DEFECTS​ ​IN​ ​AMINO​ ​ACID​ ​TRANSPORT

These are disorders caused by defective transport of amino acids across cell membranes. These
include deficits in transport across brush border epithelial cell membranes of the small intestine and
kidney tubules; transport across the basolateral membrane; and transport across the membranes of
intracellular organelles.

1.Cystinuria
This is an inherited disorder caused by defective reabsorption of cystine and other basic amino acids
such as arginine,lysine and ornithine by proximal renal tubules. It is characterised by abnormally high
urinary levels of cystine. Cystine is an oxidised disulfide homodimer of two cysteines. Accumulation
of cystine leads to crystal formation which further form cystine stones in kidneys, a condition called
nephrolithiasis. Precipitation of cystine in urine form renal calculi in the distal tubules which may
result to renal failure.
Cystinuria results from defects in either of the two protein subunits of the cystine transporter which is
distinct from the renal cysteine transporter. The two subunits are both of the solute carrier (​SLC)
family and are encoded as ​SLC3A1 ​and ​SLC3A9 ​genes. Mutations in the ​SLC3A1 ​gene lead to type I
cystinurias while mutations in ​SLC3A9 ​ lead to non type I cystinurias. Common treatment for
cystinuria involve decreased protein and salt intake, increased hydration to dilute cystine in urine and
use of drugs such as Captopril, Acetazolamide and D-penicillamine.

2. Hartnup disease
This is an autosomal recessive disorder caused by a defect in neutral amino acid transport in the apical
brush border membranes of the small intestines and in kidney proximal tubules. The transporter is a
member of the solute carrier family specifically the ​SLC6A19 ​transporter, also known as system B
which is sodium ion dependent. The ​SLC6A19​ prefers large aliphatic neutral amino acids. It transports
eight of the ten essential amino acids, namely, leucine, isoleucine, valine, methionine, phenylalanine,
tryptophan, threonine and histidine. ​SLC6A19 i​ s a major transporter of tryptophan in the intestines and
it's lack leads to Hartnup disease. Mutations in the ​SLC6A19​ gene that lead to the disease include
missense mutations, nonsense mutations, deletions and splice-site mutations.
The disease is associated with pellagra-like skin rash and episodes of cerebellar ataxia. Symptoms
begin in early childhood and may be triggered by drugs, fever, sunlight, emotional or physical stress.
There is abnormal urinary loss of tryptophan, a precursor of vitamin B3 (niacin). Most symptoms are
thus caused by a deficiency of vitamin B3 derived cofactors such as NAD+ and NADP+ and include
failure to thrive, photosensitivity, intermittent ataxia, nystagmus and tremor. Lack of tryptophan
hinders synthesis of skin structure and function. Serotonin synthesis is also hindered and this leads to
cerebellar ataxia.
A high protein diet can overcome the deficient transport of neutral amino acids in most patients. Poor
nutrition leads to more frequent and more severe attacks of the disease, which is rather asymptomatic.
Daily supplements of nicotinic acid reduces the severity of attacks.

3. Lysinuric Protein Intolerance

This a disorder that results from defects in transport of cationic amino acids across the basolateral
membrane of both intestinal enterocytes and the renal tubular cells. Intestinal enterocytes allow
transport of dietary cationic amino acid transport in blood while renal tubular cells allow cationic
amino acid excretion into the glomerular filtrate.
The disorder is inherited in an autosomal recessive manner and results in defects in transport of
cationic amino acids lysine, arginine and ornithine. The particular cationic amino acid transporter is a
heterodimeric transporter composed of proteins that are both of the solute carrier family (​SLC). ​The
subunits of the cationic amino acid transporter are encoded by the ​SLC3A2 ​ and ​SLC7A7 g​ enes. The
transport of cationic amino acids lysine, arginine and ornithine is catalysed by the ​SLC7A7​ encoded
protein whereas the ​SLC3A2 ​encoded protein is required for transport of the disulfide bonded
heterodimeric complex to the plasma membrane. Mutations in the ​SLC7A7​ gene such as deletions,
splice-site mutations and missense mutations with small deletions cause Lysinuric Protein Intolerance.
In classic form, symptoms appear at the neonatal period during weaning from breast milk or when
transitioning from milk-infant based formulas since they are rich in fats but low in proteins.
Symptoms include neurodigestive signs such a as hypotonia and poor growth; vomiting, diarrhoea and
going into coma when force fed on proteins. Feeding the affected children with protein free foods lead
to malnourishment which lead to poor muscle tone, osteoporosis with pathological features and
intellectual impairment. The low availability of arginine and ornithine in hepatocytes cause a defect in
the urea cycle resulting in hyperammonemia.
Treatment of patients with this disorder require a protein-controlled diet to reduce the risk for
hyperammonemia. Dietary supplementation with citrulline coupled up with nitrogen scavenging drugs
in urea cycle disorders such as sodium benzoate can also be used.

4. Hyperornithinemia Hyperammonemia Homocitrullinuria (HHH) Syndrome

The HHH Syndrome is also known as Mitochondrial Ornithine Transporter Deficiency. The disorder
is caused by mutations of the ​SLC25A15​,the gene that encodes for ​ORN1​, Mitochondrial Ornithine
Transporter 1,which is involved in the urea cycle and the ornithine degradation pathway.
A patient with HHH Syndrome has abnormally high ornithine levels despite having normal ornithine
transcarbamoylase function. Since the urea cycle cannot continue without ornithine inside the
mitochondria, ammonia disposal slows, and blood ammonia level rise; hyperammonemia. In the
absence of ornithine, ornithine transcarbamoylase within the mitochondria convert lysine to
homocitrulline cause high blood levels of homocitrulline hence homocitrullinuria.
Symptoms appear at neonatal stage in approximately 12% of affected individuals while the remaining
(88%) present symptoms at childhood and adult stage. The symptoms include: chronic neurocognitive
deficits such as unexplained seizures, learning disabilities; acute encephalopathy secondary to
hyperammonemia crisis; and chronic liver dysfunction.
Primary manifestation of the disease can be prevented by maintaining an age appropriate
protein-restricted diet, citrulline supplementation, and sodium phenylbutyrate to maintain plasma
concentrations of ammonia, glutamine, arginine and essential amino acids within a normal range.

By Bramwel Othieno (othienobramwel@gmail.com)