3268 PART 12 Endocrinology and Metabolism

of fructose and sucrose from the diet. A complex carbohydrate such

as cornstarch, which provides slow and sustained levels of glucose,

is useful for the long-term prevention of hypoglycemia. With proper

treatment, prognosis is good, and patients who survive childhood

develop normally.

GLOBAL CONSIDERATIONS

The GSDs and other inherited disorders of carbohydrate metabolism,

although individually rare, are reported in most ethnic populations.

The prevalent genetic variants for each disease may vary in different

ethnic populations, but clinical symptoms are remarkably similar, and

treatment guidelines apply to all. Symptomatic treatment is available

for these disorders, and today, advances in the field have resulted in

more definitive diagnosis and treatment approaches. Availability of

NBS for Pompe disease has shown that the frequency of Pompe disease

is much higher than previously estimated. This has allowed for early

treatment initiation and improved outcomes. NBS also mitigates the

long diagnostic delays and misdiagnoses often associated with Pompe

disease. The lessons learned from Pompe disease have bearing on the

other GSDs.

Acknowledgment

The author is grateful to Dr. Ghada Hijazi, Dr. Aditi Korlimarla, and

Cindy Li for their contributions to this chapter.

■ FURTHER READING

Fernandes SA et al: Benign or not benign? Deep phenotyping of liver

glycogen storage disease IX. Mol Genet Metab 131:299, 2020.

Grünert SC et al: Improved inflammatory bowel disease, wound healing and normal oxidative burst under treatment with empagliflozin

in glycogen storage disease type Ib. Orphanet J Rare Dis 15:218, 2020.

Kishnani PS et al: Glycogen storage disease type III diagnosis and

management guidelines. Genet Med 12:446, 2010.

Kishnani PS et al: The new era of Pompe disease: Advances in the

detection, understanding of the phenotypic spectrum, pathophysiology, and management. Am J Med Genet C Semin Med Genet 160c:1,

2012.

Kishnani PS et al: Diagnosis and management of glycogen storage disease type I: A practice guideline of the American College of Medical

Genetics and Genomics. Genet Med 16:e1, 2014.

Kishnani PS, Goldstein J et al; ACMG Work Group on Diagnosis and

Management of Glycogen Storage Diseases Type VI and IX: Diagnosis and management of glycogen storage diseases type VI and IX: A

clinical practice resource of the American College of Medical Genetics

and Genomics (ACMG). Genet Med 21:772, 2019.

Kronn DF et al: Management of confirmed newborn-screened patients

with Pompe disease across the disease spectrum. Pediatrics 40(Suppl 1):

S24, 2017.

Lévesque S et al: Diagnosis of late-onset Pompe disease and other

muscle disorders by next-generation sequencing. Orphanet J Rare

Dis 11:8, 2016.

Lopez-Sainz A, Dominguez F et al; European Genetic Cardiomyopathies Initiative Investigators: Clinical features and natural history

of PRKAG2 variant cardiac glycogenosis. J Am Coll Cardiol 76:186,

2020.

Porto AG et al: Clinical spectrum of PRKAG2 syndrome. Circ

Arrhythm Electrophysiol 9:e003121, 2016.

Quinlivan R et al: Pharmacological and nutritional treatment for

McArdle disease (glycogen storage disease type V). Cochrane Database Syst Rev 2014:CD003458, 2014.

Rubio-Gozalbo ME, Derks B et al; Galactokinase deficiency: lessons

from the GalNet registry. Genet Med 23:202, 2021.

Steinmann B et al: Disorders of fructose metabolism. The Online Metabolic and Molecular Bases of Inherited Disease. New York, McGrawHill, 2013.

Welling L et al: International clinical guideline for the management of

classical galactosemia: Diagnosis, treatment, and follow-up. J Inherit

Metab Dis 40:171, 2017.

Amino acids are the building blocks of proteins and serve as neurotransmitters (glycine, glutamate, γ-aminobutyric acid) or as precursors

of hormones, coenzymes, pigments, purines, or pyrimidines. Eight

amino acids, referred to as essential (histidine, isoleucine, leucine,

lysine, methionine, phenylalanine, valine, threonine, and tryptophan),

cannot be synthesized by humans and must be obtained from dietary

sources. The others can be formed endogenously. Each amino acid

has a unique degradative pathway by which its nitrogen and carbon

components are used for the synthesis of other amino acids, carbohydrates, and lipids. Disorders of amino acid metabolism and transport

(Chap. 421) are individually rare—the incidences range from 1 in

10,000 for cystinuria or phenylketonuria to 1 in 200,000 for homocystinuria or alkaptonuria—but collectively, they affect perhaps 1 in

2000 newborns. Almost all are transmitted as autosomal recessive traits.

The features of inherited disorders of amino acid catabolism are summarized in Table 420-1. In general, these disorders are named for the

compound that accumulates to highest concentration in blood (-emias)

or urine (-urias). In the aminoacidopathies, the parent amino acid is

found in excess, whereas products in the catabolic pathway accumulate

in organic acidemias. Which compound(s) accumulates depends on the

site of the enzymatic block, the reversibility of the reactions proximal to

the lesion, and the availability of alternative pathways of metabolic “runoff.” Biochemical and genetic heterogeneity are common. Six distinct

forms of hyperphenylalaninemia and nine forms of homocystinuria

(with or without methylmalonic acidemia) are recognized. Such heterogeneity reflects the complexity of amino acid metabolism requiring

multiple enzymes (gene products) for proper functioning.

The manifestations of these conditions differ widely (Table 420-1).

Some, such as sarcosinemia, produce no clinical consequences. At the

other extreme, complete deficiency of ornithine transcarbamylase is

lethal in the untreated neonate. Central nervous system (CNS) dysfunction, in the form of developmental retardation, seizures, alterations in sensorium, or behavioral disturbances, is present in more than

half the disorders. Protein-induced vomiting, neurologic dysfunction,

and hyperammonemia occur in many disorders of the urea cycle.

Metabolic ketoacidosis, often accompanied by hyperammonemia, is

frequent in organic acidemias. Some disorders produce focal tissue or

organ involvement such as liver disease, renal failure, cutaneous abnormalities, or ocular lesions.

Defects in the synthesis of nonessential amino acids (asparagine,

glutamine, serine, proline) involve predominantly the brain with neurologic symptoms, with other organs occasionally affected. Dominant

mutations in at least one of these genes cause tremor or spastic paraplegia in adults.

The analysis of plasma amino acids (by ion-exchange chromatography or liquid chromatography/tandem mass spectrometry), urine

organic acids (by gas chromatography/mass spectrometry), and plasma

acylcarnitine profile (by tandem mass spectrometry) is commonly

used to diagnose and monitor most of these disorders. The diagnosis

is confirmed by enzyme assay on cells or tissues from the patients

or, more commonly, by DNA testing. The clinical manifestations in

many of these conditions can be prevented or mitigated if a diagnosis is achieved early and appropriate treatment (e.g., dietary protein

or amino acid restriction or vitamin supplementation) is instituted

promptly. For this reason, newborn screening programs seek to identify several of these disorders. Infants with a positive screening test

need additional metabolic testing (usually suggested by the newborn

screening program) to confirm or exclude the diagnosis. Confirmed

cases should be referred to a metabolic center for initiation of therapy.

420 Inherited Disorders

of Amino Acid Metabolism

in Adults

Nicola Longo

3269 Inherited Disorders of Amino Acid Metabolism in Adults CHAPTER 420

TABLE 420-1 Inherited Disorders of Amino Acid Metabolism

AMINO ACID(S) CONDITION ENZYME DEFECT CLINICAL FINDINGS INHERITANCE

Phenylalanine Phenylketonuria Phenylalanine hydroxylase Intellectual disability, microcephaly, hypopigmented

skin and hairs, eczema, “mousy” odor

AR

DHPR deficiency Dihydropteridine reductase Intellectual disability, hypotonia, spasticity, myoclonus AR

PTPS deficiency 6-Pyruvoyl-tetrahydropterin

synthase

Dystonia, neurologic deterioration, seizures, intellectual

disability

AR

GTP cyclohydrolase I

deficiency

GTP cyclohydrolase I Intellectual disability, seizures, dystonia, temperature

instability

AR

Carbinolamine dehydratase

deficiency

Pterin-4α-carbinolamine

dehydratase

Transient hyperphenylalaninemia (benign) AR

DNAJC12 deficiency Hydroxylase co-chaperone Dystonia, parkinsonism, intellectual disability AR

Tyrosine Tyrosinemia type I

(hepatorenal)

Fumarylacetoacetate hydrolase Liver failure, cirrhosis, rickets, failure to thrive,

peripheral neuropathy, “boiled cabbage” odor

AR

Tyrosinemia type II

(oculocutaneous)

Tyrosine transaminase Palmoplantar keratosis, painful corneal erosions with

photophobia, learning disability

AR

Tyrosinemia type III 4-Hydroxyphenylpyruvate

dioxygenase

Hypertyrosinemia with normal liver function, occasional

mental delay

AR

Hawkinsinuria 4-Hydroxyphenylpyruvate

dioxygenase

Transient failure to thrive, metabolic acidosis in infancy AD

Alkaptonuria Homogentisic acid oxidase Ochronosis, arthritis, cardiac valve involvement,

coronary artery calcification

AR

Maleylacetoacetate isomerase

deficiency

Maleylacetoacetate isomerase No clinical symptoms, elevated succinylacetone in

blood and urine.

AR

Albinism (oculocutaneous) Tyrosinase Hypopigmentation of hair, skin, and optic fundus; visual

loss; photophobia

AR

Albinism (ocular) Different enzymes or transporters Hypopigmentation of optic fundus, visual loss AR, XL

DOPA-responsive dystonia Tyrosine hydroxylase Rigidity, truncal hypotonia, tremor, intellectual disability AR

GABA 4-Hydroxybutyric aciduria Succinic semialdehyde

dehydrogenase

Seizures, intellectual disability, hypotonia AR

ABAT deficiency GABA transaminase Seizures, intellectual disability, hypotonia AR

Tryptophan Hydroxykynureninuria Kynureninase Intellectual disability, spasticity AR

Histidine Histidinemia Histidine-ammonia lyase Benign AR

Urocanic aciduria Urocanase Occasional intellectual disability AR

Formiminoglutamic aciduria Formiminotransferase Occasional intellectual disability AR

Glycine Glycine encephalopathy Glycine cleavage (4 enzymes) Infantile seizures, lethargy, apnea, profound

intellectual disability

AR

Sarcosinemia Sarcosine dehydrogenase Benign AR

Hyperoxaluria type I Alanine:glyoxylate aminotransferase Calcium oxalate nephrolithiasis, renal failure AR

Hyperoxaluria type II D-Glyceric acid dehydrogenase/

glyoxylate reductase

Calcium oxalate nephrolithiasis, renal failure AR

Serine 3-PGDH deficiency Phosphoglycerate dehydrogenase Seizures, microcephaly, intellectual disability AR

PSAT1 deficiency Phosphoserine aminotransferase Seizures, microcephaly, intellectual disability AR

PSP deficiency Phosphoserine phosphatase Seizures, microcephaly, intellectual disability AR

Proline Hyperprolinemia type I Proline oxidase Benign AR

Hyperprolinemia type II Δ1

-Pyrroline-5-carboxylate

dehydrogenase

Febrile seizures, intellectual disability AR

Hyperhydroxyprolinemia Hydroxyproline oxidase Benign AR

Prolidase deficiency Prolidase Mild intellectual disability, chronic dermatitis AR

PYCR1 deficiency Pyrroline-5-carboxylate reductase 1 Wrinkly skin, joint laxity, typical facial features,

intellectual disability, osteopenia, intrauterine growth

retardation, hypotonia

AR

PYCR2 deficiency Pyrroline-5-carboxylate reductase 2 Microcephaly, hypomyelination, and reduced cerebral

white matter volume, failure to thrive, intellectual

disability, movement disorders, seizures

AR

Proline (ornithine,

arginine, citrulline)

Δ1

-Pyrroline-5-carboxylate

synthase deficiency

Δ1

-Pyrroline-5-carboxylate synthase Hypotonia, seizures, neurodegeneration, peripheral

neuropathy, joint laxity, skin hyperelasticity,

subcapsular cataracts, hyperammonemia, adult spastic

paraparesis (AD)

AR, AD

Methionine Hypermethioninemia Methionine adenosyltransferase Usually benign AR

S-Adenosylhomocysteine

hydrolase deficiency

S-Adenosylhomocysteine hydrolase Hypotonia, intellectual disability, absent tendon

reflexes, delayed myelination

AR

Glycine N-methyltransferase

deficiency

Glycine N-methyltransferase Elevated liver transaminases AR

Adenosine kinase deficiency Adenosine kinase Intellectual disability, seizures, liver dysfunction AR

(Continued)

3270 PART 12 Endocrinology and Metabolism

TABLE 420-1 Inherited Disorders of Amino Acid Metabolism

AMINO ACID(S) CONDITION ENZYME DEFECT CLINICAL FINDINGS INHERITANCE

Homocysteine Homocystinuria Cystathionine β-synthase Lens dislocation, thrombotic vascular disease,

intellectual disability, osteoporosis

AR

Homocystinuria 5,10-Methylenetetrahydrofolate

reductase

Intellectual disability, gait and psychiatric abnormalities,

recurrent strokes

AR

Homocystinuria Methionine synthase (cblE, G) Intellectual disability, hypotonia, seizures, megaloblastic

anemia

AR

Homocystinuria and

methylmalonic acidemia

Vitamin B12 lysosomal efflux and

metabolism (cblC, -D, -F, -J, -X)

Intellectual disability, lethargy, failure to thrive,

hypotonia, seizures, megaloblastic anemia

AR, XL

Cystathionine Cystathioninuria β-Cystathioninase Benign AR

Cysteine Sulfocystinuria Sulfite oxidase or molybdenum

cofactor deficiency

Seizures, intellectual disability, dislocated lenses AR

Lysine Hyperlysinemia,

saccharopinuria

α-Aminoadipic semialdehyde

synthase

Benign AR

Pyridoxine-dependent seizures L-Δ1

-Piperideine-6-carboxilate

dehydrogenase

Seizures, intellectual disability AR

Lysine, tryptophan α-Ketoadipic acidemia α-Ketoadipic acid dehydrogenase

DHTKD1

Benign AR

Lysine, tryptophan Glutaric acidemia type I Glutaryl-CoA dehydrogenase Progressive severe dystonia and athetosis,

motor delays

AR

Lysine, tryptophan Glutaric acidemia type II Electron transfer flavoproteins (ETF)

or ETF:ubiquinone oxidoreductase

Hypoglycemia, metabolic acidosis, “sweaty feet” odor,

hypotonia, cardiomyopathy

AR

Ornithine Gyrate atrophy of the choroid

and retina

Ornithine-Δ-aminotransferase Myopia, night blindness, loss of peripheral vision,

cataracts, chorioretinal degeneration

AR

Urea cycle Carbamoylphosphate

synthase-1 deficiency

Carbamoylphosphate synthase-1 Lethargy progressing to coma, protein aversion,

intellectual disability, hyperammonemia

AR

N-Acetylglutamate synthase

deficiency

N-Acetylglutamate synthase Lethargy progressing to coma, protein aversion,

intellectual disability, hyperammonemia

AR

Ornithine transcarbamylase

deficiency

Ornithine transcarbamylase Lethargy progressing to coma, protein aversion,

intellectual disability, hyperammonemia

XL

Citrullinemia type I Argininosuccinate synthase Lethargy progressing to coma, protein aversion,

intellectual disability, hyperammonemia, liver failure

AR

Argininosuccinic acidemia Argininosuccinate lyase Lethargy progressing to coma, protein aversion,

intellectual disability, hyperammonemia, trichorrhexis

nodosa

AR

Arginase deficiency Arginase Spastic tetraparesis, microcephaly, intellectual

disability, mild hyperammonemia

AR

Hyperornithinemia,

hyperammonemia,

homocitrullinuria

Mitochondrial ornithine carrier

ORNT1

Vomiting, lethargy, failure to thrive, intellectual

disability, episodic confusion, hyperammonemia,

protein intolerance

AR

Citrullinemia type 2 Mitochondrial aspartate/glutamate

carrier CTLN2

Neonatal intrahepatic cholestasis, adult presentation

with sudden behavioral changes and stupor, coma,

hyperammonemia

AR

Glutamine Glutamine synthetase

deficiency

Glutamine synthase Brain malformations, pachygyria, seizures, hypotonia,

intellectual disability, dysmorphic features, low

glutamine

AR

Glutaminase deficiency Glutaminase Epileptic encephalopathy, intellectual disability, ataxia,

elevated glutamine

AR

Asparagine Asparagine synthetase

deficiency

Asparagine synthase Epileptic encephalopathy, seizures, microcephaly,

simplified gyration pattern, hypotonia, tetraplegia,

intellectual disability

Valine Hypervalinemia Branched chain aminotransferase-2 Headache, memory impairment, failure to thrive,

hypotonia, developmental delays

AR

Isobutyryl-CoA dehydrogenase

deficiency

Isobutyryl-CoA dehydrogenase Benign AR

Isoleucine, leucine,

valine

Maple syrup urine disease Branched chain ketoacid

dehydrogenase (E1α, E1β, E2, E3

deficiency)

Lethargy, vomiting, encephalopathy, seizures,

intellectual disability, “maple syrup” odor, protein

intolerance

AR

Leucine Isovaleric acidemia Isovaleryl-CoA dehydrogenase Acidosis, ketosis, vomiting, coma, hyperammonemia,

“sweaty feet” odor, protein intolerance

AR

3-Methylcrotonyl glycinuria 3-Methylcrotonyl-CoA carboxylase Stress-induced metabolic acidosis, hypotonia,

hypoglycemia, “cat’s urine” odor

AR

3-Methylglutaconic aciduria

type I

3-Methylglutaconyl-CoA hydratase

deficiency

Stress-induced acidosis, leukodystrophy, hypotonia,

hepatomegaly

AR

3-Hydroxy-3-methylglutaric

aciduria

3-Hydroxy-3-methylglutaryl-CoA

lyase

Stress-induced hypoketotic hypoglycemia and acidosis,

encephalopathy, hyperammonemia

AR

(Continued)

(Continued)