• 1 - e: Metachromatic leukodystrophy $\to$ Arylsulfatase A
• 2 - a: Krabbe disease $\to$ $\beta$-galactocerebrosidase
• 3 - b: Fabry disease $\to$ $\alpha$-galactosidase A
• 4 - c: Farber disease $\to$ Ceramidase
• 5 - d: Wolman disease $\to$ Acid lipase (lysosomal acid lipase)

1. Diagnosis: Corneal clouding in Mucopolysaccharidosis (MPS).
2. Five types of MPS:
   • Type I: Hurler / Scheie / Hurler-Scheie ($\alpha$-L-iduronidase deficiency)
   • Type II: Hunter (Iduronate-2-sulfatase deficiency)
   • Type III: Sanfilippo (Heparan N-sulfatase / NAGLU / HGSNAT / GNS deficiency)
   • Type IV: Morquio (Galactose-6-sulfate sulfatase / $\beta$-galactosidase deficiency)
   • Type VI: Maroteaux-Lamy (Arylsulfatase B deficiency)
   • Type VII: Sly syndrome ($\beta$-glucuronidase deficiency)
3. Urinary test: Urine glycosaminoglycan (GAG) screening (toluidine blue / DMB test) followed by urine GAG electrophoresis/chromatography.
4. Metabolites in urine: Dermatan sulfate, Heparan sulfate, Keratan sulfate, Chondroitin sulfate.
5. Main organs involved: Liver, spleen (hepatosplenomegaly), skeleton/bones, heart (valvular disease, cardiomyopathy), eyes (corneal clouding, retinal degeneration), ears (sensorineural/conductive hearing loss), brain/CNS.
6. X-ray findings: Dysostosis multiplex (oar-shaped/spatulate ribs, anterior beaking/ovoid vertebral bodies, hook-like hypoplasia of lumbar vertebrae, bullet-shaped metacarpals/phalanges).
7. Types with Enzyme Replacement Therapy (ERT) available:
   • Type I (Hurler/Scheie): Laronidase (Aldurazyme)
   • Type II (Hunter): Idursulfase (Elaprase)
   • Type IVA (Morquio A): Elosulfase alfa (Vimizim)
   • Type VI (Maroteaux-Lamy): Galsulfase (Naglazyme)
   • Type VII (Sly): Vestronidase alfa (Mepsevii)
8. Causes of corneal clouding:
   • Mucopolysaccharidosis (Hurler, Scheie, Morquio, Maroteaux-Lamy, Sly — absent in Hunter and Sanfilippo)
   • Mucolipidoses (GM1 gangliosidosis)
   • Zellweger syndrome (peroxisomal disorder)
   • Congenital glaucoma (buphthalmos)
   • Congenital rubella / intrauterine infections
   • Birth trauma (forceps injury with rupture of Descemet membrane)
   • Cystinosis.

Answer: d (The majority of the hyperbilirubinemia is indirect)

• Explanation: In classic galactosemia, neonatal cholestasis develops with predominantly conjugated (direct) hyperbilirubinemia (hepatocellular injury), although mixed hyperbilirubinemia can occur.
• Statements a, b, c, e, and f are true:
  • Mode of inheritance is autosomal recessive (GALT gene mutation).
  • Enzyme deficient is galactose-1-phosphate uridyltransferase (GALT).
  • Treatment is lifelong elimination of dietary lactose and galactose.
  • Hypoglycemia occurs due to accumulation of galactose-1-phosphate inhibiting glycogenolysis and gluconeogenesis.
  • Fulminant E. coli sepsis/neonatal septicemia is a classic early complication.

1. Diagnosis & Enzyme:
   • Diagnosis: Mucopolysaccharidosis Type II (Hunter syndrome).
   • Facial characteristics: Hunter facies (coarse facial features, macrocephaly, prominent forehead, flat nasal bridge, thick lips, macroglossia).
   • X-ray findings: Dysostosis multiplex (anterior beaking/ovoid vertebral bodies, bullet-shaped phalanges).
   • Enzyme deficiency: Iduronate-2-sulfatase (IDS) deficiency.
2. Tissues and urine content: Dermatan sulfate and Heparan sulfate.
3. Mode of inheritance: X-linked recessive (Hunter syndrome is the only X-linked MPS; all other MPS types are autosomal recessive).

1. Condition: b. Homocystinuria (presents with developmental delay, failure to thrive, and acute thromboembolic episodes such as hemiparesis/stroke due to hypercoagulability).
2. Systemic examination: Ophthalmologic examination / slit-lamp examination to look for ectopia lentis (characteristically downward and inward subluxation of the lens, in contrast to upward-outward in Marfan syndrome).
3. Confirmatory investigation: Elevated plasma total homocysteine and methionine levels, positive urinary cyanide-nitroprusside test, and confirmation by enzymatic assay (cystathionine $\beta$-synthase [CBS] deficiency) or genetic testing (CBS gene).
4. Long-term treatment:
   • High-dose Pyridoxine (Vitamin ${\text{B}}_6$) (200–1000 mg/day) in ${\text{B}}_6$-responsive patients
   • Folic acid (1–5 mg/day) and Vitamin ${\text{B}}_{12}$ (1–2 mg/day)
   • Betaine (trimethylglycine) to remethylate homocysteine to methionine
   • Low-methionine diet with cysteine supplementation in ${\text{B}}_6$-non-responsive patients.

1. Laboratory finding: b. Deficient activity of acid $\beta$-galactosidase.
2. Diagnosis: Type 1 GM1 Gangliosidosis (Infantile form) (characterized by cherry-red spot, severe CNS degeneration, coarse facies, skeletal dysplasia, and hepatosplenomegaly).
3. Specific skin finding: Mongolian spots (extensive bluish-gray macules) in GM1 gangliosidosis; or Angiokeratoma (angiokeratoma corporis diffusum) seen in Fabry disease / Fucosidosis.
4. Diagnosis if hyperacusis, macrocephaly, cherry-red spot, and ABSENT organomegaly: Tay-Sachs Disease (GM2 gangliosidosis / Hexosaminidase A deficiency).

1. Diagnosis: Classic Galactosemia.
2. Enzyme deficient: Galactose-1-phosphate uridyltransferase (GALT).
3. Commonest organism: Escherichia coli (E. coli septicemia).
4. Ophthalmic manifestations: "Oil droplet" cataracts (due to accumulation of galactitol in the lens), vitreous hemorrhage, retinal detachment.
5. Treatment: Immediate and lifelong elimination of galactose and lactose from the diet (switch from breast milk/cow milk formula to soy-based or elemental formula).

1. Diagnosis: DiGeorge Syndrome (22q11.2 deletion syndrome / CATCH-22).
2. Commonest newborn presentation: Hypocalcemic seizures / tetany and cyanosis/heart failure due to congenital conotruncal cardiac defect.
3. Explanation for hypocalcemia: Primary hypoparathyroidism due to parathyroid gland hypoplasia or aplasia.
4. Cause of immunodeficiency: Thymic aplasia or hypoplasia leading to defective cell-mediated (T-cell) immunity and susceptibility to opportunistic infections (e.g., Candida, Pneumocystis).
5. Etiopathogenesis: Dysmorphogenesis of the 3rd and 4th pharyngeal pouches and arches secondary to microdeletion on chromosome 22q11.2.

1. Diagnosis: Organic Acidemia (e.g., Isovaleric Acidemia, Methylmalonic Acidemia, or Propionic Acidemia) presenting with high anion gap metabolic acidosis, mild-moderate hyperammonemia, pancytopenia/leukopenia, and encephalopathy.
   (Note: In urea cycle defects, there is severe hyperammonemia presenting with respiratory alkalosis without metabolic acidosis).
2. Abnormal odor:
   • Sweaty feet / cheesy odor: Isovaleric acidemia / Glutaric acidemia type II
   • Fruity / sweet odor: Methylmalonic acidemia / Propionic acidemia
   • Maple syrup / burnt sugar odor: Maple syrup urine disease (MSUD)
   • Mousy / musty odor: Phenylketonuria (PKU).
3. Acute management:
   • Stop all protein intake immediately (NPO).
   • Provide high intravenous caloric support with 10% dextrose (glucose infusion rate 8–10 mg/kg/min) and lipids to suppress catabolism.
   • Correct metabolic acidosis with cautious IV sodium bicarbonate.
   • L-Carnitine (100–300 mg/kg/day IV/oral) to detoxify acyl-CoA intermediates and excrete acylcarnitine esters.
   • L-Glycine (250–300 mg/kg/day) for isovaleric acidemia (forms non-toxic isovalerylglycine).
   • Cofactor trial: Vitamin ${\text{B}}_{12}$ (1–2 mg IM), Biotin (10 mg/day), Thiamine (300 mg/day).
   • Prompt hemodialysis, peritoneal dialysis, or exchange transfusion if ammonia/acidosis is severe and unresponsive to medical therapy.

1. Diagnosis: X-Linked Adrenoleukodystrophy (X-ALD) (presenting with childhood cerebral demyelination and primary adrenal insufficiency / Addison disease).
2. Mode of inheritance: X-linked recessive (ABCD1 gene mutation on Xq28).
3. Confirmatory test: Elevated plasma levels of Very Long Chain Fatty Acids (VLCFA), specifically hexacosanoic acid (C26:0) and elevated C26:0/C22:0 and C24:0/C22:0 ratios.
4. Management:
   • Replacement therapy for adrenal insufficiency: Glucocorticoids (hydrocortisone) and mineralocorticoids (fludrocortisone).
   • Early allogeneic Hematopoietic Stem Cell Transplantation (HSCT) or ex-vivo lentiviral gene therapy in early-stage cerebral ALD.
   • Symptomatic and supportive care for spasticity, seizures, and visual/hearing loss.
5. Dietary therapy: Lorenzo's oil (a 4:1 mixture of glyceryl trioleate and glyceryl trierucate) to lower saturated VLCFA levels.

1. Pathology: Retinitis Pigmentosa (Bone-spicule pigmentation of the retina with attenuated retinal vessels and waxy disc pallor).
2. Four conditions with Retinitis Pigmentosa / Retinal Dystrophy:
   • Mucopolysaccharidosis (MPS I Hurler/Scheie, MPS II Hunter, MPS III Sanfilippo)
   • Laurence-Moon-Biedl / Bardet-Biedl syndrome
   • Kearns-Sayre syndrome (mitochondrial cytopathy)
   • Refsum disease (phytanic acid storage disease)
   • Neuronal ceroid lipofuscinosis (Batten disease)
   • Abetalipoproteinemia (Bassen-Kornzweig syndrome)
   • Usher syndrome.

1. Likely diagnosis: Laurence-Moon-Biedl / Bardet-Biedl Syndrome (BBS).
2. Other abnormalities:
   • Intellectual disability / developmental delay
   • Hypogonadism (microgenitalia in males, genital anomalies in females)
   • Postaxial polydactyly / syndactyly / brachydactyly
   • Renal structural anomalies and chronic renal failure
   • Hepatic fibrosis and diabetes mellitus.
3. Ophthalmologic finding: Atypical Retinitis pigmentosa / tapetoretinal degeneration leading to early night blindness (nyctalopia) and progressive visual loss.

1. Diagnosis: Gaucher Disease (Type 1 non-neuronopathic or Type 3 chronic neuronopathic).
2. Marrow findings: Presence of Gaucher cells (large lipid-laden histiocytes/macrophages with characteristic "wrinkled tissue paper" or "crumpled tissue paper" cytoplasm, eccentric small nuclei, strongly PAS-positive).
3. Etiology: Autosomal recessive deficiency of the lysosomal enzyme Acid $\beta$-glucosidase (Glucocerebrosidase) leading to accumulation of glucocerebroside (glucosylceramide) in reticuloendothelial macrophages.
4. Radiological findings:
   • Erlenmeyer flask deformity of distal femora
   • Generalized osteopenia, cortical thinning, osteosclerosis
   • Avascular necrosis of femoral heads
   • Bone marrow infiltration and pathologic fractures.
5. Definitive treatment:
   • Enzyme Replacement Therapy (ERT): Recombinant human acid $\beta$-glucosidase (e.g., Imiglucerase [Cerezyme], Velaglucerase alfa, Taliglucerase alfa) 60 U/kg IV every alternate week.
   • Substrate Reduction Therapy (SRT) (e.g., Miglustat, Eliglustat).
   • Hematopoietic Stem Cell Transplantation (HSCT) for selected severe cases.