Which of the following is characterized by denervation atrophy of the muscles?

Carnitine palmityl transferase deficiency

Branched-chain ketoaciduria is due to a deficiency of which enzyme?

Branched-chain α-ketoacid dehydrogenase

A 45-year-old man presents to the clinic for evaluation of weakness in his arms and legs. The symptoms started gradually, and are now more noticeable and interfering with his ability to work as an electrician. On physical examination, the cranial nerves are normal, but there is weakness of his left handgrip and right leg quadriceps with loss of muscle bulk. There are obvious fasciculations over the left forearm and right thigh. Tone is increased in the arms and legs and the reflexes are brisk. Which of the following is the most likely diagnosis?

amyotrophic lateral sclerosis (ALS)

What is the metabolic abnormality associated with Zellweger syndrome?

Accumulation of very long-chain fatty acids

Accumulation of long-chain fatty acids

Accumulation of short-chain fatty acids

Accumulation of medium-chain fatty acids

A 6-year-old presents with developmental delay, musty body odor, and fair skin. Lab tests show high phenylalanine levels. What is the most appropriate management?

Tetrahydrobiopterin (BH4) supplementation

Which of the following statements about Niemann-Pick disease is false?

Type B Niemann-Pick disease is characterized by severe neurological symptoms.

Due to deficiency of sphingomyelinase.

CNS symptoms are present in type A.

Histiocytes show PAS positive inclusions, and Type A is more severe.

Neurodegenerative Disorders for UPSC-CMS: High-Yield Pediatrics Lessons

Lysosomal Storage Disorders - Enzyme's Day Off

Disorder	Enzyme Deficient	Accumulation	Key Features
Tay-Sachs	Hexosaminidase A	GM2 Ganglioside	Cherry-red macula, NO hepatosplenomegaly, hyperacusis, progressive neurodegeneration. 📌 Tay-SaX lacks heXosaminidase A.
Niemann-Pick (A/B)	Sphingomyelinase	Sphingomyelin	Cherry-red macula (Type A), hepatosplenomegaly, foam cells, neurodegeneration (Type A).
Gaucher	Glucocerebrosidase	Glucocerebroside	Hepatosplenomegaly, bone pain/crises, pancytopenia, Gaucher cells ("crumpled tissue paper"). Most common LSD.
Metachromatic Leukodystrophy (MLD)	Arylsulfatase A	Sulfatides	Central & peripheral demyelination, ataxia, motor & cognitive decline.
Krabbe (Globoid Cell)	Galactocerebrosidase	Galactosylceramide, Psychosine	Severe irritability, peripheral neuropathy, optic atrophy, globoid cells, rapid neurodegeneration.

⭐ Cherry-red macula in Tay-Sachs is due to accumulation of gangliosides in retinal ganglion cells, contrasting with surrounding normal retina.

Peroxisomal & Mitochondrial Mayhem - Powerhouse Problems

Peroxisomal (VLCFA metabolism) & mitochondrial (energy production) disorders cause severe neurodegeneration. Ragged red fibers in muscle biopsy

Disorder	Type	Inheritance	Key Defect / Gene	Core Features	Note / Mnemonic
X-ALD	Peroxisomal	X-linked	ABCD1; ↑VLCFA	Adrenal insuff., prog. neurodegen.	> ⭐ X-linked Adrenoleukodystrophy often presents with adrenal insufficiency preceding neurological symptoms; VLCFA accumulation is key.
Zellweger Synd.	Peroxisomal	AR	PEX genes; empty peroxisomes	Hypotonia, seizures, dysmorphic, hepatomegaly	"Empty peroxisomes"
MELAS	Mitochondrial	Maternal	MT-TL1 (tRNA Leu)	📌 Myopathy, Encephalopathy, Lactic Acidosis, Stroke	Stroke-like (non-vascular)
MERRF	Mitochondrial	Maternal	MT-TK (tRNA Lys)	📌 Myoclonic Epilepsy, Ragged Red Fibers	Ataxia, dementia
Leigh Syndrome	Mitochondrial	Mat/AR	mtDNA/nDNA (e.g. SURF1)	Psychomotor regress, brainstem/BG lesions	Subacute necrotizing encephalomyelopathy

Metabolic & Syndromic Twists - Metabolic Misfires & Quirks

Phenylketonuria (PKU): Phenylalanine hydroxylase deficiency. Mousy/musty odor, intellectual disability. Diet: Low Phenylalanine.
Maple Syrup Urine Disease (MSUD): Branched-chain α-ketoacid dehydrogenase deficiency. Maple syrup odor in urine/cerumen, encephalopathy. Diet: Restrict BCAAs (Leucine, Isoleucine, Valine).
Glutaric Aciduria Type 1 (GA1): Glutaryl-CoA dehydrogenase deficiency. Macrocephaly, dystonia, acute encephalopathic crises. "Bat-wing" sylvian fissures on MRI.
Rett Syndrome: MECP2 gene (X-linked dominant, primarily girls). Normal development until 6-18 months, then regression (loss of speech, purposeful hand skills), stereotypic hand movements (wringing, clapping), microcephaly.

⭐ Rett syndrome (MECP2, girls): normal development then regression, loss of purposeful hand skills, stereotypic hand movements.
Ataxia-Telangiectasia: ATM gene (Autosomal Recessive). Progressive cerebellar ataxia, oculocutaneous telangiectasias, immunodeficiency (↓IgA), ↑AFP, X-ray sensitivity.
- 📌 ATAXIA: A (ATM gene), T (Telangiectasias), A (AFP high), X (X-ray sensitivity), I (IgA deficiency), A (Ataxia).

Motor & Cerebellar Degenerations - Movement Meltdowns

⭐ Spinal Muscular Atrophy (SMA) is caused by homozygous deletion or mutation in the SMN1 gene, leading to degeneration of anterior horn cells in the spinal cord.

Feature	Spinal Muscular Atrophy (SMA)	Friedreich's Ataxia (FA)
Gene (defect)	SMN1 (deletion/mutation)	FXN (Frataxin; GAA repeat)
Inheritance	AR	AR
Key Signs	Proximal > distal weakness, hypotonia, ↓DTRs, fasciculations. Sensation intact.	Gait/limb ataxia, dysarthria, ↓DTRs (LL), +Babinski, ↓proprioception/vibration. HOCM, DM.
Onset (SMA Types)	Type 0: Prenatal; Type 1: <6 months; Type 2: 6-18 months; Type 3: >18 months	Typically 5-15 years

Spinal Cord Disorders Diagram

High‑Yield Points - ⚡ Biggest Takeaways

Tay-Sachs Disease: Cherry-red spot, GM2 ganglioside accumulation, NO hepatosplenomegaly, progressive neurodegeneration.

Niemann-Pick Disease (Type A): Cherry-red spot, sphingomyelinase deficiency, hepatosplenomegaly, rapid neurodegeneration.

Gaucher Disease: Glucocerebrosidase deficiency, hepatosplenomegaly, bone pain, Gaucher cells (crinkled paper).

Metachromatic Leukodystrophy: Arylsulfatase A deficiency, demyelination (central & peripheral), ataxia, motor regression.

Krabbe Disease: Galactocerebrosidase deficiency, globoid cells, severe irritability, optic atrophy, peripheral neuropathy.

Spinal Muscular Atrophy (SMA): SMN1 gene defect, anterior horn cell degeneration, progressive weakness, "floppy infant".

Adrenoleukodystrophy (ALD): X-linked, VLCFA accumulation, adrenal insufficiency, demyelination.

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