3253 Disorders of Purine and Pyrimidine Metabolism CHAPTER 417

TABLE 417-4 Inborn Errors of Pyrimidine Metabolism

ENZYME ACTIVITY INHERITANCE CLINICAL FEATURES LABORATORY FEATURES

Uridine-5′-monophosphate

synthetase

Deficiency Autosomal recessive Orotic acid crystalluria; obstructive

uropathy, hypochromic megaloblastic

anemia

Orotic aciduria

Pyrimidine 5′-nucleotidase Deficiency Autosomal recessive Hemolytic anemia Basophilic stippling of erythrocytes; high

levels of cytidine and uridine ribonucleotides

Pyrimidine 5′-nucleotidase Superactivity Uncertain Developmental delay, seizures, ataxia,

language deficit

Hypouricosuria

Thymidine phosphorylase Deficiency Autosomal recessive Mitochondrial neurogastrointestinal

encephalopathy

Hypouricosuria

Dihydropyrimidine

dehydrogenase

Deficiency Autosomal recessive Seizures, motor and mental retardation High levels of uracil, thymine, and

5-hydroxymethyluracil and low levels of

dihydropyrimidines in urine

Dihydropyrimidinase Deficiency Uncertain Seizures, mental retardation Dihydropyrimidinuria

Ureidopropionase Deficiency Uncertain Hypotonia, dystonia, developmental

delay

High urinary excretion of N-carbamyl-βalanine and N-carbamyl β-aminoisobutyric

acid

Carbamylphosphate

+

Aspartic acid

UTP Orotic Acid

RNA

CTP or dCTP

RNA or DNA

dUMP UDP UMP CMP

Cytidine

Uracil

β-Alanine

β-Aminoisobutyric acid

TTP

1

2

3

4

5 5

DNA

dTMP

Thymidine

Thymine

Uridine

2

FIGURE 417-4 Abbreviated scheme of pyrimidine metabolism. (1) Thymidine kinase, (2) dihydropyrimidine

dehydrogenase, (3) thymidylate synthase, (4) UMP synthase, (5) 5′-nucleotidase. CMP, cytidine-5′-

monophosphate; dTMP, deoxythymidine-5′-monophosphate; dUMP, deoxyuridine-5′-monophosphate;

TTP, thymidine triphosphate; UDP, uridine-5′-diphosphate; UMP, uridine-5′-monophosphate; UTP, uridine

triphosphate.

associated with clinical manifestations, some causing major morbidity

and mortality. Advances in genetics, along with high-performance

liquid chromatography and tandem mass spectrometry, have facilitated

diagnosis.

■ PURINE DISORDERS

HPRT Deficiency The HPRT gene is located on the X chromosome. Affected males are hemizygous for the mutant gene; carrier

females are asymptomatic. A complete deficiency of HPRT, the

Lesch-Nyhan syndrome, is characterized by hyperuricemia, selfmutilative behavior, choreoathetosis, spasticity, and mental retardation. A partial deficiency of HPRT, the Kelley-Seegmiller syndrome,

is associated with hyperuricemia but no central nervous system

manifestations. In both disorders, the hyperuricemia results from

urate overproduction and can cause uric acid crystalluria, nephrolithiasis, obstructive uropathy, and gouty arthritis. Early diagnosis and

appropriate therapy with allopurinol can prevent or eliminate all the

problems attributable to hyperuricemia without affecting behavioral or

neurologic abnormalities.

Increased PRPP Synthetase Activity Like the HPRT deficiency

states, PRPP synthetase overactivity is X-linked and results in gouty

arthritis and uric acid nephrolithiasis. Neurologic hearing loss occurs

in some families.

Adenine Phosphoribosyltransferase (APRT) Deficiency

APRT deficiency is inherited as an autosomal recessive trait. Affected

individuals develop kidney stones composed of 2,8-dihydroxyadenine.

Caucasians with the disorder have a complete deficiency (type I),

whereas Japanese individuals have some measurable enzyme activity

(type II). Expression of the defect is similar in the two populations, as is

the frequency of the heterozygous state (0.4–1.1 per 100). Allopurinol

treatment prevents stone formation.

Hereditary Xanthinuria A deficiency of xanthine oxidase causes all purine in the urine to occur

in the form of hypoxanthine and xanthine. About

two-thirds of deficient individuals are asymptomatic. The remainder develop kidney stones composed of xanthine.

Myoadenylate Deaminase Deficiency Primary (inherited) and secondary (acquired) forms

of myoadenylate deaminase deficiency have been

described. The primary form is inherited as an

autosomal recessive trait. Clinically, some persons

may have relatively mild myopathic symptoms with

exercise or other triggers, but most individuals with

this defect are asymptomatic. Therefore, another

explanation for the myopathy should be sought

in symptomatic patients with this deficiency. The

acquired deficiency occurs in association with a

wide variety of neuromuscular diseases, including

muscular dystrophies, neuropathies, inflammatory

myopathies, and collagen vascular diseases.

Adenylosuccinate Lyase Deficiency Deficiency of this enzyme is due to an autosomal

recessive trait and causes profound psychomotor

retardation, seizures, and other movement disorders. All individuals with this deficiency are mentally retarded, and most are autistic.

Adenosine Deaminase Deficiency and

Purine Nucleoside Phosphorylase Defi- ciency See Chap. 351.

3254 PART 12 Endocrinology and Metabolism

Lysosomes are heterogeneous subcellular organelles containing specific

hydrolases that allow selective processing or degradation of proteins,

nucleic acids, carbohydrates, and lipids. There are >50 different lysosomal storage diseases (LSDs), classified according to the nature

of the stored material (Table 418-1). Although all are rare diseases,

several of the more prevalent disorders are reviewed here: Tay-Sachs

disease, Fabry disease, Gaucher disease, Niemann-Pick disease, the

mucopolysaccharidoses, Pompe disease, lysosomal acid lipase deficiency (LALD), Krabbe disease, and CLN2-related Batten disease.

LSDs should be considered in the differential diagnosis of patients

with neurologic, renal, or muscular degeneration and/or unexplained

hepatomegaly, splenomegaly, cardiomyopathy, or skeletal dysplasias

and deformations. Physical findings are disease specific, and enzyme

assays or genetic testing can be used to make a definitive diagnosis.

Although the nosology of LSDs segregates the variants into distinct

phenotypes, these are heuristic; in the clinic, each disease exhibits—to

varying degrees—a spectrum of manifestations, from severe to attenuated variants.

PATHOGENESIS

Lysosomal biogenesis involves ongoing synthesis of lysosomal hydrolases, membrane constitutive proteins, and new membranes. Lysosomes originate from the fusion of trans-Golgi network vesicles with

late endosomes. Progressive vesicular acidification accompanies the

maturation of these vesicles; this gradient facilitates the pH-dependent

dissociation of receptors and ligands and also activates lysosomal

hydrolases. Lysosomes are components of the lysosome/autophagy/

mitophagy system that are regulated by the mTORC1 modulation of

the transcription factors TFEB/TFE3. This regulation is disrupted to

varying degrees in specific tissues affected by individual LSDs.

Abnormalities at any biosynthetic step can impair enzyme activation and lead to an LSD. After leader sequence clipping, remodeling

of complex oligosaccharides (including the lysosomal targeting ligand

mannose-6-phosphate as well as high-mannose oligosaccharide chains

of many soluble lysosomal hydrolases) occurs during transit through

the Golgi. Lysosomal integral or associated membrane proteins are

sorted to the membrane or interior of the lysosome by several different peptide signals. Phosphorylation, sulfation, additional proteolytic

processing, and macromolecular assembly of heteromers occur concurrently. Such posttranslational modifications are critical to enzyme

function, and defects can result in multiple enzyme/protein deficiencies.

The final common pathway for LSDs is the accumulation of specific

macromolecules within selected tissues and cells that normally have

a high flux of these substrates. The majority of lysosomal enzyme

deficiencies result from point mutations or genetic rearrangements

418 Lysosomal Storage Diseases

Robert J. Hopkin, Gregory A. Grabowski

■ PYRIMIDINE DISORDERS

The pyrimidine cytidine is found in both DNA and RNA; it is a complementary base pair for guanine. Thymidine is found only in DNA,

where it is paired with adenine. Uridine is found only in RNA and

can pair with either adenine or guanine in RNA secondary structures.

Pyrimidines can be synthesized by a de novo pathway (Fig. 417-4)

or reused in a salvage pathway. Although >25 different enzymes are

involved in pyrimidine metabolism, disorders of these pathways are

rare. Seven disorders of pyrimidine metabolism have been discovered

(Table 417-4), three of which are discussed below.

Orotic Aciduria Hereditary orotic aciduria is caused by mutations

in a bifunctional enzyme, uridine-5′-monophosphate (UMP) synthase, which converts orotic acid to UMP in the de novo synthesis

pathway (Fig. 417-4). The disorder is characterized by hypochromic

megaloblastic anemia that is unresponsive to vitamin B12 and folic

acid, growth retardation, and neurologic abnormalities. Increased

excretion of orotic acid causes crystalluria and obstructive uropathy.

Replacement of uridine (100–200 mg/kg per day) corrects anemia,

reduces orotic acid excretion, and improves the other sequelae of the

disorder.

Pyrimidine 5′-Nucleotidase Deficiency Pyrimidine 5′-

nucleotidase catalyzes the removal of the phosphate group from pyrimidine ribonucleoside monophosphates (cytidine-5′-monophosphate

or UMP) (Fig. 417-4). An inherited deficiency of this enzyme causes

hemolytic anemia with prominent basophilic stippling of erythrocytes.

The accumulation of pyrimidines or cytidine diphosphate choline is

thought to induce hemolysis. There is no specific treatment. Acquired

pyrimidine 5′-nucleotidase deficiency has been reported in lead poisoning and in thalassemia.

Dihydropyrimidine Dehydrogenase Deficiency Dihydropyrimidine dehydrogenase is the rate-limiting enzyme in the pathway of

uracil and thymine degradation (Fig. 417-4). Deficiency of this enzyme

causes excessive urinary excretion of uracil and thymine. In addition,

this deficiency causes nonspecific cerebral dysfunction with convulsive

disorders, motor retardation, and mental retardation. No specific treatment is available.

Medication Effect on Pyrimidine Metabolism A variety of

medications can influence pyrimidine metabolism. The anticancer

agents fluorodeoxyuridine and 5-fluorouracil and the antimicrobial

agent fluorocytosine cause cytotoxicity when converted to fluorodeoxyuridylate, a specific suicide inhibitor of thymidylate synthase.

Fluorocytosine must be converted to 5-fluorouracil to be effective. This

conversion is catalyzed by cytosine deaminase activity. Fluorocytosine’s

action is selective because cytosine deaminase is present in bacteria

and fungi but not in human cells. Dihydropyrimidine dehydrogenase is

involved in the degradation of 5-fluorouracil. Consequently, deficiency

of this enzyme is associated with 5-fluorouracil neurotoxicity.

Leflunomide, which is used to treat rheumatoid arthritis, inhibits

de novo pyrimidine synthesis by inhibiting dihydroorotate dehydrogenase, resulting in an antiproliferative effect on T cells. Allopurinol,

which inhibits xanthine oxidase in the purine metabolic pathway, also

inhibits the activity of orotidine-5′-phosphate decarboxylase, a step

in UMP synthesis. Consequently, allopurinol use is associated with

increased excretion of orotidine and orotic acid. There are no known

clinical effects of this inhibition.

Acknowledgment

The authors are grateful to Robert L. Wortmann for contributions to this

chapter in previous editions of the book.

■ FURTHER READING

Balasubramaniam S et al: Inborn errors of purine metabolism: Clinical

update and therapies. J Inherit Metab Dis 37:669, 2014.

Balasubramaniam S et al: Inborn errors of pyrimidine metabolism:

Clinical update and therapy. J Inherit Metab Dis 37:687, 2014.

Ben Salem C et al: Drug-induced hyperuricaemia and gout. Rheumatology (Oxford) 266:679, 2017.

Bhole V, Krishnan E: Gout and the heart. Rheum Dis Clin North Am

40:125, 2014.

Burns CM, Wortman RL: Clinical features and treatment of gout, in

Kelley and Firestein’s Textbook of Rheumatology, 10th ed, GS Firestein

et al (eds). Philadelphia, Elsevier, 2017, pp 1620–1644.

Hirano M, Peters GJ: Advances in purine and pyrimidine metabolism in health and diseases. Nucleosides Nucleotides Nucleic Acids

35:495, 2016.

Tai V et al: Genetic advances in gout: Potential applications in clinical

practice. Curr Opin Rheumatology 31:144, 2019.

Terkeltaub R (ed): Gout and Other Crystal Arthropathies. Philadelphia,

Elsevier Health Sciences, 2012.

3255 Lysosomal Storage Diseases 418 CHAPTER

TABLE 418-1 Selected Lysosomal Storage Diseases

CLINICAL FEATURES

DISORDERa

ENZYME DEFICIENCY

[SPECIFIC THERAPY] STORED MATERIAL

CLINICAL TYPES

(ONSET) INHERITANCE NEUROLOGIC

LIVER, SPLEEN

ENLARGEMENT

SKELETAL

DYSPLASIA OPHTHALMOLOGIC HEMATOLOGIC UNIQUE FEATURES

Mucopolysaccharidoses (MPS)

MPS I H, Hurler α-L-Iduronidase

[ET, HSCT]

Dermatan sulfate

Heparan sulfate

Infantile

Intermediate

AR Cognitive

degeneration

+++ ++++ Corneal clouding Vacuolated

lymphocytes

Coarse facies;

cardiovascular

involvement; joint

stiffness

MPS I H/S, Hurler/Scheie Childhood/adult Cognitive

degeneration

MPS I S, Scheie None

MPS II, Hunter Iduronate sulfatase [ET] Dermatan sulfate

Heparan sulfate

Severe infantile

Mild juvenile

X-linked Cognitive

degeneration, less

in mild form

+++ ++++ Retinal

degeneration, no

corneal clouding

Granulated

lymphocytes

Coarse facies;

cardiovascular

involvement; joint

stiffness; distinctive

pebbly skin lesions

MPS III A, Sanfilippo A Heparan-N-sulfatase Heparan sulfate Late infantile AR Severe cognitive

degeneration

+ + None Granulated

lymphocytes

Mild coarse facies

MPS III B, Sanfilippo B N-Acetyl-αglucosaminidase Heparan sulfate Late infantile AR Severe cognitive degeneration + + None Granulated lymphocytes Mild coarse facies

MPS III C, Sanfilippo C Acetyl-CoA:

α-glucosaminide

N-acetyltransferase

Heparan sulfate Late infantile AR Severe cognitive

degeneration

+ + None Granulated

lymphocytes

Mild coarse facies

MPS III D, Sanfilippo D N-Acetylglucosamine-6-

sulfate sulfatase

Heparan sulfate Late infantile AR Severe cognitive

degeneration

+ + None Granulated

lymphocytes

Mild coarse facies

MPS IV A, Morquio A N-Acetylgalactosamine6-sulfate sulfatase

[ET—trials]

Keratan sulfate

Chondroitin-6 sulfate

Childhood AR None + ++++ Corneal clouding Granulated

neutrophils

Distinctive skeletal

deformity; odontoid

hypoplasia; aortic valve

disease

MPS IV B, Morquio β-Galactosidase Childhood AR None ± ++++

MPS VI, Maroteaux-Lamy Arylsulfatase B

[ET, BMT]

Dermatan sulfate Late infantile AR None ++ ++++ Corneal clouding Granulated

neutrophils

and

lymphocytes

Coarse facies; valvular

heart disease

MPS VII β-Glucuronidase

[ET]

Dermatan sulfate

Heparan sulfate

Neonatal

Infantile

Adult

AR Cognitive

degeneration,

absent in some

adults

+++ +++ Corneal clouding Granulated

neutrophils

Coarse facies; vascular

involvement; hydrops

fetalis in neonatal form

GM2 Gangliosidoses

Tay-Sachs disease β-Hexosaminidase A GM2 gangliosides Infantile

Juvenile

AR Cognitive

degeneration;

seizures; later

juvenile form

None None Cherry red spot in

infantile form

None Macrocephaly;

hyperacusis in infantile

form

(Continued)

Endocrinology and Metabolism PART 12

3256

Sandhoff disease β-Hexosaminidases

A and B

GM2 gangliosides Infantile AR Cognitive

degeneration;

seizures

++ ± Cherry red spot None Macrocephaly;

hyperacusis

Neutral Glycosphingolipidoses

Fabry disease α-Galactosidase A

[ET, Chaperone]

Globotriaosylceramide Childhood X-linked Painful

acroparesthesias

None None Corneal dystrophy,

vascular lesions

None Cutaneous

angiokeratomas;

hypohydrosis

Gaucher disease Acid β-glucosidase

[ET, SRT]

Glucosylceramide,

glycosylsphingosine

Type 1

Type 2

Type 3

AR None

++++

–/+++

++++

+++

++++

++++

+

++++

None

Eye movements

Eye movements

Gaucher

cells in bone

marrow;

cytopenias

Adult form highly

variable

Niemann-Pick disease

A and B

Acid sphingomyelinase

[ET—trials]

Acid sphingomyelin Neuronopathic,

type A

Nonneuronopathic,

type B

AR Cognitive

degeneration;

seizures

++++ None

Osteoporosis

Macular

degeneration

Foam cells in

bone marrow

Pulmonary infiltrates

Lung failure

Glycoproteinoses

Fucosidosis α-Fucosidase Glycopeptides;

oligosaccharides

Infantile

Juvenile

AR Cognitive

degeneration

++ ++ None Vacuolated

lymphocytes;

foam cells

Coarse facies;

angiokeratomas in

juvenile form

α-Mannosidosis α-Mannosidase Oligosaccharides Infantile

Milder variant

AR Cognitive

degeneration

+++ +++ Cataracts, corneal

clouding

Vacuolated

lymphocytes,

granulated

neutrophils

Coarse facies; enlarged

tongue

β-Mannosidosis β-Mannosidase Oligosaccharides AR Seizures; cognitive

degeneration

++ None Vacuolated

lymphocytes,

foam cells

Angiokeratomas

Aspartylglucosaminuria Aspartylglucosaminidase Aspartylglucosamine;

glycopeptides

Young adult AR Cognitive

degeneration

± ++ None Vacuolated

lymphocytes,

foam cells

Coarse facies

Sialidosis Neuraminidase Sialyloligosaccharides Type I, congenital

Type II, infantile

and juvenile

AR Myoclonus;

cognitive

degeneration

++, less in type I ++, less in

type I

Cherry red spot Vacuolated

lymphocytes

MPS phenotype in

type II

Mucolipidoses (ML)

ML-II, I-cell disease UDP-NAcetylglucosamine-1-

phosphotransferase

Glycoprotein;

glycolipids

Infantile AR Cognitive

degeneration

+ ++++ Corneal clouding Vacuolated

and granulated

neutrophils

Coarse facies;

absence of

mucopolysacchariduria;

gingival hypoplasia

ML-III, pseudo-Hurler

polydystrophy

UDP-NAcetylglucosamine-1-

phosphotransferase

Glycoprotein;

glycolipids

Late infantile AR Mild cognitive

degeneration

None +++ Corneal clouding,

mild retinopathy,

hyperopic

astigmatism

Coarse facies; stiffness

of hands and shoulders

Leukodystrophies

Krabbe disease Galactosylceramidase

[BMT/HSCT]

Galactosylceramide

Galactosylsphingosine

Infantile AR Cognitive

degeneration

None None None None White matter globoid

cells

TABLE 418-1 Selected Lysosomal Storage Diseases (Continued)

CLINICAL FEATURES

DISORDERa

ENZYME DEFICIENCY

[SPECIFIC THERAPY] STORED MATERIAL

CLINICAL TYPES

(ONSET) INHERITANCE NEUROLOGIC

LIVER, SPLEEN

ENLARGEMENT

SKELETAL

DYSPLASIA OPHTHALMOLOGIC HEMATOLOGIC UNIQUE FEATURES

3257 Lysosomal Storage Diseases 418 CHAPTER

Metachromatic

leukodystrophy

Arylsulfatase A Cerebroside sulfate Infantile

Juvenile

Adult

AR Cognitive

degeneration;

dementia; psychosis

in adult

None None Optic atrophy None Gait abnormalities in

late infantile form

Multiple sulfatase

deficiency

Active site cysteine

to C

α-formylglycineconverting enzyme

Sulfatides;

mucopolysaccharides

Late infantile AR Cognitive

degeneration

+ ++ Retinal degeneration Vacuolated

and granulated

cells

Absent activity of

all known cellular

sulfatases

Disorders of Neutral Lipids

Infantile-onset LALD Acid lysosomal lipase

[ET]

Cholesteryl esters;

triglycerides

Infantile AR None +++ None None None Adrenal calcification

Childhood/adult-onset

LALD

Acid lysosomal lipase

[ET]

Cholesteryl esters Childhood AR None Hepatomegaly None None None Fatty liver disease;

cirrhosis

Farber disease Acid ceramidase Ceramide Infantile

Juvenile

AR Occasional

cognitive

degeneration

± None Macular

degeneration

None Arthropathy,

subcutaneous nodules

Disorders of Glycogen

Pompe disease Acid α-glucosidase [ET] Glycogen Infantile, late onset AR Neuromuscular ± None None None Myocardiopathy

Late-onset GAA

deficiency

Acid α-glucosidase [ET] Glycogen Variable: juvenile

to adulthood

AR Neuromuscular None None None None Respiratory

insufficiency;

neuromuscular disease

Danon disease LAMP-2 (lysosomal

associated membrane

protein-2)

Glycogen Variable: childhood

to adulthood

X-linked

(?Dominant)

Cardiomyopathy

Neuromuscular

Inconsistent

cognitive

degeneration

None None None None Myocardial vacuolar

degeneration

Neuronal Ceroid Lipofuscinoses

CLN2 (a.k.a. NCL2) TPP1 (tripeptidyl

peptidase 1) [ICV ET]

Ceroid lipofuscin Early childhood AR Neurodegenerative

Loss of motor skills

Myoclonus

Loss of vision

Cognitive loss

Wheelchair bound

by adolescence

None None Progressive vision

loss

None Symmetric retinal

progressive

degeneration by

4–6 years

aComprehensive reviews of these lysosomal storage diseases can be found in DL Valle et al: The Online Metabolic and Molecular Bases of Inherited Disease, New York, McGraw-Hill, https://ommbid.mhmedical.com/book.

aspx?bookID=2709#225069419.

Abbreviations: AR, autosomal recessive; BMT/HSCT, bone marrow or hematopoietic stem cell transplantation; ET, enzyme therapy; ICV ET, intracerebroventricular enzyme therapy; LALD, lysosomal acid lipase deficiency; SRT, substrate

reduction therapy.

3258 PART 12 Endocrinology and Metabolism

at a locus that encodes a single lysosomal hydrolase. However, some

mutations cause deficiencies of several different lysosomal hydrolases

by alteration of the enzymes/proteins involved in targeting, active site

modifications, macromolecular association, or trafficking. Nearly all

LSDs are inherited as autosomal recessive disorders except for Hunter

(mucopolysaccharidosis type II), Danon, and Fabry diseases, which are

X-linked, and two autosomal dominant conditions causing Parry type

neuronal ceroid lipofuscinosis (CLN) due to mutations in DNAJC5

or frontotemporal dementia and CLN11 due to GRN (progranulin)

mutations. Substrate accumulation leads to lysosomal distortion/

dysfunction, which has significant pathologic consequences. In addition, abnormal amounts of metabolites may also have pharmacologic

effects important to disease pathophysiology and propagation, particularly activation of the innate immune responses.

For many LSDs, the accumulated substrates are synthesized within

particular tissue sites of pathology. Other diseases have greater exogenous substrate supplies. For example, substrates are delivered by

low-density lipoprotein receptor–mediated uptake in Fabry and LALD

or by phagocytosis in Gaucher disease type 1. The threshold hypothesis

refers to a level of enzyme activity below which disease develops. Small

changes in enzyme activity near that threshold can lead to or modify

disease. A critical element of this model is that enzymatic activity can

be challenged by changes in substrate flux based on genetic background, cell turnover, recycling, or metabolic demands. Thus, a set

level of residual enzyme may be adequate for substrate in some tissues

or cells but not in others. In addition, several variants of each LSD exist

at a clinical level. These disorders therefore represent a spectrum of

manifestations that are not easily dissociated into discrete entities. The

molecular/genetic bases for such variations have not been elucidated

in any detail.

There are European Medicines Agency (EMA) and U.S. Food and

Drug Administration (FDA) treatments available for a growing number

of LSDs. The first was enzyme replacement therapy (ET) for Gaucher

disease; this has been followed by additional ETs, but subsequent

developments have included modified enzyme infusion, substrate

inhibition, hematopoietic stem cell transplant (HSCT), pharmacologic

chaperone therapy (which uses a small molecule to stabilize enzyme

produced by the mutated gene and allows it to function), intrathecal

enzyme delivery, and gene therapy. The technical ability to intervene

for most LSDs now exists but with highly variable impact. Significant

additional research is needed to reach the goals of long-term survival

with good function and quality of life.

SELECTED DISORDERS

■ TAY-SACHS DISEASE

About 1 in 30 Ashkenazi Jews is a carrier for Tay-Sachs disease (total

hexosaminidase A [Hex A] deficiency), resulting from α-chain gene

mutations. The infantile form is a neurodegenerative disease that

results in death in infancy. It is characterized by macrocephaly, loss

of motor skills, increased startle reaction, and a macular cherry red

spot. The juvenile-onset form presents as ataxia and dementia, with

death by age 10–15 years. The adult-onset disorder is characterized by

clumsiness in childhood; progressive motor weakness in adolescence;

and additional spinocerebellar and lower-motor-neuron signs and

dysarthria in adulthood; intelligence declines slowly, and psychiatric

disorders are common. Screening for Tay-Sachs disease carriers is

recommended in the Ashkenazi Jewish population. Sandhoff disease,

due to a deficiency in both Hex A and Hex B resulting from defective

β-chains, is phenotypically similar to Tay-Sachs disease with the addition of hepatosplenomegaly and bony dysplasias.

■ FABRY DISEASE

Fabry disease, an X-linked disorder and likely the most prevalent LSD,

results from mutations in GALA, which encodes α-galactosidase A.

The estimated prevalence of hemizygous males ranges from 1 in 40,000

to 1 in 3500 in selected populations. Females are expected to have a

higher prevalence of mutations, but more variable manifestations. In

males, the disease manifests with angiokeratomas (telangiectatic skin

lesions), hypohidrosis, corneal and lenticular opacities, acroparesthesia, and progressive disease of the kidney, heart, and brain vascular

systems. Abdominal pain, recurrent diarrhea, and acroparesthesias

(debilitating episodic burning pain of the hands, feet, and proximal

extremities) may appear in childhood. In females, the overall manifestations vary, except that kidney disease is uncommon. Angiokeratomas

often appear in adolescence and are punctate, dark red to blue-black,

flat or slightly raised, and usually symmetric; they do not blanch with

pressure. They are often small and can be easily overlooked. They usually are most dense between the umbilicus and the knees—the “bathing

suit area”—but may occur anywhere, including the mucosal surfaces.

Angiokeratomas also occur in several other very rare LSDs. Corneal

and lenticular lesions, detectable on slit-lamp examination, may help

in establishing a diagnosis of Fabry disease. Acroparesthesia can last

from minutes to days and can be precipitated by changes in temperature, exercise, fatigue, or fever. Abdominal pain can resemble that from

appendicitis or renal colic. Proteinuria, isosthenuria, and progressive

renal dysfunction occur in the second to fourth decades; ~5% of male

patients with idiopathic renal failure have GALA mutations. Hypertension, left ventricular hypertrophy, anginal chest pain, and congestive

heart failure can occur in the third to fourth decades. About 1–3% of

patients with idiopathic hypertrophic myocardiopathy have Fabry disease. Similarly, ~2–5% of patients with idiopathic stroke at 35–50 years

of age have GALA mutations. Leg lymphedema occurs without hypoproteinemia. Death is due to cardiovascular, renal, or cerebrovascular

disease in untreated patients. Variants with residual α-galactosidase A

activity may have late-onset manifestations that are limited to the cardiovascular system and resemble hypertrophic cardiomyopathy. Cases

with predominant cardiac, renal, or central nervous system (CNS)

manifestations have been reported. Up to 70% of heterozygous females

exhibit clinical manifestations. However, in females, heart disease is the

most common life-threatening manifestation, followed in frequency by

stroke and renal disease. In males, renal disease followed by cardiovascular disease and stroke are most life-threatening.

Gabapentin and carbamazepine diminish chronic and episodic

acroparesthesia. Chronic hemodialysis or kidney transplantation

can be lifesaving in patients with renal failure. Intravenous ET clears

stored lipids from a variety of cells. More recently a chaperone therapy (migalastat) that stabilizes the residual enzyme made by the

patient’s body has allowed oral therapy for some patients with amenable mutations. Renal insufficiency, cardiac fibrosis, and stroke are

irreversible; therefore, early institution of therapy provides the best

opportunity to prevent or slow the progression of life-threatening

complications.

■ GAUCHER DISEASE

Gaucher disease, a panethnic autosomal recessive disorder, results

from defective activity of acid β-glucosidase; ~600 GBA1 mutations

have been described in such patients. Clinically, disease variants are

classified by the absence or presence and progression of primary CNS

involvement.

Gaucher disease type 1 is a nonneuronopathic disease (i.e., absence

of early-onset or progressive CNS disease) presenting in childhood

to adulthood as slowly to rapidly progressive visceral disease. About

55–60% of patients are diagnosed at <20 years of age in white populations and at even younger ages in other groups. This pattern of

presentation is distinctly bimodal, with peaks at <10–15 years and at

~25 years. Younger patients tend to have greater degrees of hepatosplenomegaly and accompanying blood cytopenias. In contrast, older

patients have a greater tendency for chronic bone disease. Hepatosplenomegaly occurs in virtually all clinically identified patients and can

be minor or massive. Accompanying anemia and thrombocytopenia

are variable and are not directly related to liver or spleen volumes.

Severe liver dysfunction is unusual. Splenic infarctions can resemble

an acute abdomen. Pulmonary hypertension and alveolar Gaucher cell

accumulation are uncommon but life-threatening and can occur at any

age. GBA1 mutations in the heterozygous or homozygous states lead to

a significantly increased lifetime risk for developing Parkinson disease.

The basic mechanisms for this risk are unknown.

3259 Lysosomal Storage Diseases CHAPTER 418

All patients with Gaucher disease have nonuniform infiltration of

bone marrow by lipid-laden macrophages termed Gaucher cells. This

phenomenon can lead to marrow packing with subsequent infarction, ischemia, necrosis, and cortical bone destruction. Bone marrow

involvement spreads from proximal to distal in the limbs and can

involve the axial skeleton extensively, causing vertebral collapse. In

addition to bone marrow involvement, bone remodeling is defective,

with loss of total bone calcium leading to osteopenia, osteonecrosis,

avascular infarction, and vertebral compression fractures with spinal

cord involvement. Aseptic necrosis of the femoral head is common,

as is fracture of the femoral neck. The mechanism by which diseased

bone marrow macrophages interact with osteoclasts and/or osteoblasts

to cause bone disease is not well understood. Chronic, ill-defined

bone pain can be debilitating and poorly correlated with radiographic

findings. “Bone crises” are associated with localized excruciating pain

and, on occasion, local erythema, fever, and leukocytosis. These crises

represent acute infarctions of bone, as evidenced in nuclear scans

by localized absent uptake of pyrophosphate agents. Decreased acid

β-glucosidase activity (0–20% of normal) in nucleated cells establishes

the diagnosis. The enzyme is not normally present in bodily fluids. The

sensitivity of enzyme testing is poor for heterozygote detection; molecular testing by whole GBA1 sequencing is the standard. The disease frequency varies from ~1 in 1000 among Ashkenazi Jews to <1 in 100,000

in other populations; ~1 in 12–15 Ashkenazi Jews carries a Gaucher

disease allele. Four common mutations account for ~85% of the mutations in that population of affected patients: p.N370S (also known as

p.N409S), 84GG (a G insertion at cDNA position 84), p.L444P (also

known as p.L483P), and IVS-2+1 (an intron 2 splice junction mutation).

Genotype/phenotype studies indicate a significant, though not

absolute, correlation between disease type and severity and the GBA1

genotype. The most common mutation in the Ashkenazi Jewish population (p.N370S) shares, either homozygously or heteroallelically, a

100% association with nonneuronopathic or type 1 Gaucher disease.

The N370S/N370S and N370S/other mutant allele genotypes are associated with later-onset/less severe disease and with earlier-onset/severe

disease, respectively. As many as 40% of individuals with the N370S/

N370S genotype do not present clinically. Other alleles include L444P

(very low activity), 84GG (null), or IVS-2 (null) and rare/private or

uncharacterized alleles. The L444P/L444P patients frequently have

life-threatening to very severe/early-onset disease, and many, though

not all, develop CNS involvement in the first two decades of life.

Symptom-based treatment of blood cytopenias and joint replacement surgeries continue to have important roles in management.

However, regular intravenous ET has been the first-line treatment

for significantly affected patients and is highly efficacious and safe

in diminishing hepatosplenomegaly and improving hematologic values. An oral substrate reduction therapy (eliglustat tartrate), which

inhibits glycolipid synthesis, is approved as a first-line therapy for

adults. Bone disease is decreased and can be prevented, but irreversible

damage cannot be reversed, by ET. Adult patients may benefit from

adjunctive treatment with bisphosphonates or other interventions to

improve bone density. Adults who cannot be treated with enzyme,

either because it is not effective or because they have developed an

allergy or other hypersensitivities to the enzyme, may receive substrate

reduction therapy with either eliglustat tartrate or miglustat; the latter

is approved as a second-line oral therapy.

Gaucher disease type 2 is a rare, severe, progressive CNS disease that

leads to death by 2 years of age, depending on supportive care. Gaucher

disease type 3 has highly variable manifestations in the CNS and viscera.

It can present in early childhood with rapidly progressive, massive visceral disease and slowly progress to static CNS involvement that may not

be evident by standard IQ evaluations; in adolescence with dementia; or

in early adulthood with rapidly progressive, uncontrollable myoclonic

seizures and mild visceral disease. Visceral disease in type 3 is nearly

identical to that in type 1 but is generally more severe. Early CNS findings may be limited to defects in lateral gaze tracking, which may remain

static for decades. Cognitive degeneration can be slowly progressive or

static. Type 3 is much more frequent among individuals of non–Western

world descent. Visceral—but not CNS—involvement responds to ET.

■ NIEMANN-PICK DISEASES

Niemann-Pick diseases (acid sphingomyelinase deficiency [ASMD])

are autosomal recessive disorders that result from defects in acid sphingomyelinase (ASM). Types A and B are distinguished by the early age

of onset and progressive CNS disease in type A. Type A typically has its

onset in the first 6 months of life, with rapidly progressive CNS deterioration, spasticity, failure to thrive, and massive hepatosplenomegaly.

Type B has a later, more variable onset and is characterized by a progression of hepatosplenomegaly, with eventual development of cirrhosis and hepatic parenchymal and Kupffer cell replacement by foam

cells filled with sphingomyelin. Affected patients develop progressive

pulmonary disease with dyspnea, hypoxemia, and a reticular infiltrative pattern on chest x-ray. Foam cells are present in alveoli, lymphatic

vessels, and pulmonary arteries. Progressive hepatic or lung disease can

lead to death in adolescence or early adulthood. The “type B” phenotype includes some patients with slowly progressive CNS involvement.

The diagnosis is established by markedly decreased (1–10% of

normal) ASM activity in nucleated cells. There is no approved specific

treatment for Niemann-Pick disease, but intravenous ET clinical trials

are in phase 3. The efficacies of hepatic transplant (HT) or bone marrow transplantation (BMT) are not established. More complications

than expected have occurred with these interventions due to either

(1) recurrence of hepatic disease in the transplant following HT by

repopulation of bone marrow–derived ASM-deficient myeloid cells or

(2) lack of clearance of sphingomyelin in hepatocytes by ASM crosscorrection following the BMT of ASM-normal bone marrow stem cells.

Niemann-Pick C diseases are progressive CNS diseases due to

mutations in either NPC1 or NPC2 mutations in either, lysosomal

proteins involved in cholesterol and selected sphingolipid transport

out of the lysosome. They can present with liver or splenic disease, but

their major manifestations are progressive CNS disease over one to two

decades. Treatment with substrate inhibition agents (e.g., miglustat)

has shown minor CNS effects, and substrate depletion with cyclodextrin is in clinical trials for NPC1 disease.

■ MUCOPOLYSACCHARIDOSES

Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disorder caused by deficiency of α-L-iduronidase. The spectrum of involvement traditionally has been divided into three categories: (1) Hurler

disease (MPS I H) for severe deficiency with neurodegeneration, (2)

Scheie disease (MPS I S) for later-onset disease without neurologic

involvement and with relatively less severe disease in other organ

systems, and (3) Hurler-Scheie syndrome (MPS I H/S) for patients

intermediate between these extremes. MPS I H/S is characterized

by severe somatic disease, usually without major overt neurologic

deterioration. MPS I often presents in infancy or early childhood as

chronic rhinitis, clouding of the corneas, hepatosplenomegaly, and

progressive dysmorphia. As the disease progresses, nearly every organ

system can be affected. In the more severe forms, cardiac and respiratory diseases become life threatening in childhood. Skeletal disease

can be quite severe, resulting in very limited mobility. There are two

current treatments for the MPS I diseases. HSCT is the standard treatment for patients presenting at <2 years of age who appear to have or

are at risk for neurologic degeneration. Because early diagnosis and

intervention are essential, MPS I has been added to the recommended

newborn screen (NBS). HSCT results in stabilization of CNS disease

and reverses hepatosplenomegaly. It also beneficially affects cardiac

and respiratory disease. HSCT does not eliminate corneal disease or

result in the resolution of progressive skeletal disease. ET effectively

addresses hepatosplenomegaly and alleviates cardiac and respiratory

disease. The enzyme does not penetrate the blood-brain barrier and

does not directly affect CNS disease. ET and HSCT appear to have

similar effects on visceral signs and symptoms. ET poses a lower risk

of life-threatening complications and may therefore be advantageous

for patients who have attenuated manifestations without CNS disease.

A combination of ET and HSCT has been used, with ET initiated prior

to transplantation in an attempt to reduce the disease burden. The

experience with this approach is not well documented, but it appears to

have advantages over HSCT alone. It is clear that HSCT has benefited

3260 PART 12 Endocrinology and Metabolism

patients. However, late cardiac and respiratory complications of MPS I

are being reported including obstructive breathing requiring pressure

support, cardiomyopathy, and/or valve disease. Regular follow-up for

patients with MPS I is required throughout their lives even after successful HSCT.

Hunter disease (MPS II) is an X-linked disorder due to deficiency

in iduronate sulfate sulfatase and has manifestations similar to those of

MPS I, including some variants with neurologic degeneration. There is

no corneal clouding or other eye disease. Like MPS I, MPS II is clinically variable, with CNS and non-CNS variants. HSCT has not been

successful in treating CNS disease associated with MPS II. The FDA

and EMA have approved ET for the visceral manifestations of MPS II.

MPS IV or Morquio syndrome is a rare autosomal recessive condition (1 in 200,000–300,000) and is different than the other mucopolysaccharidoses in presenting as a spondyloepiphyseal skeletal dysplasia

and hyperextensibility of all joints. There are also major heart and

respiratory complications. This disorder often presents in childhood,

but the age of onset and rate of progression are quite variable. Two

variants, type A and type B, are caused by deficiencies in N-acetylgalactosamine-6-sulfatase (GALNS) and an acid β-galactosidase,

respectively. A recombinant human GALNS ET (elosulfase alfa) is

approved for the treatment of MPS IVA, making it is essential to

confirm the specific enzyme diagnosis. Treatment has been shown to

improve ambulatory mobility and decrease pain. There is no current

specific treatment for MPS IVB.

ET for Maroteaux-Lamy disease (MPS VI), arylsulfatase B deficiency, has received FDA approval as well as approval by similar agencies in other countries. This very rare autosomal recessive disorder is

characterized by hepatosplenomegaly, bone disease, heart disease, and

respiratory compromise. Short stature is also an important manifestation. Visceral signs and symptoms are similar to those in MPS I; however, MPS VI is not associated with neurologic degeneration.

MPS VII, Sly syndrome, is due to mutations in GUSB, which

encodes β-glucuronidase. Severe deficiency in this enzyme may present with fetal hydrops, which can lead to stillbirth or perinatal demise.

Other patients with MPS VII may present later with short stature,

coarse facial features, and hepatosplenomegaly. There is ET for this

disorder (vestronidase alfa-vjbk).

■ POMPE DISEASE

Acid maltase (acid α-glucosidase deficiency) due to GAA mutation,

also called Pompe disease, is the only LSD leading to primary glycogen

storage. The classic severe infantile form presents with hypotonia, myocardiopathy, and hepatosplenomegaly. This variant is rapidly progressive and generally results in death in the first year of life. However, as

with other LSDs, there are early- and late-onset forms of this disorder.

The late-onset variants may be as common as 1 in 40,000; patients

typically present with a slowly progressive myopathy that may resemble

limb-girdle muscular dystrophy. Respiratory insufficiency may be the

presenting sign or may develop with advancing disease. In late stages of

the disease, patients may require mechanical ventilation, report swallowing difficulties, and experience loss of bowel and bladder control.

Myocardiopathy is not usually present in late-onset variants of Pompe

disease.

The FDA, EMA, and similar agencies have approved ET for Pompe

disease patients of all ages. This treatment clearly prolongs life in the

infantile form, consistently resulting in improved cardiac function.

Respiratory function is also improved in most treated infants if instituted before age 6 months. Some infants demonstrate marked improvement in motor functions, while others have minor changes in muscle

tone or strength. Recently, several states have instituted NBS for Pompe

disease. In addition, newer protocols for treatment with methotrexate

and rituximab have greatly decreased antidrug antibody formation.

The combination of NBS and immunomodulation preceding ET has

greatly improved therapeutic response and long-term survival. Prevention of deterioration has been shown with GAA ET in the late-onset

forms. Early intervention with acid α-glucosidase ET in such patients

may limit or prevent deterioration, but very advanced disease will have

significant irreversible components.

■ LYSOSOMAL ACID LIPASE DEFICIENCY

Wolman syndrome (now infantile-onset LALD) and cholesterol ester

storage disease (now childhood/adult-onset LALD) are caused by

deficiency of lysosomal acid lipase (LAL) due to autosomal recessive

mutations in LIPA. The diagnosis is established by enzyme or gene

analyses of LAL or LIPA in serum/plasma or nucleated cells. LAL

hydrolyzes cholesterol esters and triglycerides delivered to the lysosome via the LDLR pathway. Accumulation of these in the tissues

leads to progressive organ dysfunction including liver disease, intestinal malabsorption, heart dysfunction, and other manifestations. The

most severe form presents in early infancy as a medical emergency

with severe failure to thrive, vomiting, and hepatosplenomegaly. The

infantile-onset LALD patients die without specific treatment by age

1 year (median age of death, 3.7 months). Childhood/adult-onset

LALD can have a variable age of initial presentation with nonspecific

signs but often involves elevated liver enzymes, nonalcoholic fatty

liver disease, cryptogenic cirrhosis, and varying severities of hepato-/

splenomegaly. Importantly, neither clinical variant manifests primary

CNS disease. Disease progresses throughout life and may result in early

(adolescence) liver cirrhosis and (early adulthood) atherosclerosis or

early death without treatment. Importantly, statins can decrease the

hypercholesterolemia but do not alter the basic progressive tissue (e.g.,

liver) pathology. The majority of the later onset patients are evaluated

by hepatology or lipidology physicians. ET for LALD has major effects

in reversing disease manifestations and was approved for patients at

all ages by the EMA, FDA, and several other country agencies in 2015

and 2016.

■ KRABBE DISEASE

Deficiency in galactocerebrosidase (GALC) causes Krabbe disease, an

autosomal recessive neurodegenerative disorder due to mutations in

GALC. Krabbe disease is panethnic but quite rare. The early infantile

form presents at an average age of 4 months and progresses rapidly,

with death at an average age of 18 months. Later onset forms also exist

and have onsets and survival that are highly variable. The early-onset

form presents with hyperirritability, feeding problems, fever, seizures,

and neurodegeneration. Blindness, hypotonia, and loss of voluntary

movement develop over time. Later onset forms present with spasticity,

ataxia, vision loss, and behavioral problems and progress to dementia

and early death. There is no FDA-approved treatment, but early presymptomatic HSCT has been used. This results in improved survival,

but neurologic problems are still common. More recently studies in

mouse and dog models have used gene therapy with dramatic improvement in both neurologic function and survival. Human studies are

being implemented.

■ NEURONAL CEROID LIPOFUSCINOSIS TYPE 2

(NCL2 OR CLN2)

There are at least 13 genes that have been associated with storage of

neuronal ceroid lipofuscin. One of these, CLN2, is due to mutations in

TPP1 and deficiency in tripeptidyl peptidase 1. This autosomal recessive neurodegenerative disorder typically presents between age 2 and

4 years, most commonly with seizures, ataxia, myoclonus, and vision

loss. Motor skill losses include sitting, walking, speech, and feeding

and lead to severe disability and eventually death at an average age of

12 years. Intellectual disability and behavioral problems also become

increasingly severe with age. Most affected children are wheelchair

bound in late childhood, and survival beyond adolescence is rare.

There are later onset patients, and there is significant clinical overlap

between CLN2 and other CLNs; confirmation of the diagnosis by gene

sequencing is essential. In 2017, the FDA/EMA approved treatment of

CLN2, cerliponase alfa, an ET that is administered by intracerebroventricular injection over several hours every 2 weeks. Administration of

cerliponase alfa is facilitated by placement of an intracerebroventricular port to allow reliable access. Currently, this is the only approved ET

that is intrathecally administered. CLN2 is the only neuronal ceroid

lipofuscinosis that has a specific treatment. Several others are in preclinical development.

3261 Glycogen Storage Diseases and Other Inherited Disorders of Carbohydrate Metabolism CHAPTER 419

■ FURTHER READING

Aldenhoven M et al: Long-term outcome of Hurler syndrome

patients after hematopoietic cell transplantation: An international

multicenter study. Blood 125:2164, 2015.

Balwani M et al: Recommendations for the use of eliglustat in the

treatment of adults with Gaucher disease type 1 in the United States.

Mol Genet Metab 117:95, 2016.

Ortiz A et al: Fabry disease revisited: Management and treatment

recommendations for adult patients. Mol Genet Metab 123:416, 2018.

Schoser B et al: Survival and long-term outcomes in late-onset Pompe

disease following alglucosidase alfa treatment: A systematic review

and meta-analysis. J Neurol 264:621, 2017.

Schulz A et al: Study of intraventricular cerliponase alfa for CLN2

disease. N Engl J Med 378:1898, 2018.

Carbohydrate metabolism plays a vital role in cellular function by providing the energy required for most metabolic processes. The relevant

biochemical pathways involved in the metabolism of these carbohydrates are shown in Fig. 419-1. Glucose is the principal substrate of

energy metabolism in humans. Metabolism of glucose generates ATP

through glycolysis and mitochondrial oxidative phosphorylation. The

body obtains glucose through the ingestion of polysaccharides (primarily starch) and disaccharides (e.g., lactose, maltose, and sucrose).

Galactose and fructose are two other monosaccharides that serve as

sources of fuel for cellular metabolism. However, their role as fuel

sources is less significant than that of glucose. Galactose is derived

from lactose (galactose + glucose), which is the disaccharide found in

milk products, and it is an important component of certain glycolipids,

glycoproteins, and glycosaminoglycans. Fructose is found in fruits,

vegetables, and honey. Sucrose (fructose + glucose) is another dietary

source of fructose and is a commonly used sweetener.

Glycogen, the storage form of glucose in animal cells, is composed

of glucose residues joined in straight chains by α1-4 linkages and

branched at intervals of 4–10 residues by α1-6 linkages. Glycogen

forms a treelike molecule and can have a molecular weight of many

millions. Glycogen may aggregate to form structures recognizable by

electron microscopy. Defects in glycogen metabolism typically cause

an accumulation of glycogen in the tissues—hence the designation

glycogen storage diseases (GSDs). The accumulated glycogen can be

structurally normal or abnormal in the various GSDs. Defects in gluconeogenesis, glycolysis or pathways involving galactose and fructose

metabolism usually do not result in glycogen accumulation.

Clinical manifestations of the various disorders of carbohydrate

metabolism differ markedly. The symptoms range from minimally

harmful to lethal. Unlike disorders of lipid metabolism, mucopolysaccharidoses, or other storage diseases, many disorders of carbohydrate

metabolism have been managed with diet therapy. However, diet

therapy alone does not prevent long-term complications, and there is

a need for definitive therapies. Genes responsible for inherited defects

of carbohydrate metabolism have been cloned, and pathogenic variants

have been identified. With the use of tools such as DNA sequencing

panels, whole exome sequencing, and whole genome sequencing, new

GSDs continue to be identified, and the phenotype of known disorders

419 Glycogen Storage

Diseases and Other Inherited

Disorders of Carbohydrate

Metabolism

Priya S. Kishnani

continues to expand as is seen in the case of GSDs type II, III, and IX.

Advances in the molecular basis of these diseases are now being used to

improve diagnosis and management. Some of these disorders are candidates for enzyme replacement therapy, substrate reduction therapy,

gene therapy, and other genomic tools, such as small interfering RNA

(siRNA) technology and CRISPR genome editing technology.

Historically, the GSDs were categorized numerically in the order in

which the enzymatic defects were identified. GSDs are also classified

based on the primary organs involved (liver, muscle, and/or heart)

and clinical manifestations. In this chapter, the GSDs will be classified

based on the organ involvement (Table 419-1). The overall frequency

of all forms of GSDs is between 1 in 20,000 to 1 in 40,000 live births

in the United States and Europe, and up to 1 in 10,000 worldwide for

some GSDs. Most are inherited as autosomal recessive traits; however,

phosphoglycerate kinase deficiency; two forms of liver and muscle

phosphorylase kinase (PhK) deficiency caused by mutations in PHKA2

and PHKA1 genes respectively, and lysosomal-associated membrane

protein 2 (LAMP2) deficiency are X-linked disorders. The most

common childhood disorders are glucose-6-phosphatase deficiency

(GSD type I), lysosomal acid α-glucosidase deficiency (GSD type II),

debrancher enzyme deficiency (GSD type III), and liver PhK deficiency

(GSD type IX). The most common adult disorder is myophosphorylase

deficiency (GSD type V).

SELECTED LIVER GLYCOGENOSES

■ DISORDERS WITH HEPATOMEGALY

AND HYPOGLYCEMIA

Type I GSD (Glucose-6-Phosphatase or Translocase

Deficiency, Von Gierke Disease) Type I GSD is an autosomal

recessive disorder caused by glucose-6-phosphatase or translocase

deficiency in liver, kidney, and intestinal mucosa. There are two subtypes of GSD I: type Ia, in which the glucose-6-phosphatase enzyme

is defective, and type Ib, in which the translocase that transports glucose-6-phosphate across the microsomal membrane is defective. The

defects in both subtypes lead to inadequate conversion of glucose-6-

phosphate to glucose in the liver and thus make affected individuals

susceptible to fasting hypoglycemia.

CLINICAL AND LABORATORY FINDINGS Persons with type I GSD may

develop hypoglycemia and lactic acidosis during the neonatal period;

however, more commonly, they exhibit hepatomegaly at 3–4 months

of age. Hypoglycemia and lactic acidosis can develop after a short

fast, typically when infants start sleeping through the night. These

children usually have doll-like facies with fat cheeks, relatively thin

extremities, short stature, and a protuberant abdomen that is due to

massive hepatomegaly. The kidneys are enlarged, but the spleen and

heart are of normal size. The hepatocytes are distended by glycogen

and fat, with large and prominent lipid vacuoles. Despite hepatomegaly,

liver enzyme levels are usually normal or near normal. Easy bruising

and epistaxis are associated with prolonged bleeding time as a result

of impaired platelet aggregation/adhesion and/or an acquired von

Willebrand–like disease. Hyperuricemia is present. Plasma lipids

abnormalities includes elevation of triglycerides, total and low-density

lipoprotein cholesterol, and phospholipids, compared to the low level

of high density cholesterol (HDL). Type Ib patients have additional

findings of neutropenia and impaired neutrophil function. Therefore,

these patients are prone to recurrent bacterial infections and chronic

oral and intestinal mucosal ulceration, which leads to severe diarrhea

and malnutrition.

LONG-TERM COMPLICATIONS Gout usually becomes symptomatic at

puberty as a result of long-term hyperuricemia in untreated patients.

Puberty is often delayed. Some women with GSD I have polycystic ovaries and menorrhagia. Several reports of successful pregnancies suggest

that fertility is not affected, although symptoms may be exacerbated

due to pregnancy-related increases in renal perfusion and maternal

blood volume. Secondary to lipid abnormalities, there is an increased

risk of pancreatitis. Patients with GSD I may be at increased risk for

3262 PART 12 Endocrinology and Metabolism

supplemented by uncooked cornstarch in small, frequent feedings

is used for treatment of both GSD

Ia and GSD Ib. Modified, extendedrelease cornstarch products that are longer acting and better tolerated are available, which may help extend the duration

of euglycemia and improve metabolic

control. Treatment of complications with

medications may be necessary, such

as citrate supplementation to prevent

and/or treat nephrocalcinosis, allopurinol to control hyperuricemia, HMGCoA reductase inhibitors and fibrate to

reduce lipids, as well as angiotensinconverting enzyme inhibitors to treat

microalbuminuria. Surgical resection,

percutaneous ethanol injections, radiofrequency ablation can be used to treat

liver adenoma. Liver transplantation can

be lifesaving for those with hepatic adenomatous disease with the risk of malignant transformation, rapid growth in

size or number, and/or severe, poor metabolic control. Kidney transplantation

may be required in those with renal glomerular dysfunction progressing to renal

failure. Individuals with GSD Ib may

require further intervention due to the

consequences of neutropenia, such as

the use of granulocyte colony-stimulating factor. More recently, empagliflozin,

renal glucose cotransporter sodium

glucose cotransporter 2 (SGLT2), has

been effectively used in GSD Ib for the

treatment of neutrophil dysfunction and

showed improvement of wound healing

and symptoms of inflammatory bowel

disease.

Type III GSD (Debrancher Defi- ciency, Limit Dextrinosis)

Type III GSD is an autosomal recessive

disorder caused by a deficiency of glycogen debranching enzyme. Debranching

and phosphorylase enzymes are responsible for the complete degradation of glycogen into glucose. When debranching

enzyme is defective, glycogen breakdown is incomplete, resulting in

abnormal glycogen accumulation with short outer chains, resembling

limit dextrin. GSD III is mainly classified as (1) GSD IIIa, with liver,

cardiac, and skeletal muscle involvement (~85% of cases), and (2) GSD

IIIb, with primarily liver involvement (~15% of cases).

CLINICAL AND LABORATORY FINDINGS The initial presentation of

GSD III is similar to that of GSD I with hypoglycemia, hepatomegaly, hyperlipidemia, and short stature, occurring in infancy and early

childhood. Hypoglycemia in GSD III can be ketotic or non-ketotic.

Patients with GSD III have elevated aminotransferase levels and normal concentrations of blood lactate and uric acid. Patients with GSD

IIIa also have a variable skeletal myopathy and cardiomyopathy that

can present early. Serum creatine kinase (CK) levels can sometimes be

used to identify patients with muscle involvement, but normal levels do

not rule out muscle enzyme deficiency. In most patients with GSD III,

there is an apparent improvement in hepatomegaly with age; however,

many patients present in late adulthood with progressive liver fibrosis,

cirrhosis progressing to liver failure, and hepatocellular carcinoma.

Hepatic adenomas may occur, although less commonly than in GSD I.

Left ventricular hypertrophy, significant scarring of the myocardium,

and life-threatening arrhythmias have been reported. Patients with

Debrancher

PaP

PbKa

PbKb

Pb Pa

α-Glucosidase

Glucose

+

Pi

ENDOPLASMIC

 RETICULUM

Glucose

LYSOSOME

Brancher

PaP

Pa Pb GSa

GSa

UTP

UDP-Gal

Gal-1-P Uridyl transferase

GSb

Phosphoglucomutase

Glucokinase,

 hexokinase

Glc-1-P

Gal-1-P

UDP-Glc

 Pyrophosphorylase

UDP-Gal-4-

 epimerase

Galactose

Galacto-

 kinase

Fructose

UDP-Glc

Glc-6-P Glc-6-P

F-6-P

F-1, 6-P2

Glyceraldehyde-3-P

1, 3-Bisphosphoglycerate

3-Phosphoglycerate

2-Phosphoglycerate

Phosphoenolpyruvate

Dihydroxyacetone-P

Phosphotriose isomerase

Glyceraldehyde Aldolase

Phosphohexose isomerase

Phosphofructokinase Fructose 1,6-

diphosphatase

Aldolase

Glyceraldehyde-3-P dehydrogenase

Phosphoglycerate kinase

Phosphoglycerate mutase

Enolase

Pyruvate kinase

Lactate dehydrogenase Pyruvate Lactate

NADH TCA

Cycle

CYTOSOL

NAD

GSb

PbKa

PbKb

G

CYTOSOL

G

G

G

G

G

Galactose

GLUT2 Glucose

Translocase

GLUT2

GLUT2

Glucose

Glucose

F-1-P Fructose

GLUT2

MITOCHONDRIA

Glc-6-Pase

FIGURE 419-1 Metabolic pathways related to glycogen storage diseases and galactose and fructose disorders.

Nonstandard abbreviations are as follows: GSa

, active glycogen synthase; GSb

, inactive glycogen synthase; Pa

, active

phosphorylase; Pb

, inactive phosphorylase; Pa

P, phosphorylase α phosphatase; Pb

Ka

, active phosphorylase β

kinase; Pb

Kb

, inactive phosphorylase β kinase; G, glycogenin, the primer protein for glycogen synthesis. (Modified with

permission from AR Beaudet, in KJ Isselbacher et al: Harrison’s Principles of Internal Medicine, 13th ed. New York, NY:

McGraw Hill; 1994.)

cardiovascular disease such as systemic hypertension. Pulmonary

hypertension—although rare—has been reported. In adult patients,

frequent fractures can occur, and radiographic evidence of osteopenia/

osteoporosis can be found; in prepubertal patients, bone mineral

content is significantly reduced. By the second or third decade of life,

many patients with type I GSD develop hepatic adenomas that can

hemorrhage and, in some cases, become malignant. End-stage renal

disease is a serious late complication. Almost all patients aged >20

years have proteinuria, and many have hypertension, kidney stones,

nephrocalcinosis, and altered creatinine clearance. In some patients,

renal function deteriorates and progresses to end-stage renal disease,

requiring dialysis or transplantation.

DIAGNOSIS Clinical presentation, hypoglycemia, lactic acidosis,

hyperuricemia and abnormal lipids values suggest that a patient may

have GSD I, and genetic testing provides a noninvasive means of

reaching a definitive diagnosis for most patients with types Ia and Ib

disease. Historically, a definitive diagnosis required a liver biopsy to

demonstrate the enzyme deficiency.

TREATMENT The first line of treatment in GSD I is avoidance of

fasting and frequent feedings. A diet high in complex carbohydrates

3263 Glycogen Storage Diseases and Other Inherited Disorders of Carbohydrate Metabolism CHAPTER 419

TABLE 419-1 Features of Glycogen Storage Diseases and Galactose and Fructose Disorders

TYPE/COMMON NAME BASIC DEFECT CLINICAL FEATURES COMMENTS

Liver Glycogenoses

Disorders with Hepatomegaly and Hypoglycemia

Ia/von Gierke Glucose-6-phosphatase Growth retardation, enlarged liver and kidney,

hypoglycemia, elevated blood lactate, cholesterol,

triglycerides, and uric acid

Common, severe hypoglycemia.

Complications in adulthood include hepatic

adenomas, hepatic carcinoma, osteoporosis,

pulmonary hypertension, and renal failure.

Ib Glucose-6-phosphate

translocase

As for Ia, with additional findings of neutropenia and

neutrophil dysfunction, increased risk for infections,

mucosal ulceration, and periodontal disease, inflammatory

bowel disease, hypothyroidism

~20% of type I

IIIa/Cori or Forbes Liver and muscle

debranching enzyme

Childhood: Hepatomegaly, growth failure, muscle

weakness, cardiomyopathy, cardiac arrhythmias,

hypoglycemia, hyperlipidemia, elevated liver

aminotransferases, CK, urinary Glc4

Common, intermediate severity of

hypoglycemia, yet severe cases are seen.

Adulthood: Proximal and distal muscle atrophy and

weakness; peripheral neuropathy with preferential median

nerve involvement; variable cardiomyopathy, liver fibrosis,

cirrhosis, progressive liver failure, risk for HCC in some

Liver fibrosis/cirrhosis, hepatic adenoma

and carcinoma can occur. Muscle

weakness can progress to need for

ambulatory aids such as wheelchair. Risk of

life threatening arrhythmia.

IIIb Liver debranching

enzyme (normal muscle

debrancher activity)

Liver symptoms same as in type IIIa; no muscle symptoms ~15% of type III

IV/Andersen Branching enzyme Hepatic form: Failure to thrive, hypotonia, hepatomegaly,

progressive liver cirrhosis and failure (death usually before

fifth year); a small subset do not have liver progression

with extrahepatic involvement such as myopathy and

cardiomyopathy later in life

Neuromuscular forms: Perinatal and congenital forms lead

to death in the neonatal period. Childhood form presents

with myopathy, cardiomyopathy, typical systemic findings.

Adult form (APBD): Bilateral lower limb weakness and

spasticity, neurogenic bladder, peripheral neuropathy,

cognitive impairment

One of the rarer glycogenoses. Other

neuromuscular variants exist.

VI/Hers Liver phosphorylase Hepatomegaly, variable hypoglycemia, hyperlipidemia,

ketosis, growth retardation, liver fibrosis, and hepatocellular

carcinoma

Often underdiagnosed, severe cases being

recognized

IX/liver PhK deficiency

IX α2 (PHKA2)

IX β (PHKB)

IX γ2 (PHKG2)

Liver PhK

Liver and muscle PhK

Liver PhK

Hypoglycemia, hyperketosis hepatomegaly, chronic liver

disease, hyperlipidemia, elevated liver enzymes, growth

retardation

Clinical phenotype of IX γ2 is more severe than IX α2;

with significant variability among patients, marked

hepatomegaly, recurrent hypoglycemia, liver cirrhosis

GSD IXα2 is a common, X-linked, (GSD IX

γ2) clinical variability within and between

subtypes; severe cases being recognized

across different subtypes

00a/liver glycogen synthase

deficiency

Glycogen synthase Fasting hypoglycemia and ketosis, elevated lactic acid,

alanine levels and hyperglycemia after glucose load, no

hepatomegaly

Decreased liver glycogen stores

GSD XI/Fanconi-Bickel

syndrome

Glucose transporter 2

(GLUT2)

Failure to thrive, short stature, hypophosphatemic rickets,

metabolic acidosis, hepatomegaly, proximal renal tubular

dysfunction, impaired glucose and galactose utilization

Rare, consanguinity in 70%

Muscle Glycogenoses

Disorders with Muscle-Energy Impairment

V/McArdle Muscle phosphorylase Exercise intolerance, muscle cramps, myoglobinuria

on strenuous exercise, increased CK, “second-wind”

phenomenon

Common, male predominance

VII/Tarui Phosphofructokinase—M

subunit

As for type V, with additional findings of compensated

hemolysis, hyperuricemia, ‘out of wind phenomena’

Prevalent in Ashkenazi Jews and Japanese

IX/muscle PhK deficiency

IX α1 (PHKA1) IX γ1 (PHKG1)

Muscle PhK Exercise intolerance, cramps, myalgia, myoglobinuria; no

hepatomegaly

X-linked (PHKA1), AR (PHKG1)

X/Phosphoglycerate kinase

deficiency

Phosphoglycerate kinase As for type V, with additional findings of hemolytic anemia

and CNS dysfunction

Rare, X-linked

Phosphoglycerate mutase

deficiency

Phosphoglycerate

mutase—M subunit

As for type V Rare, most patients African American

Lactate dehydrogenase

deficiency

Lactic acid

dehydrogenase—M

subunit

As for type V, with additional findings of erythematous

skin eruption and uterine stiffness resulting in childbirth

difficulty in females

Rare

XII/Fructose 1,6-bisphosphate

aldolase A deficiency

Fructose 1,6-bisphosphate

aldolase A

As for type V, with additional finding of hemolytic anemia,

splenomegaly, jaundice

Rare

XIII/β-Enolase deficiency Muscle β-enolase Exercise intolerance Rare

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3264 PART 12 Endocrinology and Metabolism

GSD IIIa may experience muscle weakness in early childhood that can

become severe after the third or fourth decade of life, resulting in use of

assistive devices and wheelchair dependence. Patients also experience

exercise intolerance. The pattern of muscle weakness is variable, and

both proximal and distal muscle weakness are seen. Peripheral neuropathy may become discernible later in life; however there are opposing

views concerning the existence of peripheral neuropathy in GSD III.

Individuals with GSD IIIa are at an increased risk of osteoporosis. In

addition, polycystic ovaries are reported in female patients with GSD

III, and some patients develop features of polycystic ovarian syndrome,

such as hirsutism and irregular menstrual cycles. Reports of successful

pregnancy in women with GSD III suggest that fertility is normal.

DIAGNOSIS Hypoglycemia is a presenting symptom in only about half

of patients with GSD III, and therefore the diagnosis should be considered in patients with hepatomegaly and typical biochemical parameters. In the past, the diagnosis was confirmed by deficient or absent

debranching enzyme activity in liver, skeletal muscle, or fibroblasts. In

patients with GSD IIIb, enzyme activity is low in liver and normal in

muscle. With the availability of molecular genetic testing, reliance on

invasive tests such as liver and muscle biopsies is declining. DNA-based

analyses now provide a noninvasive way of subtyping these disorders in

most patients. Liver histology has distended hepatocytes due to glycogen buildup; areas of periportal fibrosis are also noted very early in the

disease course along with some fat infiltration.

TREATMENT Debrancher enzyme deficiency prevents complete

glycogenolysis in GSD III, but gluconeogenesis is intact. Hence, a

high-protein diet with complex carbohydrates supplemented with

uncooked cornstarch in small, frequent feedings is effective in preventing hypoglycemia. Individuals with GSD III may benefit from

dietary lipid manipulation, such as the implementation of a high-fat

diet or a modified ketogenic diet or use of medium-chain triglyceride

supplementation, yet careful monitoring of liver function, morphology, lipid profile and growth is necessary given the potential impact

on underlying liver disease. Blood ketones and glucose should be

evaluated during times of stress. Liver and heart transplantation may

be considered in those with severe hepatic or cardiac involvement.

Diet therapy is not effective in preventing the progression of hepatic

disease, cardiomyopathy, and myopathy. Muscle disease continues to

progress and is a significant unmet need for these patients.

Type IX GSD (Liver Phosphorylase Kinase Deficiency)

Defects of PhK cause a heterogeneous group of glycogenoses. The

PhK enzyme complex consists of four subunits (α, β, γ, and δ). Each

subunit is encoded by different genes (X chromosome as well as

autosomes) that are differentially expressed in various tissues. PhK

deficiency can be divided into several subtypes on the basis of the

gene/subunit involved, the tissues primarily affected, and the mode

of inheritance.

The most common subtype is GSD IX α2 an X-linked liver PhK

deficiency caused by pathogenic variants in the PHKA2 gene, which

is also one of the most common liver glycogenoses. PhK activity may

also be deficient in erythrocytes and leukocytes but is normal in muscle. Typically, a child between the ages of 1 and 5 years presents with

growth failure and hepatomegaly. Despite delayed onset of puberty

and growth continuing well into late teenage years, children typically

TABLE 419-1 Features of Glycogen Storage Diseases and Galactose and Fructose Disorders

TYPE/COMMON NAME BASIC DEFECT CLINICAL FEATURES COMMENTS

Disorders with Progressive Skeletal Muscle Myopathy and/or Cardiomyopathy

II/Pompe Lysosomal acid

α-glucosidase

Classic infantile: Hypotonia, muscle weakness, cardiac

enlargement and failure, fatal early.

Nonclassic infantile: Presentation within first year of life

with less severe cardiomyopathy and slower progression

than the classic form.

Late onset (juvenile and adult): Absence of cardiomyopathy

in first year of life. Progressive skeletal muscle weakness

and atrophy, proximal muscles and respiratory muscles

seriously affected.

Common, undetectable or very low level of

enzyme activity in infantile form; variable

residual enzyme activity in late-onset form

PRKAG2 deficiency AMP-activated gamma 2

protein kinase

Severe cardiomyopathy and early heart failure (9–55 years).

Congenital fetal form is rapidly fatal with hypertrophic

cardiomyopathy and WPW syndrome. Other involvement

includes myalgia, myopathy, and seizures.

Autosomal dominant

Danon disease Lysosomal-associated

membrane protein 2

(LAMP2)

Severe cardiomyopathy, WPW pattern, and heart failure

(8–15 years); myopathy, retinopathy or maculopathy,

learning disability, cognitive and attention deficits may be

present.

Very rare, X-linked

XV; Late-onset polyglucosan

body myopathy

Glycogenin-1 Adult-onset proximal muscle weakness, severe

cardiomyopathy necessitating cardiac transplantation in

some cases, nervous system involvement uncommon

Autosomal recessive, rare

Galactose Disorders

Galactosemia with

uridyltransferase deficiency

Galactose 1-phosphate

uridyltransferase

Vomiting, hepatomegaly, jaundice, cataracts, amino

aciduria, failure to thrive

Long-term complications exist despite early

diagnosis and treatment.

Galactokinase deficiency Galactokinase Cataracts, neonatal bleeding diathesis, encephalopathy

and high levels of liver transaminases.

Benign in some cases, more severe

phenotype has been reported in others.

Uridine diphosphate galactose

4-epimerase deficiency

Uridine diphosphate

galactose 4-epimerase

Similar to transferase deficiency with additional findings of

hypotonia and nerve deafness

Benign variant exists.

Fructose Disorders

Essential fructosuria Fructokinase Asymptomatic, positive urine reducing substance Benign, autosomal recessive

Hereditary fructose intolerance Fructose 1,6-bisphosphate

aldolase B

Vomiting, lethargy, failure to thrive, hepatic failure, aversion

to sweets, severity of symptoms depending on age/quantity

of sugar ingested

Prognosis good with early diagnosis and

fructose restriction, autosomal recessive

Fructose 1,6-diphosphatase

deficiency

Fructose

1,6-diphosphatase

Episodic hypoglycemia, hyperlactic acidemia, and

ketoacidosis usually following illness, hepatomegaly

Avoid fasting, good prognosis.

Abbreviations: CK, creatine kinase; CNS, central nervous system; HCC, hepatocellular carcinoma; M, muscle; PhK, phosphorylase kinase; WPW, Wolff-Parkinson-White.

(Continued)