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VII. METABOLIC GENETIC DISORDERS INVOLVING 

DEGRADATION PATHWAYS

Most complex biomolecules are recycled by degradation into simpler molecules, which can
then be eliminated or used to synthesize new molecules. Malfunctions in degradation path-
ways will result in the accumulation (or “storage”) of complex biomolecules within the cell.
For example, lysosomal enzymes catalyze the stepwise degradation of glycosaminoglycans
(GAGs; formerly called mucopolysaccharides), sphingolipids, glycoproteins, and glycolipids.

Lysosomal storage disorders (or mucopolysaccharidoses)

are caused by lysosomal enzyme

deficiencies required for the stepwise degradation of GAGs that result in the accumulation of
partially degraded GAGs within the cell, leading to organ dysfunction. 

A. Mucopolysaccharidosis Type I (MPS I).

1.

MPS I is an autosomal recessive genetic disorder caused by 

57 different mutations in the

IDUA  gene

on 

chromosome 4p16.3

for 

-L-iduronidase

that catalyzes the reaction that

removes 

-L-iduronate residues from heparan sulfate and dermatan sulphate during

lysosomal degradation. 

2.

MPS I is the prototypical mucopolysaccharidoses disorder. MPS I presents as a contin-
uum from severe to mild clinical symptoms, and MPS I affected individuals are best
described as having either 

severe symptoms (MPS IH; Hurler syndrome); intermediate symp-

toms (MPS IH/S; Hurler-Scheie syndrome);

or 

mild symptoms (MPS IS; Scheie syndrome).

3.

MPS IH (Hurler syndrome) is most commonly caused by two nonsense mutations which
result in a 

normal tryptophan 

S

S

nonsense

substitution at position 402 (W402X) or in a 

nor-

mal glutamine 

S

S

nonsense

substitution at position 70 (Q70X). 

4.

The W402X mutation accounts for 55% of cases in the Australasian population. The Q70X
mutation accounts for 65% of cases in the Scandinavian population. 

5.

These mutations result in elevated heparan sulphate and dermatan sulphate excretion in
the urine, reduced/absent 

-L-iduronidase activity, and 

heparan sulfate 

and 

dermatan sul-

fate

accumulation.

6. Prevalence.

The prevalence of MPS IH is 1/100,000 and of MPS IS is 1/500,000. 

7. Clinical features of MPS IH (Hurler syndrome) include:

infants initially appear normal up to 

≈

9

months of age but then develop symptoms; coarsening of facial features, thickening of alae
nasi, lips, ear lobules, and tongue; corneal clouding; severe visual impairment; progressive
thickening heart valves leading to mitral and aortic regurgitation; dorsolumbar kyphosis;
skeletal dysplasia involving all the bones; linear growth ceases by 3 years of age; hearing loss;
chronic recurrent rhinitis; severe mental retardation; and zebra bodies within neurons. 

B. Gaucher Disease (GD).

1.

GD is an autosomal recessive genetic disorder caused by mutations in the 

GBA gene

on

chromosome 1q21

for 

-glucosylceramidase,

which hydrolyzes glucocerebroside into glu-

cose and ceramide.

2. GD is the most common lysosomal storage disorder

. GD presents as a continuum of clinical

symptoms and is divided into three major clinical types 

(Types 1, 2, and 3)

which is useful

in determining prognosis and management of the individual. 

3.

GD is most commonly caused by either a missense mutation which results in a 

normal

asparagine 

S

S

serine

substitution at position 370 (N370S), a missense mutation which

results in a 

normal leucine 

S

S

proline

substitution at position 444 (L444P), a 84GG muta-

tion, or a IVS2+1 mutation. 

4.

The N370S, L444P, 84GG, and IVS2

1 mutations account for 95% of cases in the

Ashkenazi Jewish population. These mutations result in absent/near absent ß-glucosylce-
ramidase activity and 

glucosylceramide (and other glycolipids)

accumulation.

5.

If one parent has GD (gg), the risk that a partner of Ashkenazi Jewish descent is a het-
erozygote is 

5% (1 out of 18 individuals) due the high carrier rate in the general

Ashkenazi Jewish population.

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6. Prevalence.

The prevalence of Type I GD is 1/855 in the Ashkenazi Jewish population. 

7. Clinical features of Type I GD include:

bone disease (e.g., focal lytic lesions, sclerotic

lesions, osteonecrosis) is the most debilitating pathology of Type I GD; hepatomegaly;
splenomegaly; cytopenia and anemia due to hypersplenism, splenic sequestration, and
decreased erythropoiesis; and pulmonary disease (e.g., interstitial lung disease, alveolar/
lobar consolidation; pulmonary hypertension); no primary CNS involvement. 

C. Hexosaminidase A Deficiency (HAD).

1. Acute infantile HAD (Tay-Sachs disease; TSD)

is the prototypical HAD. HAD presents as a

group of neurodegenerative disorders caused by lysosomal accumulation of 

GM2 ganglio-

side

. 

2.

TSD is an autosomal recessive genetic disorder caused by mutations in the 

HEXA gene

on

chromosome 15q23-q24

for 

hexosaminidase 

-subunit

,

which catalyzes the reaction that

cleaves the terminal ß-linked N-acetylgalactosamine from GM2 ganglioside. 

3.

TSD is most commonly caused by either a 

4-bp insertion in exon 11 mutation

(

TATC1278)

which produces a frameshift and a premature STOP codon or a 

RNA splicing mutation in

intron 12

(

1IVS12) which produces unstable mRNAs, which are probably rapidly

degraded.

4.

The 

TATC1278 and the 1IVS12 mutations account for 95% of cases in the Ashkenazi

Jewish population. These mutations result in absent/near absent hexosaminidase A activ-
ity and 

GM2 ganglioside

accumulation.

5. Prevalence.

The prevalence of TSD is 1/324,000 births in the Ashkenazi Jewish population

since the advent of population-based carrier screening. The prevalence of TSD was
1/3,600 births in the Ashkenazi Jewish population before the advent of population-based
carrier screening.

6. Clinical features of TSD include:

infants initially appear normal up to 3 to 6 months of age

but then develop symptoms; progressive weakness and loss of motor skills; decreased
attentiveness; increased startled response; a 

cherry red spot in the fovea centralis

of the

retina; generalized muscular hypotonia; later, progressive neurodegeneration, seizures,
blindness, and spasticity occur followed by death at 

2 to 4 years of age. 

D. Other Genetic Disorders Involving Degradation Pathways.

These include: mucopolysacchari-

dosis type II (MPS II; Hunter syndrome); mucopolysaccharidosis type IIIA (MPS IIIA;
Sanfilippo A syndrome); mucopolysaccharidosis type IVA (MPS IVA; Morquio A syndrome);
Niemann-Pick (NP) type 1A disorder; Fabry disorder; Krabbe disorder; and metachromatic
leukodystrophy (MLD). 

VIII. SUMMARY TABLES OF METABOLIC GENETIC DISORDERS

(Tables 12-1, 12-2, 12-3, 12-4, 12-5, and 12-6)

IX. SELECTED PHOTOGRAPHS OF METABOLIC GENETIC

DISORDERS 

(Figure 12-1)

Chapter 12

Genetics of Metabolism

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12-1

Metabolic Genetic Disorders Involving Carbohydrate Pathways

Genetic Disorder

Gene/Gene Product Chromosome 

Clinical Features

Galactosemia

GALT gene/galactose-1-

Feeding problems in the newborn, failure to thrive, 

phosphate uridylyltransferase 

hypoglycemia, hepatocellular damage, bleeding 

9p13

diathesis, jaundice, and hyperammonemia; sepsis 
with E. coli, shock, and death may occur if the 
galactosemia is not treated

Asymptomatic fructosuria 

KHK gene/ketohexokinase or 

Presence of fructose in the urine

fructokinase
2p23.3-23.2

Hereditary fructose 

ALDOB gene/fructose 1-

Failure to thrive, fructosuria, hepatomegaly, jaundice, 

intolerance

phosphate aldolase B

aminoaciduria, metabolic acidosis, lactic acidosis, 

9q21.3-q22.2

low urine ketones, recurrent hypoglycemia and 
vomiting at the age of weaning when fructose or 
sucrose (a disaccharide that is hydrolyzed to glucose 
and fructose) is added to the diet, and infant and 
adults are asymptomatic until they ingest fructose 
or sucrose

Lactose intolerance

LCT gene/lactase-phlorizin 

Diarrhea, crampy abdominal pain localized to the 

hydrolase 

periumbilical area or lower quadrant, flatulence, 

2q21

nausea, vomiting, audible Borborygmi, stools that 
are bulky, frothy, and watery, and bloating after milk 
or lactose consumption

GSD type Ia; von Gierke

G6PC gene/glucose-6-phosphatase

Accumulation of glycogen and fat in the liver and 

17q21

kidney resulting in hepatomegaly and renomegaly, 

GSD type Ib; von Gierke

SLC37A4 gene/glucose-6-

severe hypoglycemia, lactic acidosis, hyperuricemia, 

phosphate translocase

hyperlipidemia, hypoglycemic seizures, doll-like 

11q23

faces with fat cheeks, relatively thin extremities, 
short stature, protuberant abdomen, and neutropenia 
with recurrent bacterial infections.

GSD type V; McArdle

PYGM gene/muscle glycogen 

Exercise-induced muscle cramps and pain, “second 

phosphorylase

wind” phenomenon with relief of myalgia and fatigue 

11q13

after a few minutes of rest, episodes of myoglobinuria, 
increased resting basal serum creatine kinase (CK) 
activity, onset typically occurs around 20–30 years of 
age; clumsiness, lethargy, slow movement, and 
laziness in preadolescents. 

GSD type II; Pompe

GAA gene/lysosomal acid 

Muscle and heart are affected

a-glucosidase
17q25.2-q25.3

GSD type IIIa; Cori

AGL gene/amylo-1,6glucosidase, 

Muscle and liver are affected

4-a-glucanotransferase 
(or glycogen branching enzyme)
1p21

GSD type IV; Andersen

GBE1 gene/glucan(1,4-a-) 

Muscle and liver are affected

branching enzyme 1 (or glycogen 
branching enzyme)
3

GSD type VI; Hers

PYGL gene/liver glycogen 

Liver is affected 

phosphorylase
14q11.2-q24.3

GSD type VII; Tarui

PFKM gene/muscle 

Muscle is affected

phosphofructokinase
12q13.11

GSD, glycogen storage disease.

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Genetics of Metabolism

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12-2

Metabolic Genetic Disorders Involving Amino Acid Pathways

Genetic Disorder

Gene/Gene Product Chromosome

Clinical Features

Phenylalanine hydrolase 

PAH gene/phenylalanine hydrolase

No physical signs are apparent in neonates with PAH 

deficiency (classic 

12q23.2

deficiency; diagnosis is based on detection of 

phenylketonuria [PKU])

elevated plasma PAH concentration (

1,000 umol/L 

for classic PKU) and normal BH

4

cofactor metabolism;

a dietary phenylalanine tolerance of 

500 mg/day;

untreated children with classic PKU show impaired
brain development, microcephaly, epilepsy, severe
mental retardation, behavioral problems, depression,
anxiety, musty body odor, and skin conditions like
eczema.

Hereditary tyrosinemia 

FAH gene/fumarylacetoacetate 

Diagnosis is based on detection of elevated plasma 

type I

hydrolase

succinylacetone concentration, elevated plasma 

15q23-q25

tyrosine, methionine, and phenylalanine concentra-
tions, elevated urinary tyrosine metabolite (e.g., 
hydroxyphenylpyruvate) concentration, elevated 
urinary 

-aminolevulinic acid; cabbagelike odor; 

untreated children with HTI show sever liver 
dysfunction, renal tubular dysfunction, growth  
failure, and rickets.

Maple syrup urine 

BCKDHA gene/E1a subunit of 

Untreated children with MSUD show maple syrup odor 

disease

branched-chain ketoacid 

in cerumen 12–24 hours after birth, elevated plasma 

dehydrogenase complex (BCKD)

branched-chain amino acid concentration, ketonuria,

19q13.1-q13.2

irritability, poor feeding by 2–3 days of age, deepening 

BCKDHB gene/E1ß subunit of BCKD

encephalopathy including lethargy, intermittent 

6q14

apnea, opisthotonus, and stereotyped movements like 

DBT gene/E2 subunit of BCKD

“fencing” and “bicycling” by 4–5 days of age; acute 

1p31

leucine intoxication (leucinosis) associated with 
neurological deterioration due to the ability of leucine 

to interfere with the transport of other large neutral 
amino acids across the blood–brain barrier thereby 
reducing the amino acid supply to the brain. 

t a b l e

12-3

Metabolic Genetic Disorders Involving Lipid Pathways

Genetic Disorder

Gene/Gene Product Chromosome

Clinical Features

Medium-chain acyl-

ACADM gene/medium-chain acyl-

Hyperketotic hypoglycemia, vomiting, and lethargy 

coenzyme A 

coenzyme A dehydrogenase

triggered by either a common illness (e.g., viral 

dehydrogenase 

1p31

gastrointestinal or upper respiratory tract infections) 

deficiency

or prolonged fasting (e.g., weaning the infant from
nighttime feedings) which may quickly progress to
coma and death; hepatomegaly and acute liver dis-
ease; children are normal at birth and present 
between 3 and 24 months of age; later presentation
into adulthood is possible.

Smith-Lemli-Opitz 

DHCR7 gene/7-

Prenatal and postnatal growth retardation, microcephaly,

syndrome

dehydrocholesterol reductase

moderate to severe mental retardation, cleft palate, 

11q12-q13

cardiac defects, underdeveloped external genitalia 
and hypospadias in males, postaxial polydactyly, 
Y-shaped 2-3 toe syndactyly, downslanting palpebral 
fissures, epicanthal folds, anteverted nares, and 
micrognathia.

Familial 

LDLR gene/low-density lipoprotein 

Premature heart disease as a result of atheromas 

hypercholesterolemia

receptor

(deposits of LDL-derived cholesterol in the coronary 

19p13.1-13.3

arteries), xanthomas (cholesterol deposits in the skin 

APOB gene/apolipoprotein B-100

and tendons), arcus lipoides (deposits of cholesterol 

2p23-p24

around the cornea of the eye), homozygote and 

PCSK9gene/proprotein convertase 

heterozygote phenotypes are known, homozygotes 

subtilisin/kexin type 9

develop severe symptoms early in life and rarely live 

1p32-34.1

past 30 years of age, heterozygotes have plasma 

PCSK9 gene Tyr142Stop, Cys679Stop, 

cholesterol level twice that of normal.

Arg46Leu mutations

Hypocholesterolemia

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12-4

Metabolic Genetic Disorders Involving the Urea Cycle Pathway

Genetic Disorder

Gene/Gene Product Chromosome

Clinical Features

Ornithine 

OTC gene/ornithine

Infants initially appear normal but then rapidly develop

transcarbamylase 

transcarbamylase

hyperammonemia, cerebral edema, lethargy, anorexia,

deficiency

Xp21.1

hyperventilation or hypoventilation, hypothermia, 

Carbamoylphosphate 

CPS1 gene/carbamoylphosphate

seizures, neurologic posturing, and coma; in infants 

synthetase I deficiency

synthetase 1

with partial enzyme deficiencies, the symptoms may be 

Argininosuccinic acid 

2q35

delayed for months or years, the symptoms are more 

synthetase deficiency 

ASS gene/argininosuccinic

subtle, the hyperammonemia is less severe, and 

(or citrullinemia type I)

acid synthetase

ammonia accumulation can be triggered by illness or 

9q34

stress throughout life.

Argininosuccinic acid 

ASL gene/argininosuccinic 

OTC deficiency and CPSI deficiency are the most severe 

lyase deficiency 

acid lyase

types of urea cycle disorders.

(or argininosuccinic 

7cen-q11.2

aciduria)

Arginase deficiency (or

ARG1 gene/arginase 

hyperargininemia)

6q23

N-acetyl glutamine 

NAGS gene/N-acetyl 

synthetase deficiency

glutamate synthetase
17q21.3

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12-5

Metabolic Genetic Disorders Involving Transport Pathways

Genetic Disorder

Gene/Gene Product Chromosome

Clinical Features

Menkes disease

ATP7A gene/copper-

Infants initially appear normal up to 2–3 months of age 

transporting ATPase 1

but then develop hypotonia, seizures, failure to thrive,

Xq12-q1

loss of developmental milestones, changes in hair 
(short, coarse, twisted, lightly pigmented, “steel wool”
appearance), jowly facial appearance with sagging 
cheeks, temperature instability, hypoglycemia, urinary 
bladder diverticula, and gastric polyps. Without early 
treatment with parenteral copper, MND progresses to 
severe neurodegeneration and death by 7 months 

→

3 years of age.

Wilson disease

ATP7B gene/copper 

Symptoms occur in individuals from 3–50 years of age,

transporting ATPase 2

recurrent jaundice, hepatitislike illness, fulminant 

13q14.3-q21.1

hepatic failure, tremors, poor coordination, loss of 
fine motor control, chorea, masklike facies, rigidity, 
gait disturbance, depression, neurotic behaviors, 
Kayser-Fleischer rings (deposition of copper in 
Descemet membrane of the cornea), blue lunulae of
the fingernails, and high degree of copper storage in
the body. 

HFE-associated 

HFE gene/hereditary

Excessive storage of iron in the liver, heart, skin, 

hereditary 

hemochromatosis protein

pancreas, joints, and testes; abdominal pain,  

hemochromatosis

6p21.3

weakness, lethargy, weight loss, and hepatic fibrosis;
without therapy, symptoms appear in males at 
40–60 years of age and in females after menopause.

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