3271 Inherited Disorders of Amino Acid Metabolism in Adults CHAPTER 420

The parents need to be counseled about the natural history of the disease and its recurrence risk in future pregnancies. In some cases, parents need testing because they might have a disorder themselves (such

as glutaric acidemia type 1, methylcrotonyl coenzyme A carboxylase

deficiency, primary carnitine deficiency, or fatty acid oxidation defects)

since mothers with these conditions can sometimes be identified by

abnormal newborn screening results in their offspring. Some metabolic disorders can remain asymptomatic until adult age, presenting

only when fasting or severe stress requires full activity of affected metabolic pathways to provide energy.

Selected disorders that illustrate the principles, properties, and

problems presented by the disorders of amino acid metabolism are

discussed in this chapter.

THE HYPERPHENYLALANINEMIAS

The hyperphenylalaninemias (Table 420-1) result from impaired

conversion of phenylalanine to tyrosine. The most common and

clinically important is phenylketonuria (frequency 1:16,500), which

is an autosomal recessive disorder characterized by an increased concentration of phenylalanine and its by-products in body fluids and

by severe intellectual disability if untreated in infancy. It results from

reduced activity of phenylalanine hydroxylase. The accumulation of

phenylalanine inhibits the transport of other amino acids required for

protein or neurotransmitter synthesis, reduces synthesis and increases

degradation of myelin, and leads to inadequate formation of norepinephrine and serotonin. Phenylalanine is a competitive inhibitor of

tyrosinase, a key enzyme in the pathway of melanin synthesis, resulting

in hypopigmentation of hair and skin. Untreated children with classic

phenylketonuria are normal at birth but fail to attain early developmental milestones, develop microcephaly, and demonstrate progressive

impairment of cerebral function. Hyperactivity, seizures, and severe

intellectual disability are major clinical problems later in life. Electroencephalographic abnormalities; “mousy” odor of skin, hair, and

urine (due to phenylacetate accumulation); and a tendency to develop

hypopigmentation (compared to the family background) and eczema

complete the devastating clinical picture. In contrast, affected children

who are detected and treated at birth show none of these abnormalities.

TREATMENT

Phenylketonuria

To prevent intellectual disability, diagnosis and initiation of dietary

treatment of classic phenylketonuria must occur before the child

is 2 weeks of age. For this reason, newborns in North America,

Australia, and Europe are screened by determinations of blood phenylalanine levels. Abnormal values are confirmed using quantitative

analysis of plasma amino acids. Dietary phenylalanine restriction

is usually instituted if blood phenylalanine levels are >360 μmol/L.

Treatment consists of a special diet low in phenylalanine and supplemented with tyrosine since tyrosine becomes an essential amino

acid in phenylalanine hydroxylase deficiency. With therapy, plasma

phenylalanine concentrations should be maintained between 120

and 360 μmol/L. Dietary restriction should be continued and monitored indefinitely. Compliance with the strict diet is often difficult

as patients become older; increased levels of phenylalanine in

adults can cause deficits in executive function or psychiatric symptoms. Oral tetrahydrobiopterin (5–20 mg/kg per d), an essential

cofactor of phenylalanine hydroxylase, can reduce phenylalanine

levels in some patients with phenylketonuria in conjunction with

a low-protein diet. Pegvaliase is a pegylated form of phenylalanine

ammonia lyase, a bacterial enzyme that converts phenylalanine to

trans-cinnamic acid and ammonia. This injectable drug can substantially reduce phenylalanine levels, allowing a normal diet. The

bacterial origin of pegvaliase can cause immune reactions that limit

its use in some patients with phenylketonuria.

Women with phenylketonuria can become pregnant. If maternal

phenylalanine levels are not strictly controlled before and during

pregnancy, their offspring are at increased risk for congenital

defects and microcephaly (maternal phenylketonuria). After birth,

these children have severe intellectual disability and growth retardation. Pregnancy risks can be minimized by continuing lifelong

phenylalanine-restricted diets and assuring strict phenylalanine

restriction 2 months prior to conception and throughout gestation.

■ THE HOMOCYSTINURIAS

(HYPERHOMOCYSTEINEMIAS)

The homocystinurias are nine biochemically and clinically distinct

disorders (Table 420-1) characterized by increased concentration of the

sulfur-containing amino acid homocysteine in blood and urine.

Classic homocystinuria, the most common (frequency 1:450,000),

results from reduced activity of cystathionine β-synthase (Fig. 420-1),

the pyridoxal phosphate–dependent enzyme that condenses homocysteine with serine to form cystathionine. Most patients present

between 3 and 5 years of age with dislocated optic lenses and intellectual disability (in about half of cases). Some patients develop a marfanoid habitus and radiologic evidence of osteoporosis.

Life-threatening vascular complications (affecting coronary, renal,

and cerebral arteries) can occur during the first decade of life and are

the major cause of morbidity and mortality. Classic homocystinuria

can be diagnosed with analysis of plasma amino acids, showing elevated methionine and presence of free homocystine. Total plasma

homocysteine is also extremely elevated (usually >100 μM). Elevated

levels of methionine can be also detected by neonatal screening, but

milder variants can be missed by this approach. Treatment consists of a

TABLE 420-1 Inherited Disorders of Amino Acid Metabolism

AMINO ACID(S) CONDITION ENZYME DEFECT CLINICAL FINDINGS INHERITANCE

Isoleucine 2-Methylbutyryl-glycinuria 2-Methylbutyryl-CoA

dehydrogenase

Benign AR

2-Methyl-3-hydroxybutyryl-CoA

dehydrogenase deficiency

2-Methyl-3-hydroxybutyryl-CoA

dehydrogenase

Developmental regression, seizures, and rigidity

sometimes triggered by illnesses

XL

3-Oxothiolase deficiency 3-Oxothiolase Fasting-induced acidosis and ketosis, vomiting,

lethargy

AR

Isoleucine,

methionine,

threonine, valine

Propionic acidemia

(pccA, -B, -C)

Propionyl-CoA carboxylase Metabolic ketoacidosis, hyperammonemia, hypotonia,

lethargy, coma, protein intolerance, intellectual

disability, hyperglycinemia

AR

Multiple carboxylase/

biotinidase deficiency

Holocarboxylase synthase or

biotinidase

Metabolic ketoacidosis, diffuse rash, alopecia,

seizures, intellectual disability

AR

Methylmalonic acidemia

(mutase, cblA, B, racemase)

Methylmalonyl-CoA mutase/

racemase or cobalamin reductase/

adenosyltransferase

Metabolic ketoacidosis, hyperammonemia,

hypertonia, lethargy, coma, protein intolerance,

intellectual disability, hyperglycinemia

AR

Abbreviations: AD, autosomal dominant; AR, autosomal recessive; Cbl, cobalamin; DOPA, dihydroxyphenylalanine; GABA, γ-aminobutyric acid; GTP, guanosine

5′-triphosphate; XL, X-linked.

(Continued)

3272 PART 12 Endocrinology and Metabolism

5,10-Methylene

THF

Methylene tetrahydrofolate reductase (MTHFR)

N5-methyl

THF

Methyl-cobalamin

Cobalamin (B12)

cbl C, D, F, J, X

Glycine

Serine

Tetra-hydrofolate (THF)

Remethylation Methionine Synthase

Reductase (cblE)

Methionine

Synthase (cblG) Methionine

Betaine

Dimethylglycine

Betaine homocysteine

methyltransferase

Homocysteine

Serine

Glycine

Creatine

Cystathionine AMP

`-Ketobutyrate Cysteine

Cystathionine β

synthase (B6)

Cystathionase (B6)

Adenosine

Trans-sulfuration

Methyl transfer

ATP

Methionine adenosyl

transferase (MAT)

S-adenosyl methionine

Methyltransferases

N-methylglycine

(Sarcosine)

Glycine N-methyltransferase

CH3

S-adenosyl homocysteine

S-adenosyl homocysteine

hydrolase

CH3-S-(CH2)2-CH-COOH

NH2

Guanidinoacetate

Guanidinoacetate

methyltransferase

Adenosine

kinase

FIGURE 420-1 Pathways, enzymes, and coenzymes involved in the homocystinurias. Methionine transfers a methyl group during its conversion to homocysteine. Defects in

methyl transfer or in the subsequent metabolism of homocysteine by the pyridoxal phosphate (vitamin B6

)-dependent cystathionine β-synthase increase plasma methionine

levels. Homocysteine is transformed into methionine via remethylation. This occurs through methionine synthase, a reaction requiring methylcobalamin and folic acid.

Deficiencies in these enzymes or lack of cofactors is associated with decreased or normal methionine levels. In an alternative pathway, homocysteine can be remethylated

by betaine:homocysteine methyl transferase.

special diet restricted in protein and methionine. In approximately half

of patients, oral pyridoxine (25–500 mg/d) produces a fall in plasma

methionine and homocysteine concentration in body fluids. Folate

and vitamin B12 deficiency should be prevented by adequate supplementation. Betaine is also effective in reducing homocysteine levels by

favoring its remethylation to methionine.

The other forms of homocystinuria are the result of impaired

remethylation of homocysteine to methionine. This can be caused by

defective methionine synthase or reduced availability of two essential

cofactors, 5-methyltetrahydrofolate and methylcobalamin (methylvitamin B12). In contrast to cystathionine β-synthase, elevated levels of

free homocystine are associated with low levels of methionine in the

plasma amino acid profile in remethylation defects. Therapy in these

cases requires administration of methylfolate, hydroxycobalamin (an

activated form of vitamin B12), and betaine.

Hyperhomocysteinemia refers to increased total plasma concentration of homocysteine with or without an increase in free homocysteine

(disulfide form). Hyperhomocysteinemia, in the absence of significant

homocystinuria, is found in some heterozygotes for the genetic defects

noted above or in homozygotes for milder variants. Changes of homocysteine levels are also observed with increasing age; with smoking; in

postmenopausal women; in patients with renal failure, hypothyroidism, leukemias, inflammatory bowel disease, or psoriasis; and during

therapy with drugs such as methotrexate, nitrous oxide, isoniazid, and

some antiepileptic agents. Homocysteine can act as an atherogenic

and thrombophilic agent, and increased total plasma homocysteine

has been associated with an increased risk for coronary, cerebrovascular, and peripheral arterial disease as well as for deep-vein thrombosis. In addition, hyperhomocysteinemia and folate and vitamin B12

deficiencies have been associated with an increased risk of neural tube

defects in pregnant women and dementia (Alzheimer’s type) in the

general population. Vitamin supplements are effective in reducing

plasma homocysteine levels in these cases, although there are limited

effects on cardiovascular disease.

ALKAPTONURIA

Alkaptonuria is a rare (frequency 1:200,000) disorder of tyrosine

catabolism in which deficiency of homogentisate 1,2-dioxygenase

(also known as homogentisic acid oxidase) leads to excretion of large

amounts of homogentisic acid in urine and accumulation of oxidized homogentisic acid pigment in connective tissues (ochronosis).

Alkaptonuria may go unrecognized until middle life, when degenerative joint disease develops. Prior to this time, about half of patients

might be diagnosed for the presence of urine that becomes dark with

standing or addition of alkali. Foci of gray-brown scleral pigment

and generalized darkening of the concha, anthelix, and, finally, helix

of the ear usually develop after age 30. Low back pain usually starts

between 30 and 40 years of age. Ochronotic arthritis is heralded by

pain, stiffness, and some limitation of motion of the hips, knees, and

shoulders. Acute arthritis may resemble rheumatoid arthritis, but

small joints are usually spared. Pigmentation of heart valves, larynx,

tympanic membranes, and skin occurs, and occasional patients

develop pigmented renal or prostatic calculi. Pigment deposition

in the heart and blood vessels leads to aortic stenosis necessitating

valve replacement, especially after 60 years of age. The diagnosis

should be suspected in a patient whose urine darkens to blackness.

Homogentisic acid in urine is identified by urine organic acid analysis. Ochronotic arthritis is treated symptomatically with pain medications, spinal surgery, and arthroplasty (Chap. 371). Nitisinone

(2-[2-nitro-4-trifluoromethylbenzoyl]-1,3-cyclohexanedione), a

drug used in tyrosinemia type I, at low dose (10 mg/d) reduces

urinary excretion of homogentisic acid and delays progression and

improves clinical signs of alkaptonuria.

UREA CYCLE DEFECTS

Excess ammonia generated from protein nitrogen is removed by the

urea cycle, a process mediated by several enzymes and transporters

(Fig. 420-2, Table 420-1). Complete absence of any of these enzymes

usually causes severe hyperammonemia in newborns, while milder