Metabolic Disorders and Systemic Diseases Affecting the Nervous System

The intense metabolic activity of the nervous system (both central and peripheral) makes it vulnerable to damage by a wide variety of metabolic disorders, both congenital (inborn errors of metabolism, i.e., metabolic diseases in the narrower sense of the term) and acquired (e.g., toxic). These disorders manifest themselves clinically as metabolic encephalopathy and metabolic neuropathy, of which there are many different types. Similar manifestations arise when the nervous system is involved by systemic diseases (e.g., endocrinopathy or vasculitis) and paraneoplastic syndromes.

6.8.1 Congenital Metabolic Disorders

Note

Metabolic diseases are caused by hereditary enzyme defects. They usually present in early childhood but sometimes not until many years later. They can be roughly divided into disorders of lipid, amino acid, and carbohydrate metabolism. Wilson disease is due to a disturbance of copper metabolism.

General clinical features The following findings in children and adolescents suggest the presence of a metabolic disease:

A positive family history.
Delayed motor and cognitive development.
A slowly worsening course.
Progressive spasticity.
Progressive dementia.
Optic nerve involvement.
Epileptic seizures.
Accompanying polyneuropathy and myopathy.

General diagnostic evaluation The diagnostic workup includes the following:

The taking of a comprehensive personal and family history.
A clinical neurologic (neuropediatric) examination.
Amino acid screening of the urine.
Measurement of the serum concentration of glucose, ammonia, lactate, and pyruvate, and screening for the lysosomal enzymes arylsulfatase A, hexosaminidase, and β-galactosidase.
Light- and electron-microscopic examination of biopsied tissue samples, with routine and special stains.
Radiologic examination of the skeleton.
MRI of the brain.
If indicated, specific genetic testing.

Disorders of Lipid Metabolism

Lipid storage diseases are due to faulty enzymatic degradation of individual lipid substances, leading to deposition of the intermediate products of lipid metabolism in various internal organs (liver, spleen, bone marrow) and in the nervous system. Disorders in which these nondegradable metabolites accumulate mainly in the neurons of the brain are characterized by degeneration of the cerebral cortex or of the subcortical nuclear areas (lipidoses); disorders in which they accumulate mainly in white matter are characterized by demyelination of the cerebral white matter and/or peripheral nerve sheaths (leukodystrophies). The lipid storage diseases affecting the nervous system are listed in ▶ Table 6.23. Two examples of the radiologic appearance of the brain in the leukodystrophies are shown in ▶ Fig. 6.54.

**Table 6.23** Lipidoses and leukodystrophies affecting the nervous system
Diseases	Clinical features	Particularities and treatment
Lipidoses
GM1 gangliosidoses and GM2 gangliosidoses	Infantile progressive encephalopathy, progressive myopathy in adults; possibly myoclonus, convulsions, visual impairment, progressive spasticity, and dementia; muscle atrophy and progressive weakness	Galactosidase deficiency in GM1 gangliosidoses; hexosaminidase deficiency in GM2 gangliosidoses, including Tay–Sachs disease and Sandhoff disease, with characteristic cherry-red spot. The causes of these conditions are currently untreatable
Fabry disease (angiokeratoma corporis diffusum)	Onset of symptoms in childhood or adolescence; burning pain in the limbs, particularly in warm surroundings; deficient sweating; maculopapular, purplish-red skin changes; renal failure; frequent strokes	X-linked inheritance; α-galactosidase deficiency with intracellular accumulation of trihexosylceramides. Enzyme replacement therapy with agalsidase- α (a recombinant form of α-galactosidase) lessens limb pain and improves renal function
Gaucher disease, juvenile and adult forms	Diverse neurologic manifestations, gaze paresis, bulbar signs, spasticity, polyneuropathy, psychosis, dementia, myoclonus, epileptic seizures	Autosomal recessive inheritance, glucocerebrosidase deficiency; foam cells in bone marrow. Treatment possible with enzyme replacement therapy or inhibition of glucoceramide synthesis with miglustat. Bisphosphonate is given for bone stabilization
Niemann–Pick disease	Progressive developmental delay beginning in the first year of life; juvenile forms with encephalopathy or hepatomegaly, progressive dementia, spasticity, and ataxia as well as epileptic seizures and psychosis	Autosomal recessive inheritance; genetic defect on chromosome 18, more common in Ashkenazi Jews. Substrate reduction therapy with miglustat
Refsum disease (heredopathia atactica polyneuritiformis)	Onset of symptoms in middle age; night blindness due to retinitis pigmentosa, hearing loss, polyneuropathy with areflexia and gait ataxia; mental abnormalities	Lack of phytanic acid α-dehydrogenase, accumulation of phytanic acid in the body (liver, kidneys, nervous system). A low-phytanic-acid diet and plasmapheresis are effective treatments
Cerebrotendinous xanthomatosis (cholestanol storage disease)	Onset of symptoms in adolescence or later; intellectual disability; juvenile cataracts, progressive spasticity and ataxia; xanthomas, particularly on extensor tendons and Achilles tendons; polyneuropathy and muscle atrophy	Autosomal recessive inheritance; impaired synthesis of bile acids; accumulation of cholestanol in plasma and brain, tendon xanthomas. The administration of bile acids (chenodeoxycholic acid) combined with a statin can alleviate symptoms
Neuronal ceroid lipofuscinosis (Batten–Kufs disease)	Presentation in infancy and early childhood (Spielmeyer–Vogt type) or in adulthood (Kufs disease); ataxia, myoclonus, epileptic seizures, progressive visual loss, and mental deterioration	Waxy waste products (ceroid lipofuscins) are stored intracellularly and lead to cell death. Only symptomatic and palliative treatment is possible at present
Leukodystrophies
Metachromatic leukodystrophy	Late infantile type: from the age of 1 year onward, spastic weakness progressing toward quadriplegia, loss of mental function, areflexia, bulbar and pseudobulbar signs, optic atrophy; juvenile type: onset at age 2–10 y, elevated CSF protein, white matter hypodensity in CT and hyperintensity in T2-weighted MRI	Autosomal recessive inheritance; lack of arylsulfatase A; accumulation of sulfatide in the brain, peripheral nerves, and other tissues; demonstration of low arylsulfatase A concentration in leukocytes and urine. Stem-cell transplantation can slow or arrest the progression of the disease
Globoid cell leukodystrophy (Krabbe disease)	Infantile, juvenile, and adult types; spasticity, optic atrophy, and polyneuropathy	Lack of galactocerebrosidase. The treatment is symptomatic and palliative; in late stages, stem-cell transplantation may be possible
Adrenoleukodystrophy ( ▶ Fig. 6.54a)	Most patients are male; in the first two decades of life, they develop a spastic gait, visual impairment, and mental changes; adrenal insufficiency may arise in adulthood	X-linked deficiency of the enzyme lignoceroyl coenzyme A synthetase. The progression of the disease can be slowed or arrested with a diet low in fatty acids and by stem-cell transplantation. Patients with adrenomyeloneuropathy have these manifestations and polyneuropathy as well

Disorders of Amino Acid and Uric Acid Metabolism

**Table 6.24** Disorders of amino acid and urate metabolism
Disease	Clinical features	Remarks
Phenylketonuria	Clinical manifestations from the age of 6 months onward, if untreated: intellectual disability, epileptic seizures, spasticity, tremor, hypopigmentation	Autosomal recessive inheritance; lack of hydroxylation of phenylalanine to tyrosine; neonatal screening (Guthrie test) The treatment is with a strictly low-phenylalanine diet
Maple syrup urine disease	Presentation in the neonatal period: impaired alertness, diminished muscle tone, intellectual disability	Impaired degradation of branched amino acids; sweet-smelling urine (like maple syrup) Treated with a protein-free diet and dialysis if indicated
Hartnup disease	Bouts of pellagra-like dermatitis, accompanied by episodes of ataxia, nystagmus, and gait unsteadiness, progressive dementia, and spasticity	Impaired tubular and intestinal reabsorption of tryptophan; aminoaciduria A high-protein diet may be beneficial
Homocystinuria	Arterial and venous thromboembolism, lens ectopy, intellectual disability	Impairment of methionine metabolism Low-methionine, high-cystine diet, and thrombosis prophylaxis with acetylsalicylic acid

The more common disorders of these types include phenylketonuria (an autosomal recessive disorder of amino acid metabolism), maple syrup urine disease, Hartnup disease, and homocystinuria ( ▶ Table 6.24).

Disorders of Carbohydrate Metabolism

These disorders include the monosaccharides (e.g., galactosemia), the glycogenoses, and the mucopolysaccharidoses ( ▶ Table 6.25). Myoclonus epilepsy, a type of mucopolysaccharidosis, is characterized by generalized epileptic seizures, myoclonus, and dementia.

**Table 6.25** Disorders of carbohydrate metabolism
Disease	Clinical features	Remarks
Galactosemia	Onset in infancy: failure to thrive, retardation, jaundice, cataracts	Impaired enzymatic degradation of galactose; accumulation of the phosphorylated form in the liver, kidneys, lenses, and brain Treated with a lactose-free, low-galactose diet
Glycogenoses, types I–XI	Accumulation of glycogen in the liver, kidneys, muscles, and brain; clinically, hepatic dysfunction, possibly myopathy, intellectual disability, epileptic seizures	Impaired enzymatic degradation of glycogen Enzyme replacement therapy can slow the progression of type II glycogenosis (Pompedisease, α-glucosidase deficiency)
Mucopolysaccharidoses	Pfaundler–Hurler syndrome: onset in infancy, corneal opacification, joint swelling, dwarfism, intellectual disability, possibly quadriparesis due to spinal cord compression Scheie syndrome: juvenile type, with slow progression Progressive myoclonus epilepsy (Lafora type): generalized epileptic seizures, myoclonus, progressive dementia, psychosis	In Pfaundler–Hurler syndrome and Scheie syndrome, acidic mucopolysaccharides are deposited in various tissues because of hydrolase deficiency In progressive myoclonus epilepsy, mucopolysaccharides are deposited in the form of Lafora bodies in the brain, muscles, and liver In rare cases, disease progression can be slowed by enzyme replacement therapy with iduronidase (Aldurazyme) or stem-cell transplantation

Fig. 6.54 T2-weighted MRI images of two patients with congenital metabolic disorders. (a) A 27-year-old man with quadriparesis, somewhat worse in the lower limbs, because of adrenoleukodystrophy. There are symmetric signal abnormalities in the white matter, particularly in the posterior zones of the cerebral hemispheres. (b) A 43-year-old man with polyglucosan body disease. Here, too, there are symmetric signal abnormalities in the white matter; the brain is atrophic as well.

Disorder of Copper Metabolism: Wilson Disease

Etiology and pathogenesis Hepatolenticular degeneration (Wilson disease), an autosomal recessive disorder whose genetic locus lies on the long arm of chromosome 13, involves a disturbance of copper metabolism. The concentration of the copper transport protein ceruloplasmin is abnormally low and, as a result, the serum free copper concentration is high and an abnormally large amount of copper is eliminated in the urine. Free copper is deposited in the liver, the edge of the cornea (producing the typical Kayser–Fleischer ring), and the brain.

Clinical features Hepatopathy or hemolytic anemia dominates the clinical picture in childhood and the neurologic and psychiatric manifestations come later; the most impressive of these is a coarse postural and intention tremor of the limbs (recognizable on extension of the arms to both sides, e.g., as a “flapping tremor”). Dysarthria, dystonia, and rigidity are common, as are mental abnormalities (depression, personality changes, or even psychotic episodes).

Diagnostic evaluation The Kayser–Fleischer ring, a brown ring around the periphery of the cornea, helps establish the diagnosis. MRI reveals cortical atrophy, enlarged ventricles, and signal abnormalities in the basal ganglia.

Treatment This disease is treated with D-penicillamine (a chelating agent) or zinc sulfate (a copper uptake inhibitor). A diet containing as little copper as possible is recommended (e.g., no organ meats, chocolate, nuts, or mushrooms). Caution: copper deficiency may arise. This initially manifests itself with anemia and leukopenia and may lead to myeloneuropathy and pancytopenia.

Other Metabolic Disorders

Several other metabolic disorders are mentioned here for completeness; some of them have no known cause. Myoclonus epilepsy and adult polyglucosan body disease ( ▶ Fig. 6.54b) are polyglucosan storage diseases. Both are characterized by progressive spasticity, ataxia, and dementia.

Reye syndrome is probably of multifactorial origin. A few days after a viral illness, the patient becomes progressively somnolent, with nausea, delirium, and cerebral edema.

In the various types of α-lipoproteinemia, the serum cholesterol and triglyceride levels are abnormally low. These disorders are clinically characterized by ataxia, nystagmus, oculomotor disturbances, and polyneuropathy, in combination with retinitis pigmentosa. These manifestations are often accompanied by acanthocytosis (Bassen–Kornzweig).