical method(Abortion pills) to terminate…Dr.LISA +27730423979women Clinic is committed to providing the highest quality of obstetrical and gynecological care to women of all ages. Our dedicated staff aim to treat each patient and her health concerns with compassion and respect.Our dedicated group of receptionists, nurses, and physicians have worked together as a teamof receptionists, nurses, and physicians have worked together as a team wwww.lisywomensclinic.co.za/
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
Pulmonary Thromboembolism - etilogy, types, medical- Surgical and nursing man...VarunMahajani
Disruption of blood supply to lung alveoli due to blockage of one or more pulmonary blood vessels is called as Pulmonary thromboembolism. In this presentation we will discuss its causes, types and its management in depth.
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
Couples presenting to the infertility clinic- Do they really have infertility...Sujoy Dasgupta
Dr Sujoy Dasgupta presented the study on "Couples presenting to the infertility clinic- Do they really have infertility? – The unexplored stories of non-consummation" in the 13th Congress of the Asia Pacific Initiative on Reproduction (ASPIRE 2024) at Manila on 24 May, 2024.
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
2. • Disorders of Amino Acid Metabolism (tyrosinemia,
homocystinuria, NKH, MSUD, and PKU)
• Urea Cycle Defects
• Disorders of Organic Acid Metabolism ( propionic
acidemia, isovaleric acidemia, methylmalonic aciduria,
and glutaric aciduria)
• Disorders of Fatty Acid Metabolism (MCAD)
• Disorders of Carbohydrate Metabolism (hereditary
fructose intolerance, galactosemia, and GSDs)
• PEROXISOMAL DISORDERS (Zellweger syndrome, X-
linked adrenoleukodystrophy)
• MUCOPOLYSACCHARIDOSES (MPS) (Hurler syndrome)
• SPHINGOLIPIDOSES (Gaucher disease, Niemann-Pick
disease)
3. Disorders of Amino Acid Metabolism
• Disorders of amino acid metabolism include
• tyrosinemia,
• homocystinuria,
• NKH,
• MSUD, and
• PKU.
4. Phenylketonuria
• PKU is inherited in an autosomal recessive
• Classic PKU results from a deficiency of the
PAH enzyme, which is responsible for
converting phenylalanine into tyrosine.
• Other forms of PKU can be caused by
deficiencies in the synthesis of biopterin,
which is cofactor for the PAH enzyme.
6. • Women of childbearing age with PKU must
maintain strict adherence to their diet
because of the teratogenic effects of elevated
phenylalanine.
• Infants born to mothers with uncontrolled
PKU can have microcephaly, growth
retardation, developmental delay, and
congenital heart disease.
7. • Treatment
• Phenylalanine-restricted diet in infancy, ideally
continued throughout lifetime.
• More recently, a synthetic form of biopterin
has become clinically available and allows
further liberalization of diet in some patients.
8. Tyrosinemia
• There are five known inherited disorders of
tyrosine metabolism.
• We will address tyrosinemia types I .
9. Tyrosinaemia (type 1)
• Tyrosinaemia type 1 results from a block in the
catabolism of tyrosine, producing byproducts
which damage the liver and kidney.
• Clinical features of tyrosinaemia
• Early onset (severe) liver disease with
coagulopathy, proximal renal tubulopathy
• Late onset: Faltering growth and rickets
(secondary to renal Fanconi)
• Development of hepatocellular carcinoma in late
childhood/adolescence
10. • Diagnosis
• Tyrosine is raised in the plasma and the
presence of succinylacetone in urine is
pathognomonic.
• Confirm by liver enzymology
(fumarylacetoacetase).
11. • Treatment
• Dietary restriction of tyrosine and
phenylalanine with or without liver
transplantation;
• however, the drug Nitisinone (NTBC)is now
used in some patients to create a block
upstream of the pathway of tyrosine
metabolism, leading to accumulation of less
toxic metabolites.
12. Maple Syrup Urine Disease (MSUD)
• MSUD results from deficient activity of the BCKD
(branched-chain keto acid dehydrogenase )
• occurs in approximately 1 in 200,000 births.
• It derives its name from the sweet smelling
urine of affected patients.
• Deficiency of this enzyme leads to accumulation
of the BCAAs including leucine, isoleucine, and
valine.
• Much of the toxicity is related to the elevated
level of leucine, which is neurotoxic.
13. Clinical Manifestations
(Vary According to Level of Functional Enzyme Present)
• Severe forms present in infancy with lethargy,
vomiting, hypotonia, seizures, and/or death.
14. • Patients with intermediate levels of enzyme
can present during childhood or adulthood
with episodic neurologic decompensation,
often during an intercurrent illness.
• Chronic progressive forms of MSUD exist and
can present with gradual neurologic problems
including seizures and developmental delay.
15. • Diagnosis:
• Elevated branch-chain amino acids plus
alloisoleucine
• Elevated branch-chain oxo-acids on urinary
organic acids
• Enzymology on fibroblasts
• Ammonia, lactate, and bicarbonate are often
normal.
• Treatment
• Restriction of intake of the BCAAs.
• The enzyme cofactor thiamine is given in the
hope of improving residual enzyme activity.
16. Homocystinuria
• Homocystinuria is an autosomal recessive
condition.
• classically caused by cystathionine beta-
synthase deficiency. This enzyme is
responsible for metabolizing homocysteine to
cystathionine.
• Pyridoxine is a cofactor for this enzyme.
18. • Treatment
• 50% of patients will respond to pyridoxine
supplementation.
• Folate should also be supplemented as
depletion affects response.
• Other treatment modalities include
methionine-restricted, cystine-supplemented
diet.
• Betaine is effective at lowering homocysteine .
19. Nonketotic Hyperglycinemia
• NKH results from defects in the glycine
cleavage system.
• Glycine is a neurotransmitter; excitatory
centrally and inhibitory peripherally.
20. • Clinical features
• Increased fetal movements (inutero seizures)
• Hiccups and hypotonia.
• Progressive apnea/encephalopathy.
• Seizures.
• Developmental delay.
• EEG shows a burst suppression pattern;
21. • Diagnosis:
• elevated glycine on urinary or plasma amino
acids.
• CSF glycine to plasma glycine ratio greater
than 0.08 is diagnostic of NKH.
• Ketosis and acidosis are not seen.
• Enzymology ;is traditionally assessed in the
liver, but a new assay using lymphocytes is
now available.
22. • Treatment
• Sodium benzoate and dextromethorphan may
help to reduce seizure activity and increase
arousal in some patients.
• Sodium-Valproic Acid (Depakene) should be
avoided since it can raise CSF glycine levels.
23. Urea Cycle Defects
(Disorders of Protein/Nitrogen Metabolism)
• In normal individuals, excess nitrogen is
converted into urea, which is excreted in the
urine by a process known as the urea cycle.
• A defect in this cycle will lead to abnormal
nitrogen metabolism, and an elevation in
ammonia, which at high levels is neurotoxic.
• Excess nitrogen is also stored as glutamine and
glycine, which are also elevated in these
disorders.
• All disorders of the urea cycle are inherited in an
autosomal recessive manner, except OTC
deficiency, which is inherited in an X-linked
manner.
24. Clinical features of Urea cycle defects:
• Vomiting (may be a cause of cylical vomiting)
• Encephalopathy. (intoxication following symptom
free period in neonate) .
• Tachypnoea (ammonia stimulate respiratory
center)
• Progressive spastic diplegia and developmental
delay (arginase deficiency)
• Milder forms can present during childhood with
episodic encephalopathy triggered by
intercurrent metabolic stress.
25. • Diagnosis
• The specific deficient enzyme in a patient with
a suspected urea cycle defect can be identified
by examining the patterns of urine organic
acids and plasma amino acids.
• Final confirmation of the diagnosis requires
enzymology.
27. • Treatment
• Acute treatment during crisis periods is
centered around reducing the levels of
ammonia by
• dialysis and IV medications designed to
provide alternative mechanisms of nitrogen
excretion, such as sodium benzoate and
phenylbutyrate.
28. Disorders of Organic Acid Metabolism
• Defects in the catabolism of amino acids
result in the accumulation of organic acids
which are detected in urine.
• Disorders of organic acid metabolism include
• propionic acidemia, isovaleric acidemia,
methylmalonic aciduria, and glutaric aciduria.
29. • Propionic acidaemia (PA) and methylmalonic
aciduria (MMA) result from blocks in
branched-chain amino acid degradation,
• isovaleric acidaemia (IVA) is the result of a
block in leucine catabolism.
• glutaric aciduria type 1 (GA-1) results from a
block in lysine and tryptophan metabolism.
30. Clinical features of organic acidaemias
• Acute neonatal encephalopathy (intoxication), or
chronic intermittent forms
• Dehydration ·
• Marked acidosis (↑anion gap), ketosis .
• Neutropenia +/- thrombocytopenia (acute marrow
suppression)
• Progressive extra pyramidal syndrome (MMA, PA) basal
ganglia necrosis
• Renal insufficiency (MMA)
• Pancreatitis .
• Cardiomyopathy (PA, MMA)
• Patients with isovaleric acidemia are often described as
having a peculiar body odor (sweaty feet)
31. • Diagnosis
• Both the acylcarnitine profile and urine
organic acid profile are essential in making a
diagnosis.
32. • Treatment
• Protein restriction.
• Carnitine supplementation (provides alternate
methods of propionic acid and methylmalonic
acid secretion).
• There are B12 responsive forms of methylmalonic
aciduria.
• Propionate is partly produced by gut organisms,
therefore decompensation in PA and MMA may
be precipitated by constipation.
• Metronidazole is used in MMA and PA to alter
the gut flora to reduce propionate production
and help avoid constipation.
33. Glutaric Aciduria Type 1
• Glutaric aciduria type 1 is due to a deficiency in glutaryl-
CoA .
• Clinical Manifestations:
• Macrocephaly
• Normal development before catastrophic decompensation
(usually <1 year)
• Choreoathetosis and dystonia (basal ganglia involvement)
• Magnetic resonance imaging features: bifrontotemporal
atrophy, subdural haematomas, basal ganglia decreased
signal
34. • Diagnosis
• Elevated levels of glutaric acid in the urine or
CSF.
• Abnormal acylcarnitine profile.
• Patients do not generally have hypoglycemia,
acidosis, or hyperammonemia.
• Treatment
• Lysine and tryptophan restricted diet.
• Carnitine supplementation.
• Support during intercurrent illnesses.
35. Disorders of Fatty Acid Metabolism
• The fat oxidation defects commonly present with
hepatic, cardiac or muscle symptoms.
• Fatty acids are a major fuel source in the fasted
state
• Fatty acids are oxidized by most tissues except
the brain, which is reliant on hepatic fatty acid for
ketone production.
• Fatty acids are the preferred substrate for cardiac
muscle.
• during prolonged exercise they are a vital energy
source for skeletal muscle.
36. • Long-chain free fatty acids are esterified in
the cell cytosol and then enter the
mitochondria as fatty acylcarnitines.
• Medium- and short-chain fatty acids are able
to enter the mitochondria directly.
• They then undergo beta oxidation until they
become acetyl-CoA, which is then used to
make ketone bodies.
• These disorders are all inherited in an
autosomal recessive manner.
37. Medium-chain acyl-CoA.
dehydrogenase (MCAD) deficiency
• MCAD deficiency is the commonest fat oxidation
disorder.
• Clinical features of MCAD deficiency
• Hypoketotic hypoglycaemia(During prolonged fasting)
• Encephalopathy
• Reye-like syndrome: hepatomegaly, deranged liver
function
• Mean age at presentation 15 months, commonest
precipitant is diarrhoea
• Sudden infant death (consider in older infant> 6
months)
38. • Diagnosis
• Detection requires a strong clinical suspicion .
• The presence or absence of ketosis should be
sought in all cases of hypoglycaemia.
• Plasma-free fatty acids are raised, while
ketone formation is impaired.
• Urinary organic acids reveal a characteristic
dicarboxylic aciduria in the acute state.
• Acylcarnitines are elevated .
39. • Management
• Prevention is better than cure.
• Once the diagnosis is known, further
decompensations can be avoided by
employing an emergency regimen of glucose
polymer drinks during intercurrent illnesses or
admission for a 10% dextrose infusion if the
drinks are not tolerated.
40. Disorders of Carbohydrate
Metabolism
• Disorders of carbohydrate metabolism
include:
• hereditary fructose intolerance,
• galactosemia,
• and the GSDs (Glycogen storage disease)
41. Galactosemia
• Galactosemia is a result of deficient (galactose-1-
phosphate uridyl transferase)
• Most patients present in the first or second week of life
with hepatomegaly, jaundice, vomiting, hypoglycemia,
hypotonia, and cataracts (oil droplet cataract)
• Neonates also present with Escherichia coli sepsis.
42. • Diagnosis
• Diagnosis is based on the clinical picture, the
presence of reducing substances in the urine
• Enzymology : by measuring the level of
galactose 1 phosphate uridyltransferase (Gal
1-Put) in red cells.
• Galactosaemia should be considered in all
cases of severe early-onset jaundice.
43. • Treatment includes a lactose-free diet
throughout life.
• Long-term complications, in spite of good
control, thought to be due to endogenous
production of galactose from glucose.
• Includes: developmental delay, particularly
involving speech, feeding problems and
infertility in girls.
44. Hereditary Fructose Intolerance
• It is result from a defect of fructose 1,6-bisphosphate
aldolase.
• When patients are exposed to fructose, they can have
gastrointestinal symptoms with nausea and vomiting,
seizures, and coma.
• Liver failure and proximal renal tubule defects can be
seen.
• Exacerbations may occur following exposure to
fructose contained in medicines
• A chronic form can also develop leading to growth
failure and chronic renal and liver damage.
• Treatment :Lifelong avoidance of fructose.
45. Glycogen Storage Disorders
• Glucose is stored in the liver and muscles as
glycogen.
• The glycogen storages disorders are a large class
of disorders that cause defects in glycogen
production or utilization.
• They primarily present with either muscle or liver
abnormalities or both.
• Hepatic forms present with hepatomegaly and
hypoglycaemia,
• the muscle forms present with weakness and
fatigue.
46. GSD Ia (von Gierke disease)
• Enzyme :Glucose-6-phosphatase
• Major Organ Involvement: Liver, kidney
47. • Clinical Features :
• Hypoglycemia ; Fasting tolerance is limited,
usually 1 -4 h.
• Massive hepatomegaly in the absence of
splenomegaly is strongly suggestive of a hepatic
GSD because glycogen is not stored in the spleen.
• Nephromegaly is common.
• Abnormal fat distribution results in 'doll-like'
faces and thin limbs.
• Long-term complications include renal
insufficiency, liver adenomas with potential for
malignant change, gout, osteopenia and
polycystic ovaries.
48. • Investigations: show raised plasma lactate levels,
hyperuricaemia and hyperlipidaemia.
• Treatment consists of frequent feeds during the
day with continuous feed overnight.
• From age 2, uncooked corn starch is introduced
as a slow-release form of glucose, prolonging the
gap between feeds.
• Allopurinol controls the uric acid level in the
blood.
• Liver transplantation is reserved for patients
with malignant change in an adenoma or failure
to respond to dietary treatment.
49. GSD II (Pompe disease)
• Enzyme :Lysosomal alpha-glucosidase , acid maltase deficiency
• Major Organ Involvement: Muscle,
• Clinical Features : generalized Myopathy, cardiomyopathy,
hypotonia, weakness, hyporeflexia and large tongue.
• ECG reveals giant QRS complexes.
• Vacuolated lymphocytes are seen on the blood film.
• Confirmatory enzymology is performed on fibroblasts.
• ERT (enzyme replacement therapy )recently available, which
extends life expectancy.
50. • GSD III Debrancher (Cori disease): affects
liver and muscle.
• GSDIV Brancher (Andersen disease), GSD VI
(Hers disease) and GSD IX: affects liver.
• GSD V (McArdle disease) and GSD VII(Tarui
disease): affects Muscles.
51. PEROXISOMAL DISORDERS
• Peroxisomes harbour many vital cellular
functions, including
• the synthesis of plasmalogens, (essential
constituents of cell walls), cholesterol and bile
acids, and
• the oxidation of very long- chain fatty acids
and breakdown of phytanic acid (vitamin A)
and glyoxylate.
52. • Disorders are biochemically characterized by
the number of functions impaired.
• Multiple enzymes affected (peroxisomal
biogenesis defects) - Zellweger syndrome (ZS)
• Several enzymes involved- rhizomelic
chondrodysplasia punctata (RCDP)
• Single enzyme block- X-linked
adrenoleukodystrophy (XALD), Refsum
disease, hyperoxaluria
53. • Inheritance is autosomal recessive with the
exception of the XALD.
• The first-line investigation is very-long-chain
fatty acids which are elevated in ZS and XALD.
• Further investigation requires fibroblast
studies.
54. Zellweger syndrome
• ZS is the classic peroxisomal biogenesis
disorder with distinctive dysmorphic features.
• prominent forehead, hypertelorism, large
fontanelle.
55. • Clinical features of Zelweger syndrome
• Dysmorphic faces;
• Severe neurological involvement including
hypotonia, seizures and psychomotor retardation.
• Sensorineural deafness.
• Ocular abnormalities - retinopathy, cataracts
• Hepatomegaly and liver dysfunction
• Calcific stippling (especially knees and shoulders)
• Faltering growth.
56. • Diagnosis
• Loss of all peroxisomal functions - raised very-
long-chain fatty acids, phytanate and bile acid
intermediates and decreased plasmalogens.
• Confirmatory enzymology on fibroblasts.
58. X-linked adrenoleukodystrophy
(XALD)
• The paediatric cerebral form presents with severe
neurological degeneration, usually between 5 and 10
years.
• Brothers in the same family may present at different
ages.
• Clinical features of XAID
• School failure, behaviour problems
• Visual impairment
• Quadreplegia
• Seizures (late sign)
• Adrenal insufficiency
59. • Adrenal involvement may precede or follow
neurological symptoms by years.
• Some only develop neurological symptoms,
and others just have adrenal insufficiency.
• All males developing adrenal failure should
have very-long-chain fatty acid
measurements taken to ensure that the
diagnosis is not missed.
60. • Diagnosis
• Elevated very-long-chain fatty acids, blunted
synacthen response or frank hypoglycaemia.
• Neuroimaging shows bilateral, predominantly
posterior, white-matter invotvement.
• The differential diagnosis for neurodegeneration
in the school-age child includes:
• Subacute sclerosing panencephalitis .
• Batten disease
• Wilson disease
• Niemann-Pick C disease.
61. • Management
• Lorenzo's oil (oleic and erucic acid) normalizes
the very-long-chain fatty acids.
• Bone marrow transplantation is the mainstay
of therapy in patients before
neurodegeneration and those diagnosed after
presentation with adrenal insufficiency.
• Adrenal function should be closely monitored,
and steroid replacement therapy should be
given once it is indicated.
62. MUCOPOLYSACCHARIDOSES (MPS)
• Mucopolysaccharides (glycosaminoglycans) are
structural molecules integral to connective
tissues such as cartilage.
• Degradation occurs within lysosomes, requiring
specific enzymes.
• Patients with MPS appear normal at birth and
usually present with developmental delay in the
first year.
• The features of storage become more obvious
with time.
65. • Hurler syndrome is the classical MPS with storage
affecting the body and CNS.
• Sanfillipo syndrome predominantly affects the
CNS.
• Morquio and Maroteaux-Lamy syndromes affect
the body with Atlantoaxial instability often
necessitating prophylactic cervical spinal fusion in
the first 2-3 years.
• Hunter syndrome is phenotypically similar to
Hurler syndrome, however there is no corneal
clouding and scapular nodules are seen.
66. Hurler syndrome
• Hurler syndrome typifies the MPS group and
their associated clinical problems.
• The enzyme deficiency is a-iduronidase, a
deficiency .
68. • Radiographs show a characteristic skeletal
dysplasia known as dysostosis multiplex
• The earliest radiographic signs are thick ribs
and ovoid vertebral bodies.
• The lower ribs are broad and spatulate .
• The skull is large, the orbits shallow and the
sella turcica shoe shaped or J-shaped .
69. • The bones of the upper extremities become short and
taper toward the ends, often with enlargement of the
mid-portions.
• The ends of the radius and ulna angulate toward each
other.
• claw hand of the patient with Hurler syndrome is
pathognomonic of dysostosis multiplex.
• The metacarpals are broad at their distal ends and
taper at their proximal ends.
• The phalanges are thickened and bullet-shaped.
70. • The clavicle is absolutely characteristic, while the
lateral portion may be hypoplastic or even
absent.
• The vertebrae are hypoplastic, scalloped
posteriorly and beaked anteriorly, especially at
the thoracolumbar junction .
• There is anterior vertebral wedging, with
typically a hooked-shaped vertebre.
71. • Diagnosis
• Urinary screen for glycosaminoglycans (raised
dermatan and heparan sulphate).
• Enzymology confirmed on white cells.
72. • Management
• Treatment depends on early recognition to
allow early bone marrow transplantation,
which significantly modifies the phenotype.
• Enzyme replacement clinical trials are
currently underway.
• Supportive care is the mainstay of
untransplanted patients, with particular
regard to the chest and airway requiring 3-
monthly sleep studies.
73. SPHINGOLIPIDOSES
• Sphingolipids are complex membrane lipids.
• They are all derived from ceramide and can be divided
into three groups:
• cerebrosides, sphingomyelins and gangliosides.
• Lysosomal hydrolases break these molecules down;
• deficiencies result in progressive storage and disease.
• Typical features include psychomotor retardation,
neurological degeneration including epilepsy, ataxia
and spasticity, with or without hepatosplenomegaly.
75. • Diagnosis
• The presence of vacuolated lymphocytes on
the blood film is a further clue.
• Hexosaminidase A deficiency is confirmed on
white cell enzymology.
• Management
• Currently, management is supportive.
However, research into substrate-deprivation
therapy, thereby avoiding accumulation in the
first place, is under investigation.
76. Gaucher disease
• Glucocerebrosidase deficiency results in the
accumulation of cerebroside in the visceral
organs +/- the brain depending on the type.
• Clinical features of Gaucher disease
• Type 1
• Non-neuronopathic (commonest)
• Splenomegaly > hepatomegaly
• Anaemia, bleeding tendency
• Skeletal pain, deformities, osteopenia
• Abdominal pain (splenic infarcts)
77. • Type 2
• Acute neuronopathic
• Severe CNS involvement (especially bulbar),
rapidly progressive
• Convergent squinting and horizontal gaze palsy
• Hepatosplenomegaly
• Type 3
• Sub-acute neuronopathic
• Convergent squint and horizontal gaze palsy
(early sign)
• Splenomegaly > hepatomegaly
• Slow neurological deterioration
78. • Diagnosis
• Elevated angiotensin-converting enzyme (ACE)
and acid phosphatase are markers for the
disease.
• Bone marrow aspiration may reveal Gaucher cells
• White cell enzymes for glucocerebrosidase give
the definitive diagnosis.
• The enzyme chitotriosidase is markedly elevated
and may be used to follow disease activity.
79. • Management
• Enzyme replacement therapy is effective in
visceral disease in types 1 and 3.
• Bone marrow transplant has been used in the
past, and may have benefit for cerebral
involvement in type 3.
• Splenectomy has been used to correct
thrombocytopenia and anaemia and relieve
mechanical problems but may accelerate disease
elsewhere.
• There is no effective treatment for type 2.
81. Type 1 (sphingomyelinase deficiency)
• Clinical features of type 1
• Type A (infantile)
• Feeding difficulties
• Hepatomegaly > splenomegaly
• Cherry-red spot ·
• lung infiltrates
• Neurological decline, deaf, blind, spasticity
82. • Type B (visceral involvement)
• Milder course, no neurological involvement
• Hepatosplenomegaly
• Pulmonary infiltrates .
• Ataxia
• Hypercholesterolaemia
83. • Diagnosis
• Bone marrow aspirate for Niemann-Pick cells.
• White cell enzymes.
• Genotyping may help distinguish between the
two types before the onset of neurological
signs.
• Management
• Supportive.