Metabolic Disorders

Patricia L. Musolino

Katherine B. Sims

INHERITED METABOLIC DISEASES WITH NEUROLOGICAL INVOLVEMENT

This section is designed to allow the reader to quickly screen through the main metabolic disorders w/ neurological si/sx presenting during infancy or childhood. The first subsection presents diagnostic algorithms. The subsequent subsection presents more detailed information about specific disorders. A current expert review for each disease is referenced from the NCBI/NIH GeneReviews chapter where their up-to-date contact information is also available. Detailed instructions on diagnostic testing can be found through www.genereviews.org (see Tables 7.1, 7.2 and 7.3, Figures 7.1, 7.2 and 7.3, and Table 7.4).

TABLE 7.1 Most Common Presentations of Neurologic Metabolic Diseases by Age

Age	Neonatal 1-28 d	Late Infancy 1-12 mo	Childhood	Adolescence/Adulthood
Neuro si/sx	lethargy, diff feeding, hypotonia, irritability, seizures	lethargy or coma w/ nonfocal neuro exam a/w fasting	psych d/o, ataxia, movement d/o, recurrent episodes of coma, paraplegia, seizures, visual d/o	movement d/o, psych d/o, ataxia, peripheral neuropathy, seizures, recurrent episodes of confusion
Other si/sx	Vomiting, abnl respiration, metab acidosis, urine maple syrup smell (MSUD), sweaty foot odor ( isovaleric acidemia, glutaric aciduria type II)	recurrent vomiting, liver dysfunction, metabolic acidosis	vomiting, bone deformities, coarse facies, hepatosplenomegaly	recurrent rhabdomyolysis, myoglobinuria, cardiomyopathy
DDx	UCD, OTC, aminoacidopathies, MSUD, organic acidurias, fatty acid oxidation defects, medium chain ACoA dehydrogenase deficiency (MCAD)	same as for neonatal +: peroxisomal and lysosomal disease, Niemann-Pick, l-cell disease, MPS VII, alpha-1-antitrypsin, hemochromatosis	lysosomal d/o: Gaucher III, NCLs, Niemann-Pick, RCD	Movement d/o: metal metab d/o, RCD, neurotransmitter disorders, intermediary metab d/o Peripheral Neuropathy. porphyrias, Refsum, PDH, CT×, Wilson, Fabry, ALD, RCD. Spastic paraparesis: UCD, homocysteine remethylation defects, biotinidase def, PKU, NKH, DRD, cerebral folate def, CT×, ALD, lysosomal, Sjögren-Larsson Recurrent confusion: UCD, porphyria, homocysteine remethylation disorders, CTX Chronic psych sx. homocystinuria, Wilson disease, lysosomal d/o, NCLs, NKH, MPS III
Adapted from Paritosh P. Pocket Pediatrics. Philadelphia, PA: Lippincott Williams & Wilkins; 2009.

TABLE 7.2 Basic Initial Workup for Suspected Metabolic Disorder

Test/Study	Abnormalities of Interest
Urine: collect each fresh sample separately in clean container and stored at 4°C (short term). Freeze at-20°C. Compare samples collected before and after Rx.	Smell (special odor), look (special color) Acetone Reducing substances Keto acids (DNPH) pH Sulfitest Sulfite oxidase Electrolytes (Na⁺, K⁺, phos) Uric acid (search for hyperuricuria) Organic acids (quantitative)
Blood: 5 mL plasma (heparinized) at-20°C and10 mL whole blood in EDTA (for molecular DNA studies) and blood on filter paper(“Guthrie test”)	Blood cell count Electrolytes (look for anion gap, glucose, calcium) Blood gas (pH, pCO₂, HCO3”, pū₂) Uric acid Prothrombin time Transaminases (and other liver tests) Plasma ammonia (on ice) Lactic acid (on ice; STAT processing) Pyruvic acid (requires special de-proteinization tube) 3-OH-butyrate, acetoacetate (ketones) Free fatty acids Serum amino acids (quantitative)
CSF: neurotransmitters (collected in specific tubes & transported in dry ice); collect 2 mL STAT (on ice) for chemistries & lactic acid	Opening and closing pressures Cell count, protein, glucose (obtain simultaneous serum glucose) Lactic acid (on ice) Pyruvate Ammonia Amino acids Neurotransmitters, neopterins, biopterins, MTHF
ECHO/EKG	Cardiomyopathy in storage diseases
CXR/KUB	Organomegaly
	Nephrocalcinosis
Adapted from Saudubray JM, Charpentier C. Chapter 66. In: Scriver CR, et al. (eds). The Metabolic and Molecular Bases of Inherited Diseases. 8th ed. New York, NY: McGraw-Hill; 2000, with permission.

TABLE 7.3 Advanced Workup for Suspected Metabolic Disorder

Study	Abnormalities of Interest
MRI/MRS brain	T1, T2 abnormalities; lactate, NAA, creatine peak analysis
Skin biopsy (fibroblast culture)	Enzyme analysis in cultured fibroblasts (FAO, PDH/PC) Staining for lipids, glycogen, cholesterol, fatty acids NP-C (cholesterol esterification, filipin staining) DNA analysis
	EM for storage inclusions (lysosomal, mitochondrial)
Muscle biopsy	Light & electron microscopy, immunohistochemistry, trichrome for ragged red fibers (RRF, mitochondrial diseases), lipid storage
	Different patterns of myotubular organization in myopathies
Liver, muscle biopsy (fresh & frozen at -70)	Electron transport chain (ETC activity), coenzymeQ10, acylcarnitines & carnitines (free, total, esterified) Staining for accumulation of lipids, glycogen, cholesterol, fatty acids; immunohistochemistry
EMG/SSEP	Lower motor neuron disease pattern
	Neuropathies
	Myopathies
Brain US (neonates)	White matter changes Ventriculomegaly
	Intraventricular hemorrhage (IVH)
	Neonatal strokes

FIGURE 7.1 Metabolic Emergencies: Anion Gap Metabolic Acidosis. Adapted from Saudubray JM, Charpentier C. In: Scriver CR, et al. (eds). The Metabolic and Molecular Bases of Inherited Diseases. 8th ed. New York, NY: McGraw-Hill; 2000 and Fenichel GM. Clinical Pediatric Neurology. 6th ed. Philadelphia, PA: Saunders, Elsevier; 2009.

FIGURE 7.2 Metabolic Emergencies: Neonatal Hyperammonemia. Adapted from Saudubray JM, Charpentier C. In: Scriver CR, et al. (eds). The Metabolic and Molecular Bases of Inherited Diseases. 8th ed. New York, NY: McGraw-Hill; 2000 and Fenichel GM. Clinical Pediatric Neurology. 6th ed. Philadephia, PA: Saunders, Elsevier; 2009.

FIGURE 7.3 Metabolic Emergencies: Metabolic Coma. Adapted from Saudubray JM, Charpentier C. In: Scriver CR, et al. (eds). The Metabolic and Molecular Bases of Inherited Diseases. 8th ed. New York, NY: McGraw-Hill; 2000 and Fenichel GM. Clinical Pediatric Neurology. 6th ed. Philadelphia, PA: Saunders, Elsevier; 2009.

TABLE 7.4 Differential Diagnosis of Lactic Acidosis

Erroneous elevation	Poor collection technique (use of a tourniquet, slow blood flow), poor sample handling (not on ice or processing delay), physiologic, anaerobic exercise
Systemic diseases	Hypoxia, hypotension, shock, sepsis, renal failure, cardiac failure/cardiomyopathy, short bowel syndrome (D-lactate)
Cerebral diseases (can cause ↑ CSF lactate levels)	Prolonged seizures, meningitis/encephalitis, cerebral ischemia, malignancy, other metabolic disorders
Metabolic diseases	Amino acid disorders, organic acidurias, urea cycle defects, pyruvate metabolism disorders, Krebs cycle defects, mitochondrial OXPHOS disorders, fatty acid oxidation disorders, disorders of liver glycogen metabolism, disorders of liver gluconeogenesis, biotinidase deficiency
Other	Thiamine deficiency
	Toxin exposure (carbon monoxide, methanol)

Management of Metabolic Emergencies

When suspected metabolic disorder or unknown source of metabolic acidosis, hyperammonemia, or coma, Start Rx Before confirmation of diagnosis.

1. STOP protein, fat, galactose, & fructose

2. Consult metabolic specialist

3. Remove metabolites

Hyperammonemia: immediate hemodialysis (HD) for coma, ventilator dependency, or signs of cerebral edema
Acidosis: give bicarbonate w/ frequent ABGs, severely acidotic → HD
Organic acidemia: Vitamin B₁₂ (1 mg) IM for B₁₂ responsive form of methylmalonic acidemia. Biotin (10 mg) PO or NGT for biotin-responsive carboxylase deficiency. May need HD or peritoneal dialysis if coma
Urea cycle defect: 6 cc/kg of 10% arginine HCL IV over 90 min

FIGURE 7.4 Progressive Spastic Paraparesis Associated with Metabolic Disorders. Adapted from Sedel F, Fontaine B, Saudubray JM, et al. Hereditary spastic paraparesis in adults associated with inborn errors of metabolism: a diagnostic approach. J Inherit Metab Dis. 2007;30(6):855-864, with permission.

4. Prevent catabolism

IV glucose (calories needed to keep euglycemia) D10 150 cc/kg/d w/ electrolytes
STOP protein (after 24-48 h restart essential amino acids), IV lipids should be given for urea cycle defects

Diagnostic Algorithms by Main Presenting Symptoms

Progressive Spastic Paraplegia

See Figure 7.4.

Ataxia

See Figures 7.5 and 7.6.

Epilepsies Associated with Metabolic Diseases

See Figure 7.7 and Table 7.5.

Movement Disorders and Extrapyramidal Signs

See Figures 7.8 and 7.9.

Peripheral Neuropathy Secondary to Inborn Error of Metabolism

See Figure 7.10.

Ocular Findings in Inborn Errors of Metabolism

See Table 7.6.

FIGURE 7.5 Acute Ataxia Associated with Metabolic Disorders. Adapted from Saudubray JM, Charpentier C. In: Scriver CR, et al. (eds). The Metabolic and Molecular Bases of Inherited Diseases. 8th ed. New York, NY: McGraw-Hill; 2000, with permission.

FIGURE 7.6 Progressive Ataxia Associated with Metabolic Disorders. Adapted from Saudubray JM, Charpentier C. In: Scriver CR, et al. (eds). The Metabolic and Molecular Bases of Inherited Diseases. 8th ed. New York, NY: McGraw-Hill; 2000, with permission.

FIGURE 7.7 Epilepsies Associated with Metabolic Disorders. Adapted from Sedel F, Fontaine B, Saudubray JM, et al. Hereditary spastic paraparesis in adults associated with inborn errors of metabolism: a diagnostic approach. J Inherit Metab Dis. 2007;30(6):855-864⁵⁰ and Wolf NC. Epilepsy in inborn errors of metabolism. Epileptic Disord. 2005; 7 (2): 67-81, with permission.⁵¹

TABLE 7.5 Anticonvulsants to be Avoided in Metabolic Disorders

Disease	Drugs that may Exacerbate Epilepsy or Metabolic Attacks
PME	Phenytoin, carbamazepine, gabapentin, vigabatrin, tiagabine, lamotrigine
GLUT-1 deficiency	Diazepam, phenobarbital, oxcarbamazepine
Porphyrias	Valproate, lamotrigine, oxcarbamazepine, carbamazepine, phenytoin, topiramate
Urea cycle defects	Valproate
Mitochondrial disorders	Valproate

FIGURE 7.8 Movement Abnormalities Associated with Metabolic Disorders.

FIGURE 7.9 Movement Disorders Associated with Metabolic Disorders, Characterized by Onset and MRI Findings. Adapted from Sedel F, Saudubray JM, Roze E, et al. Movement disorders and inborn errors of metabolism in adults: a diagnostic approach. J Inherit Metab Dis. 2008;31(3):308-318, with permission.⁵⁰

FIGURE 7.10 Peripheral Neuropathies Associated with Metabolic Disorders. Adapted from Sedel F, Baumann N, Turpin JC, et al. Psychiatric manifestations revealing inborn errors of metabolism in adolescents and adults. J Inherit Metab Dis. 2007;30(5):631-641, with permission.

TABLE 7.6 Ocular Findings Associated with Metabolic Disorders

	Disorder
Optic glioma	NF type I
Retinitis pigmentosa	Peroxisomal disorders Sjögren-Larsson syndrome (ichthyosis, spastic paraplegia, MR)
	NCL disorders
	Refsum disease
	Kearns-Sayre syndrome
	Pantothenate kinase deficiency/infantile neuroaxonal dystrophy
	Bardet-Biedl syndrome (obesity, polydactyly, MR)
	Usher type II (deafness, severe MR)
	Joubert (MR, vermis atrophy, hyperventilation episodes)
	NARP
	MILS
	Abetalipoproteinemia
	Congenital defects of glycosylation
	RCD
	LCHAD
	Mucopolysaccharidoses type I, II, III, IV
Macular degeneration (cherry-red spots)	MLD Niemann-Pick disease Wolman disease Galactosialidosis GM1 gangliosidosis GM2 gangliosidosis
Optic atrophy or central blindness	ALD MLD Krabbe disease Zellweger spectrum Refsum disease MELAS LHON Canavan disease 3-methylglutaconic aciduria NCL disorders Homocystinuria
Lens dislocation	Sulfite oxidase deficiency Molybdenum cofactor deficiency Homocystinuria Marfan syndrome Ehlers-Danlos syndrome
Neonatal cataracts	Galactosemia Galactokinase deficiency Tyrosinemia type II Peroxisomal disorders Glucose-6-phosphate dehydrogenase deficiency Sorbitol dehydrogenase deficiency Lowe syndrome Cockayne syndrome Congenital infection (syphilis, rubella, mumps)
Infantile cataracts	RCD Sialidosis α-mannosidosis Mevalonic aciduria
Adapted from Saudubray JM, Charpentier C. In: Scriver CR, et al. (eds). The Metabolic and Molecular Bases of Inherited Diseases. 8th ed. New York, NY: McGraw-Hill; 2000, with permission.

DISEASES AFFECTING METABOLIC PATHWAYS

Metal Metabolic Disorders

Wilson Disease¹

Familial hepatolenticular degeneration

Defect: Defect in copper-transporting ATPase 2, (ATP7B).

FHx: AR, Mediterranean descent

Presentation: Classically p/w movement d/o (tremors, poor coordination, loss fine-motor, choreathetosis) + hepatic failure. Hepatic failure predominates in children w/ onset at < 10 y. If onset in 2nd decade, one neurologic
si/sx such as gait or speech disturbance, unchanged for years & then development of movement d/o (e.g., dysarthria, dystonia, dysdiadochokinesia, facio-linguo-pharyngeal rigidity, & gait difficulties). Other sx: rest & action tremor (rubral tremor) ± chorea & parkinsonism. Psychiatric si/sxprecedes movement d/o in 20% of cases.

Other si/sx: Hepatic failure/cirrhosis, corneal Kayser-Fleischer ring (seen in 100% cases w/ CNS involvement) & azure lunulae of the fingernails. Fanconi syndrome.

Prognosis: Variable. Can have normal life span if therapy instituted early.

Dx: Imaging: MRI: cerebral atrophy, T2 hypointensity of the globus pallidus, & T2 hyperintensity of caudate, putamen, thalamus, dentate nucleus, & pons. Labs: Low serum copper & ceruloplasmin. Elevated LFTs, increased urinary copper. Liver biopsy: Elevated copper in liver w/ assay of copper content by spectrometry (copper content > 250 mcg dry weight of liver). Definitive dx: Neuro-ophthalmologic slit-lamp exam showing corneal Kayser-Fleischer rings, mutational analysis (ATP7B). Screen siblings.

Rx: Lifelong; copper-chelating agents: D-penicillamine, trientine, tetrathiomolybdate; zinc, antioxidants, restriction of foods very high in copper. Liver transplant controversial.

Aceruloplasminemia²

Defect: Mutation of the ceruloplasmin gene (CP) on chromosome 3q25. Accumulation of iron in liver, pancreas, brain, & retina.

FHx: AR

Presentation: Very rare, p/w progressive neurodegeneration resulting in dystonia or chorea, dementia, retinal degeneration, & cerebellar ataxia.

Other si/sx: Microcytic anemia, diabetes.

Dx: Imaging: MRI: iron accumulation (T2 hypointensity) in the putamen, caudate, thalamus, dentate nuclei. Labs: Undetectable serum ceruloplasmin, ↓ iron, ↓ copper, ↑ ferritin, microcytic anemia. LFTs normal. Biopsy: liver iron deposits in hepatocytes & RE system. Definitive dx: DNA mutation analysis (CP).

Rx: Iron chelators (e.g., desferrioxamine, FFP), antioxidants. Avoid iron supplements.

Hemochromatosis³

Prevalence: High carrier rate (1:250), but very low incidence (phenotypic) in children.

Defect: Classic type I: C282Y gene. Class II juvenile: AR hemojuvelin gene (HFE2) and hepcidin antimicrobial peptide (HAMP). Class III: AR transferrin receptor-2 (TFR2). Class IV: AD ferroportin (FPN1).

FHx: All AR except Class IV, which is AD.

Presentation: More common in adults, but can be seen as early as 2 y (in children: cardiomyopathy & gonadal failure). Neurologic signs include: parkinsonism, cerebellar ataxia, dementia, myoclonus, action tremor, cervical dystonia.

Other si/sx: Cirrhosis & primary hepatocellular carcinoma, arthritis, DM, bronze skin pigmentation.

Prognosis: Depends on progression of disease before therapy. Children often die of cardiac cause.

Dx: Imaging: Normal MRI (may have brain atrophy). Labs: High serum iron, transferrin saturation, & ferritin. Biopsy: Hepatic iron is the most sensitive index of preclinical disease. Confirmed by hepatic iron index score >1.9 or hepatic iron >80 µmol/g dry weight of liver or grade 3 or 4 on Perls stain. Definitive dx: Liver biopsy & genetic testing.

Rx: Phlebotomy for ferritin >300 mcg/L in men; ferritin > 200 mcg/L in women, regardless of the presence or absence of symptoms.

Neurodegeneration with Brain Iron Accumulation (NBIA)⁴

Infantile Neuronal Dystrophy (INAD; Seitelberger disease)

FHx: AR; PLA2G6 mutations.

Presentation: Progressive degeneration of CNS and PNS. Infantile hypotonia followed by spasticity, opisthotonic posturing, optic atrophy. Death usually by 5 y.

Pathology: Axonal spheroids on skin or nerve biopsy.

Dx: MRI: diffuse cerebellar hyperintensity and atrophy ± iron in basal ganglia. EMG: anterior horn cell dysfunction, denervation. NCλζ normal; ERG, normal.

Rx: Symptomatic

Pantothenate Kinase-Associated Neurodegeneration (PKAN)

Defect: Pantothenate kinase deficiency, PANK2 mutations.

FHx: AR

Presentation: Onset 7 to 10 y w/ dystonia, dysphagia, parkinsonism, choreathetosis, and retinitis pigmentosa. Cognitive and psychiatric disorders, along w/ spasticity follow.

Prognosis: Spastic quadriplegia and death within 5 to 10 y.

Dx: Imaging: T2 hyperintensity w/ surrounding hypointensity in medial globus pallidius (“eye of the tiger sign”). Definitive dx: PANK2 mutation analysis.

Rx: Symptomatic, deep brain stimulation for dystonia.

Menkes: Trichopolydystrophy⁵

Defect: Defect in the intestinal transport of copper, ATP7A gene mutation.

FHx: X-linked recessive.

Presentation: Symptoms result from secondary deficiency of copper-dependent enzymes (cytochrome-c-oxidase, dopamine-beta-hydroxylase, lysyl oxidase, etc.). Most marked are neurodegenerative changes and connective tissue abnormalities. Infants are usually hypotonic, progressing to spastic quadriparesis. Autonomic dysfunction, temperature instability, and hypoglycemia are seen in neonates.

Other si/sx: Sparse, poorly pigmented, pili torti (kinky hair), osteogenesis imperfecta, high arched palate, micrognathia, fullness of the cheeks, occipital horns.

Prognosis: Progressive encephalopathy leaves patients vegetative by 1 y, death usually by 1.5 to 2 y, no therapy. Cases surviving up to 20 y have been described.

Dx: Labs: Low plasma ceruloplasmin; copper microscopic examination of the hair (pili torti seen in carriers). Biopsy: Skin for enzyme assay in cultured fibroblasts. Definitive dx: ATP7A mutation analysis. Prenatal testing.

Rx: subcutaneous injections of copper histidine or copper chloride before 10 d of age normalizes developmental outcome.

Peroxisomal Disorders⁶

Refsum Disease (Phytanic Acid Oxidase Deficiency)

Defect: Defect of phytanoyl-CoA hydroxylase (PAHX or PHYH gene).

FHx: AR, more common in Scandinavian, British, German, & French.

Presentation: Insidious onset in 1st through 3rd decade w/ night blindness (retinitis pigmentosa), recurrent or chronic polyneuropathy (often symmetric, distal, vibration > pain & temp), palpable nerves, cerebellar ataxia, dysmetria, dysarthria. When presenting in infants, severe hypotonia w/ absent DTRs seen. Symptoms made worse by fasting. Other si/sx: sensorineural hearing loss, cardiomyopathy, ichthyosis, pes cavus.

Prognosis: Variable, progressive w/ periods of stability & exacerbations. Death may occur from sudden cardiac event.

Dx: Imaging: MRI: symmetrical T2 hyperintensity involving the corticospinal tracts, cerebellar dentate nuclei, & corpus callosum (only seen on infantile form). Labs: ↑ plasma branched-chain FAs (mostly phytanic acid), ↑ CSF protein (1-7 g/L). Biopsy: Skin for enzyme assay in cultured fibroblasts. Definitive dx: PAHX or PHYH mutation analysis.

Rx: Dietary modification to avoid phytanic acid ± plasmapheresis.

X-linked Adrenoleukodsytrophy (XALD), see Chapter 9.

Zellweger Spectrum disorders, see Chapter 9.

Lysosomal Disorders

GM1 Gangliosidosis⁷ (type I: infantile, type II: late infantile/juvenile, & type III: adult)

Defect: Beta-galactosidase deficiency, GLB1 gene mutation.

FHx: AR.

Presentation: Type I (infantile onset): difficulty feeding/failure to thrive, hypotonia. Type II (late infantile/juvenile): initially ataxia, strabismus, & dysarthria, followed by seizures, mental regression, & spasticity.

Other si/sx: Type 1: hepatosplenomegaly, deafness, mental retardation, kyphoscoliosis, vertebral & hip dysplasia (resembling Hurler disease, but w/o corneal opacities & w/ macular cherry-red spots [50%]), renal disease, dilated and/or hypertrophic cardiomyopathy.

Type II: no visceromegaly & only mild skeletal abnormalities.

Prognosis: Death typically occurs within 1 y in the infantile form. Later onset associated with survival into 1st or 2nd decade.

Dx: Imaging: T2 hyperintensity of posterior putamen. Labs: Low betagalactosidase activity in leukocytes. Biopsy: Liver, heart, kidney, fibroblast show accumulation of gangliosides. Definitive dx: Beta-galactosidase activity in leukocytes & GLB1 molecular testing.

Rx: Symptomatic or Miglustat (inhibitor of glucosylceramide synthase)

GM2 Gangliosidosis, type I⁸: Tay-Sachs Disease (infantile, juvenile/chronic adult forms)

Defect: Hexosaminidase A deficiency; HEXA mutations.

FHx: AR, Ashkenazi Jews with high carrier rate.

Presentation: Infantile form (most common): persistent startle reaction to sound, developmental regression, followed by paralysis, dementia, & blindness. Juvenile onset (late-onset form; onset late childhood to adulthood): childhood clumsiness or incoordination, can see psychiatric presentation; associated findings include: proximal muscle weakness (typically LE

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