Basics of Metabolism and Pediatric Neurology

The complexity and fascination for metabolic diseases can be introduced by unfolding the story of vitamin B₁₂ (cobalamin [Cbl]). While its deficiency in adults is suspected in the presence of megaloblastic anemia and ataxic paraparesis (subacute combined degeneration), the deeper plot rises in children with inborn errors of vitamin B₁₂ metabolism. Their failure to convert Cbl into its two active forms, methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl), which are essential cofactors for methionine synthase (MS) and methylmalonyl CoA mutase, respectively, leads to hyperhomocysteinemia with hypomethioninemia (HC) and methylmalonic acidemia (MMA). Hyperhomocysteinemia leads to vascular diseases, especially in the most common cause of homocystinuria associated with deficiency of cystathionine beta synthase (CBS). The hypomethioninemia keeps folate building as 5-methyl-tetrahydrofolate (MTHF), which renders it useless for the synthesis of purine and, therefore, DNA. The resulting gastrointestinal (glossitis and diarrhea) and hematologic (anemia) deficits are reversed by folate replacement.

^*Methionine is high when CBS deficiency causes hyperhomocysteinemia. MeCbl deficiency leads to homocystinuria and hypomethioninemia in the absence of methylmalonic aciduria. Megaloblastic anemia and leukoencephalopathy are early clinical clues, especially in a patient with progressive spastic paraparesis.

The neurologic deficits are independent of purine synthesis and hematologic signs but inversely correlate with the degree of anemia and macrocytosis. Abnormal myelination presumably results from either a deficiency of S-adenosylmethionine or the accumulation of methylmalonate and methylpropionate into branched-chain fatty acids. When the combined hepatic synthesis of MeCbl and AdoCbl is impaired, both methionine synthase and methylmalonic-CoA mutase are affected and a different phenotype arises, MMA-HC.

Spectrum of Vitamin B₁₂-Requiring Disorders

Subacute Combined Degeneration (SCD)	Methylmalonic Aciduria (MMA)	Homocystinuria (HC)	MMA-HC

Spastic paraparesis and sensory ataxia (corticospinal tracts and dorsal columns) with peripheral neuropathy MeCbl deficiency (adult onset): spastic paraparesis with cervical cord atrophy and symmetric periventricular leukoencephalopathy	Profound ketotic hyperglycinemic encephalopathy in the setting of selective necrosis of the globus pallidus^a with early death or severe developmental retardation in survivors	Marfanoid habitus, myopia with downward lens dislocation, livedo reticularis, developmental delay, brittle bones (osteoporosis), seizures, and thromboembolic strokes from homocysteine-induced endothelial injury	Dysmorphic face, hypotonia, ataxia, seizures, optic atrophy, psychomotor delay, and hemolytic-uremic syndrome (HUS): azotemia, thrombocytopenia microangiopathic hemolytic anemia, transient callosal splenium edema
MeCbl, methylcobalamin.
^aSelective necrosis of the globus pallidus is also seen in propionic acidemia, pyruvate dehydrogenase deficiency, kernicterus, and carbon monoxide poisoning.

Diagnosis of Vitamin B₁₂ Deficiency

Profound vitamin B₁₂ deficiency leads to pancytopenia with hypoproliferative anemia characterized by macrocytosis, hypersegmentation of neutrophils, and signs of ineffective erythropoiesis (elevated lactate dehydrogenase and indirect bilirubin). In milder vitamin B₁₂ deficiency, the following algorithm replaces the Schilling test and the evaluation for antibodies against parietal cells (nonspecific) and intrinsic factor (insensitive).

^*Methylmalonic acid concentration reflects intracellular vitamin B₁₂ stores and exhibits higher specificity for low vitamin B₁ status than any other metabolite including homocysteine. (Adapted from Marks PW, Zukerberg LR. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 30-2004. A 37-year-old woman with paresthesias of the arms and legs. N Engl J Med. 2004;351(13):1333-1341.)

Carbohydrate Metabolism: Inherited Muscle Glycogenoses


McArdle Disease (Type V)	Pompe Disease (Type II)	Galactosemia
AR, chromosome 11	AR, chromosome 17q	AR
Exercise-induced cramps and myoglobinuria, with “second wind.” Progressive proximal weakness in one-third of patients. Forearm ischemic test: lactate increases <5 mg/dL above baseline. Biopsy: subsarcolemmal blebs. No phosphorylase activity.	Neonates: profound generalized hypotonia and CHF. Young adults: Proximal arm and distal leg weakness (scapuloperoneal pattern). Encephalopathy from accumulation of glycogen in the brain. Biopsy: large PAS-positive vacuoles. No acid maltase activity in fibroblasts.	Newborn: failure to thrive, white matter disease, cataracts, and megalencephaly. Later: hepatosplenomegaly (with coagulopathy) and ovarian failure.

Mitochondrial Metabolism

(See also Mitochondrial diseases, Glutaric aciduria type I, Mitochondrial encephalomyopathy syndromes, and Mitochondrial myopathies.)

Mitochondrial DNA (mtDNA) is a small circular molecule that possesses its own genetic material, is inherited from the mother, and has no introns. Each mtDNA encodes 22 transfer RNAs (tRNA), 13 polypeptides, and 2 ribosomal RNAs (rRNA). The mtDNA-encoded genes supply crucial components of the respiratory or electron transport chain. However, the vast majority of the mitochondrial proteins are encoded in the nuclear DNA (nDNA), which can cause diseases with varying heritability patterns:

Autosomal recessive: Krebs cycle disorders such as fumarase deficiency (microcephaly, neutropenia, and thrombocytopenia) and α-ketoglutarate dehydrogenase complex deficiency (B₁-dependent microcephaly and hypertrophic cardiomyopathy)
X-linked recessive: intermittent ataxia with lactic acidosis due to PDHC deficiency (B₁-dependent myopathy, lactic acidosis, corpus callosum agenesis, and facial dysmorphism), and ornithine transcarbamylase deficiency (see Urea cycle defects)

Disorders of Oxidative Phosphorylation (Electron Transport Chain)

In addition to the above toxins, mitochondrial disease can also be acquired such as in Reye syndrome and zidovudine treatment.

Tissues with high oxidative metabolism have a relatively low threshold for, and are especially vulnerable to, mtDNA mutation. Thus, most mtDNA disorders are encephalomyopathies, disorders where brain and muscle are primarily affected (see Mitochondrial diseases).

Lipid Metabolism


Carnitine Palmitoyl Transferase Deficiency	Medium Chain Acyl-CoA (MCAD) Deficiency	X-Linked Adrenoleukodystrophy
AR, chromosome 1	AR, chromosome 1	X-linked, ALDP gene
Intolerance to sustained exercise (muscle pain and swelling) without cramps. Long fasting may trigger symptoms without ketones. High CK and myoglobinuria during attacks. Muscle biopsy: lipid droplets.	Recurrent coma and/or vomiting and confusion. Low or no ketones during attacks. Cardiomyopathy may be present. It is the main cause of carnitine deficiency (carnitine is <20 µmol/mg). L-carnitine replacement is indicated.	Posterior demyelination and Addison disease in males associated with progressive quadri- or paraparesis (spinal form: adrenomyeloneuropathy). High level of very long chain fatty acids in plasma, RBCs, WBCs or fibroblasts.

Primary Carnitine Deficiency		Secondary Carnitine Deficiency
Carnitine transporter deficiency, MCAD		Excessive production of Acyl-CoA
Recurrent acute encephalopathy with hypotonia, cardiac myopathy, lactic acidosis, high ammonia, hypoglycemia, and liver dysfunction. Episodes are triggered by infection or starvation. Rx: L-carnitine 60 mg/kg/d (IV), or 200 mg PO/d		Free carnitine is trapped in acyl-carnitine esters subsequently lost in urine. Organic acidurias are the major cause. Also seen in Reye syndrome, valproate hepatotoxicity, malnutrition, pregnancy, liver failure, TPN (total parenteral nutrition), and renal tubular disease
Acylcarnitine:carnitine ratio >0.4, low free carnitine (<10 µmol/mg)		Acylcarnitine:carnitine ratio >0.4, low free carnitine (<20 µmol/mg)

Purine Metabolism Disorders

ADA, adenosine deaminase; AICAR, aminoimidazole carboxamide ribotide; AMP, GMP, and IMP, adenosine, guanosine, and inosine monophosphate; FAICAR, formyl AICAR; GDA, guanine deaminase; HGPRT, hypoxanthine-guanine phosphoribosyltransferase; PNP, purine nucleoside phosphorylase; PRPP, phosphoribosyl pyrophosphate; SAICAR, succinyl AICAR; S-AMP, adenylosuccinate; XO, xanthine oxidase.

HGPRT Deficiency: Lesch-Nyhan Syndrome	PRPP Synthetase Superactivity	Adenylosuccinase Deficiency
X-linked	X-linked	AR, chromosome 22
Choreoathetosis with developmental delay, dystonia, hypotonia, leg spasticity, self-mutilation (biting)^a, and hyperuricemia. Renal but not CNS damage is prevented by allopurinol (xanthine oxidase inhibitor)	Sensorineural deafness +/− ataxia or hypotonia. Tophaceous gout in heterozygotic female carriers. Uric acid increased in affected males. Xanthine and hypoxanthine are high in plasma and CSF	Autism, abnormal movements, growth and psychomotor delay, seizures, amaurosis, hypotonia, and vermal cerebellar hypoplasia. S-adenosine and SAICAR are elevated in plasma and CSF.
^aExcept for the associated self-injurious tongue biting, the oromandibular and lingual dystonia of Lesch-Nyhan syndrome is similar to that seen in chorea-acanthocytosis and tardive dyskinesia.

Uric acid should be elevated in both plasma and urine: HGPRT deficiency in Lesch-Nyhan syndrome (LNS) and the de novo synthetic disorder PRPP superactivity. Children with LNS may have normal uric acid because of higher renal clearance. They are classified as CP until renal complications or gout discloses the etiology.

Immunodeficiency disorders are common with ADA and PNP deficiencies. The latter may present with spastic diplegia, as in LNS, because HGPRT, although not defective, lacks the substrates normally provided by PNP.

Urea Cycle Defects

ASS and ASL, argininosuccinate synthase and lyase, respectively; CPS, carbamoyl phosphate synthetase; OTC, ornithine transcarbamylase deficiency.

Hyperammonemia From Selected Urea Cycle Disorders

OTC Deficiency (Type II)	CPS Deficiency (Type I)	Arginase Deficiency	ASS and ASL Deficiencies
X-linked dominant	AR	AR	AR
Neonatal encephalopathy and death or developmental delay. Variant: episodic headache and ataxia, also occurring in females in association with ophthalmoplegia.	Neonatal encephalopathy or recurrent vomiting and lethargy with abnormal eye movements. Hyperventilation may cause respiratory alkalosis.	Childhood onset of progressive spastic paraparesis, seizures, and developmental delay with recurrent vomiting. Hyperventilation may induce alkalosis.	Neonatal encephalopathy or chronic ataxia, developmental delay, seizures, recurrent vomiting, and trichorrhexis nodosa
↑ NH₃, orotic aciduria, ↓ plasma citrulline	↑ NH₃, ↓ plasma citrulline	↑ NH₃, ↑ plasma arginine	↑ NH₃, Orotic aciduria, ↑ citrulline, citrullinuria

Neonatal hyperammonemia algorithm

Respiratory ↑ pH

↑ Urine organic acids (metabolic ↓pH): congenital lactic acidosis, organic aciduria, and fatty acid oxidation defects; If normal → citrulline
↑↑↑ Citrulline (>1000 µM): ASS deficiency; ↑↑ (100-300 µM): ASL deficiency; if normal (6-20 µM) → plasma/CSF glycine
↑↑↑ Glycine: nonketotic hyperglycinemia; normal → transient neonatal hyperammonemia; absent/trace → urinary orotic acid
↑↑ Orotic acid: OTC deficiency; ↓: CPS deficiency

Amino acid metabolism

Hyperphenylalaninemia

Lowe (Oculocerebrorenal) Syndrome X-Linked	Canavan Disease AR Inheritance
Golgi PI-biP-5-phosphatase def-Renal Fanconi syndrome	Aspartoacylase deficiency Spongiform encephalopathy
Cataracts, glaucoma, hypotonia, MR, renal rickets	Macrocephaly and hypotonia followed by UMN signs, seizures, and optic atrophy
↓ NH3, ↑ PO4, AA, and albumin in urine	↑ NAA in blood, urine, and CSF


Classic Phenylketonuria AR Inheritance	Tyrosinemia (Tyrosinosis I) AR Inheritance
Phenylalanine hydroxylase deficiency	Fumaryl acetoacetate hydrolase deficiency
MR (dysmyelination), persistent vomiting, microcephaly, hypopigmentation, eczematoid skin, and abnormal behavior. There is musty odor in urine. Tremor, hypertonia, and hyperactivity may be present. Infantile spasms and GTC seizures may occur in childhood.	Acute encephalopathy, liver failure, and renal tubular Fanconi syndrome. Painful disesthesias from acute motor axonal neuropathy are most common. Acute intermittent porphyria with GBS-like picture can develop from inhibition of δ-ALA by succinylacetone. A rotten cabbage odor is noted.
↑ Phe (>20 mg/dL), ↓ Tyr, urinary excretion of phenylketones	↑ Tyr (>3 mg/dL), ↑ α-fetoprotein, ↑ δ-ALA, ↑ succinylacetone
Dihydropteridine reductase deficiency also known as atypical phenylketonuria or phenylketonuria type 2, which impairs resynthesis of tetrahydrobiopterin (BH4), the cofactor of phenylalanine, tyrosine, and tryptophan hydroxylases, causes a global reduction of biogenic monoamines (serotonin, dopamine, epinephrine, and norepinephrine).

Sulfur-containing amino acids

Homocystinuria can also be caused by MTHFR deficiency.

Classic homocystinuria AR inheritance

Cysthathionine synthetase deficiency

Strokes, MR, ectopia lentis, marfanoid habitus, psychiatric and extrapyramidal disease. Many respond to vitamin B₆ replacement

Oasthouse disease AR inheritance

Methionine malabsorption

MR, fine white hair, seizures, and ↑ urinary excretion of α-OH-butyrate

Organic Acidurias

Branched-chain aminoacids (BCAA)

		Maple Syrup Urine Disease Fulminant or intermittent encephalopathy and brain edema in neonates with ketoacidosis. There is restricted diffusion in the posterior limb of the internal capsule, thalami, pons, and cerebellar white matter due to intramyelinic edema.^* High BCAAs in urine give its classic odor. ^A similar pattern of restricted diffusion is seen in nonketotic hyperglycinemia and Canavan disease. Multiple Carboxylase Deficiency* It causes breathing, cutaneous, and neurologic deficits (ataxia, myoclonus, and DD) with crisis of ketoacidosis and high ammonia (see Biotinidase deficiency).
Isovaleric acidemia	Propionic acidemia	Methylmalonic acidemia
AR	AR, biotin-dependent	AR, B₁₂-dependent
Neonatal MSUD-like presentation. There is a chronic infantile form. “Sweaty feet” smell in urine is characteristic.	Episodic ketotic hyperglycinemia with acidosis and hyperammonemia. A bleeding diathesis (with tendency for ICH) and sepsis-like picture are effects from pancytopenia. Recurrent acidosis, growth retardation, seizures, dystonia, and/or chorea in survivors.
	↑ T2W MRI signal in the caudate and putamen	↑ T2W MRI signal in the globus pallidus
Isovaleryl-lysine in urine, ↓ isovaleryl CoA dehydrogenase activity in fibroblasts	↑ Propionate, ↑ glycine, ↑ β-hydroxypropionate, ↑ methylcitrate, ↓ propionyl CoA activity in fibroblasts	↑ Methylmalonate, ↑ propionyl CoA, ↑ propionate, ↑ glycine, ↑ ammonia.
Treatment: glycine dexotifies isovaleryl CoA, ↓ leucine intake	Biotin, protein restriction, carnitine, metronidazole reduces propionate by gut bacteria	Cobalamin, protein restriction, carnitine, betaine for associated homocystinuria
General treatment for all organic acidurias: carnitine, peritoneal dialysis

Hyperglycinemias


Nonketotic Hyperglycinemia: Glycine Encephalopathy	Ketotic Hyperglycinemia: Inborn Errors of Metabolism
AR	AR; see Organic acidurias
Progressive neonatal encephalopathy after protein feedings is initiated. Hypotonia and myoclonic seizures. Hiccups should suggest the diagnosis.	Propionic acidemia Methylmalonic acidemia Isovaleric acidemia Acquired: valproic acid
Abnormal myelination and abnormal or absent corpus callosum. No GCS activity. ↑ Glycine	Organic acids accumulate, ↑ ammonia, ketoacidosis, hypoglycemia, lactic acidosis

Tryptophan Disorders


Hartnup Disease	Hypertryptophanemia	Hydroxykynurenuria
Photosensitive rash, episodic personality changes, depression, psychosis, headache, and ataxia. Treatment: nicotinamide 50-300 mg/d	Pellagra-like rash, mental retardation, ataxia	Mental retardation, migraine-like headaches
	Rashes with neurological disease are seen in other vitamin deficiencies: thiamine and biotinidase
Tryptophanuria	↑ Tryptophan	↑ Acetoacetate


Lysinuric Intolerance	Hyperlysinemia	Glutaric Aciduria I
↓ Ornithine → secondary urea cycle dysfunction. Postprandial encephalopathy, DD, MR, psychosis, and seizures. Treatment: citrulline.	MR, poor growth, variable neurologic deficits.	Deficiency of glutaryl CoA dehydrogenase. See Glutaric Aciduria I.

Peroxisomal Disorders

Peroxisomes are 40 times more abundant in oligodendrocytes than neurons or astrocytes. Their main function is H₂O₂ metabolism, phospholipid biosynthesis, fatty acids β-oxidation for very-long-chain fatty acids (VLCFA), cholesterol and dolichol synthesis, and pipecolic and phytanic acid degradation.

Disorders of Peroxisome Assembly (Group 1: Common Features are Hepatic Disease, Retinopathy, Deafness, and Developmental Delay)

Disorders of Single Protein Function (Group 2)

Zellweger syndrome

Neonatal adrenoleukodystrophy

Infantile Refsum disease

Rhizomelic chondrodysplasia punctata

Refsum disease (HMSN type 4)

X-linked adrenoleukodystrophy (ALD)

Glutaric aciduria type III

Hyperoxaluria type I

Any patient presenting with retinal pigmentation and peripheral neuropathy and recurrent encephalopathy should be screened for VLCFA, phytanic acid, and pristanic acid. Central cerebellar and posterior brain white matter disease may be seen in these patients.

Zellweger syndrome (cerebro-hepato-renal syndrome) consists of psychomotor arrest, seizures, hypotonia with arthrogryposis (camptodactyly, knee and ankle deformities), facial dysmorphism (high forehead with flat facies), and brain malformations, including hypoplastic corpus callosum and migration abnormalities (pachygyria and polymicrogyria). VLCFA and pipecolic acid are high; RBC plasmalogen is low.

Infantile Refsum patients have developmental delay, pigmentary retinopathy, deafness, dysmorphic features, hepatomegaly, and neuropathy.

Rhizomelic chondrodysplasia punctata (3-oxoacyl-CoA thiolase deficiency) presents with short (rhizomelic) proximal limbs, microcephaly, mental retardation, cataracts, dysmorphic face, and ichthyosis. X-ray shows “stippled” epiphyses. Low plasmalogen and increased phytanic acid are the biochemical findings.

Refsum disease (HMSN type 4, phytanoyl-CoA hydroxylase deficiency, PAHX gene) presents with cataracts, retinitis pigmentosa, sensorineural deafness, chronic hypertrophic neuropathy, and ataxia, and variable anosmia, cardiomyopathy, and ichthyosiform desquamation. Phytanic acid and pipecolic acid are increased.

X-linked ALD (peroxisomal ATPase Binding Casette Protein [ABCD1] gene, lignoceroyl CoA synthetase deficiency, Xq28) cause inflammatory demyelination in the parieto-occipital (85%) or frontal (15%) regions with garland of contrast enhancement, beginning at 4 to 10 years and progressing rapidly to a vegetative state. It also affects the adrenal cortex and Leydig cells of the testes. Adrenal insufficiency occurs in 85% or cases. Whereas adrenoleukodystrophy presents in boys, adrenomyeloneuropathy can affect men and women. Adrenomyeloneuropathy with spastic paraparesis and distal sensory loss and Addison disease are alternative phenotypes in young adults. VLFA is high in serum and fibroblasts. Heterozygotes have a 20% false negative rate.

Lysosomal Disorders: Sphingolipidoses

Gaucher Disease (β-Glucosidase or Glucocerebrosidase Deficiency)

Glucocerebrosidase (or saposin C) deficiency leads to the accumulation of glucocerebroside (glucosylceramide). This is a relatively common disorder among Ashkenazi Jews with a carrier frequency of 1:18 in individuals. Type I does not affect the central nervous system. Type II and III refer to the rapidly and slowly progressive forms, respectively. They are heralded by hepatosplenomegaly and followed by myoclonic seizures, bone pain, strabismus, horizontal supranuclear gaze palsy, spasticity, ataxia, and dementia. Gaucher cells (macrophages filled with insoluble glycolipids) can be identified in the spleen, lymph nodes, and bone marrow. Enzyme replacement therapy, bone marrow transplantation, and miglustat are available treatment strategies.

GM₁ Gangliosidosis (β-Galactosidase Deficiency)

The infantile and late infantile/juvenile forms show developmental regression with epileptic encephalopathy and spasticity, but only the infantile form exhibit skeletal dysplasia, dysmorphism (“pseudo-Hurler”), and cherry-red macula. The adult form manifests progressive dysarthria, dystonia, spasticity, and cerebellar ataxia. A juvenile parkinsonian phenotype has been reported. Brain MRI shows T2-weighted thalamic hypointensity in infantile forms; putamen hyperintensity in older forms. Bone marrow biopsy shows vacuolated Gaucher-like cells and foamy histiocytes.

GM₂ Gangliosidosis (Hexosaminidase Deficiency)

More common among Ashkenazi Jews, it is known as Tay-Sachs disease when due to deficiency of hexosaminidase A; and known as Sandhoff disease when both hexosaminidase A and B are deficient. Classic infantile-onset Tay-Sachs begins with excessive startle followed by spastic motor regression, cherry-red macula, progressive blindness, deafness, macrocephaly, and epileptic encephalopathy. Brain MRI shows T2-weighted thalamic hypointensity. The late-infantile and juvenile forms present with psychiatric features, ataxia, and upper or lower motor neuron disease and progress into dementia and visual loss. Adults may mimic slowly progressive motor neuron disease, spinal muscular atrophy, or spinocerebellar degeneration. Sandhoff disease displays a Tay-Sachs phenotype but with visceromegaly. Biopsy findings are similar to GM₁ gangliosidosis.

Fabry Disease (Galactosidase A Deficiency, Anderson-Fabry Disease)

This X-linked recessive disorder (only non-AR sphingolipidosis) is due to deficiency of galactosidase A, which leads to infarction-causing deposition of globotriaosylceramide (ceramide trihexosamide) in the vascular endothelium. It may present with episodic neuropathic pain crises or chronic acroparesthesias, early-onset ischemic or hemorrhagic strokes, sensorineural hearing loss, paroxysmal vertigo associated with compression of the vestibulo-cochlear nerve by a megadolichobasilar artery, myocardial infarction, nephropathy, hypohydrosis, lower-trunk angiokeratomas, cataracts, and/or corneal whorls on slit-lamp. Brain MRI may show high T1 signal in the posterior thalamus (pulvinar sign), which is shown as calcified on head CT. Ceramide trihexosamide is measurable in urine. Electron microscopy shows tightly packed lamellated cytoplasmic inclusions in the cell bodies on perineurium of peripheral nerves.

Niemann-Pick Disease (Sphingomyelinase Deficiency Due to SMPD1 Mutations in NPA and NPB; Impaired Transport of Endocytosed Cholesterol Due to NPC1 [95%, 18q] and NPC2 [4%, 14q] Mutations)

Type A is the severe neurovisceral form of infants associated with cherry-red macula, progressive hepatosplenomegaly, psychomotor regression, hypotonia, and seizures, most often in Jewish families. Type C affects all ethnic groups and is the most common. In this type, ataxia and dystonia are followed by gelastic cataplexy, seizures, dementia, and supranuclear vertical gaze palsy, with or without hepatosplenomegaly. Biopsy with filipin staining of skin fibroblasts, bone marrow, or liver shows foamy cells or “sea-blue” histiocytes. High chitotriosidase activity and tau CSF levels serve as screening test. Treatment with miglustat should be considered.

Metachromatic Leukodystrophy (Arylsulfatase A or Saposin B Deficiency)

Deficiency of arylsulfatase A or its activator, saposin B, leads to accumulation of cerebroside sulfate which causes progressive (frontal-predominant) central and peripheral demyelination. NCV is <30 m/s even when reflexes are brisk. Progressive spastic quadriparesis may be associated with blindness, seizures, dementia, and peripheral neuropathy. High urinary sulfatides serve as screening test. Ballooned macrophages with “metachromatic” (brown-purple) sulfatide deposits with cresyl violet staining are diagnostic on brain and nerve specimens.

Krabbe Disease (Galactocerebroside β-Galactosidase Deficiency)

Deficiency of β-galactocerebrosidase (GALC) or its activator, saposin A (in late onset cases), leads to accumulation of globoid cells (altered macrophages), which causes astrocytic gliosis with parieto-occipital demyelination. Features are spasticity with areflexia due to demyelinating peripheral neuropathy, ataxia, dementia, and optic atrophy with vision loss. Isolated spastic paraparesis may occur in adult onset cases. Diagnosis requires deficient GALC enzyme activity in leukocytes and molecular genetic testing of GALC. High psychosine levels can also help establish the diagnosis.

Galactosialidosis (β-Galactosidase and Neuraminidase Deficiencies)

Types I and II are also known as sialidosis, which develop only with neuraminidase deficiency. The adult, type I form, presents in the fourth decade with gait impairment, myoclonus, and decreased color vision with night blindness associated with cherry-red spot, nystagmus, and hyperreflexia. The infantile or type II form has a classic mucopolysaccharidosis phenotype with developmental regression, hepatosplenomegaly, severe dysostosis multiplex, deafness, ataxia, and cherry-red spot. The juvenile or type III form, common in Japan, shows skeletal dysplasia, dysmorphism, corneal clouding, cherry-red spots, and angiokeratomatous rash in the buttocks and inguinal regions. Urinary oligosaccharides are increased. Diagnosis requires ascertainment of CTSA gene mutations.

Lysosomal Disorders: Mucopolysaccharidoses

Lysosomal storage disorders are due to deficiency of enzymes needed to break down glycosaminoglycans, including heparan sulfate, dermatan sulfate, keratan sulfate, chondroitin sulfate, and hyaluronan. Quantitative glycosaminoglycans in urine with electrophoresis is preferred for diagnosis over the low sensitive screening for urinary mucopolysaccharides. Dysostosis multiplex on radiology is characteristic.

Mucopolysaccharidosis Type I (Hurler Syndrome)

Deficiency of α-L-iduronidase causes accumulation and excretion of dermatan sulfate and heparan sulfate in the cornea, collagen, and leptomeninges. Slow developmental regression begins at 2 years of age. The “Hurler phenotype” consists of dwarfism, macroglossia, coarse facial features, corneal clouding, deafness, dysostosis multiplex, developmental delay, abdominal hernia, stiff joints, and visceromegaly. There may be macrocephaly with prominent perivascular or Virchow-Robin spaces and communicating hydrocephalus likely related to a thick dura. Scheie syndrome is an allelic disorder with a mild Hurler phenotype.

Mucopolysaccharidosis Type II (Hunter Syndrome)

The only X-linked mucopolysaccharidosis is due to deficiency of iduronate-2-sulfatase and begins in childhood rather than infancy and progresses slower than MPS I. Blindness is due to retinal degeneration instead of corneal clouding.

Mucopolysaccharidosis Type III (Sanfilippo Syndrome)

Deficiency of α-N-acetyl-glucosaminidase causes only visceral accumulation of heparan sulfate. Despite profound developmental delay, aggressiveness, and hyperactivity, there are relatively mild or no somatic features other than hirsutism and synophrys. Deafness and seizures may occur.

Mucopolysaccharidosis Type IV (Morquio Syndrome)

Deficiency of α-N-acetyl-glucosamine-6-sulfatase causes visceral accumulation of keratan sulfate. Unlike other mucopolysaccharidoses, intelligence is preserved and short stature is caused by short-trunk dwarfism. The source of visual loss is corneal clouding. Cervical cord compression is the most severe complication: hypoplasia of the odontoid causes atlantoaxial subluxation and instability.

Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome)

Deficiency of arylsulfatase B causes accumulation and excretion of dermatan sulfate. Patients have the typical Hurler phenotype but with normal intelligence. Hydrocephalus may result from from pachymeningitis and myelopathy from dural thickening and/or vertebral abnormalities.

Porphyrias

The porphyrias are a group of rare disorders with defects in heme biosynthesis that result in cutaneous signs, neuropsychiatric signs, or both. Heme causes feedback inhibition of δ-aminolevulinic acid (ALA) synthetase, the first enzyme in the heme synthetic pathway.

Acute intermittent porphyria (AIP), inherited in an autosomal dominant fashion, is caused by mutations in the porphobilinogen deaminase gene (PBGD, 11q), limiting the enzyme activity by 50%. Most individuals with the enzyme deficiency never have any clinical symptoms. ALA and porphobilinogen (PBG) highly excreted in urine

Symptoms of AIP can be similar to those of lead poisoning (lead is inhibitor of ALA dehydratase; in lead poisoning ALA but not PBG urinary excretion increases): a predominantly axonal motor peripheral neuropathy, which may mimic the Guillain-Barré syndrome (without much protein elevation in CSF) also affecting the radial and peroneal nerves, and autonomic abnormalities, particularly hypertension and tachycardia. Seizures, either partial or generalized, may occur as a manifestation of AIP or be secondary to hyponatremia which develops in one-third of the attacks. Treatment with antiseizure medications may worsen the picture. Psychiatric symptoms may range from delirium, mood change, anxiety, depression, or an acute or chronic psychosis, which can lead to the misdiagnosis of conversion disorder. Gastrointestinal symptoms due to autonomic neuropathy include abdominal pain (which may lead to unnecessary abdominal surgeries), vomiting, constipation, and diarrhea. These may occur alone or in combination with neurologic or psychiatric symptoms. A number of inductors and triggers of AIP are known, among them:

Inductors of ALA Synthetase	Environmental Triggers
Barbiturates	Menses
Antiepileptic drugs^a	Pregnancy
Analgesics	Starvation
Sulfonamides	Emotional stress
Sedatives	Intercurrent infections
Birth control pills	Smoking/alcohol intake
^aAcceptable antiepileptics are clobazam, clonazepam, lorazepam, gabapentin, and vigabatrin; there are no data on levetiracetam.(from http://porphyria.eu/he/content/anticonvulsants.)

Screening is facilitated by random urinary PBG measurement. Diagnosis is established using the Watson-Schwartz test for quantitative measurement of urinary PBG and ALA. Urine may turn dark red or black (due to porphyrin or porphobilin formation) after exposure to air and light. Pathologically, demyelinating lesions of central and peripheral nervous system may be found. Treatment consists of a combination of propranolol (up to 100 mg every 4 hours), which may reverse autonomic manifestations, intravenous heme arginate, used for neuropathy and abdominal symptoms, acceptable antiseizure medications, codeine or meperidine for pain, and chlorpromazine for psychotic bouts.

Dopamine and Catecholamine Metabolic Disorders

5-HTP, 5-hydroxytryptophan; AR, aldose reductase; BH₄, tetrahydrobiopterin; DHPR, dihydropteridin reductase (deficiency: high BH₂, low BH₄); GCH-1, GTP cyclohydrolase; NH₂P₃, dihydroneopterin triphosphate; PH, phenylalanine hydroxylase; PLP, pyridoxal phosphate or pyridoxine (B6), cofactor of AADC; PTP, 6-pyruvoyl-tetrahydropterin; PTPS, PTP synthase (deficiency: high neopterin to biopterin ratios); SR, sepiapterin reductase. Residual tyrosine hydroxylase (TH) activity is predictive of the predominance of dystonia (high TH activity) or parkinsonism (low TH activity) in biogenic amine disorders. GCH I deficiency and SR deficiency are the only disorders that do not result in hyperphenylalaninemia and cannot, therefore, be detected by neonatal screening.

BH₄ serves as a cofactor for tyrosine, tryptophan, and phenylalanine hydroxylases. The CSF patterns of biopterin and catecholamine metabolites can be of diagnostic utility:

GCH1 deficiency: low CSF biopterin and neopterin, low HVA and HIAA
Tyrosine hydroxylase deficiency: low CSF HVA, normal HIAA and biopterin
Tryptophan hydroxylase deficiency: low HIAA, normal HVA and biopterin
Sepiapterin reductase deficiency: low HIAA, low HVA, normal to high biopterin
AADC deficiency: low HVA/HIAA, high 3-O-MD/5-HTP, normal biopterin
Parkin gene mutation: low CSF biopterin, normal neopterin

The first five are considered among the syndrome of “dopa-responsive dystonia” (DRD). Dopamine transporter (DAT) deficiency (AR, SLC6A3 mutations) may lead to an infantile-onset, levodopa-unresponsive progressive dystonia-parkinsonism syndrome. Diagnosis is suspected with a HVA:5-HIAA ratio > 4.0 and a normal DAT SPECT scan.

Symptoms vary depending on the predominant catecholamine deficiency:

Norepinephrine Deficiency	Dopamine Deficiency
Ptosis and miosis	Oculogyric crisis
BP liability and postural hypotension	Parkinsonism, dystonia, and tremor
Paroxysmal diaphoresis, salivation, and temperature instability	Axial hypotonia with limb dystonia (most typical in AADC and SR deficiencies)

Norepinephrine System

The locus ceruleus (LC), in the dorsolateral pontine tegmentum, is the major cluster of norepinephrine (NE)-synthesizing neurons, projecting diffusely to throughout the CNS. The NE system has a major role in arousal, attention, and stress response. In the brain, NE also contributes to long-term potentiation, pain modulation, and control of local blood flow.

BH₄: tetrahydrobiopterin; PH: phenylalanine hydroxylase; AADC: amino acid decarboxylase.

DOH: dopamine hydroxylase deficiency causes disabling orthostatic hypotension and congenital ptosis.

The main mechanism of NE inactivation is its presynaptic reuptake via a selective NE transporter, followed by metabolism by monoamine oxidase A (MAO A) and catechol-O-methyltransferase (COMT), with formation of 3-methoxy-4-hydroxyphenylglycol (MHPG), measurable in CSF.

Mechanisms to Increase NE	Common Medications
Decrease presynaptic reuptake	Cocaine, tricyclics, amphetamines
Decrease postsynaptic reuptake (COMT)	Tolcapone, entacapone
Inhibit MAO A	Clorgyline
Inhibit MAO B	Selegiline (Deprenyl)
Inhibit both MAO A and B (nonselective)	Pargyline
Block NE vesicle storage	Reserpine, tetrabenazine
Block tyrosine hydroxylase	α-Methyltyrosine

Adrenergic Receptors (and Blockers)

The striatum contains high concentrations of α2c receptors in dopaminergic terminals. Idazoxan, an α2c antagonist, experimentally reduces L-dopa-induced dyskinesia in Parkinson disease.

Serotonin System

Serotonin (5-hydroxytryptamine, 5-HT) has an important neuromodulatory action mediated by a large variety of 5-HT receptor subtypes. The central serotonergic system has been implicated in cognition, emotion, impulse control, circadian and sleep-wake cycle regulation, and pain modulation. The raphe nuclei provide 5-HT inputs to the basal ganglia circuits and prefrontal cortex. 5-HT is degraded by MAO A to 5-hydroxy indole acetic acid (5-HIAA)

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