Inherited Defects of MembraneTransport¶

Chapter 432 | Part 12: Endocrinology and Metabolism · Part 12 – Endocrinology & Metabolism · Chapter 432

Key Clinical Points¶

Cystinuria is the most common inherited defect of membrane transport, characterized by hexagonal cystine crystals in urine.
Lysinuric protein intolerance (LPI) involves a basolateral transporter defect (SLC7A7) causing secondary urea cycle impairment and hyperammonemia.
Citrullinemia type 2 (citrin deficiency) is rare in Caucasians but affects ~1:20,000 people with ancestry from East Asia; it presents with hyperammonemia between ages 20–50.
Hartnup disease results from a defect in the B0AT1 transporter (SLC6A19), leading to pellagra-like symptoms due to tryptophan malabsorption and neutral aminoaciduria.
Cystinosis (CTNS gene) causes lysosomal cystine accumulation; the nephropathic form leads to renal failure by age 10 without treatment.
Management of cystinuria involves high fluid intake (>4 L/d), urine alkalinization (pH >7.5), and cystine solubilizing drugs (penicillamine, tiopronin).
Cysteamine bitartrate is the specific therapy for cystinosis to deplete lysosomal cystine.
Hartnup disease is distinguished from dietary niacin deficiency by the presence of neutral aminoaciduria.

1. DEFINITION & OVERVIEW¶

• Overview: Membrane transporters mediate the passage of amino acids, oligopeptides, urea, sugars, cations, anions, vitamins, water, and other molecules across cellular membranes. • Molecular Basis: ◦ Transporters are encoded by members of the solute-carrier gene (SLC) superfamily. ◦ Located on plasma membranes or intracellular organelles. ◦ Clinical presentation depends on cellular/tissue distribution and the presence or absence of redundant transporters. • Definition (Harrison's 22e): Inherited defects impairing the transport of selected amino acids that can present in adults are discussed here as examples of the abnormalities encountered; others are considered elsewhere in this text.

2. EPIDEMIOLOGY¶

• Cystinuria: ◦ Worldwide frequency: 1 in 7,000. ◦ Homozygotes excrete 2400–7200 μmol (600–1800 mg) of cystine daily. ◦ Accounts for 1–2% of all urinary tract calculi; 4–5% of stones in children. • Lysinuric protein intolerance: ◦ Most common in Finland (1 in 60,000), southern Italy, and Japan; rare elsewhere. • Citrullinemia type 2: ◦ Rare in Caucasians; affects ~1:20,000 people with ancestry from Japan, China, and Southeast Asia. • Hartnup disease: Frequency 1 in 24,000. • Cystinosis: Frequency 1 in 100,000–200,000.

3. ETIOLOGY & PATHOPHYSIOLOGY¶

• Cystinuria: ◦ Cause: Defective transporters in the apical brush border of proximal renal tubule and small intestinal cells. ◦ Mechanism: Impaired reabsorption/excessive excretion of lysine, arginine, ornithine, and cystine (all dibasic in acidic urine). ◦ Risk: Cystine is poorly soluble → predisposes to renal, ureteral, and bladder stones. ◦ Variants: ◦ Type A: SLC3A1 mutation (chromosome 2p16.3) → membrane glycoprotein defect. ◦ Type B: SLC7A9 mutation (chromosome 19q13) → b0,+ amino acid transporter defect. ◦ Note: SLC3A1 ensures correct processing of the b0,+ transporter; mutations in either lead to similar disease. • Lysinuric protein intolerance: ◦ Cause: Defect in renal tubular reabsorption and intestinal transport of lysine, arginine, and ornithine (cystine spared). ◦ Mechanism: Basolateral membrane defect → secondary impairment of the urea cycle. ◦ Genetics: SLC7A7 (chromosome 14q11.2) encodes y+LAT transporter; associates with 4F2 heavy chain to form y+L. ◦ Immune Dysfunction: Likely due to nitric oxide overproduction from arginine trapping in white blood cells. • Citrullinemia type 2: ◦ Cause: Recessive deficiency of mitochondrial aspartate-glutamate carrier AGC2 (citrin). ◦ Mechanism: Reduced cytoplasmic aspartate → impaired argininosuccinate formation → impaired urea cycle; also impairs malate-aspartate NADH shuttle. ◦ Genetics: SLC25A13 (chromosome 7q21.3). • Hartnup disease: ◦ Cause: Autosomal recessive defect in neutral amino acid transporter B0AT1. ◦ Genetics: SLC6A19 (chromosome 5p15) → requires collectrin or ACE2 for surface expression. ◦ Mechanism: Defective intestinal/renal transport of alanine, serine, threonine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, glutamine, asparagine, and histidine (excreted at 5–10x normal). • Cystinosis: ◦ Cause: Autosomal recessive mutation in CTNS gene. ◦ Mechanism: Defective lysosomal cystine/proton transporter (cystinosin) → cystine accumulates in lysosomes → forms crystals due to poor solubility.

4. CLINICAL FEATURES¶

• Cystinuria: ◦ Symptoms: Typical of urolithiasis (hematuria, flank pain, renal colic, obstructive uropathy, infection). ◦ Timing: Usually 2nd or 3rd decade; can occur in first year of life. • Lysinuric protein intolerance: ◦ Childhood: Hepatosplenomegaly, protein intolerance, episodic ammonia intoxication. ◦ Adult: Severe osteoporosis, pancreatitis, impaired renal function, pulmonary alveolar proteinosis, autoimmune disorders, immune deficiency. • Citrullinemia type 2: ◦ Children: Neonatal intrahepatic cholestasis, failure to thrive, dyslipidemia. ◦ Adults (20–50 years): Sudden onset of recurring hyperammonemia with neuropsychiatric symptoms (altered mental status, irritability, seizures, coma-like encephalopathy). ◦ Other: Hypertriglyceridemia, pancreatitis, hepatoma, fatty liver. • Hartnup disease: ◦ Symptoms: Pellagra-like skin lesions; variable neurologic manifestations (spastic paraplegia, cerebellar ataxia, emotional lability, frank delirium). ◦ Trigger: Exacerbation of erythematous, eczematoid skin rash. • Cystinosis: ◦ Nephropathic form: Renal Fanconi syndrome → rickets (1st year) → renal failure by age 10 without treatment. ◦ Juvenile form: Proteinuria slowly leading to kidney failure. ◦ Nonnephropathic: Photophobia from cystine crystals in cornea. ◦ Late-onset: Hepatomegaly/splenomegaly (1/3 of cases), vacuolar myopathy (weakness, swallowing difficulty, GI dysmotility, pulmonary insufficiency). ◦ Associated conditions: Hypothyroidism and blindness.

5. DIFFERENTIAL DIAGNOSIS¶

• Cystinuria vs. Other Stones: ◦ Cystinuria accounts for 1–2% of all urinary tract calculi; 4–5% in children. • Hartnup Disease vs. Dietary Niacin Deficiency: ◦ Hartnup features pellagra-like symptoms but includes neutral aminoaciduria (absent in dietary deficiency). • Cystinosis vs. Other Renal Failure: ◦ Cystinosis identified by cystine crystals in cornea (slit lamp) and measurement of cystine content in white blood cells or DNA testing (CTNS gene).

6. INVESTIGATIONS & DIAGNOSIS¶

Cystinuria Diagnosis:
Identify hexagonal cystine crystals in urine.
Quantify urinary amino acids (cystine, lysine, arginine, ornithine).
Lysinuric Protein Intolerance Diagnosis:
Genetic testing for SLC7A7.
Citrullinemia Type 2 Diagnosis:
Genetic testing for SLC25A13.
Hartnup Disease Diagnosis:
Identify neutral aminoaciduria.
Genetic testing for SLC6A19.
Cystinosis Diagnosis:
Slit lamp examination (cystine crystals in cornea).
DNA testing (CTNS gene) or measurement of cystine content in white blood cells.

7. MANAGEMENT & TREATMENT¶

Cystinuria Management:
High fluid intake (>4 L/d).
Urine alkalinization (pH >7.5).
Cystine solubilizing drugs (penicillamine, tiopronin).
Lysinuric Protein Intolerance Management:
[No specific management details provided in source].
Citrullinemia Type 2 Management:
[No specific management details provided in source].
Hartnup Disease Management:
[No specific management details provided in source].
Cystinosis Management:
Cysteamine bitartrate (specific therapy to deplete lysosomal cystine).

8. PROGNOSIS & COMPLICATIONS¶

• Cystinuria: Risk of progressive renal insufficiency from recurrent urolithiasis. • Lysinuric Protein Intolerance: Adult complications include osteoporosis, pancreatitis, pulmonary alveolar proteinosis, and immune deficiency. • Citrullinemia Type 2: Without treatment, most symptomatic patients die with cerebral edema within a few years. • Cystinosis: ◦ Pre-treatment: Life span <10 years. ◦ Current treatment: Survival into late forties.

9. KEY PEARLS & CLINICAL TRAPS¶

• Cystinuria: Hexagonal crystals in urine → indicates SLC3A1 or SLC7A9 defect. • Hartnup Disease: Pellagra-like symptoms + neutral aminoaciduria = Hartnup (distinguishes from Niacin deficiency). • Citrullinemia Type 2: High citrulline/arginine with low glutamine → indicates SLC25A13 (citrin) defect. • Cystinosis: Slit lamp exam showing cystine crystals in cornea is a hallmark for CTNS mutation.

Reference Tables¶

TABLE 432-1 Genetic Disorders of Amino Acid Transport DISORDER Cystinuria Lysinuric protein intolerance Hartnup disease…¶

Harrison's 22e, p.3374

DISORDER	SUBSTRATES	TISSUES MANIFESTING TRANSPORT DEFECT	MOLECULAR DEFECT	MAJOR CLINICAL MANIFESTATIONS	INHERITANCE
Cystinuria	Cystine, lysine, arginine, ornithine	Proximal renal tubule, jejunal mucosa	Shared dibasic-cystine transporter SLC3A1, SLC7A9	Cystine nephrolithiasis	AR
	Lysine, arginine, ornithine	Proximal renal tubule, jejunal mucosa	Dibasic transporter SLC7A7	Protein intolerance, hyperammonemia, intellectual disability
Hartnup disease	Neutral amino acids	Proximal renal tubule, jejunal mucosa	Neutral amino acid transporter SLC6A19	Constant neutral aminoaciduria, intermittent symptoms of pellagra	AR
	Histidine	Proximal renal tubule, jejunal mucosa	Histidine transporter	Intellectual disability
Iminoglycinuria	Glycine, proline, hydroxyproline	Proximal renal tubule, jejunal mucosa	Shared glycine–amino acid transporter SLC6A20, SLC6A18, SLC36A2	None	AR
	Glutamic acid, aspartic acid	Proximal renal tubule, jejunal mucosa	Shared dicarboxylic amino acid transporter SLC1A1	None
Hyperargininemia	Arginine, lysine, ornithine	Ubiquitous	CAT2 cationic amino acid transporter SLC7A2	Hyperargininemia, Hyperammonemia (?)	AR
	Leucine, isoleucine, valine	Plasma membrane of blood-brain barrier	Branched-chain amino acid transporter SLC7A5	Microcephaly, intellectual disability, seizures, autism
Citrullinemia type 2	Aspartate, glutamate, malate	Inner mitochondrial membrane	Mitochondrial aspartate/ glutamate carrier 2 SLC25A13	Sudden behavioral changes with stupor, coma, hyperammonemia	AR
	Ornithine, citrulline	Inner mitochondrial membrane	Mitochondrial ornithine carrier SLC25A15	Lethargy, failure to thrive, intellectual disability, episodic confusion, hyperammonemia, protein intolerance
Epileptic encephalopathy	Aspartate, glutamate, malate	Inner mitochondrial membrane	Mitochondrial aspartate/ glutamate carrier 1 SLC25A12	Intellectual disability, epilepsy, hypotonia, cerebral atrophy, and hypomyelination	AR
	Glutamate	Inner mitochondrial membrane	Mitochondrial glutamate carrier SLC25A22	Intellectual disability, epilepsy
Epileptic encephalopathy	Glutamic acid, aspartic acid	Presynaptic glutamatergic nerve endings	EEAT2 Neuronal dicarboxylic amino acid transporter SLC1A2	Developmental and Epileptic Encephalopathy	AD
	Glutamic acid, aspartic acid	Presynaptic glutamatergic nerve endings	EEAT1 Neuronal dicarboxylic amino acid transporter SLC1A3	Episodic ataxia
Brain serine deficiency	Alanine, serine, cysteine, threonine	Neuronal cells	ASCT neutral amino acid transporter SLC1A4	Progressive microcephaly, intellectual disability, spasticity	AR
	Glycine	Astrocytes and neuronal cells	GLYT1 astrocyte glycine transporter SLC6A9	Arthrogryposis, apnea, axial hypotonia, spasticity, intellectual disability
Hyperekplexia-3	Glycine	Neuronal cells	GLYT2 Presynaptic glycine transporter SLC6A5	Exaggerated startle response, hypertonia, apnea	AR
	Proline, glycine, leucine, and alanine, glutamine	Neuronal cells synaptic vesicles	NTT4 synaptic vesicle neutral amino acid transporter SLC6A17	Intellectual disability, tremor
Deafness	Glutamic acid	Neuronal cortical synaptic vesicles	VGLUT3 vesicular glutamate transporter SLC17A8	Deafness	AD
	Glutamine	Retinal photoreceptors	SLC38A8	Foveal hypoplasia, optic nerve decussation defects, anterior segment dysgenesis
Retinitis pigmentosa	Arginine, lysine, ornithine	Retinal photoreceptors	Cationic amino acid transporter SLC7A14	Retinitis pigmentosa, blindness	AR
	Taurine	Retinal cells	TAUT taurine transporter SLC6A6	Nystagmus, vision loss, retinal degeneration
Cystinosis	Cystine	Lysosomal membranes	Lysosomal cystine transporter	Renal failure, hypothyroidism, blindness	AR