1802410
| Question | Answer |
| Phenylketonuria | Phenylalanine hydroxylase deficiency AR, Prevalence: 1/15,000 Clinical untreated: MR, Seizures, Autism, Eczema, light complexion, mousy odor, substantia nigra may lack pigment Dx: Phe > 1200 umol/L Rx: phe-restricted diet, in some BH4, large neutral amino acids, recombinant PEG-PAL |
| Maple Syrup Urine Disease | Incidence: 1/150,000 Autosomal Recessive Deficiency: branched-chain beta-ketoacid decarboxylase NBS marker: High leucine Clinical: MR, vomiting first week of life Rx: diet restricted in BCAA, Thiamine (B1) |
| Homocystinuria | AR, Incidence: 1/150,000 Def: Cystathione beta-synthase NBS marker: high methionine Sx: MR, dislocation of lens, seizures, thrombosis, scoliosis, pectus excavatum, arachnodactyly, osteoporosis Dx: positive cyanide nitroprusside test (detects high homocystine in urine), confirm with plasma homocystine elevation Rx: enzyme cofactor pyridoxal phosphate helps some (usually Ile278Thr), dipyridamole, ASA |
| Galactosemia | AR, Incidence: 1/55,000 Def: galactose 1-phophate uridyl transferase NBS marker: Galactose, GALT (EMERGENCY) Clinical: vomiting, lethargy, FTT, jaundice, cataracts, MR, cirrhosis Rx: diet without galactose and lactose |
| Biotinidase Deficiency | Gene: AR, 1/32,000 NBS marker: Biotinidase activity Sx: alopecia, rash |
| Hypothyroidism | Incidence: 1/2,000 NBS marker: T4, TSH |
| Adrenal Hyperplasia | Incidence: 1/15,000 NBS marker: 17-hydroxyprogesterone |
| Arginase Deficiency | AR NBS marker: Arginine Clinical: hyperammonemia, progressive spasticity, ID |
| Arginosuccinic aciduria (Agininosuccinicate lyase deficiency) | Markers: ASA, Cit Sx: trichorrhexis nodosa |
| Citrullinemia-1 (Argininosuccinicate synthase deficiency) | AR Markers: Cit |
| Citrullinemia-II (Citrin-mitochondrial aspartate-glutamate transporter deficiency) | Sx: neonatal hempatitis, adult-onset citrullinemia Dx: high ornintine, high ammonia, Citrulline Dx: AR, gene SLC25A13 Rx: low protein diet |
| Carbomyl Phophate Deficiency | Marker: Ala, Low Cit Clinically urine orotic acid is low (helps DDx between OTC where it is high) |
| N-acetyl glutamate synthase | Marker: Ala, low cit |
| Ornithine transcarbamylase deficiency | XD Deficiency: Ornithine carbamyl transferase deficiency NBS marker: Ala, low cit Clinical: hyperammonemia, coma, death in early infancy in males Rx: dextrose, IV ammonul, IV arginine hydrochloride, hemodialysis, liver transplantation |
| Hyperammonemia-Hyperornithinemia-Homocitrullinuria Syndrome (HHH) | Marker: orn Sx: episodic hyperammonemia Dx: high ornithine, high homocitrulline Gene: AR, Ornithine Transporter (ORNT1) transports ornithine into mitochondria. Rx: low protein, citrulline supplement |
| Tyrosinemia I | Gene: AR, 1/5000 French Canadians Enzyme: Fumarylacetoacetate NBS Marker: succinylacetone Sx: liver failure, cirrhosis, hepatic cancer (35-40%) by 5 yo, renal fanconi syndrome, FTT, neurologic crises Dx: UOA + succinylacetone, PAA high Tyr and Met Rx: NTBC, low Phe/Tyr diet, liver transplant |
| Tyrosinemia II | Gene: AR Enzyme: Tyrosine Aminotransferase Marker: Tyrosine Sx: ID, corneal dystrophy, hyperkeratosis, erosions of palms and soles Dx: PAA high Tyr, UOA high 4-OH-phenyl lactate and N-acetyltyrosine Rx: low tyrosine diet |
| Tyrosinemia III (4-hydroxyphenylpyruvic acid deoxygenate deficiency) | Marker: Tyrosine |
| Propionic Acidemia | Sx: poor feeding, FTT, vomiting, acidosis, hypoglycemia, bone marrow suppression, renal disease, cardiomyopathy, pancreatitis Gene: AR, propionyl-CoA carboxylase NBS Marker: C3 Dx: UOA 3-OH propionic acid, met of propionyl CoA (tigylglycine, propionylglycine, methylcitrate) Rx: low protein diet, restrict precursors VOMIT (Val, Met, Ile, Thr, odd chain FA), carnitine, biotin, carbiglu?, metronidazole? |
| Methylmalonic Aciduria | Gene: AR, methylmalonyl-CoA mutase NBS marker: C3 Sx: hypotonia, poor feeding, acidosis, DD, macrocytic anemia, bone marrow suppression, renal disease, cardiomyopathy, pancreatitis Dx: UOA - high methylmalonic acid, met of propionyl CoA carboxylase Rx: low protein diet, restrict precursors VOMIT (Val, Met, Ile, Thr, odd chain FA), carnitine, biotin, carbiglu?, metronidazole? |
| Methylmalonyl-CoA mutase deficiency | Marker: C3 |
| Cobalamin defects A, B (Adenosylcobalamin) | Marker: C3 MMA only |
| Cobalamin defects C, D | Markers: C3, Met Cobalamin C most common MMA and homocystinuria |
| Multiple carboxylase deficiency | Markers: C3, C5OH |
| 3-hydroxyisobutyric aciduria | Marker: C4OH |
| Isovaleric Acidemia | Gene: AR, deficiency of isovaleryl CoA dehydrogenase Sx: metabolic acidosis, odor of sweaty feet, poor feeding, vomiting, lethargy, coma, seizures NBS Marker: C5 Dx: metabolic acidosis, increased AG, high amonia, UOA isovaleric and 3-OH isovaleric acid, ketones Rx: low protein, formula (Valex), glycine, carnitine |
| 2-methylbutyrylglycinuria | Marker: C5 |
| 3-Methylcrotonyl-CoA carboxylase deficiency (3-MCC) | Gene: AR, MCCA, MCCB NBS Marker: C5OH Sx: highly variable, most asymptomatic, some decompensate with metabolic acidosis Dx: UOA - 3-methylcrotonylglycine Rx: diet low leucine, carnitine, glycine |
| 3-hydroxy-3-methylglutaryl-CoA lyase deficiency (HMG) | Marker: C5OH, C6DC Dx: UOA 3-OH-3-methylglutaric, 3-methylglutaconic, 3-methylglutaric, 3-OH-isovaleric |
| Betaketothiolase deficiency | Marker: C5:1, C5OH |
| Methylglutaconic aciduria | Marker: C5OH, C5:1 |
| 2-Methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency | Marker: C5OH |
| Glutaric aciduria type 1 | Gene: AR, Old Order Amish of PA Enzyme: 3-OH glutaric NBS Marker: High C5-DC Sx: macrocephaly, episodic encphalopathy, cerebral palsy-like dystonia, MRI with basal ganglia changes and cortical atrophy Path: defect in lys metabolism Rx: dietary restriction of gltarigenic amino acids (lysine, tryptophan, hydroxylysine) |
| Malonic aciduria | Marker: C3DC |
| Carnitine uptake defect | Marker: Low C0 |
| Carnitine palmitoyl transferase deficiency type I | Marker: C0 |
| Short chain acyl-CoA dehydrogenase deficiency | Marker: C4 |
| Medium chain acyl-CoA dehydrogenase deficiency | AR, ACADM gene, 1/12,000 Sx: hypoketotic hypoglycemia, acute episodes on increased energy demand may induce vomiting, lethargy, seizures, and hepatomegaly, first crisis fatal 25% NBS Marker: C8, C6, C10 Dx: acylcarnitine profile, low free carnitine, UOA high C6-C10 dicarboxylics Rx: IV glucose, carnitine |
| Very long-chain acyl-CoA dehydrogenase deficiency | Markers: C14:1, C14, C14:2 Sx: cardiomyopathy, hepatomegaly, rhabdomyolysis, SIDS |
| Long-chain hydroxyacyl-CoA dehydrogenase deficiency | Markers: C16OH, C18:1OH Sx: cardiomyopathy, hypotonia, rhabdomyolysis, NBS HELLP |
| Tri-functional protein deficiency | Markers: C16OH, C18:1OH |
| Carnitine palmitoyl transferase deficiency type II | Markers: C16, C18:1 |
| Glutaric Aciduria II (Multiple acyl-CoA dehydrogenase deficiency) | AR Markers: C4, C5, C5DC, C8, C14 Sx: hypotonia, hepatomegaly, acidosis, hypoglycemia |
| Carnitine/acylcarnitine translocase deficiency | Markers: C16, C18:1 |
| 2,4-Dienoyl-CoA reductase deficiency | Markers: C10:2 |
| Hydroxyacyl-CoA dehydrogenase deficiency | Markers: C4OH |
| Transfusion and NBS | High ornithine |
| Liver failure and NBS | High methionine |
| Renal failure and NBS | High C5DC, C6DC |
| Hemolysis and NBS | High C3, C18:1 |
| MCAD carriers and NBS | C5DC |
| Valproic acid and NBS | Low C0 |
| Pavilion acid and NBS | C5 |
| Alkaptonuria | AR Def: Homogentisic acid oxidase Blocks breakdown of homogentisic acid (metabolite of tyrosine), which accumulates in urine and darkens on exposure to air Sx: arthritis, ochronosis (dark pigment in cartilage and joints, dark ear wax Rx: ? high dose ascorbic acid, ? NTBC |
| Carbamoyl Phosphate Synthase Deficiency | AR Deficiency: Carbamoyl Phosphate Synthase Clinical: hyperammonemia, coma, death |
| Hereditary Fructose Intolerance | AR Def: Fructose 1-phophate aldolase, AR aldolase B defect Clinical: FTT, vomiting, jaundice, seizures Dx: fructose in urine, enzyme assay on intestinal musoca or liver bx sample Rx: dietary restriction of fructose |
| von Gierke disease | Glycogen Storage Disease type 1 |
| Glycogen Storage Disease Type 1 | Sx: hepatomegaly, hypoglycemia after fasting 3-4 hours, epistaxis, 1b has neutropenia and chronic infections Gene: AR, 1a Glucose-6-phophatase (Breaks down glycogen in liver, G6PC gene), 1b translocase deficiency (SLC374A gene) Dx: hypoglycemia, elevated TG/chol, lactate, uric acid, no response to glucagon |
| Cori Disease | Glycogen Storage Disease type III |
| Glycogen Storage Disease Type III | AR Def: Amylo-1,6-glucosidase aka debrancher enzyme Sx: hepatomegaly, hypoglycemia, muscle weakness Rx: frequent feeding, avoiding prolonged periods of fasting |
| Anderson Disease | Glycogen Storage Disease type IV |
| Glycogen Storage Disease Type IV | AR Def: Glycogen Brancher Enzyme Leads to long glycogen with few branches that can't be broken down by enzymes Sx: hypotonia, abnormal liver function/failure Rx: liver transplant |
| Glycogen Storage Disease Type VI | AR/X-linked Def: hepatic phosphorylase Obstructs glycogen degradation Sx: hepatomegaly, hypoglycemia, FTT Rx: carbohydrate supplementation |
| McArdle Disease | Glycogen Storage Disease Type V |
| Glycogen Storage Disease Type V | AR Def: Muscle phophorylase Breaks down muscle glycogen Sx: muscle cramps in teen years |
| Pompe Disease (GSD-II) | Sx: Heart failure, weakness, hepatomegaly, late hearing loss, osteopenia, motor/speech delay, GE reflux/dysphagia Gene: AR, Lysosomal alpha-1,4-glucosidase Dx: enzyme assay of WBC or fibroblasts |
| Congenital Adrenal Hyperplasia | AR Def: 21-hydroxylase (90%), 11beta-hydroxylase, 3beta-hydroxylase Sx: Virilization, salt wasting (25% - present with circulatory collapse, hyponatremia, hyperkalemia) |
| Androgen Insensitivity | XR Def: Androgen receptor Sx: 46,XY with female external genitalia, primary amenorrhea, inguinal hernia with testes (must be removed due to malignancy risk) |
| Familial Hypercholesterolemia | Multiple loci: LDL receptor (LDLR, AD, LOF), Apoprotein B-100 (APOB, AD, LOF), PCSK9 protease (AD, GOF) Sx: early coronary artery disease, xanthoma, premature arcus corneae (peripheral corneal opacity) Dx: quantification of LDL receptor function in skin fibroblasts, or identification of mutation Rx: dietary restriction of cholesterol, statins, homozygotes - LDL apheresis |
| Hurler Syndrome (MPS type 1) | Gene: AR, IDUA, 1/100,000 Enzyme: alpha-L-iduronidase Sx: onset 6-12 mo, MR, dysostosis multiplex, CORNEAL CLOUDING, HSM, hearing loss, coarse facial features, death by mid-adolescence, mild variant w/o CNS (scheie type IS) Dx: +MPS spot test, metachromatic granules in cells, enzyme assay, DNA Rx: HSCT transplant with matched donor, ERT (somatic sx, no effect on CNS) |
| Hunter Syndrome (MPS Type II) | Gene: XR, IDS, 1/70,000 Enzyme: iduronate sulfate sulfatase Sx: presents 2-5 yo, HEARING LOSS, recurrent infections, diarrhea, poor growth, coarse face, HSM, joint stiffness Dx: + MPS spot, excess dermatan and heparan sulfate in urine, decreased activity of enzyme in serum or WBC, gene analysis (carrier females best identified by DNA) Rx: enzyme replacement helps somatic features some, but no change in CNS |
| Sanfilippo syndrome (MPS Type III) | 4 subtypes, all AR Sx: 2nd year, mild coarse features, behavioral problems, dementia, fits, chronic diarrhea, insomnia, seizures Most common MPS Dx: increased urinary heparan and chondroitin sulfate, MPS may be pos or neg, enzyme assay, DNA (can't clinically distinguish subtypes, need DNA) Rx: none :(, treatment in trials IIIA def: heparan S-sulfaminidase IIIB def: N-ac-alpha-D-glucosaminidase IIIC def: Ac-CoA-alpha-glucosaminidase, N-acetyltransferase IIID def: N-ac-glucosamine-6-sulfate sulfatase |
| Morquio Syndrome (MPS Type IV) | AR IV A def: galactosamine-6-sulfatase IV B def: Beta-galactosidase Sx: 2-3 yo, short stature, thoracic deformity, kyphoscoliosis, normal intelligence Dx: Keratan sulfate in urine, enzyme deficiency (elosulfase alfa) |
| Maroteaux-Lamy Syndrome (Mucopolysaccharidosis Type V) | AR Def: arylsulfatase B, N-acetyl galactosamine, alpha-4-sulfate sulfatase Sx: early childhood, coarse facial features, kyphosis, restriction of joint mobility, short stature, thoracic deformity, corneal clouding, cardiac valve anomalies, normal intelligence. Mild form can present as adult. Dx: increased urinary dermatan sulfate excretion, arylsulfatase B deficiency in WBC or fibroblasts Rx: ERT (Naglazyme) |
| Sly Syndrome (Mucopolysaccharidosis Type VII) | AR Def: beta-glucoronidase Sx: variable presentation, kyphoscoliosis, hip dysplasia, coarse facial features, HSM, corneal clouding, cardiac abnormalities, MR, prenatal form with hydrops and fetal ascites Dx: increased urinary GAG, enzyme deficiency in serum, WBC, or fibroblasts |
| Tay-Sachs Disease | Infantile GM2 gangliosidosis, 1/4000 AJ Deficiency hexosaminidase A Gene: HEXA, AR, 1 in 3600 in Ashkenazi Path: Accumulation of syphingolipid, GM2 ganglioside, synthesized in brain. Sx: Infantile - 6 mo, exaggerated startle, seizures, developmental regression, blindness, cherry-red spot, vision loss, deafness, spasticity, seizures, death usually by age 3; Juvenile-onset (2-4 yo) and adult-onset forms with more variability. Eval: enzyme activity, cherry red spot Dx: reduced hexosaminidase A levels in serum, WBC or fibroblasts, gene analysis Path: accumulation of GM2 gangliosides in the brain Rx: symptomatic and palliative |
| Gaucher Disease | AR, GBA1 gene, beta-glucocerebrosidase deficiency; Type I 1/400-1/1000 AJ Type 1: most common, non-neuronopathic, ashkenazi jewish founder mutations Sx: adult onset, most common, febrile episodes, joint and limb pains, HSM, tendency to fracture, CNS spared Type 2: fulminant neuronopathic, fatal during infancy with spasticity, seizures, regression, death by 2 yo Type 3: chronic neuronopathic, death in childhood or early adult life Dx: "foam cells" in bone marrow (macrophages filled with lipid material), deficient beta-glucocerebrosidase activity in leukocytes Rx: symptomatic, splenectomy, ERT with recombinant beta-glucocerebrosidase, substrate reduction with miglustat reversibly inhibits glucosylceramide synthase (1st step in glycosphingolipid synthesis), clinical trials - eliglustat tartrate |
| Niemann-Pick Disease | AR, ~1/150,000 Def: sphingomyelinase Sx: FTT, hepatomegaly, cherry-red-spot, developmental regression 1 yo, death by 4 yo, Dx: foam cells in bown marrow, deficiency of enzyme |
| Lesch-Nyhan Disease | XR Def: hypoxanthinge guanine phophoribosyltransferase Result: increased levels of phosphoribosylpyrophosphate leads to increased rate of purine synthesis and accumulation of uric acid Sx: MR, uncontrolled movements, self-mutilation, spasticity Rx: allopurinol can inhibit uric acid formation |
| Adenosine deaminase deficiency | AR Dx: severe combined immunodeficiency, confirmed with enzyme deficiency in RBC Rx: bone marrow transplantation |
| Purine nucleoside phosphorylase | AR Sx: severe viral infections due to impaired T-cell function Rx: irradiated RBC for temporary improvement in immune function |
| Hereditary orotic aciduria | AR Def: orotate phosphoribosyltransferase, orotidine 5'-phosphate decarboxylase Sx: megaloblastic anemia, FTT, developmental delay |
| Acute intermittent porphyria | Gene: HMBS, AD, 1/20,000 Def: prophobilinogen (PBG) deaminase Sx: onset puberty, acute attacks, abdominal pain, weakness, neuropathy, vomiting, CNS effects (confusion, emotional upset, hallucinations), NO SKIN FINDINGS Dx: high urine delta-aminolevulinic acid (ALA) and high porphobilinogen (PBG) during acute attack. Path: nonrmal enzyme used in biosynthesis of heme, hgb, and hepatic cytochrome P450 enzymes. Drugs, chemicals, steroids, fasting activates hepatic alpha-ALA synthetase that leads to high ALA & PBG levels causing sx Rx: stop or treat precipitant (medication, infection, EtOH, dehydration, smoking, poor caloric intake), IV dextrose, IV hemin, intubate if bulbar paralysis |
| Hereditary coproporphyria | AD Def: coproporphyrinogen oxidase Sx: abdominal pain, CNS effects, photosensitivity in 1/3rd |
| Porphyria Variegata | AD, more common in Southern African Afrikaans Def: Protoporphyrinogen oxidase Sx: abdominal pain, CNS effects, photosensitivity |
| Congenital erythropoietic porphyria | AR Def: uroporphyrinogen III synthase Sx: hemolytic anemia, photosensitivity, red-browth discoloration of teeth (red fluorescence under UV light) |
| Erythropoietic protoporphyria | AD Def: ferrochelatase Sx: photosensitivity, liver disease Rx: beta-carotene |
| Wilson Disease | Gene: ATP7B (13q14.3); AR Def: ATPase membrane copper transport protein Sx: present age 3-50 yo, liver disease (jaundice, autoimmune hepatitis, hepatic failure, chronic liver disease), spasticity, rigidity, dysphagia, cirrhosis, Kayser-Fleischer ring, psychiatric disturbance Dx: copper storage in liver, low serum ceruloplasmin and copper, high urinary copper excretion, abnormal copper loading test Rx: D-penicillamine, trientine |
| Menkes disease | Gene: XR, ATP7A, 1/100,000 Def: ATPase membrane copper transport protein Sx: FTT, vomiting, hypotonia, seizures, progressive neuro deterioration, death from recurrent respiratory infection usually by 3 yo, kinky/brittle hair Dx: serum copper and ceruloplasmin very low Rx: exogenous copper w/ limited effect :( |
| Zellweger Syndrome | AR Def: peroxisomal enzymes Sx: dysmorphic features, hypotonia, large anterior fontanelle, cataracts, large liver, renal cysts, death by age 1 yo, 50% epiphyseal calcifications, neuronal heterotopias, early death (6-12 mo) Dx: raised plasma long-chain fatty acids |
| Adrenoleukodystrophy | Gene: ABCD1 (Xq28), XLR, 1/20,000 Sx: Childhood - ADHD, disability w/i 2 yo; Adrenomyeloneuropathy - late 20s progressive paraparesis, sphincter disturbance, adrenocortical dysfxn; adrenocortical insufficiency only - majority by age 7.5 yo, 20% carrier females Path: ABC transporter in peroxisome membrane, accumulation of saturated VLCFA Dx: High VLCFA, molecular testing (92% seq, 6% del/dup) Rx: lorenzo's oil (limited), HSCT early in course as soon as MRI changes noted, corticosteroids for adrenal insufficiency, gene therapy lentiviral vector in autologous hematopoietic stem cells with arrest of cerebral demyelination in 2 boys |
| Myolconic Epilepsy and Ragged Red Fiber Disease MERRF | Genetics: Mt, Mutation in lysine tRNN, m.8344G>A, m.8356T>C Sx: myoclonic epilepsy, myopathy with ragged-red fibers, optic atrophy, hearing impairment, dementia, renal dysfunction, DM, cardiomyopathy Path: complexes I and IV severely affected Rx: symptomatic, palliative, coenzyme Q10, L-carnitine |
| Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like Episodes MELAS | Genetics: Mutation in leucine (UUR) tRNA, m.3243A>G (80% pt), m.3271T>C, heteroplasmic Sx: encephalopathy, stroke-like episodes, seizures, dementia, migraine, lactic acidosis, short stature, type 2 DM, SNHL Rx: arginine (vasodilator, will decrease risk of stroke) |
| Leigh Disease | Genetics: nuclear and mt, heteroplasmic, ATPase subunit 6 gene; nuclear X-linked E1alpha subunit mutation (girls more common), 50% SURF1 (involved cytochrome oxidase), PDH mutations, complex I/II/IV Sx: early onset progressive neurodegeneration, hypotonia, DD, optic atrophy, respiratory abnormalities |
| Leber Hereditary Optic Neuropathy | Genetics: Mt, largely homoplasmic, 70% m.1178A>G in ND4 subunit of complex I, 15% m.3460G>A, 5% m.14484T>C Sx: rapid onset of blindness in young adult due to optic nerve atrophy, vascular toruosity of central retinal vessels, circumpapillary telangiectatic macroangiopathy, strong sex bias (50% male carriers get sx, only 10% females), occasional cardiac conduction defects Eval: visual field assessments, ERG, VEP Rx: no treatment, avoid smoking and EtOH |
| Barth Syndrome | XR Def: uncertain - mitochondrial cardiolipids are deficient and 3-methylglutaconic acid levels in urine are elevated Gene: TAZ sx: dilated cardiomyopathy, growth retardation, neutropenia |
| Guthrie Test | blood from newborns were used to induce growth in bacteria strain Bacillus subtilis, which requires Phe for growth, |
| Maternal Phenylketonuria | Children born to mothers with PKU. Increased risk of mental retardation. ? reduced ability of the mother to deliver appropriate amount of tyrosine to fetus in utero Rx: Phe <360 umol/L 3 months before conception |
| Smith-Lemli-Opitz Syndrome | Gene: sterol delta-7-reductase (DHCR7) Sx: MR, autism, microcephaly, hypotonia, FTT, 2-3 toe syndactyly, ptosis, cataracts, hypgenitalism, cleft palate Dx: low cholesterol, elevated 7-DHC Rx: cholesterol supplementation may improve growth and behavior, no effect on development |
| Neurodegeneration, Ataxia, and Retinitis Pigmentosa NARP | Heteroplasmic mutation in subunit 6 of ATPase (Complex V), m.8993T>G Sx: night blindness, followed years later by neuro sx, dementia in older patients, seizures, severe form can present as Leigh disease |
| Na Benzoate and Na Phenylbutyrate | Removal of NH3 via alternative pathway. Ammonia -> Glycine -> Hippurate. Ammonia -> Glutamine -> Phenylacetyl glutamine. Then peed out! |
| Gyrate Atrophy | Sx: Blindness and chorioretinal degeneration Dx: PAA with increased ornithine, normal ammonia Path: AR defect in OAT enzyme Rx: low arnginine diet |
| Creatine Deficiency Syndromes | Sx: MR, seizures, hypotonia, autism Dx: plasma and/or urine guanidinoacetic acid, MRI with MRS (Cr), molecular GAMT: high urine/plasma GAA, low urine Cr AGAT: low urine/plasma GAA, low urine Cr SLC6A8: normal GAA, high urine Cr, High urine creatine/creatinine ratio Gene: 2 very rare AR (AGAT, GAMT), XL Cr transporter (SLC6A8) Rx: creatine for AGAT and GAMT, low arg and orn for GAMT, ? none for XL transporter deficiency |
| Cystinosis | Sx: Infantile (onset <1, FTT, renal fanconi, low phos rickets, fair hair and skin, photophobia, corneal erosions, hypothyroidism, normal IQ, delayed puberty, DM, male infertility), Juvenile (hair and skin), Adult (mild eye disease) Gene: AR, defect in cystine transporter CTNS, (stuck in lysosomes) Dx: +/- nitroprusside, plasma cys normal, cystine in WBC, molecular genetics Rx: cysteamine, symptomatic renal disease, may need renal tx |
| Nonketotic Hyperglycinemia | Sx: intractable seizures (may have prenatal onset), hypotonia, severe IDD, hiccups in utero, some rare later onset variants and transient form resolving by 8 weeks Gene: AR, defect in glycine cleavage enzyme Dx: increased glycine in CSF, CSF:plasma gly ratio > 0.08, molecular testing Rx: Na benzoate, low protein diet, dextromethorphan, none very effective |
| Canavan Disease | Gene: ASPA (17pter-p13, Aspartoacylase); AR, Ashkenazi Jewish carrier 1/40 Sx: onset 3-5 months, hypotonia, progressive leukodystrophy, macrocephaly, later optic atrophy, seizures, never sit/walk/speak, later spasticity Eval: HIGH urine N-acetyl aspartic acid (NAA), also seen on MRS Gene: AR, ashkenazi Jewish (3 common muations, 84% E285A) Dx: increased N-acetylaspartic acid on UOA and MRS, build up of NAA in brain leads to demyelination Rx: none :( Life expectancy to teens |
| Pyruvate Dehydrogenase Deficiency | Most common cause of congenital lactic acidosis. 5 proteins in complex, mutations in XL E1alpha most frequent, most de novo |
| Mitochondrial Depletion Syndromes | Decreased ratio of mitochondrial/nuclear DNA. Genetics: AR, heterogeneous, POLG1, TK2 Sx: hepatic failure, hypoglycemia, CNS |
| Pearson Syndrome | Anemia, bone marrow failure, lactic acidosis, exocrine pancreatic failure, RTA |
| Kearns-Sayre Syndrome | Genetics: mtDNA 5-kb large deletion, heteroplasmic, generally sporadic, likely due to maternal gonadal mosaicism Sx: Progressive external opthalmoplegia, cardiac conduction block, RP, ataxia, lactic acidosis, ataxia |
| N-glycosylation defects | Amide linkage to asparagine N-glycan assembly ER or cytosol Sugars transferred en block from dolichol. Processing in ER or Golgi. Serum transferrin isoelecctric focusing. |
| O-glycosylation defects | Linkage through -OH on serine or threonine. Transfer single sugars onto growing glycan backbone. Includes ABO blood groups, exostoses I and II proteins, proteoglycans, congenital muscular dystrophies. |
| PMM2-CDG (CDG 1a) | AR, PMM2 deficiency Most common CDG Sx: multiple system, hypotonia, IDD, seizures, ataxia, RP, strabismus, liver disease, coagulopathy, FTT, inverted nipples, lipodystrophy Dx: Abnl transferrin isoelectric focusing |
| MPI-CDG (CDG 1b) | Mannose-6-phophate isomerase def Sx: hepatic and GI sx with vomiting, GI bleeding, protein-losing, enteropathy, liver disease, coagulopathy, hepatic fibrosis, minimal neurologic involvement Rx: oral mannose |
| SRD5A3-CDG (CDG 1q) | Steroid 5-alpha-3 reductase deficiency (dolichol synthesis defect) Sx: 6 mo to 12 years, severe ID, ataxia, cerebellar hypoplasia, coloboma, optic atrophy, glaucoma, microophthalmia, heart defects, liver dysfunction, ichthyosis |
| Fabry Disease | XL, 1/40,000-60,000 Sx (males): onset 9 yo, peripheral neuropathy, acroparesthesias, angiokeratomas, lens/corneal opacities, late renal and CV disease, chronic lung disease with fibrosis. Sx (females): onset 13 yo, fatigue, stroke, ~10% renal failure Dx: enzyme assay (may miss females) Rx: dilantin/tegretol for neuropathy, renal transplant, ERT |
| Rhizomelic Chondrodysplasia Punctata | Genetics: 1/100,000, Peroxisomal disorder, PEX7 most common (encodes PTS2 receptor) Sx: skeletal dysplasia, cataracts, ichthyotic skin rash, IDD, occ CHD, cleft palate Dx: low plasmalogenes, HIGH phytanic acid, normal VLCFA |
| I-cell disease | Lysosomal processing defect. Path: Failure to add phosphate group to mannose residue of lysosomal enzymes which is required to target enzymes to lysosomes. Sx: coarse facies, skeletal changes, growth retardation, ID, survival < 10 yo Dx: increased plasma activity multiple lysosomal enzymes with deficient activity in fibroblasts, neg MPS spot |
| Impaired tetrahydrobiopterin metabolism | Incidence: <1/1,000,000 Path: Defect in pterin 4-alpha-carbinolamine dehyratase (PCD) or dihydropteridine reductase (DHPR) Rx: low-phe diet, L-dopa, 5-HT, carbidopa, (+ folinic acid for DHPR patients) |
| Impaired tetrahydrobiopterin synthesis | Incidence: <1/1,000,000 Path: Defect in GTP-cyclohydrolase or 6-pyruvoyltetrahydropterin synthase Rx: low-phe diet, L-dopa, 5-HT, carbidopa, and pharmacological doses of BH4 |
| Dopa-responsive Dystonia | Path: Deficiency in sepiaterin reductase, enzyme in BH4 synthesis. |
| Sandhoff Disease | Gene: HEXB Path: impairs activity of hexosaminidase A and B |
| Deafness mtDNA | Progressive SNHL, often induced by aminoglycosides from homoplasmic m.1555A>G in 12S rRNA gene Nonsyndromic SNHL, from homoplasmic m.7445A>G mutation in 12S rRNA gene |
| Lipoprotein Lipase Deficiency | Rx: gene therapy adeno-associated virus vector injected IM decreased frequency of pancreatitis |
| Metachromatic leukodystrophy | Arylsulfatase A (ARSA), AR Path: inability to degrade neurotoxic sulfatides Sx: neurodegenerative disorder, infantile form fatal by 5 yo Rx: lentiviral vector expressing supraphysiological levels of ARSA arrested neurodegeneration in 3 patients |
| Krabbe Disease | Gene: GALC (14q31); Calactocerebrocidase; AR Sx: infantile form - irritability to sensory stimuli, muscle hypertonicity, progressive neuro deterioration, peripheral neuropathy, WM disease, elevated CSF protein; later onset - 6 mo to 5th decade, weakness, vision loss, intellectual regression Eval: CT - nonspecific, diffuse cerebral atrophy of GM/WM; MRI - demyelination of the brainstem and cerebellum. Low GALC enzyme activity, abnl EEG, low nerve conduction velocity Dx: GALC targeted mutation 30-kb deletion (45% europeans, 35% mexicans); 809G>A mutation (50% late onset Krabbe) Rx: HSCT before sx. |
| Urine oligosaccharide chromatography | Lysosomal storage disorders (glycoproteinoses) I-cell disease CDG IIb |
| Lysinuric Protein Intolerance | Gene: AR, rare Sx: FTT, osteoporosis Path: defect intestinal dibasic amino acid transport Dx: cationic amino acids are low or low nl; high gln, ala, ser, pro, cit, gly; massive high lys in urine; high NH3 and orotic acid after meals Rx: low protein diet, citrulline |
| Hartnup Disease | AR Path: disorder neutral amino acid transport Sx: tryp (niacin) deficiency, most have no sx |
| Cystinuria | Gene: AR, SLC3A1 type 1; 1/7000 Path: defect dibasic amino acid transporter active in GI tract and renal tubular epithelium Sx: renal stones Rx: urine alkalinization, increase fluids, D-penicillamine |
| Pyridoxine-dependent seizures | Refractory perinatal seizures that respond to 50-100 mg IV B6 Inborn error of lysin catabolism |
| Cerebral Folate Deficiency | Sx: 4-6 months, irritable, slowed head crowth, ID, dyskinesias, cerebellar ataxia, OA and blindness after 3 yo Dx: Low levels 5-methyltetrahydrofolate (active metabolite of folate) in CSF. Blood folate levels normal. Rx: folinic acid |
| GLUT1 deficiency | Gene: AD, most new mutations Sx: seizures 1st year of life, DD, MR Dx: low CSF glucose <40-45 Path: Defect in glucose transporter across blood-brain-barrier. Rx: ketogenic diet |
| Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE) | Gene: AR, TYMP gene Sx: external ophthalmoplegia (PEO), gastrointestinal dysmotility (often pseudoobstruction), cachexia, diffuse leukoencephalopathy, peripheral neuropathy, and mitochondrial dysfunction |
| Chronic Progressive External Ophthalmoplegia (CPEO) | Gene: mt or nuclear, AD or AR Sx: CPEO, RP, limb weakness, fatigue Recurrence risk: most females with single mtDNA deletion have a very low (<1-5%) chance of transmitting the disease to their offspring |
| Refsum Disease | Gene: AR, PHYH Enzyme: Phytanoyl-CoA Hydroxylase Sx: cerebellar ataxia, polyneuropathy, RP, high CSF protein Eval: high phytanic acid Rx: phytanic acid restricted diet |
| Farber lipogranulomatosis | Ceramidase deficiency Very rare Sx: painful, deformed joints, subcutaneous nodules, ID |
| Wolman Disease (Acid Lipase Deficiency) | Sx: HSM, FTT, adrenal Ca++ Milder variant: cholesterol ester storage disease |
| Schindler Disease | Sx: progressive ID, blindness, seizures, hypotonia, rare cause of neuraxonal dystrophy Enzyme: lysosomal N-acetylgalactosaminidase |
| Pycnodysostosis | Enzyme: lysosomal cathepsin K Sx: skeletal dysplasia |
| Happle Syndrome | Gene: XLD, male lethal unless rare hypomorphic mutation, CDPX2 Sx: epiphyseal calcification (CDP), asymmetric dwarfing, asymmetric cataracts, microphthalmia, linear hyperkeratotic erythroderma, alopecia Dx: plasma sterol analysis, molecular defect in delat8-delta7 sterol isomerase (EBP) |
| Fructose 1,6 bisphosphatase Def | Disorder of gluconeogenesis Conversion of F-1,6 BP to F6P Sx: severe hypoglycemia, lactic acidemia, liver dysfunction, FTT, hypotonia |
| Sulfite Oxidase Deficiency/ Molybdenum Cofactor Deficiency | Occurs in isolation or with xanthine oxidase def (molybdenum cofactor def) Sx: drug-resistent seizures, lens dislocation, ID Eval: MRI - T2 prolongation of white mater and caudate nuclei (consistent w/ edema) Eval: low uric acid, elevated S-sulfocysteine |
| Porphyria Cutanea Tarda | Most common type Sx: adult d/o, lesions on sun-exposed skin, liver diease (cirrhosis 40%), EtOH and estrogen aggravate sx Dx: urine/stool coproporphyrins Path: defects in uroporphyrinogen decarboxylase Rx: avoid triggers, phlebotomy |
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