[NEURO3] 2.8.08 INHERITED DISEASES OF THE NERVOUS SYSTEM.pdf

NEUROSCIENCES III INHERITED DISEASES OF THE NERVOUS SYSTEM 10 04 23 MAELA P. PALISOC, MD, DPPS, FCNSP, FPNA...

NEUROSCIENCES III INHERITED DISEASES OF THE NERVOUS SYSTEM 10 04 23 MAELA P. PALISOC, MD, DPPS, FCNSP, FPNA LE 2 | MOD 8| TRANS 08 OUTLINE I. Overview on Inborn Error of Metabolism A. Scope of Inborn Error of Metabolism II. Disorders of Amino Acid A. Phenylketonuria B. Maple Syrup Urine Disorder C. Related Organic Acidemia D. Urea Cycle Defect III. Disorders of Carbohydrate Metabolism A. Galactosemia IV. Lysosomal Storage Diseases A. Mucopolysaccharidoses B. Sphingolipidoses C. Glycoproteinoses Figure 1. Cellular Cycle V. Disorder in Lipid Metabolism: VLCL – Peroxisomal disorder II. DISORDERS OF AMINO ACID A. Adrenoleukodystrophy A. PHENYLKETONURIA (PKU) VI. Disorders of Purine and Pyrimidine Metabolism  Autosomal recessive disorder A. Lesch – Nyan Syndrome  Enzyme defect: low / absent (deficiency) of Phenylalanine VII. Mitochondrial Disease hydroxylase (PAH) VIII. When to Suspect Inborn Error of Metabolism  ☤ or its cofactor Tetrahydrobiopterin IX. Diagnostics  ☤ Failure to hydrolyze phenylalanine to tyrosine cause the accumulation of the metabolites in the body and the LEGENDS brain. Must know Lecturer Book Presentation OldTrans  PAH gene ★ ☤ 🕮 ⎘ ✐  Chr. 12 found in liver, kidney, and pancreas (NOT in [lec] [bk] [pt] [ot] brain, skin, fibroblast)  Consequences OBJECTIVES  inability to hydroxylate phenylalanine to tyrosine  Describe the causes of inherited disorder of the nervous  Different biochemical phenotype (degree of phenylalanine system elevation) depend on residual PAH activity  Describe the presentation of a patient with an inborn error of  ☤ or the degree of enzyme deficiency metabolism  Summarize the clinical findings that should prompt metabolic work up I. INBORN ERROR OF METABOLISM  Inherited disorder caused by mutation in the genes coding for proteins that functions in metabolism  MOST are inherited as autosomal recessive, 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 Figure 2. PKU in cellular level  Additional genes SEVERE PAH DEFICIENCY (CLASSIC PKU) A. SCOPE OF INBORN ERROR OF METABOLISM  Classic PKU – previous term (IEM)  Brain – main organ damage by PKU  Disorder of amino acid metabolism: PKU, MSUD and related  Plasma phenylalanine level > 20 mg/dL – severe PKU organic acidemia, UCD  Levels between 2 mg/dL and 10 mg/dL: mild  Disorder of carbohydrate metabolism: Galactosemia phenyalaninemia  Lysosomal storage disease: MPS, GP, SP  ☤ In affected infants with plasma concentration of > 20 mg/dL,  Disorder of lipid metabolism: VLCF – Peroxisomal disorder: excess phenylalanine is metabolized into phenyl ketones Adrenoleukodystrophy which are excreted in the urine giving rise to the term  Disorder of purine and pyrimidine: Lesch-Nyhan Syndrome phenylketonuria.  Mitochondrial disease [NEURO3] Araos, Borromeo, Gonzales, Ong, Portic TH Paulino 1 of 19 2.8.08 INHERITED DISEASE OF THE NERVOUS SYSTEM  Phenylalanine metabolized into PHENYLKETONES (phenylpyruvate and phenylacetic acid)  excreted in the urine  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 Figure 5. Symptoms of Untreated PKU DIAGNOSIS  NBS after 24 hours of life (☤ false negative if done earlier)  ☤ In infants with positive screening results diagnosis should be confirmed.  Confirmatory test  Quantitative plasma phenylalanine concentration > 10 mg/dL and low or normal tyrosine 1 to 4 mg/dL  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  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. Figure 3. Features of Severe PAH Deficiency  Maintain blood phenylalanine between 2 and 6 mg/dL throughout life UNTREATED PHENYLKETONURIA (PKU)  ☤ Discontinuation of therapy even in adulthood cause deterioration of IQ and cognitive performance.  Lighter complexion: blonde hair, blue eyes  Seborrheic dermatitis / eczematoid rash OUTCOME OF PKU  Microcephaly and growth retardation – common findings  Outcome of classic PKU is excellent.  Profound intellectual disability: IQ below 35 in 50 to 70% of  Normal intelligence if treated within 10 days of life patients (if it remains untreated)  Reversible cognitive dysfunction is associated with  ☤ Profound intellectual disability develops gradually. ACUTE ELEVATION of plasma phenylalanine in adults  Hyperactive with autistic behaviors (older and untreated and children with PKU. children)  If the elevated level has been SUSTAINED, the dysfunction  Movement disorder: purposeful hand movement, rhythmic may not be reversible. rocking, and athetosis  Treatment with modified preparation of tetrahydrobiopterin  ☤ PKU is suspected in a child with neurodevelopmental delay has shown good responses in some individuals with PKU. of unknown origin. B. MAPLE SYRUP URINE DISORDER  ☤ 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. Figure 4. Untreated PKU [NEURO3] Araos, Borromeo, Gonzales, Ong, Portic TH Paulino 2 of 19 2.8.08 INHERITED DISEASE OF THE NERVOUS SYSTEM DIAGNOSIS  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 1st 24 hours of life  Ketoacids may be detected using Qualitative test  Few drop of 2,4 DiNitroPhenylHydralazine plus urine = (+) yellow precipitate (POSITIVE RESULT) TREATMENT  Acute state  Hydration and rapid removal – BCAAs and metabolites from the tissues and body fluids  Control acidosis and seizure Figure 6. MSUD in Cellular Level  Parenteral fluid containing glucose should be started (see appendix for larger picture)  Hemodialysis – most effective therapy in critically ill patient and should be instituted promptly.  Autosomal recessive disorder  ☤ Significant decrease in plasma levels of leucine,  Enzyme defect: Oxidative decarboxylation of the isoleucine, and valine are usually evident within 24- Branched Chain Keto Acid via BCKA dehydrogenase hours post-dialysis. complex  Exchange transfusion for coma  Consequence: Accumulation of BCKA  Cerebral edema: Mannitol / Diuretics and hypertonic saline  -ketoisocaproic acid  ☤ Sufficient calories and nutrients should be provided IV  -ketoisovaleric acid or orally ASAP to reverse the patient’s catabolic state.  -keto--methylvaleric acid  Treatment after recovery: Dietary free in BCAA  Coenzyme use Vitamin B12 (thiamine)  ☤ Synthetic formula devoid of leucine, isoleucine, and valine are available commercially. CLASSIC MSUD (MOST SEVERE)  Healthy at birth PROGNOSIS  Poor feeding and vomiting – 1st days of life  The long-term prognosis of affected children remains  Lethargy and coma – may ensue within a few days guarded for MSUD.  Rapid deterioration of condition leading to death in first  Severe ketoacidosis, cerebral edema, and death few weeks or months of life if left untreated  May occur during stressful situation – infection and  Seizure occur in most infants, bulging fontanel, lower CN surgery dysfunction may be seen  Cognitive and neurologic deficits – common sequelae  Severe hypoglycemia – common (50%)  ☤ Correction of the blood glucose concentration does C. RELATED ORGANIC ACIDURIA not improve the clinical condition.  Signs of acute encephalopathy  ☤ Patients with uncontrolled or poorly controlled disease develop signs of acute encephalopathy. PHYSICAL EXAMINATION  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 NEUROLOGIC FINDINGS  Mistakenly thought as generalized SEPSIS and MENINGTIIS  DEATH Figure 7. Clinical approach to infants with organic acidemia LABORATORY FINDINGS (see appendix for larger picture)  KETOSIS, Hypoglycemia without Metabolic Acidosis  ☤ Aside from the severe hypoglycemia, routine  ☤ Algorithm for clinical approach in infant with organic laboratory findings are usually unremarkable except acidemia. There are numerous types of organic acidemia. for varying degree of ketosis.  ☤ Their clinical manifestations are same but differ in the defective enzymes involve. NEUROIMAGING  ☤ Majority present with ketosis, acidosis, hypoglycemia, and  Neuroimaging in the acute state may cause cerebral edema hyperammonemia. Some with elevated lactate. but after recovery from cerebral edema, there comes the  ☤ To differentiate it from one and the other are the present of cerebral atrophy which may be seen in neuroimaging of the ketosis and skin manifestation and characteristic odor. brain. [NEURO3] Araos, Borromeo, Gonzales, Ong, Portic TH Paulino 3 of 19 2.8.08 INHERITED DISEASE OF THE NERVOUS SYSTEM DEFICIENCIES WITH KETOSIS Table 5. Glutaric Acidemia Type 1 (Lysine Metabolism)  Methylmalonic acidemia Defective enzyme Glutaryl CoA dehydrogenase  Propionic acidemia or protein  Beta-ketothiolase deficiency Clinical features Dystonia, dyskinesia, degeneration  Multiple carboxylase deficiency of the caudate, and putamen,  Isovaleric acidemia FRONTOTEMPORAL ATROPHY Treatment Aggressive treatment of intercurrent KETOSIS + CHARACTERISTIC ODOR illness, Protein, lysin and tryptophan  Isovaleric acidemia RESTRICTION  Multiple carboxylases deficiency Diagnosis NBS and urine organic acid analysis  ☤ has skin manifestation aside from characteristic odor and ketosis  ☤ involve in lysine pathway of amino acid and has different TYPES 🖥 clinical manifestation Table 1. Propionic Acidemia (BCAA Metabolism) GLUTARIC ACIDEMIA 1 🖥 Defective enzyme Propionyl-CoA carboxylase  Frequently undiagnosed or misdiagnosed or protein  Normal development until 2 years’ old Clinical features Hypotonia, vomiting, lethargy, coma,  Neurologic deteriorating KETOACIDOSIS, HYPOGLYCEMIA  Infection / Encephalitic / Reye syndrome-like illness HyperNH4, bone marrow  Following routine immunization suppression, growth delay,  Signs and Symptoms intellectual disability, physical  Hypotonia disability  Dystonia Treatment During acute episodes, high-dose  Choreoathetosis glucose and aggressive fluid  Seizure resuscitation, protein  Macrocephaly (70%) RESTRICTION.  Stroke-like episodes (70%) Diagnosis NBS and urine organic acid analysis  ☤ associated with infarction of the basal ganglia Table 2. Methylmalonic Acidemia (BCAA Metabolism)  Neuroimaging Defective enzyme Methyl malonyl-CoA mutase  Frontotemporal atrophy with a bat wing or protein appearance (characteristic finding) (black arrow) Clinical features Hypotonia, vomiting, lethargy, coma,  Mistaken for child abuse or as NON-accidental trauma due KETOACIDOSIS, HYPOGLYCEMIA to → Intraretinal and subdural (red arrow) hemorrhage 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 Isovaleryl-CoA dehydrogenase or protein Clinical features Characteristic SWEATY FEET ODOR, KETOACIDOSIS, HYPOGLYCEMIA, HyperNH4, vomiting, lethargy, ACIDOSIS, Figure 8. Glutaric Acidemia in Imaging 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 Holocarboxylase synthetase or protein Clinical features CHARACTERISTIC CAT URINE ODOR, KETOACIDOSIS, RASH, ALOPECIA, seizures, hypotonia, developmental delay, defective T- and Bcell immunity, hearing loss, ELEVATED LACTATE Figure 9. Inborn Errors of Amino Acids Metabolism associated with Peculiar Odor Treatment Biotin and carnitine (see appendix for larger picture) Diagnosis NBS and urine organic acid analysis [NEURO3] Araos, Borromeo, Gonzales, Ong, Portic TH Paulino 4 of 19 2.8.08 INHERITED DISEASE OF THE NERVOUS SYSTEM D. UREA CYCLE DEFECT (UCD) 🖥  Misdiagnosed  SEPSIS  ☤ may succumb without correct diagnosis INFANT AND OLDER CHILDREN  Acute hyperammonemia  Vomiting  Neurologic abnormalities  Ataxia, confusion, agitation, irritability, combativeness, psychosis progress to coma Figure 10. Ammonia  ☤these manifestations may alternate with series of lethargy and somnolence that may progress to coma  Catabolism of AA results in production of ammonia  NO SPECIFIC FINDINGS in routine laboratory when  Ammonia (NH4) in high concentration hyperammonemia is caused by in UCD  Toxic to the CNS  Resulting in hyperammonemia or accumulation of urea ★ CAUSES OF HYPERAMMONEMIA 🖥 cycle metabolites Table 6. Causes of Hyperammonemia  Most common genetic cause of HYPERAMMONEMIA in Due to UCD Due to Organic acidemia infants  Low BUN  Severe acidosis  Autosomal recessive except for OTC deficiency  Unexplained increase  Ketonuria ALT & AST UREA CYCLE METABOLISM 🖥  Acute Liver Failure  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 12. IEM causing Hyperammonemia  ☤ this is table showing different diagnosis of hyperammonemia. Hyperammonemia due to urea cycle defect can be differentiated with organic acidemia by the presence of decrease or low blood urea.  ☤ some patient may initially present with unexplained liver function test elevation or transaminases elevation and even met the criteria for acute liver failure Figure 11. Urea Cycle Enzyme  ☤ in infant with organic acidemia, hyperammonemia is ★ Mnemonics: commonly associated with acidosis as well as ketonuria. Ordinarily, Careless Crappers Are Also Frivolous About Urination UREA CYCLE DEFECT 🖥 CLINICAL MANIFESTATION OF HYPERAMMONEMIA 🖥  ☤ All enzymes in the urea cycle are autosomal recessive NEONATAL PERIOD except for Ornithine transcarbamylase which is x-linked  Brain dysfunction located in the mitochondrial matrix  Normal at birth  Symptomatic following dietary protein CARBAMOYL PHOSPHATE SYNTHETASE 1(CPS1)  Refusal to eat, vomiting, lethargy, deep coma, seizures are  Complete absence of enzyme common  Most severe and FATAL  Increase ICP  HyperNH4 crisis  Bulging fontanel & dilated pupils  NORMAL to LOW Orotic acid  PE may reveal hepatomegaly in addition to obtundation [NEURO3] Araos, Borromeo, Gonzales, Ong, Portic TH Paulino 5 of 19 2.8.08 INHERITED DISEASE OF THE NERVOUS SYSTEM ORNITHINE TRANSCARBAMYLASE DEFICIENCY (OTC)  Most common  X-linked recessive ★  Severe in male  ☤ characterized biochemically by catastrophic elevation of blood NH4  INCREASED Orotic acid excretion CITRULLINEMIA  2nd most common  Markedly increased citrulline and arginine (50-100 times normal) ARGININOSUCCINIC ACIDURIA  Marked increased in Argininosuccinic acid in: Plasma, Urine, CSF ARGINASE / HYPERARGININEMIA Figure 14. Galactosemia in Cellular Level  Least common  Increase arginine in: Plasma, CSF TYPES CLASSIC GALACTOSEMIA  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 13. Urea Cycle ONE MORE TIME III. DISORDERS OF CARBOHYDRATE METABOLISM A. GALACTOSEMIA  Autosomal recessive disorder  Enzyme defect:  Galactose-1-phosphate uridyltransferase (GALT)  GALT gene  Chr. 9  Consequences  Accumulation of galactose-1-phosphate  Liver  Eyes  Kidney Figure 15. Classic Galactosemia Signs and Symptoms  Brain [NEURO3] Araos, Borromeo, Gonzales, Ong, Portic TH Paulino 6 of 19 2.8.08 INHERITED DISEASE OF THE NERVOUS SYSTEM UNTREATED GALACTOSEMIA IV. LYSOSOMAL STORAGE DISEASES  Cataract at 4 and 8 weeks of life A. MUCOPOLYSACCHARIDOSES  ☤ due to accumulation of galactitol  Hereditary progressive disease  Vitreous hemorrhage  Defect  Hepatic failure and Cirrhosis  Mutation of genes coding for lysosomal enzyme  Ascites  Consequences  Splenomegaly  Accumulation of undegraded macromolecules  Intellectual disability  Glycosaminoglycan (GAG’s) within lysosomes  Escherichia coli  Seven subtypes  Common complication with high frequency and cause of  Different glycosaminoglycan in each cases (share death similar symptoms)  ☤ Neonatal sepsis is a common complication  ☤ Differ according to the nature of storage and although  ☤ the onset of E. coli sepsis often precedes the diagnosis each of the disorder can cause a variety of different of Galactosemia symptoms, many MPS share similar symptoms such as  Pseudotumor cerebri corneal clouding, short stature, and joint stiffness.  Occur and cause bulging anterior fontanel  Autosomal recessive disorder  If untreated  Except HUNTER disease –X-linked recessive  Death from liver and kidney failure  Sepsis within a day TYPES  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  NBS  ☤ with the availability of newborn screening for galactosemia, it is possible to identify and treat patients earlier than before. Figure 16. MPS I spectrum of disease  Initial test (see appendix for larger picture)  (+) Reducing sugar  Urine  ☤ More appropriate to view MPS as continuous spectrum of  ☤ While the patient is on diet containing human milk, disease, with the most severely affected individual known cow’s milk, or any of the formula containing lactose as hurler on one end of the spectrum, and the less severely  Confirmatory test affected individual known as Scheie on the other end  Direct enzyme assay using erythrocytes / quantitative which is a whole range of different severity in between erythrocyte GALT analysis MPS I: HURLER SYNDROME  Severe progressive disorder TREATMENT  Multiple organ involvement  Early diagnosis and treatment  Premature death  Improved prognosis  10 years’ old  Cataract regress  Normal at birth  No visual impairment  Inguinal hernia and failed neonatal hearing test  Galactose free diet  Early signs  Commercially available non-lactose milk  Diagnosis  Calcium supplement reverses  6 - 24 months  Growth failure  ☤ with evidence of hepatosplenomegaly, coarse facial  Renal dysfunction features, corneal clouding, large tongue, enlarged head,  Hepatic dysfunction joint stiffness, short stature, and skeletal dysplasia.  ☤ All galactose containing food should be removed from the  Acute cardiomyopathy diet on initial suspicion of galactosemia.  C24 carbon chain length)  Progressive dysfunction of adrenal cortex and NS  Gene defect Figure 23. Glycoproteinoses Types  Mutation in ABCD1 gene (see appendix for larger picture)  ☤ the defective gene ABCD1 encodes for peroxisomal membrane protein  ☤ for Glycoproteinoses we talk about 6 disorders. ☤ ASPARTYLGLUCOSAMINURIA  The clinical features include coarse facies, developmental disability, speech delay, hepatomegaly, and angiokeratoma.  Hearing loss is not affected, additional neurologic symptoms are seizures and microcephaly. ☤ FUCOSIDOSIS  The clinical manifestation includes coarse facies, developmental disability, hepatosplenomegaly, and angiokeratoma.  Fucosidosis don’t have corneal clouding and hearing loss. Neurologic symptoms include seizures and spastic quadriplegia. Figure 25. Pathogenesis of X – ALD ☤ MANNOSIDOSIS  ☤ This is a schematic illustration of molecular mechanism  The clinical feature is similar with Hurler- like facial associated with the pathogenesis of ALD. appearance.  ☤ In a normal situation, the ABCD1 gene encodes  There is also mental retardation, skeletal abnormalities, adrenoleukodystrophy protein, which blocks the very long hearing loss, and hepatosplenomegaly chain fatty acid transport to peroxisome.  ☤ What happens in X-ALD is the mutated ABCD1 gene ☤ SIALIDOSIS 1 AND 2 encodes a defective adrenoleukodystrophy protein and  Share similar characteristics. the defective transport leads to the impaired degradation  The clinical features include cherry red macular spot, and subsequent accumulation of the very long chain fatty insidious vision loss, cataracts, progressive myoclonus and acid with resultant continue elongation of the ataxia with normal intelligence and negative hearing loss. progressively longer fatty acids.  ☤ SIALIDOSIS II  ☤ Finally, the nervous system and the adrenal cortex are  they have coarse facial feature, hepatomegaly, growth affected leading to neurodegeneration and Adrenocortical delay and dysostosis multiplex. insufficiency.  The treatment for Glycoproteinosis is Supportive Care FORM V. Disorder of the Lipid Metabolism - X – ALD CHILDHOOD CEREBRAL FORM Peroxisomal disorder: VERY LONG CHAIN  3 predominant phenotypes FATTY ACIDS  ☤ These 3 predominant phenotypes are  ☤ Child-onset cerebral form  ☤ Adrenomyeloneuropathy (or Adrenomyopathy)  ☤ Isolate Adrenal Insufficiency (Addison’s disease)  Childhood-onset CEREBRAL form  best known – 35% seen in individual  Development is normal in the 1st 3 to 4 years of life  At 4 to 8 years’ old  Behavioral or cognitive changes  Most common manifestation  Hyperactivity  Inattention  Worsening school performance  ☤ in a child who are previously been a good Figure 24. Classification of Peroxisomal Disorders student [NEURO3] Araos, Borromeo, Gonzales, Ong, Portic TH Paulino 10 of 19 2.8.08 INHERITED DISEASE OF THE NERVOUS SYSTEM  MISDIAGNOSED as Attention deficit disorder or TREATMENT hyperactivity (ADHD)  Lorenzo’s oil/diet rich in oleic erucic acid  Progressive disease is variable  VLCAF restriction  Complete symptom development at 6 months to 2 years  Lorenzo's oil  Vegetative state at 1.9 years from the first symptom (mean  decrease hexacosanoic acid-C26-0 interval)  DOES NOT stop of reverse cerebral disease  Continue on vegetative state for >10 years  ☤ once it has begun  ☤ the use of Lorenzo’s oil is investigational and CLINICAL MANIFESTATION should be performed in the context of a clinical  Auditory discrimination research protocol  ☤ Auditory discrimination is usually impaired although  Adrenal insufficiency or adrenocortical hypofunction tone perception is preserved. This may be evidence in  ☤ Included in treatment is corticosteroid replacement for difficulty using the telephone or greatly impaired adrenal insufficiency or adrenocortical hypofunction. performance on intelligence test in items that are  ☤ It may be lifesaving and increase general strength and presented verbally well-being, but it does not alter the course of neurologic  Spatial orientation disability.  ☤ is often impaired  Avoid complication: adrenal insufficiency  Disturbance of vision  Contracture, coma, and swallowing disturbances. hearing  involvement of parietooccipital cortex rather than the eye visual loss and seizure of optic tract abnormality  ☤ most difficult neurologic problems are those related to  Ataxia contracture, coma, swallowing injuries associated with  Poor handwriting defect of spatial orientation and impaired vision and  Seizure hearing, and seizure.  ☤ occur in nearly ALL patients  Maybe 1st manifestation of the disease  Strabismus  Progressive disease  Spasticity  Paralysis  Visual and hearing loss  Loss of ability to speak and swallow  ☤ Child-onset cerebral adrenoleukodystrophy tends to progress rapidly with increasing spasticity and paralysis as Figure 27. Lorenzo’s oil well as visual and hearing loss and loss of ability to speak and swallow  Adrenal insufficiency VI. DISORDER OF PURINE METABOLISM  Life threatening complication A. LESCH-NYHAN DISEASE (LND)  Impaired cortisol 85% of patient  X-linked recessive (Rare) of Purine Metabolism  Enzyme defect DIAGNOSIS & TREATMENT  Deficiency of hypoxanthine guanine phosphoribosyl transferase (HGPRT) DIAGNOSIS  ☤ The HGPRT gene has been localized to the long  Clinical Presentation arm. This enzyme is normally present in each cell in  Suggestive MRI features the body.  white matter lesions  HGPRT gene: Xq26-q27  occipital findings  All body cell (highest concentration in brain – basal  frontal and corpus callosum ganglia)  VLCFA in plasma, RBC, or cultured skin fibroblast  Consequences  most specific and important laboratory is the  overproduction of uric acid demonstration of very high VLCFA  Mutation analysis: identification of carriers  ☤ most reliable in terms of identification of carriers Figure 28. LND in cellular Level Figure 26. MRI of X – ALD [NEURO3] Araos, Borromeo, Gonzales, Ong, Portic TH Paulino 11 of 19 2.8.08 INHERITED DISEASE OF THE NERVOUS SYSTEM TYPES TREATMENT CLASSIC LND  Prevention of renal failure due to Hyperuricemia  SELF MUTILATION: hallmark of the disease  ☤ we manage LND to focus on the prevention of renal  Normal at birth failure by pharmacologic treatment of hyperuricemia  ☤ infant with LND have no apparent neurological  High fluid intake dysfunction. After several months, developmental delay  Allopurinol and neurologic signs have been apparent.  Low-purine intake is also required  4 months  Self-mutilation is managed through  Hypotonic  Behavioral management  Recurrent vomiting  Use of restrain / removal of teeth  Difficulty with secretion  Prevention of accumulation of uric acid will NOT alter  8 to 12 months neurologic manifestation of the disease  Extrapyramidal signs  ☤ Despite treatment, behavioral and neurological  Dystonia symptoms are unaffected.  Spasticity  Cognitive function: mild to moderate intellectual disability VII. MITOCHONDRIAL DISEASES  1-year-old: self-injurious behavior (SIB) begins with self- biting  Finger, mouth, and buccal mucosa are mutilated  ☤ Self biting is intense and causes tissue damage and may result in amputation of finger and substantial loss of tissue around the lips.  ☤ The intensity of self-injurious behavior generally requires that patients be restrained, and when restraints are removed, patients with Lesch Nyhan may appear terrified and stereotypically place a finger in their mouth.  ☤ The patient may ask for restrains to prevent elbow movement when the restrains are placed or replaced.  ☤ He may appear relaxed or cheerful. Figure 30. Mitochondrial Disease  Seizure in 50% (Swaiman 2017) (see appendix for larger picture)  Complication: renal failure and self-mutilation ☤ LEIGH DISEASE OR SUBACUTE NECROTIZING  ☤Most significant complication ENCEPHALOPATHY  a severe neurologic disorder that commences at birth.  Manifested as DIFFUSED ENCEPHALOPATHY and CENTRAL RESPIRATORY INSUFFICIENCY associated with LACTIC ACIDOSIS.  Patients typically die in 2-3 years usually due to respiratory failure. ☤ ALPERS DISEASE  is characterized by:  Seizure  Brain atrophy  Neuronal necrosis  Hearing and vision are also affected  In addition, hypotonia, loss of mental function and hepatic insufficiency are also noted. ☤ KEARNS-SAYRE SYNDROME Figure 29. LND signs and symptoms  is characterized by:  Progressive external ophthalmoplegia  Ptosis DIAGNOSIS  Atypical retinitis pigmentosa  Dystonia + self-mutilation = LND  Ragged-red fiber myopathy  ☤ dystonia plus self-mutilation of the mouth and fingers  Ataxia suggest LND  Deafness  Highly suggestive of HGPRT deficiency plus neurologic  Cardiomyopathy symptoms (best confirmed)  Typically occurs before age 20 years old  Serum UA > 4 to 5 mg UA/dl  Urine UA: Creatine ratio > 3 to 4:1 ☤ MERRF OR MYOCLONIC EPILEPSY WITH RAGGED RED  Definitive diagnosis FIBER, MYOCLONUS, AND MYOCLONIC EPILEPSY  Measurement of HGPRT enzyme in blood and tissue  A progressive disorder characterized by uncontrolled muscle (erythrocyte lysate assay) contraction--the myoclonic seizure.  ☤ individual with classic LND have near zero enzyme  Dementia, Ataxia, and Myopathy showing ragged-red fiber activity indicative of mitochondrial proliferation in a specialized stain  Molecular technique red biopsy  Identification of CARRIERS [NEURO3] Araos, Borromeo, Gonzales, Ong, Portic TH Paulino 12 of 19 2.8.08 INHERITED DISEASE OF THE NERVOUS SYSTEM ☤ MELAS, OR MITOCHONDRIA ENCEPHALOPATHY LACTIC OTHER DIAGNOSTIC TESTS ACIDOSIS AND STROKE-LIKE EPISODE  CSF lactate and pyruvate  a progressive neurodegenerative disease characterized by  X-rays of vertebrae and long bone repeated episodes of chemical strokes.  MRI / Ct scan  Associated with myopathy and lactic acidosis with clinical  Tissue biopsy (liver, skin, muscle, conjunctivae, manifestation of: lymphocytes) for microscopy, ultrastructural and biochemical  Migraine headache studies  Vomiting  Seizure URINE METABOLIC SCREENING  Deafness  Focal neurologic deficit  May progress to dementia. VIII. WHEN TO SUSPECT INBORN ERROR OF METABOLISM  Neurologic regression or arrest of development  A delay in motor development and severe hypotonia with no evident cause ⎘ (☤ according to Doc’s Audio – hypotonia with evident cause)  Presence of the following neurologic signs*  Certain non-neurologic abnormalities** Figure 31. Urine Metabolic screen panel  Occurrence of a neurologic disorder of similar or undetermined type in a sibling or other member of the family BIOCHEMICAL PROFILE A. PRESENCE OF THE FOLLOWING SIGNS*  Excessive and persistent acousticomotor reaction  Marked rigidity, tonic spasms, and head retraction  Peripheral neuropathy  Choreic movements, dystonic postures, or ataxia  Respiratory dysrhythmias without lung disease  Recurrent changes in sensorium with vomiting B. CERTAIN NON-NEUROLOGIC ABNORMALITIES**  Visceromegaly  Poor feeding, diarrhea, failure to thrive  Dysmorphic facial features  Skeletal changes  Skin and hair changes  Disturbances in respiratory, renal, and liver functions Figure 31. Biochemical Profile IX. DIAGNOSTICS A. ROUTINE NBS (5 DISEASE)  ☤ The mnemonics for GALAK--Glucose, ABG, Lactate,  Congenital hypothyroidism Ammonia and Ketone.  Congenital adrenal hyperplasia  ☤ for ORGANIC ACIDURIA (OA), you expect to have ketosis,  Phenylketonuria hyperammonemia, lactic acidosis, and hypoglycemia  G6PD  ☤ for UREA CYCLE DEFECT, HYPERAMMONEMIA is the  Galactosemia most prominent biochemical profile  ☤ for FATTY ACID OXIDASE, there is increase in Lactate B. EXPANDED NBS and Ammonia, and Decrease in Glucose, and you can find  Amino acid disorder Normal pH/Acidosis  Fatty acid disorder  ☤ for MSUD, Prominent is the KETOSIS and  Organic acid HYPOGLYCEMIA. You can also see Acidosis (Ketoacidosis)  Urea cycle defect  Biotinidase deficiency TREATMENT AND PROGNOSIS  Cystic fibrosis  Depends on the disease  Hemoglobinopathies C. DIAGNOSTIC BLOOD TEST X. REFERENCES  ABG (Acidosis) Maela Palisoc MD’s PPT Lecture Video  Ammonia Batch 2023 and Batch 2024 Trans  Amino Acid Books:  Lactate / Pyruvate Nelson: Textbook of Pediatrics 21st Edition  Glucose Swaiman: Pediatric Neurology 6th Edition  Uric acid Menkes: Child Neurology 7th Edition  Cholesterol  Carnitine, Ceruloplasmin, VLCFA TH Note: Will make another Trans for the Synch Session  [NEURO3] Araos, Borromeo, Gonzales, Ong, Portic TH Paulino 13 of 19 2.8.08 INHERITED DISEASE OF THE NERVOUS SYSTEM XI. APPENDIX Figure 6. MSUD in Cellular level Figure 7. Approach to infant with Organic Acidemia [NEURO3] Araos, Borromeo, Gonzales, Ong, Portic TH Paulino 14 of 19 2.8.08 INHERITED DISEASE OF THE NERVOUS SYSTEM Figure 9. Inborn Errors of AA metabolism associated with peculiar odor Table 1 – 5. Types of Related Organic acidemia Figure 16. MPS I Spectrume of Disease [NEURO3] Araos, Borromeo, Gonzales, Ong, Portic TH Paulino 15 of 19 2.8.08 INHERITED DISEASE OF THE NERVOUS SYSTEM Figure 18. Recognition pattern of MPS Figure 19. Types of MPS (I, II, and III) [NEURO3] Araos, Borromeo, Gonzales, Ong, Portic TH Paulino 16 of 19 2.8.08 INHERITED DISEASE OF THE NERVOUS SYSTEM Figure 20. Types of MPS (I, II, III, IV, and VI) Figure 22. Sphingolipidoses Type [NEURO3] Araos, Borromeo, Gonzales, Ong, Portic TH Paulino 17 of 19 2.8.08 INHERITED DISEASE OF THE NERVOUS SYSTEM Figure 23. Glycoproteinoses Types Bonus Tabulated form of MPS [NEURO3] Araos, Borromeo, Gonzales, Ong, Portic TH Paulino 18 of 19 2.8.08 INHERITED DISEASE OF THE NERVOUS SYSTEM Figure 30. Mitochondrial Disease Figure 31. GALAK Table (FAVORITE NI DOC so MEMORIZE) [NEURO3] Araos, Borromeo, Gonzales, Ong, Portic TH Paulino 19 of 19