[Durgical](https://durgical.com/en/) › [DurgiPedia](https://durgical.com/en/durgipedia/) › [General pathology](https://durgical.com/en/general-pathology/) › [Central nervous system](https://durgical.com/en/general-pathology/areas/cns/) › Inherited metabolic diseases of the brain

# Inherited metabolic diseases of the brain

- Lesion

Missing enzymes can fill neurons with stored material, destroy white matter or starve the brain of energy, mostly from childhood.

Updated Nov 12, 2026

## Key points

- Tay-Sachs: hexosaminidase A deficiency, GM2 ganglioside in neurons; swollen neurons with whorled membranous bodies on electron microscopy; cherry-red macular spot; more frequent in Ashkenazi Jews.
- Krabbe: galactocerebrosidase deficiency; globoid cells (multinucleated macrophages) in white matter.
- Metachromatic leukodystrophy: arylsulfatase A deficiency; sulfatide stains metachromatically.
- X-linked adrenoleukodystrophy: ABCD1 defect, very long chain fatty acids accumulate; white matter loss with adrenal insufficiency in boys.
- MELAS: stroke-like episodes, lactic acidosis, often the m.3243A>G tRNA mutation; ragged red fibres in muscle.
- Leigh syndrome: symmetric necrosis with vessel proliferation in basal ganglia, thalamus and brainstem in infants.

## What it is

Inborn errors of metabolism injure the CNS in three main ways. In neuronal storage diseases a lysosomal enzyme is missing and its substrate fills neurons, which swell and die (Tay-Sachs, Niemann-Pick, mucopolysaccharidoses). In leukodystrophies myelin cannot be made or maintained, so white matter is lost symmetrically (Krabbe, metachromatic leukodystrophy, adrenoleukodystrophy). In mitochondrial encephalomyopathies, defects in oxidative phosphorylation, often from mitochondrial DNA mutations, damage the most energy-hungry tissues: brain, muscle and retina.

## Structure

- Storage neurons: ballooned cell bodies with pale foamy cytoplasm; stored lipid stains with PAS or Luxol fast blue depending on type.
- Leukodystrophies: symmetric loss of myelin with sparing of subcortical U fibres in many types; gliosis and macrophages.
- Mitochondrial disease: ragged red fibres (Gomori trichrome) and COX-negative fibres in muscle biopsy.

## Inherited metabolic diseases of the CNS

| Disease | Defect | Stored material or lesion | Clue |
| --- | --- | --- | --- |
| [Tay-Sachs disease](https://durgical.com/en/conditions/tay-sachs-disease/) | Hexosaminidase A | GM2 ganglioside in neurons | Cherry-red spot, infant regression |
| [Niemann-Pick disease type A](https://durgical.com/en/conditions/niemann-pick-disease/) | Sphingomyelinase | Sphingomyelin in neurons and macrophages | Hepatosplenomegaly, cherry-red spot |
| [Mucopolysaccharidoses (Hurler)](https://durgical.com/en/conditions/hurler-syndrome/) | Alpha-L-iduronidase and others | Glycosaminoglycans | Coarse face, corneal clouding |
| [Krabbe disease](https://durgical.com/en/conditions/krabbe-disease/) | Galactocerebrosidase | Globoid cells, myelin loss | Infant irritability, spasticity |
| [Metachromatic leukodystrophy](https://durgical.com/en/conditions/metachromatic-leukodystrophy/) | Arylsulfatase A | Sulfatide (metachromatic) | Motor regression, neuropathy |
| [X-linked adrenoleukodystrophy](https://durgical.com/en/conditions/x-linked-adrenoleukodystrophy/) | ABCD1 transporter | Very long chain fatty acids | Boys with behaviour change and adrenal failure |
| [MELAS](https://durgical.com/en/conditions/melas/) | Mitochondrial tRNA | Cortical stroke-like lesions | Lactic acidosis, ragged red fibres |
| [Leigh syndrome](https://durgical.com/en/conditions/leigh-syndrome/) | Many oxidative phosphorylation genes | Symmetric brainstem and basal ganglia necrosis | Infant hypotonia, high lactate |

## Clinical notes

- Most present in infancy or childhood with developmental regression, seizures, spasticity or vision loss.
- Newborn screening, enzyme assays and genetic testing make the diagnosis; some have enzyme, cell or gene therapy.

## Memory aid

Store, strip or starve: storage diseases fill neurons, leukodystrophies strip white matter, mitochondrial disorders starve energy-hungry cells.

## Test yourself

Think of the answer, then tap the question to see it.

## Which enzyme is deficient in Tay-Sachs disease?

Hexosaminidase A, so GM2 ganglioside accumulates in neurons.

## What are globoid cells?

Multinucleated macrophages full of galactocerebroside in the white matter of Krabbe disease.

## What muscle biopsy finding suggests a mitochondrial encephalomyopathy?

Ragged red fibres on Gomori trichrome stain, from accumulated abnormal mitochondria.

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## Elsewhere in DurgiPedia

- [Lysosomal storage diseases](https://durgical.com/en/biochemistry/topics/lysosomal-storage-diseases/)
- [Lysosomal ganglioside breakdown](https://durgical.com/en/biochemistry/pathways/lysosomal-ganglioside-breakdown/)

## Connections

## Related 5

- [How a single gene causes disease: enzymes, receptors and structural proteins](https://durgical.com/en/general-pathology/how-a-single-gene-causes-disease-enzymes-receptors-and-structural-proteins/)
- [Nonclassic inheritance: repeat expansions, mitochondrial genes, imprinting, mosaicism](https://durgical.com/en/general-pathology/nonclassic-inheritance-repeat-expansions-mitochondrial-genes-imprinting-mosaicis/)
- [Intracellular accumulations: cholesterol, proteins, hyaline, glycogen](https://durgical.com/en/general-pathology/intracellular-accumulations-cholesterol-proteins-hyaline-glycogen/)
- [Metabolic and mitochondrial myopathies](https://durgical.com/en/general-pathology/metabolic-and-mitochondrial-myopathies/)
- [Adrenocortical insufficiency](https://durgical.com/en/general-pathology/adrenocortical-insufficiency/)

## Related conditions 10

- [Tay–Sachs disease](https://durgical.com/en/conditions/tay-sachs-disease/)
- [Niemann–Pick disease](https://durgical.com/en/conditions/niemann-pick-disease/)
- [Gaucher disease](https://durgical.com/en/conditions/gaucher-disease/)
- [Hurler syndrome (mucopolysaccharidosis type I)](https://durgical.com/en/conditions/hurler-syndrome/)
- [Krabbe disease (globoid cell leukodystrophy)](https://durgical.com/en/conditions/krabbe-disease/)
- [Metachromatic leukodystrophy](https://durgical.com/en/conditions/metachromatic-leukodystrophy/)
- [X-linked adrenoleukodystrophy](https://durgical.com/en/conditions/x-linked-adrenoleukodystrophy/)
- [MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes)](https://durgical.com/en/conditions/melas/)
- [Leigh syndrome](https://durgical.com/en/conditions/leigh-syndrome/)
- [Leber hereditary optic neuropathy (LHON)](https://durgical.com/en/conditions/leber-hereditary-optic-neuropathy/)

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Educational content on the mechanisms of disease; not a diagnostic or treatment guide and no substitute for a health professional's advice. No doses are given.

Sources: [Tay-Sachs disease: MedlinePlus Genetics](https://medlineplus.gov/genetics/condition/tay-sachs-disease/) (MedlinePlus, US National Library of Medicine, 2026); [X-linked adrenoleukodystrophy: MedlinePlus Genetics](https://medlineplus.gov/genetics/condition/x-linked-adrenoleukodystrophy/) (MedlinePlus, US National Library of Medicine, 2026); [Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes: MedlinePlus Genetics](https://medlineplus.gov/genetics/condition/mitochondrial-encephalomyopathy-lactic-acidosis-and-stroke-like-episodes/) (MedlinePlus, US National Library of Medicine, 2026).

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Representative model, for educational purposes only.

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Source: https://durgical.com/en/general-pathology/inherited-metabolic-diseases-of-the-brain/
License: CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Cite as: DurgiPedia (durgical.com), https://durgical.com/en/general-pathology/inherited-metabolic-diseases-of-the-brain/