Metabolic Diseases

Symptoms

Metabolic defect

Clinical manifestations

Myopathy, stress intolerance

Mitochondrial disorder

Electron transport chain defects

Lysosomal disorder

Glycogen storage disease type II, Danon’s disease

Defect in purine metabolism

Myoadenylate deaminase deficiency

Neuropathy

Lysosomal disorder

Fabry’s disease, Krabbe’s disease, metachromatic leukodystrophy

Peroxisomal disorder

Refsum’s disease, adrenoleukodystrophy/adrenomyeloneuropathy

Mitochondrial disorder

Electron transport chain defects

Defect in cholesterol metabolism

Cerebrotendinous xanthomatosis

Defect in heme biosynthesis

Porphyria

Spinal muscular atrophy

Lysosomal disorder

GM₂ gangliosidosis

Spasticity

Mitochondrial disorder

Electron transport chain defects

Lysosomal disorder

GM₁ gangliosidosis, GM₂ gangliosidosis, Gaucher’s disease type 3, Krabbe’s disease, metachromatic leukodystrophy, Salla disease

Peroxisomal disorder

Refsum’s disease, adrenoleukodystrophy/adrenomyeloneuropathy

Defect in cholesterol metabolism

Cerebrotendinous xanthomatosis

Defect in urea cycle

Arginase deficiency

Progressive ataxia

Mitochondrial disorder

Pyruvate dehydrogenase deficiency, electron transport chain defects

Lysosomal disorder

GM₂ gangliosidosis, metachromatic leukodystrophy, Niemann-Pick disease type C, sialidosis, Salla disease

Peroxisomal disorder

Refsum’s disease, adrenoleukodystrophy/adrenomyeloneuropathy

Defect in cholesterol metabolism

Cerebrotendinous xanthomatosis

Defect in copper metabolism

Wilson’s disease

Defect in lipid metabolism

Abetalipoproteinemia

Extrapyramidal symptoms

Mitochondrial disorder

Electron transport chain defects

Lysosomal disorder

GM₁ gangliosidosis, GM₂ gangliosidosis (Tay-Sachs disease, Sandhoff’s disease), metachromatic leukodystrophy, Niemann–Pick disease type C, neuronal ceroid lipofuscinosis (Spielmeyer–Vogt disease, Kufs’ disease)

Peroxisomal disorder

Adrenoleukodystrophy

Defect in cholesterol metabolism

Cerebrotendinous xanthomatosis

Defect in copper metabolism

Wilson’s disease

Defect in purine metabolism

Lesch-Nyhan syndrome

Organic acid disorder

Glutaric aciduria type I

Leukodystrophy/leukoencephalopathy (specific patterns of distribution)

Mitochondrial disorder

Lysosomal disorder

Peroxisomal disorder

Defect in cholesterol metabolism

Organic acid disorder

Electron transport chain defects

Krabbe’s disease, metachromatic leukodystrophy

Adrenoleukodystrophy

Cerebrotendinous xanthomatosis

Canavan’s disease

(Myoclonic) epilepsy

Mitochondrial disorder

Lysosomal disorder

Pyruvate dehydrogenase deficiency, electron transport chain defects

Sialidosis, neuronal ceroid lipofuscinosis (Spielmeyer-Vogt disease, Kufs’ disease)

Behavioral abnormalities, psychosis, dementia

Mitochondrial disorder

Lysosomal disorder

Electron transport chain defects

Fabry’s disease, GM₂ gangliosidosis (Tay–Sachs disease, Sandhoff’s disease), Gaucher’s disease type 3, metachromatic leukodystrophy, Niemann-Pick disease type C, neuronal ceroid lipofuscinosis (Spielmeyer-Vogt disease, Kufs’ disease)

Peroxisomal disorder

Adrenoleukodystrophy

Defect in cholesterol metabolism

Cerebrotendinous xanthomatosis

Defect in copper metabolism

Wilson’s disease

Defect in amino acid metabolism

Homocystinuria

Defect in urea cycle

Ornithine transcarbamylase deficiency

Loss of vision

Mitochondrial disorder

Electron transport chain defects

Lysosomal disorder

Neuronal ceroid lipofuscinosis (Spielmeyer-Vogt disease), sialidosis

Peroxisomal disorder

Refsum’s disease

Defect in urea cycle

Ornithine aminotransferase deficiency

Ophthalmoplegia

Mitochondrial disorder

Electron transport chain defects

Lysosomal disorder

Gaucher’s disease type 3, Niemann-Pick disease type C

Stroke, stroke-like episodes

Mitochondrial disorder

Electron transport chain defects

Lysosomal disorder

Fabry’s disease

Defect in amino acid metabolism

Homocystinuria, methylene tetrahydrofolate reductase deficiency

Defect in urea cycle

Ornithine transcarbamylase deficiency

Recurrent attacks of ataxia

Mitochondrial disorder

Pyruvate dehydrogenase deficiency, electron transport chain defects

Defect in amino acid metabolism

Branched-chain organic aciduria, methylene tetrahydrofolate reductase deficiency

Defect in urea cycle

Ornithine transcarbamylase deficiency

Recurrent psychiatric symptoms

Defect in amino acid metabolism

Methylene tetrahydrofolate reductase deficiency

Organic acid disorder

Branched-chain organic acid disorder

Defect in urea cycle

Ornithine transcarbamylase deficiency

Defect in heme biosynthesis

Acute porphyria

Mitochondrial Diseases

Definition of Mitochondrial Diseases

The term “mitochondrial diseases” does not apply to all disorders of metabolism in mitochondria: it refers only to impairments of the energy metabolism, particularly those of the electron transport chain (respiratory chain), and in part also to disturbances of the immediate pyruvate metabolism and the citrate cycle.

Epidemiology

The estimated prevalence of mitochondrial diseases is 15 per 100 000 head of population.

Physiology and Etiology

Mitochondria are cellular organelles surrounded by a double membrane; inside these organelles, diverse metabolic processes take place (Fig. 17.1):

• Dehydrogenation and decarboxylation of pyruvate to acetyl CoA.

• The subsequent citrate cycle.

• Oxidative phosphorylation in the electron transport chain.

• β-Oxidation of fatty acids.

• Parts of the urea cycle.

The electron transport chain, in which the reoxidation of coenzymes is coupled to the synthesis of adenosine triphosphate (ATP)—the central energy source of the cell—consists of five enzyme complexes:

• Complex I: ubiquinone reductase.

• Complex II: succinate dehydrogenase.

• Complex III: cytochrome c oxidoreductase.

• Complex IV: cytochrome c oxidase (COX).

• Complex V: ATP synthase.

Mitochondria are inherited maternally and contain several copies of their own mitochondrial DNA (mtDNA). The mitochondrial DNA consists of a circular double strand of 16 569 base pairs; it codes for 13 polypeptides of the electron transport chain (mit genes) and also for two ribosomal RNAs and 22 transfer RNAs (syn genes). The majority of mitochondrial proteins, however, are encoded by nuclear DNA (nDNA) and are imported into the mitochondria after synthesis. Gene products of nDNA are also essential for maintaining and replicating the mtDNA. Normally, an organism contains only one mtDNA species. When a mutation occurs, a cell often contains both mutant mtDNA and wildtype mtDNA (heteroplasmy), with both being randomly distributed during cell division. As a result, one cell may receive only mutant DNA and another only wild-type DNA (segregation). Cell functions are only affected when the proportion of mutant mtDNA within a cell exceeds a critical threshold level. This explains, in part, the different manifestations of mtDNA mutations within a family.

Fig. 17.1 Mitochondrial metabolism.

PDH, pyruvate dehydrogenase Electron transport chain (respiratory chain):

Complex I	—ubiquinone reductase
Complex II	—succinate CO oxidoreductase
Complex III	—cytochrome c oxidoreductase
Complex IV	—cytochrome c oxidase (COX)
Complex V	—ATP synthase
CoQ	—coenzyme Q
Cyt c	—cytochrome c

**Table 17.2** Symptoms of electron transport chain defects
*Organ*	*Symptoms*
Central nervous system	Epilepsy, stroke-like episodes, lethargy, coma, psychosis, retardation, spasticity, dystonia, ataxia, paraparesis, myoclonus, cranial nerve defects, strabismus, nystagmus, central hypotension, cortical blindness, sensorineural loss of hearing
Peripheral nervous system	Sensorimotor axonal neuropathy
Muscles	Hypotension, weakness, stress intolerance, ptosis
Eyes	Retinitis pigmentosa, optic atrophy, cataract
Heart	Cardiomyopathy (usually hypertrophic), arrhythmia, impaired conduction
Liver	Liver failure (especially in infancy)
Pancreas	Exocrine pancreatic insufficiency
Gastrointestinal tract	Vomiting, diarrhea, villous atrophy, intestinal pseudo-obstruction
Kidney	Proximal tubulopathy with aminoaciduria, focal segmental glomerulosclerosis
Endocrine system	Diabetes mellitus, diabetes insipidus, short stature, hypothalamic hypogonadism, hypothyroidism, hypoparathyroidism, adrenal dysfunction, primary ovarian dysfunction
Bone marrow	Anemia, leukopenia, pancytopenia
Skin	Pigmentation anomalies, hypertrichosis, alopecia, hair follicle anomalies

Clinical Features

Defects in the mitochondrial electron transport chain may manifest in any organ and at any age during life. They may show very variable patterns of inheritance, and they may be chronic or rapidly progressive. Table 17.2 presents an overview of possible symptoms of an electron transport chain defect. The cardinal symptoms of pyruvate dehydrogenase (PDH) deficiency include developmental delay, epilepsy, ataxia, and progressive encephalopathy.

If there are two symptoms that cannot be explained otherwise, and particularly if they belong to different organ systems, the possibility of a mitochondrial disorder should be considered.

However, mitochondrial disease can also manifest as pure myopathy. Typical constellations of clinical features have been grouped together and designated as syndromes (Table 17.3). Whereas mtDNA-coded defects causing typical syndromes are found more often in adults, mutations of nuclear genes causing variable symptoms predominate in children (Table 17.3

Only gold members can continue reading. Log In or Register to continue