Inherited Diseases of the Nervous System PDF

**OUTLINE** I. **Overview on Inborn Error of Metabolism** a. Scope of Inborn Error of Metabolism II. **Disorder of Amino Acid** a. Phenylketonuria b. Maple Syrup Urine Disorder c. Related Organic Acidemia d. Urea Cycle Defect III. **Disorders of Carbohydrate Metabolism*...

**OUTLINE** I. **Overview on Inborn Error of Metabolism** a. Scope of Inborn Error of Metabolism II. **Disorder of Amino Acid** a. Phenylketonuria b. Maple Syrup Urine Disorder c. Related Organic Acidemia d. Urea Cycle Defect III. **Disorders of Carbohydrate Metabolism** e. Galactosemia IV. **Lysosomal Storage Disease** f. Mucopolysaccharidoses g. Sphingolipidoses h. Glycoproteinoses V. **Disorders in Lipid Metabolism: VCL -- Peroxisomal disorder** i. Adrenoleukodystrophy VI. **Disorders of Purine and Pyrimidine Metabolism** j. Lesch-Nyhan Syndrome VII. **Mitochondrial Diseases** VIII. **When to Suspect Inborn Error of Metabolism** IX. **Diagnostics** X. **Cases: Plenary Session** XI. **Appendix** +-----------------------+-----------------------+-----------------------+ | **LEGEND** | | | +=======================+=======================+=======================+ | ⭐ | 🖊️ | 📖 | | | | | | Must | Lecture | Book | | | | | | Know | *\[lec\]* | *\[bk\]* | +-----------------------+-----------------------+-----------------------+ OBJECTIVE {#objective.TransOutline} ========= Describe the causes of inherited disorders of the nervous system Describe the presentation of a patient with an inborn error of metabolism Summarize the clinical finding that should prompt metabolic workup I. INBORN ERROR OF METABOLISM {#inborn-error-of-metabolism.TransOutline} ========================== Inherited disorder caused by mutation in the genes coding for proteins that functions in metabolism **AUTOSOMAL RECESSIVE- most inherited** rarely autosomal dominant / x-linked The disorder may cause complete dysfunction of the enzyme or may be partial or incomplete. Modifying etiologic factors: Environmental Epigenetic Microbiome factors - Additional genes SCOPE OF INBORN ERROR OF METABOLISM (IEM)⭐ {#scope-of-inborn-error-of-metabolism-iem.TransSubtopic1} ------------------------------------------ +-----------------------------------+-----------------------------------+ | **DISORDER OF AMINO ACID** | **PKU** | | | | | | **MSUD** | | | | | | **UCD** | | | | | | **Organic acidemia** | +===================================+===================================+ | **DISORDER OF CARBOHYDRATE | **GALACTOSEMIA** | | METABOLISM** | | +-----------------------------------+-----------------------------------+ | **LYSOSOMAL STORAGE DISEASE** | **MPS, GP, SP** | +-----------------------------------+-----------------------------------+ | **DISORDER OF LIPID METABOLISM** | **VLCF- PEROXISOMAL DISORDER: | | | Adrenoleukodytrophy** | +-----------------------------------+-----------------------------------+ | **DISORDER OF PURINE AND | **Lesch-Nyhan Syndrome** | | PYRIMIDINE** | | +-----------------------------------+-----------------------------------+ | **MITOCHONDRIAL DISEASE** | **Leigh disease** | +-----------------------------------+-----------------------------------+ DISORDER OF AMINO ACID {#disorder-of-amino-acid.TransOutline} ====================== A. PHENYLKETONURIA (PKU) {#a.-phenylketonuria-pku.TransSubtopic1} ------------------------ - **Autosomal RECESSIVE disorder** - Enzyme defect: low or absent (deficient) of **Phenylalanine Hydroxylase (PAH)** - Cofactor: **Tetrahydrobiopterin** - Failure to hydrolyze phenylalanine to tyrosine cause the accumulation of the metabolites in the body or brain - **PAH Gene** -- found in liver, kidney, and pancreas (NOT in brain, skin fibroblast) - Consequences: inability to hydroxylate phenylalanine to tyrosine - Different biochemical phenotype (degree of phenylalanine elevation) depends on residual PAH activity **Figure 1. PKU MECHANISM** Severe PAH Deficiency (CLASSIC PKU) {#severe-pah-deficiency-classic-pku.TransSub-subtopic2} ----------------------------------- - Brain -- main organ damage - Severe PKU - Plasma Phenylalanine level -- MORE than 20mg/dl - MILD Phenylaninemia - Levels between 2 mg/dL and 10 mg/dL - In affected infants with plasma concentration of \> 20 mg/dL, excess phenylalanine is metabolized into phenyl ketones which are excreted in the urine giving rise to the term phenylketonuria - Phenylalanine metabolized into PHENYLKETONES (phenylpyruvate and phenylacetic acid) 🡪 excreted in the urine #### Clinical features: {#clinical-features.TransSub-subtopic3} - Musty / mousey odor due to phenylacetic acid - Appears healthy / normal at birth - Severe vomiting: (early sign) misdiagnosed as pyloric stenosis - Delayed intellectual development by 4 to 9 months - Neurologic signs: seizures (25%), spasticity, hyperreflexia, and tremors - More than 50% - abnormal EEG  UNTREATED PHENYLETONURIA (PKU) {#untreated-phenyletonuria-pku.TransSub-subtopic2} ------------------------------ - Suspected to have neurodevelopmental delay of unknown origin #### Clinical Features: {#clinical-features-1.TransSub-subtopic3} - Lighter complexion: blonde hair, blue eyes - Seborrheic dermatitis / eczematoid rash - Microcephaly and growth retardation -- common findings - Profound intellectual disability: IQ below 35 in 50 to 70% of patients (if it remains untreated) - Profound intellectual disability develops gradually. - Hyperactive with autistic behaviors (older and untreated children) - Movement disorder: purposeful hand movement, rhythmic rocking, and athetosis **Figure 3:** **Symtoms Of Untreated Pku** DIAGNOSIS {#diagnosis.TransSub-subtopic2} --------- - Confirmatory test - Quantitative plasma phenylalanine concentration \> 10 mg/dL and low or normal tyrosine 1 to 4 mg/dL - NBS after 24 hours of life (false negative if done earlier) - In infants with positive screening results diagnosis should be confirmed. - Simple diagnostic test: Urine Ferric Chloride - Identification of phenyl ketones in the urine by ferric chloride may offer a simple test for diagnosis of infants with unknown cause of developmental and neurologic abnormalities. TREATMENT {#treatment.TransSub-subtopic2} --------- - Goal of therapy: Reduced phenylalanine level in the plasma and brain - Mainstay of treatment: Lifelong low phenylalanine diet 🡪 Start treatment: If more than 10 mg/dL - Started as soon as the diagnosis is established - Commercially available formula free or low phenylalanine - Monitoring of blood 2x per week for the first 6 months and 2x per month thereafter. - Maintain blood phenylalanine between 2 and 6 mg/dL throughout life - Discontinuation of therapy even in adulthood cause deterioration of IQ and cognitive performance. OUTCOME OF PKU {#outcome-of-pku.TransSub-subtopic2} -------------- - Outcome of classic PKU is excellent. - Normal intelligence if treated within 10 days of life - Reversible cognitive dysfunction is associated with ACUTE ELEVATION of plasma phenylalanine in adults and children with PKU. - If the elevated level has been SUSTAINED, the dysfunction may not be reversible. - Treatment with modified preparation of tetrahydrobiopterin has shown good responses in some individuals with PKU B. MAPLE SYRUP URINE DISORDER {#b.-maple-syrup-urine-disorder.TransSubtopic1} ----------------------------- - **Autosomal RECESSIVE DISORDER** - Enzyme defect: **Oxidative decarboxylation of the Branched Chain** **Keto Acid via BCKA dehydrogenase complex** - Coenzyme: **vitamin B12 (thiamine)** - Consequence: **Accumulation of BCKA** - á-ketoisocaproic acid - á-ketoisovaleric acid - á-keto-â-methylvaleric acid - The deficiency of branched chain keto -- dehydrogenase results in MSUD, whereas deficiency of enzyme mediating more distal steps results in accumulation of enzyme specific organic acid excreted in the urine. - Thus, giving those inborn error metabolisms the eponyms of organic acidemia and organic aciduria. This disorder typically causes metabolic acidosis which usually occurs in the first day of life. CLASSIC MSUD (MOST SEVERE) {#classic-msud-most-severe.TransSub-subtopic2} -------------------------- - Healthy at birth - Poor feeding and vomiting -- 1^st^ days of life - Lethargy and coma -- may ensue within a few days - Rapid deterioration of condition leading to death in first few weeks or months of life if left untreated - Seizure occur in most infants, bulging fontanel, lower CN dysfunction may be seen - Severe hypoglycemia -- common (50%) - Correction of the blood glucose concentration does not improve the clinical condition. - Signs of acute encephalopathy - Patients with uncontrolled or poorly controlled disease develop signs of acute encephalopathy. #### PHYSICAL EXAMINATION: {#physical-examination.TransSub-subtopic3} - Hypertonic and muscle rigidity (alternate with flaccidity and repetitive abnormal movement of extremities) - 🖊️Periods of hypertonicity may alternate with bouts of flaccidity manifested as repetitive movements of extremities such as boxing and bicycling movement. - Severe opisthotonos - Odor maple syrup in urine and sweat #### NEUROLOGICAL EXAM FINDINGS: {#neurological-exam-findings.TransSub-subtopic3} - Mistakenly thought as generalized SEPSIS and MENINGITIS \--\> DEATH LABORATORY FINDINGS {#laboratory-findings.TransSub-subtopic2} ------------------- - KETOSIS, Hypoglycemia without Metabolic Acidosis - Aside from the severe hypoglycemia, routine laboratory findings are usually unremarkable except for varying degree of ketosis. NEUROIMAGING {#neuroimaging.TransSub-subtopic2} ------------ - ACUTE \--\> CEREBRAL EDEMA - After recovery from cerebral edema \--\> CEREBRAL ATROPHY {#section.TransSub-subtopic2} DIAGNOSIS {#diagnosis-1.TransSub-subtopic2} --------- - Maple syrup odor in urine, sweat, and cerumen - Can do expanded NBS - Once positive, can confirmed by Amino Acid Analysis: - Plasma levels Leucine, Isoleucine, Valine markedly elevated in 1^st^ 24 hours of life - Ketoacids may be detected using Qualitative test - Few drop of 2,4 DiNitroPhenylHydralazine plus urine = (+) yellow precipitate (POSITIVE RESULT) TREATMENT {#treatment-1.TransSub-subtopic2} --------- - Acute state - Hydration and rapid removal -- BCAAs and metabolites from the tissues and body fluids - Control acidosis and seizure - Parenteral fluid containing glucose should be started - Hemodialysis -- most effective therapy in critically ill patient and should be instituted promptly. - Significant decrease in plasma levels of leucine, isoleucine, and valine are usually evident within 24-hours post-dialysis. - Exchange transfusion for coma - Cerebral edema: Mannitol / Diuretics and hypertonic saline - Sufficient calories and nutrients should be provided IV or orally ASAP to reverse the patient's catabolic state. - Treatment after recovery: Dietary free in BCAA - Synthetic formula devoid of leucine, isoleucine, and valine are available commercially PROGNOSIS {#prognosis.TransSub-subtopic2} --------- - The long-term prognosis of affected children remains guarded for MSUD. - Severe ketoacidosis, cerebral edema, and death - May occur during stressful situation -- infection and surgery - Cognitive and neurologic deficits -- common sequelae C. RELATED ORGANIC ACIDURIA {#c.-related-organic-aciduria.TransSubtopic1} ---------------------------  **Figure 4. Organic Aciduria Clinical Approach** - Algorithm for clinical approach in infant with organic acidemia. There are numerous types of organic acidemia. - Their clinical manifestations are same but differ in the defective enzymes involve. - Majority present with ketosis, acidosis, hypoglycemia, and hyperammonemia. Some with elevated lactate. - To differentiate it from one and the other are the present of ketosis and skin manifestation and characteristic odor. DEFICIENCIES WITH KETOSIS {#deficiencies-with-ketosis.TransSub-subtopic2} ------------------------- - Methylmalonic acidemia - Propionic acidemia - Beta-ketothiolase deficiency - Multiple carboxylase deficiency - Isovaleric acidemia KETOSIS + CHARACTERISTC ODOR {#ketosis-characteristc-odor.TransSub-subtopic2} ---------------------------- - Isovaleric acidemia - Multiple carboxylases deficiency - has skin manifestation aside from characteristic odor and ketosis ⭐ TYPES {#types.TransSub-subtopic2} ------- {#section-1.TransSubtopic1} +-----------------------------------+-----------------------------------+ | **Table 1. Propionic Acidemia | | | (BCAA Metabolism)** | | +-----------------------------------+-----------------------------------+ | Defective enzyme or protein | Propionyl-CoA carboxylase | +-----------------------------------+-----------------------------------+ | Clinical features | Hypotonia, vomiting, lethargy, | | | coma, KETOACIDOSIS, HYPOGLYCEMIA | | | HyperNH4, bone marrow | | | suppression, growth delay, | | | intellectual disability, physical | | | disability | +-----------------------------------+-----------------------------------+ | Treatment | During acute episodes, high-dose | | | glucose and aggressive fluid | | | resuscitation, protein | | | RESTRICTION. | +-----------------------------------+-----------------------------------+ | Diagnosis | NBS and urine organic acid | | | analysis | +-----------------------------------+-----------------------------------+ | **Table 2. Methylmalonic Acidemia | | | (BCAA Metabolism)** | | +-----------------------------------+-----------------------------------+ | Defective enzyme or protein | Methyl malonyl-CoA mutase | +-----------------------------------+-----------------------------------+ | Clinical features | Hypotonia, vomiting, lethargy, | | | coma, KETOACIDOSIS, HYPOGLYCEMIA | | | HyperNH4, bone marrow | | | suppression, growth delay, | | | intellectual disability, physical | | | disability | +-----------------------------------+-----------------------------------+ | Treatment | During acute episodes, high-dose | | | glucose and aggressive fluid | | | resuscitation, protein | | | RESTRICTION | +-----------------------------------+-----------------------------------+ | Diagnosis | NBS and urine organic acid | | | analysis | +-----------------------------------+-----------------------------------+ | **Table 3. Isovaleric Acidemia | | | (BCAA Metabolism)** | | +-----------------------------------+-----------------------------------+ | Defective enzyme or protein | Isovaleryl-CoA dehydrogenase | +-----------------------------------+-----------------------------------+ | Clinical features | Characteristic [SWEATY FEET | | | ODOR], KETOACIDOSIS, | | | HYPOGLYCEMIA, HyperNH4, vomiting, | | | lethargy, ACIDOSIS, intellectual | | | disability, bone marrow | | | suppression, neonatal death | +-----------------------------------+-----------------------------------+ | Treatment | Controlled leucine intake | | | | | | glycine and carnitine | +-----------------------------------+-----------------------------------+ | Diagnosis | NBS and urine organic acid | | | analysis | +-----------------------------------+-----------------------------------+ +-----------------------------------+-----------------------------------+ | **Table 4. Multiple Carboxylase | | | Deficiency** | | | | | | **(BCAA Metabolism)** | | +-----------------------------------+-----------------------------------+ | Defective enzyme or protein | Holocarboxylase synthetase | +-----------------------------------+-----------------------------------+ | Clinical features | CHARACTERISTIC [CAT URINE | | | ODOR], KETOACIDOSIS, | | | RASH, ALOPECIA, seizures, | | | hypotonia, developmental delay, | | | defective T- and Bcell immunity, | | | hearing | | | | | | loss, ELEVATED LACTATE | +-----------------------------------+-----------------------------------+ | Treatment | Biotin and carnitine | +-----------------------------------+-----------------------------------+ | Diagnosis | NBS and urine organic acid | | | analysis | +-----------------------------------+-----------------------------------+ | **Table 5. Glutaric Acidemia Type | | | 1 (Lysine Metabolism)** | | +-----------------------------------+-----------------------------------+ | Defective enzyme or protein | Glutaryl CoA dehydrogenase | +-----------------------------------+-----------------------------------+ | Clinical features | Dystonia, dyskinesia, | | | degeneration of the caudate, and | | | putamen, FRONTOTEMPORAL ATROPHY | +-----------------------------------+-----------------------------------+ | Treatment | Aggressive treatment of | | | intercurrent illness, Protein, | | | lysin and tryptophan RESTRICTION | +-----------------------------------+-----------------------------------+ | Diagnosis | NBS and urine organic acid | | | analysis | +-----------------------------------+-----------------------------------+ - Involve in LYSINE pathway of amino acid and has different clinical manifestation GLUTARIC ACIDEMIA 1 {#glutaric-acidemia-1.TransSub-subtopic2} ------------------- - Frequently undiagnosed or misdiagnosed - Normal development until 2 years' old - Neurologic deteriorating - Infection / Encephalitic / Reye syndrome-like illness - Following routine immunization #### CLINICAL FEATURES: {#clinical-features-2.TransSub-subtopic3} - Signs and Symptoms - Hypotonia - Dystonia - Choreoathetosis - Seizure - Macrocephaly (70%) - Stroke-like episodes (70%) - associated with infarction of the basal ganglia - Neuroimaging - Frontotemporal atrophy with a bat wing appearance (characteristic finding) (black arrow) - Mistaken for child abuse or as NON-accidental trauma due to → Intraretinal and subdural (red arrow) hemorrhage **Figure 5: Inborn Error Of Metabolism Table** **Figure 6. Neuroimaging of Glutamic Acidemia** D. UREA CYCLE DEFECT (UCD) {#d.-urea-cycle-defect-ucd.TransSubtopic1} -------------------------- - **Autosomal RECESSIVE except OTC deficiency** - **Catabolism of AA results in production of ammonia** - **Ammonia (NH4) in high concentration** - Toxic to the CNS - Resulting in hyperammonemia or accumulation of urea cycle metabolites - Most common genetic cause of HYPERAMMONEMIA in infants UREA CYCLE METABOLISM {#urea-cycle-metabolism.TransSub-subtopic2} --------------------- - Absence of ENZYME for conversion leads to accumulation of substrate - Defects in the enzyme catalyzing the 5 STEPS of urea cycle pathway - Enzymes - Carbamoyl phosphate synthetase 1(CPS1) - Ornithine transcarbamylase (OTC) - Argininosuccinate synthetase (ASS) - Argininosuccinate lyase (ASL) - Arginase1 - N-acetylglutamate synthetase (NAG) - catalyze the synthesis of NA which is an obligatory activator for the CPS1 enzyme - Any metabolic pathway in the absence of any of this enzyme in the step leads to the accumulation of the substrate. **Figure 7: Urea Cycle Pathway** **MNEMONICS:** **Old Colorful Cats Always Ask For Awesome Umbrella** CLINICAL MANIFESTATIONS OF HYPERAMMONEMIA {#clinical-manifestations-of-hyperammonemia.TransSub-subtopic2} ----------------------------------------- #### NEONATAL PERIOD {#neonatal-period.TransSub-subtopic3} - Brain dysfunction - Normal at birth - Symptomatic following dietary protein - Refusal to eat, vomiting, lethargy, deep coma, seizures are common - Increase ICP - Bulging fontanel & dilated pupils - PE may reveal hepatomegaly in addition to obtundation - Misdiagnosed - SEPSIS- deadly; kaya need ma diagnose correctly #### INFANT AND OLDER CHILDREN {#infant-and-older-children.TransSub-subtopic3} - Acute hyperammonemia - Vomiting - Neurologic abnormalities - Ataxia, confusion, agitation, irritability, combativeness, psychosis → progress to coma - ⭐ these manifestations may alternate with series of lethargy and somnolence that may progress to coma - NO SPECIFIC FINDINGS in routine laboratory when hyperammonemia is caused by in UCD +-----------------------------------+-----------------------------------+ | **Table 6. Causes of | | | Hyperammonemia ⭐** | | +-----------------------------------+-----------------------------------+ | **Due to UCD** | **Due to Organic acidemia** | +-----------------------------------+-----------------------------------+ | 1. Low BUN | 4. Severe acidosis | | | | | 2. Unexplained increase ALT & | 5. Ketonuria | | AST | | | | | | 3. Acute Liver Failure | | +-----------------------------------+-----------------------------------+ ####  {#section-2.TransSub-subtopic3} **Figure 8: Hyperammonemia** - Hyperammonemia due to urea cycle defect can be differentiated with organic acidemia by the presence of decrease or low blood urea. - Some patients may initially present with unexplained liver function test elevation or transaminases elevation and even met the criteria for acute liver failure - In infant with organic acidemia, hyperammonemia is commonly associated with acidosis as well as ketonuria. UREA CYCLE DEFECT {#urea-cycle-defect.TransSub-subtopic2} ----------------- - All enzymes in the urea cycle are autosomal recessive except for Ornithine transcarbamylase which is x-linked located in the mitochondrial matrix CARBOMYL PHOSPHATE SYNTHETASE 1 (CPS1) {#carbomyl-phosphate-synthetase-1-cps1.TransSub-subtopic2} -------------------------------------- - Complete absence of enzyme - Most severe and FATAL - HyperNH4 crisis - NORMAL to LOW Orotic acid ORNITHINE TRANSCARBAMYLASE DEFICIENCY (OTC) {#ornithine-transcarbamylase-deficiency-otc.TransSub-subtopic2} ------------------------------------------- - Most common - X-linked recessive ⭐ - Severe in male - characterized biochemically by catastrophic elevation of blood NH4 - INCREASED Orotic acid excretion CITRULLINEMIA {#citrullinemia.TransSub-subtopic2} ------------- - 2^nd^ Most common - Markedly increased citrulline and arginin (50-100 times normal) ARGININOSUCCINIC ACIDURIA {#argininosuccinic-aciduria.TransSub-subtopic2} ------------------------- - Marked increased in Argininosuccinic acid in: Plasma, Urine, CSF {#section-3.TransSub-subtopic2} ARGINASE HYPERARGININEMIA {#arginase-hyperargininemia.TransSub-subtopic2} ------------------------- - Least common - Increase arginine in: Plasma, CSF DISORDER OF CARBOHYDRATE METABOLISM {#disorder-of-carbohydrate-metabolism.TransOutline} =================================== GALACTOSEMIA {#galactosemia.TransSubtopic1} ------------ - Autosomal recessive disorder - Enzyme defect: - Galactose-1-phosphate uridyltransferase (GALT) - GALT gene - Chr. 9 - Consequences - Accumulation of galactose-1-phosphate 1. Liver 2. Eyes 3. Kidney 4. Brain CLASSIC GALACTOSEMIA {#classic-galactosemia.TransSub-subtopic2} -------------------- - Normal at birth - Onset of symptoms - By the end of the first week of life - When milk feeding begins - Prolonged period of jaundice - Started at 4 and 10 days of life - 1st several weeks - Hepatomegaly - Hypothrombinemia - Edema - CNS symptoms - Lethargy - Irritability - Hypotonia due to cerebral edema - Anorexia, vomiting, and diarrhea - After appearance of CNS symptoms - Other symptoms - Hypoglycemia - Mild - Seizure - Feeding difficulties - Poor weight gain - or failure to regain birth weight - Renal dysfunction **Figure 9: Galactosemia** UNTREATED GALACTOSEMIA {#untreated-galactosemia.TransSub-subtopic2} ---------------------- - Cataract at 4 and 8 weeks of life - due to accumulation of galactitol - Vitreous hemorrhage - Hepatic failure and Cirrhosis - Ascites - Splenomegaly - Intellectual disability - Escherichia coli - Common complication with high frequency and cause of death - Neonatal sepsis is a common complication - the onset of E. coli sepsis often precedes the diagnosis of Galactosemia - Pseudotumor cerebri - Occur and cause bulging anterior fontanel - If untreated - Death from liver and kidney failure - Sepsis within a day - Delay diagnosis at birth leads to - Liver damage (cirrhosis) - Brain (intellectual disability) - Irreversible and increasingly severe - Complete withdrawal of lactose from the diet results in improvement of acute symptoms DIAGNOSIS {#diagnosis-2.TransSub-subtopic2} --------- - Newborn Screening - with the availability of newborn screening for galactosemia, it is possible to identify and treat patients earlier than before. - Initial test - (+) Reducing sugar - Urine - While the patient is on diet containing human milk, cow's milk, or any of the formula containing lactose - Confirmatory test - Direct enzyme assay using erythrocytes / quantitative erythrocyte GALT analysis TREATMENT {#treatment-2.TransSub-subtopic2} --------- - Early diagnosis and treatment - Improved prognosis - Cataract regress - No visual impairment - Galactose free diet - Commercially available non-lactose milk - Calcium supplement reverses - Growth failure - Renal dysfunction - Hepatic dysfunction - All galactose containing food should be removed from the diet on initial suspicion of galactosemia. - Various non-lactose-containing milk substitutes are available. - Adequate calcium supplementation reverses growth failure and renal as well as hepatic dysfunction. - Cataract regress in most patients have no impairment of vision. - Early diagnosis and treatment have improved the prognosis of galactosemia. LYSOSOMAL STORAGE DISEASES {#lysosomal-storage-diseases.TransOutline} ========================== MUCOPOLYSACCHARIDOSES {#mucopolysaccharidoses.TransSubtopic1} --------------------- - Hereditary progressive disease - Defect: Mutation of genes coding for lysosomal enzyme - Consequences - Accumulation of undegraded macromolecules - Glycosaminoglycan (GAG's) within lysosomes - Seven subtypes - Different glycosaminoglycan in each case (share similar symptoms) - Differ according to the nature of storage and although each of the disorder can cause a variety of different symptoms, many MPS share similar symptoms such as corneal clouding, short stature, and joint stiffness. - Autosomal recessive disorder - **⭐ Except** HUNTER disease -- X-linked recessive TYPES {#types-1.TransSub-subtopic2} -----  **Figure 10. MPS I spectrum of disease** - More appropriate to view MPS as continuous spectrum of disease, with the ⭐**most severely affected individual known as hurler** on one end of the spectrum, and the ⭐**less severely affected individual known as Scheie** on the other end which is a whole range of different severity in between MPS I: HURLER SYNDROME {#mps-i-hurler-syndrome.TransSubtopic1} ---------------------- - Severe progressive disorder - Multiple organ involvement - Premature death - Usually by 10 years old - Normal at birth - Inguinal hernia and failed neonatal hearing test - Early signs - Diagnosis - at 6-24 months - With evidence of hepatosplenomegaly, coarse facial features, corneal clouding, large tongue, enlarged head, joint stiffness, short stature, and skeletal dysplasia. - Acute cardiomyopathy - \